IMPACT OF RET PROTO-ONCOGENE ANALYSIS ON THE CLINICAL MANAGEMENT OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2

array:24 ["pii" => "S1807593222030058" "issn" => "18075932" "doi" => "10.1590/S1807-59322006000100011" "estado" => "S300" "fechaPublicacion" => "2006-02-01" "aid" => "3005" "copyright" => "CLINICS" "copyrightAnyo" => "2006" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2006;61:59-70" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S180759322203006X" "issn" => "18075932" "doi" => "10.1590/S1807-59322006000100012" "estado" => "S300" "fechaPublicacion" => "2006-02-01" "aid" => "3006" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2006;61:71-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "REVIEW" "titulo" => "SEPSIS: EMERGING ROLE OF NITRIC OXIDE AND SELECTINS" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "71" "paginaFinal" => "76" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 696 "Ancho" => 992 "Tamanyo" => 84949 ] ] "descripcion" => array:1 [ "en" => "Role of selections and excessive nitric oxide in sepsis-related tissue injury." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Abhijit Chandraa, Perenlei Enkhbaatarb, Yoshimitshu Nakanob, Lillian D Traberb, Daniel L. Traberb" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Abhijit" "apellidos" => "Chandraa" ] 1 => array:2 [ "nombre" => "Perenlei" "apellidos" => "Enkhbaatarb" ] 2 => array:2 [ "nombre" => "Yoshimitshu" "apellidos" => "Nakanob" ] 3 => array:2 [ "nombre" => "Lillian D" "apellidos" => "Traberb" ] 4 => array:2 [ "nombre" => "Daniel L." "apellidos" => "Traberb" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S180759322203006X?idApp=UINPBA00004N" "url" => "/18075932/0000006100000001/v1_202212060829/S180759322203006X/v1_202212060829/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1807593222030046" "issn" => "18075932" "doi" => "10.1590/S1807-59322006000100010" "estado" => "S300" "fechaPublicacion" => "2006-02-01" "aid" => "3004" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "fla" "cita" => "Clinics. 2006;61:53-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "ORIGINAL RESEARCH" "titulo" => "DOES ENDOTHELIAL DYSFUNCTION CORRELATE BETTER WITH WAIST-TO-HIP RATIO THAN WITH BODY MASS INDEX OR WAIST CIRCUMFERENCE AMONG OBESE PATIENTS?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "53" "paginaFinal" => "58" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Nivaldo Ribeiro Villela, Luiz Guilherme Kraemer Aguiar, Luciana Bahia, Daniel Bottino, Eliete Bouskela" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Nivaldo Ribeiro" "apellidos" => "Villela" ] 1 => array:2 [ "nombre" => "Luiz Guilherme Kraemer" "apellidos" => "Aguiar" ] 2 => array:2 [ "nombre" => "Luciana" "apellidos" => "Bahia" ] 3 => array:2 [ "nombre" => "Daniel" "apellidos" => "Bottino" ] 4 => array:2 [ "nombre" => "Eliete" "apellidos" => "Bouskela" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222030046?idApp=UINPBA00004N" "url" => "/18075932/0000006100000001/v1_202212060829/S1807593222030046/v1_202212060829/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "REVIEW" "titulo" => "IMPACT OF RET PROTO-ONCOGENE ANALYSIS ON THE CLINICAL MANAGEMENT OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "59" "paginaFinal" => "70" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Sergio Pereira de Almeida Toledo, Marcelo Augusto Cortina Gonçalves dos Santos Rodrigo de Almeida Toledo, Delmar Muniz Lourenço Júnior" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Sergio Pereira" "apellidos" => "de Almeida Toledo" ] 1 => array:3 [ "nombre" => "Marcelo Augusto Cortina Gonçalves dos Santos Rodrigo" "apellidos" => "de Almeida Toledo" "email" => array:1 [ 0 => "cortina_marcelo@hotmail.com" ] ] 2 => array:2 [ "nombre" => "Delmar Muniz Lourenço" "apellidos" => "Júnior" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Genetic Endocrinology Unit (LIM-25), Internal Medicine Department, São Paulo University Medical School, São Paulo/SP, Brazil" "identificador" => "aff1" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2594 "Ancho" => 1542 "Tamanyo" => 374908 ] ] "descripcion" => array:1 [ "en" => "Electropherograms showing five different types of RET mutations in MEN2, using a DNA sequencer (ABI 310 DNA Sequencer - Applied Biosystems, USA)" ] ] ] "textoCompleto" => "INTRODUCTIONMultiple endocrine neoplasia type 2 (MEN2) is associated with the occurrence of 3 inherited endocrine tumors: medullary thyroid carcinoma (MTC), primary hyperparathyroidism (HPT), and pheochromocytoma (PHEO). Multiple endocrine neoplasia type 2 is transmitted by an autosomal dominant gene, which imposes the need of genetic screening of all family members at risk having inherited a predisposition to this condition. The 3 neoplasias involved are derived from neural crest cells, such as C thyroid cells, parathyroid oxyphilic and chief cells, and chromaffin cells of the adrenal medulla. Sympathetic, parasympathetic, and enteric ganglia and the urogenital tract have been also reported as expressing high levels of several hormonal and nonhormonal substances produced by the affected glands.<a class="elsevierStyleCrossRefs" href="#bib1">1–13,18–20</a>Despite all efforts performed towards the management of MEN2, this condition is still an underdiagnosed, or late-diagnosed disease in many areas of the world. Presently, molecular DNA diagnosis to identify RET mutations is mandatory for all MEN2 cases and for their relatives at risk for a predisposition to MEN2. This diagnostic procedure is turning out to be a fundamental tool in early MEN2 diagnosis, enabling correct therapeutic surgical management.<a class="elsevierStyleCrossRef" href="#bib12">12</a>MOLECULAR MEDICINEIn 1986, with the identification of DNA polymorphisms in chromosome 10 in large MEN2 genealogies, the study of the RET proto-oncogene gained further interest.<a class="elsevierStyleCrossRef" href="#bib10">10</a> Transfection DNA studies of several MTC tumors revealed important foci of proliferation in NIH-3T3 cells, represented by the presence of different genetic DNA sequences.<a class="elsevierStyleCrossRef" href="#bib10">10</a> Among these sequences, one – RET (rearranged during transfection) – was present in all tumor specimens. Soon afterwards, the RET sequence was localized in the chromosome band 10q11.2.<a class="elsevierStyleCrossRef" href="#bib10">10,</a><a class="elsevierStyleCrossRefs" href="#bib13">13–15</a> The RET gene has 60 kb of the human genome spread through 21 exons, with 60 to 287 base pairs (bp), having a 24 kb intron between the first and second exons and encoding a protein of approximately 1,100 amino acids.<a class="elsevierStyleCrossRefs" href="#bib13">13,16</a> In 1993, Mulligan et al and Donnis-Keller et al (1993) identified the first missense mutations in the RET extracellular RETdomain in patients with MTC and MEN2.<a class="elsevierStyleCrossRefs" href="#bib21">21,22</a>RET is the only gene that has been associated with MEN2, and gametic mutation in this proto-oncogene has been extensively studied. Management of MEN2 using DNA sequencing information represents an excellent example of how molecular DNA diagnosis may improve clinical management.<a class="elsevierStyleCrossRefs" href="#bib1">1,3,6,8,13,23</a>CLASSIFICATION<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a> summarizes the accepted classification of MEN2, as suggested by the international consensus on MEN.<a class="elsevierStyleCrossRef" href="#bib1">1</a> This classification is based on clinical pictures of affected MEN2 patients.<elsevierMultimedia ident="tbl1"></elsevierMultimedia>Thyroid cancer is a relatively rare event comprising 0.6% and 1.6% of all carcinomas affecting men and women, respectively.<a class="elsevierStyleCrossRef" href="#bib24">24</a> Medullary thyroid carcinoma comprises 10% of all thyroid cancers, presenting as sporadic (75%) or inherited (25%) forms. Multiple endocrine neoplasia type 2 has an estimated prevalence of 1 in 30,000 individuals, and more than 90% of RET carriers will develop MTC.<a class="elsevierStyleCrossRefs" href="#bib1">1,8,25</a> The international consensus on MEN estimates that 95% of MEN2 patients have a detectable RET mutation. Mutations in exons 10, 11, and 16 are present in 90% to 95% of cases.<a class="elsevierStyleCrossRef" href="#bib1">1</a>Multiple endocrine neoplasia type 2A comprises 75% of all MEN2 cases. In MEN2A, MTC is prevalent in almost 100% of patients, whereas PHEO (50%) and HPT (20%–30%) are less frequently expressed. The mean age of clinical diagnosis of MEN2A is 20 to 40 years, but this should soon decrease, as new young RET mutation carriers are recognized and treated earlier in life.<a class="elsevierStyleCrossRef" href="#bib8">8</a>The familial form of MTC (FMTC) comprises 20% of all MEN2 cases, and it is characterized by the presence of MTC in the absence of both PHEO and HPT, both in index cases and affected family members. Usually in FMTC, MTC tends to present less aggressive behavior and better prognosis than in MEN2A or MEN2B.<a class="elsevierStyleCrossRefs" href="#bib13">13,26</a>Five percent (5%) of MEN2 cases have the phenotype of MEN2B, the most aggressive form of MTC. This form is characterized by the association of MTC, PHEO, marfanoid habitus, and mucosal neuromas (lips, tongue, eyebrows, and intestinal tract), whereas the presence of HPT is very rare.<a class="elsevierStyleCrossRef" href="#bib13">13</a> Medullary thyroid carcinoma in MEN2B usually appears very early, usually before 12 months of age.<a class="elsevierStyleCrossRefs" href="#bib8">8,27</a>MEDULLARY THYROID CARCINOMA (MTC)Affected families usually have several members with MTC.<a class="elsevierStyleCrossRef" href="#bib8">8</a> Ever since molecular diagnosis has been performed, increasing incidences and prevalences of inherited forms of MTC have been reported. Familial forms of MTC are constitutive events that lead to bilateral, multicentric thyroid cancer. Among several bioactive substances secreted by thyroid C cells, calcitonin is the most representative and the best tumor marker for MTC.<a class="elsevierStyleCrossRefs" href="#bib4">4,9</a>Thyroid C-cell hyperplasia is usually the earlier histologic abnormality in MTC and represents a premalignant stage. It initially occurs as small foci, progressing to nodular diffuse hyperplasias that may evolve to focal and finally to metastatic MTC.<a class="elsevierStyleCrossRefs" href="#bib28">28–32</a> The usual clinical presentation of MTC is a solitary thyroid nodule.<a class="elsevierStyleCrossRefs" href="#bib28">28–32</a> At the stage of palpable thyroid nodules, MTC measures at least 1 cm, and 50% of patients already have local neck lymph node metastases and more rarely lung, liver, and bone metastases.<a class="elsevierStyleCrossRefs" href="#bib33">33,34</a> It has been suggested that routine calcitonin measurements should be performed in all patients with solid thyroid nodules, since this procedure would permit presurgical diagnosis of the sporadic form of MTC as well as in familial MTC index cases, permitting the establishment of an adequate surgical plan.<a class="elsevierStyleCrossRefs" href="#bib35">35,36</a> Fine-needle biopsy followed by immunocytochemistry for calcitonin is also helpful for the presurgical diagnosis of MTC.<a class="elsevierStyleCrossRefs" href="#bib1">1,11,12,37–40</a> Total thyroidectomy associated with extensive resection of neck lymph nodes is the only effective treatment for MTC, as the tumor is usually resistant to iodo-, chemo-, and radiotherapy.<a class="elsevierStyleCrossRefs" href="#bib1">1,11,12</a> In early diagnosed cases, C-cell hyperplasia is predominant, and neck lymph node resection may be less massive.<a class="elsevierStyleCrossRefs" href="#bib1">1,11,12</a>Genetic sequencing of MTC has resulted in dramatically lower mortality rates. Before Genetic sequencing was available, mortality rates for MEN2 were up to 20%, whereas after RET mutation analysis, mortality has been as low as 5% in some samples.<a class="elsevierStyleCrossRef" href="#bib1">1</a>PHEOCHROMOCYTOMA (PHEO)Five to fifteen percent of all PHEOs are associated with MEN2, and most of them (90%) are benign. Pheochromocytomas associated with MEN2 are usually located on the adrenals (90%), but extra-adrenal cases have been reported.<a class="elsevierStyleCrossRef" href="#bib1">1</a> Most tumors (50%–80%) are bilateral. Patients with PHEO/MEN2 present a pretumoral stage characterized by nodular or diffuse hyperplasia of chromaffin adrenal cells.<a class="elsevierStyleCrossRefs" href="#bib1">1,41–48</a> The diagnosis of PHEO is usually accomplished after the recognition of MTC (40%–50%); however, it may occur before or synchronously with MTC diagnosis.<a class="elsevierStyleCrossRefs" href="#bib1">1,41</a> Thus, RET analysis should be considered in all PHEO cases.<a class="elsevierStyleCrossRef" href="#bib1">1</a>Notably, the possibility of an undiagnosed PHEO must be ruled out in all MTC patients before surgery to avoid the intrasurgical risk of an adrenal hypertensive crisis. Since a contralateral tumor may appear many years after the first diagnosis, PHEO/MEN2 patients need long-term follow-up. Image studies with MIBG (metaiodobenzylguanidine) and serum/urinary measurements of catecholamines are useful in this task.<a class="elsevierStyleCrossRefs" href="#bib1">1,41</a>HYPERPARATHYROIDISM (HPT)Hyperparathyroidism associated with MEN2 (HPT/MEN2) results from a hyperplastic process of parathyroid chief cells involving the 4 parathyroid glands. In most HPT/MEN2 cases (68%), associated adenomas have been also reported.<a class="elsevierStyleCrossRefs" href="#bib1">1,49</a> Primary HPT associated with MEN2 is a mild disease presenting slightly elevated concentrations of PTH and calcium. Several measurements may be needed to enable the biochemical diagnosis of HPT.<a class="elsevierStyleCrossRef" href="#bib1">1</a> In early-diagnosed MEN2 cases, HPT tends to be asymptomatic. Late-diagnosed cases are usually symptomatic, and renal stones are usually reported as the first clinical symptom. Osteoporosis may occur in such cases. During neck surgery for MTC in MEN2 cases, enlarged parathyroid glands are frequently found.<a class="elsevierStyleCrossRef" href="#bib1">1</a>Two surgical approaches have been used for HPT in MEN2. In the first approach, the 4 parathyroid glands are removed and half of a gland is implanted in the nondominant forearm. In the other approach, 3 1/2 glands are removed. Postsurgical euparathyroidism is less often achieved in HPT/MEN2 than in sporadic primary HPT, and its recurrence rate may be high.<a class="elsevierStyleCrossRefs" href="#bib1">1,49</a> When HPT is present, parathyroidectomy and total thyroidectomy are usually performed during the same surgical stage.<a class="elsevierStyleCrossRef" href="#bib50">50</a>Prior to 1993, i.e., before the advent of genetic analysis for RET, all individuals at risk for MTC, PHEO, and HPT underwent annual screening (from 6 years of age). This procedure usually included measurements of basal and stimulated calcitonin, serum and urinary catecholamines, calcium, and PTH. RET genetic analysis is indicated for all patients with MTC or PHEO.<a class="elsevierStyleCrossRef" href="#bib1">1</a> In apparently sporadic HPT, in the absence of other clinical suspicion for hereditary MEN2, analysis for RET is not usually performed.<a class="elsevierStyleCrossRef" href="#bib1">1</a>HIRSCHSPRUNG DISEASE (HSCR)A nonendocrine entity such as congenital megacolon or Hirschsprung disease (HSCR) has been described in association with gametic inactivating RET mutations and MEN2 cases. This disorder is due to an embryonic defect in the enteric nervous system. In HSCR associated with MEN2, myenteric and submucosal plexi are affected in extensive areas of the distal enteric tube. Most patients present with intestinal obstruction and constipation. Colectomy is frequently performed at early ages in order to correct intestinal transit.<a class="elsevierStyleCrossRefs" href="#bib31">31,51</a>MOLECULAR ASPECTSThe RET proto-oncogene encodes for a tyrosine kinase cell membrane receptor. The extracellular domain of this protein is rich in cysteine residues, and it is encoded by the first 10 exons of RET. Exon 11 encodes for the transmembrane domain, and the 2 intracellular domains of the protein are encoded by 10 other exons.<a class="elsevierStyleCrossRefs" href="#bib8">8,36,52,53</a>The RET extracellular domain includes coding for a cadherin-binding site that is important in intercellular signaling. Extracellular cysteines play an important role in receptor dimerization. At least 10 RET isoforms have been reported as result of 5’ and 3’ splicing of exon 21; however, their physiological function still partially unknown.<a class="elsevierStyleCrossRefs" href="#bib8">8,36,53</a>The protein encoded by RET plays an important role in embryologic migration and development of neural crest-derived cells, such as thyroid C cells, chromaffin adrenal cells, sympathetic, parasympathetic, and enteric ganglia cells, as well as in urogenital tract.<a class="elsevierStyleCrossRef" href="#bib13">13</a> The RET protooncogene is also expressed in parathyroid cells derived from branchial arches. Binding proteins such as GDNF (glial cell line-derived neurotrophic factor) and its receptor, GFRα-1 (GDNF family receptor alpha one) interact with the RET-encoded extracellular protein, promoting cell survival of central and peripheral neurons. The RET protooncogene also plays an essential role in renal and enteric neural development.<a class="elsevierStyleCrossRefs" href="#bib13">13,54,55</a>Once coupled, ligands and their respective receptors give rise to a ligand-receptor complex that promotes RET receptor monomer dimerization through disulfite bonds. Intracellular tyrosine residues are self-phosphorylated. This process is followed by a complex signaling pathway in which mitotic-activating protein kinases (MAPKs) amplify signaling pathways to cell nuclei, promoting cell mobility and survival.<a class="elsevierStyleCrossRefs" href="#bib6">6,35,56</a>The same dimerization process occurs independently of ligand binding when activating RET germline mutations (constitutive mutation) are present in the RET extracellular domain, favoring the development of the neoplastic phenotypes. RET mutations encode for the intracellular protein that leads to disturbances in the substrate catalytic core affinity, favoring the appearance of the neoplastic process.<a class="elsevierStyleCrossRefs" href="#bib6">6,35,56</a>Biochemical and transfection studies of tyrosine kinase have revealed differential RET expressions at the cell membrane level. Thus, cysteine residues next to the 5’ region (such as mutant codons 609 and 611) present lower protein expression compared to codon 634 mutations, located next to the transmembrane domain. The potency of cell neoplastic transformation of codon 634 RET mutations is clearly higher than that occurring in codons 609 and 611. This finding may be due to modulation of expression of mature RET-encoded protein receptors at the cell membrane, where most of the RET-encoded protein expression occurs.<a class="elsevierStyleCrossRefs" href="#bib56">56,57</a> Thus, most patients with MEN2 who harbor RET 634 mutations will have thyroid, adrenal, and parathyroid tumors, whereas patients with 609 or 611 mutations will present only thyroid cancer. Further, tissue-specific sensitivity may also be modulated by codon-specific RET mutations. Tissue sensitivity is therefore high in thyroid tissue, intermediate in the adrenals, and low in parathyroid glands.<a class="elsevierStyleCrossRef" href="#bib3">3</a> These observations may also explain why activating RET mutations are usually associated with MEN2, whereas inactivating RET mutations are associated with HSCR. Mutations in codons 618 and 620 usually result in RET-encoded receptor amounts sufficient to transform thyroid and possibly adrenal cells, but insufficient to produce disturbances in normal intestinal gangliogenesis. Hirschsprung disease may be considered a polygenic disease, because RET, GDNF, endothelin receptor-2 genes, and genes located at 9q31 and 22q11 bands are involved.<a class="elsevierStyleCrossRefs" href="#bib6">6,8</a>GENOTYPE-PHENOTYPE CORRELATIONSMultiple endocrine neoplasia type 2A (MEN2A)The genotype-phenotype correlations in MEN2 are summarized in <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>. The vast majority of MEN2A cases (98%) harbors a missense RET mutation, primarily in exon 10 and 11 and in codons 609, 611, 618, 620, 630, and 634, which comprise a small 25-amino-acid domain.<a class="elsevierStyleCrossRef" href="#bib3">3</a> Rarely, small insertions in codons 635 and 637 have been reported. Codon 634 is involved in 85% of MEN2A mutations; 52% of them have a Cys634Arg mutation, and 26% present the Cys634Tyr mutation. Further, MTC tumor aggressiveness induced by these 2 mutations differ: metastases tend to be more frequent and early in Cys634Arg cases, as compared to Cys634Tyr cases.<a class="elsevierStyleCrossRefs" href="#bib1">1,13,58,59</a><elsevierMultimedia ident="tbl2"></elsevierMultimedia>In relatives of patients presenting an increased incidence of HPT and the absence of PHEO, a 12 bp duplication was found between codons 634 and 635, corresponding to 4 amino acids and co-segregated with a Cys634Arg mutation.<a class="elsevierStyleCrossRefs" href="#bib8">8,13</a> Recently, Nunes et al, of our laboratory, described a case with double RET mutations (Val648Ile/Cys634Arg).<a class="elsevierStyleCrossRefs" href="#bib52">52,60</a> In this family, 2 siblings were Val648Ile carriers and so far have presented neither clinical nor biochemical abnormalities compatible with MEN2A. The other 2 affected siblings presented the usual Cys634Arg RET mutation and early classical MTC presentation. The father presented a rare phenotype of MEN2A associated with an ectopic ACTH-producing PHEO. He was an obligatory carrier of the double RET mutation. The MEN2A in this specific case had a relatively mild presentation.<a class="elsevierStyleCrossRefs" href="#bib52">52,60</a>Mutations in the RET intracellular protein receptor domain RET in codons 790 and 804 are rarely associated with MEN2A. Mutations associated with codon 804 are frequent in FMTC. In most of these cases, thyroid tumor tends to present a late onset, slow course, and low aggressiveness, when compared to phenotypes presenting RET extracellular-domain mutations. These patients may exhibit incomplete neoplastic transformation induced by the 804 mutation; however, aggressive MTC tumors and even death due to MTC have been reported in cases harboring codon 804 mutations.<a class="elsevierStyleCrossRefs" href="#bib8">8,61</a>Hirschsprung disease has been described in association with MEN2A or FMTC cases that are associated with mutations primarily in codons 609, 611, 618, and 620.<a class="elsevierStyleCrossRefs" href="#bib8">8,62,63</a>FAMILIAL MEDULLARY THYROID CARCINOMA(FMTC)Most FMTC cases (85%) present RET mutations in exons 10 and 11. The Cys618Ser genotype is found in 33% of cases; the Cys634Tyr genotype is found in 30% cases; whereas, the Cys634Arg genotype is rarely associated with this phenotype.<a class="elsevierStyleCrossRefs" href="#bib1">1,8</a> Mutations in codons 609, 611, and 620 and those of Glu768Asp, Val804Leu, and Val804Met occurring in tyrosine kinase domains are accepted to be related to FMTC, even though they may also occur in MEN2A. Other mutations in RET tyrosine kinase domains, such as in codons 790, 791, and 891, have been reported.<a class="elsevierStyleCrossRefs" href="#bib1">1,8,57</a>Less frequently, hot spots and mutations, such as those in codons 630, 790, 791, 891, and a 12 bp duplication between codons 634 and 635, have been reported in FMTC families, associated with an indolent form of MTC.<a class="elsevierStyleCrossRefs" href="#bib8">8,64</a>Additionally, a 9 bp duplication in RET exon 8 creating a new cysteine residue in the extracellular portion of the RET protein receptor was reported in a FMTC family, possibly associated with HSCR. The affected case did not present germline mutations in exons 10, 11, 13, 14, or 15 or somatic mutations in exons 11, 13, 15, and 16, suggesting the neoplastic activity of this mutation.<a class="elsevierStyleCrossRef" href="#bib26">26</a>Recently, a new exon 8, Gly533Cys RET mutation was reported in 76 FMTC carriers belonging to a family of Spanish extraction in which 229 individuals were at risk.<a class="elsevierStyleCrossRef" href="#bib65">65</a>Multiple endocrine neoplasia type 2B (MEN2B)A RET intracellular tyrosine kinase domain mutation, Met918Thr, has been reported in 95% of MEN2B cases.<a class="elsevierStyleCrossRef" href="#bib56">56</a> In 4 families with MEN2B from Germany, United Kingdom, and Australia, an Ala883Phe substitution in exon 15 was described, comprising 4% of all MEN2B phenotypes reported to date.<a class="elsevierStyleCrossRefs" href="#bib8">8,13,56</a> Some rare mutations have been described, such as Ser922Tyr and a double mutation in codon 804 and Tyr806Cys occurring in the same allele, which was detected in a patient with MEN2B.<a class="elsevierStyleCrossRef" href="#bib13">13</a>Genotype-phenotype correlations in MEN2 have a major and immediate impact in clinical medicine, since genetic testing may differentiate RET carriers from noncarriers. RET carriers should undergo total thyroidectomy at ages that depend on the mutated codon,<a class="elsevierStyleCrossRefs" href="#bib1">1,67</a> following the MEN consensus (<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>). Conversely, noncarriers of the RET mutation should be excluded from annual clinical follow-up, an expensive and stressing procedure for patients. In skillful surgical hands, the risks of neck surgery are minimal even in children. False positives in genetic testing are exceedingly low.<a class="elsevierStyleCrossRefs" href="#bib1">1,10</a> All these data have generated an international consensus on MEN regarding which MTC patients should undergo surgery at ages preferably less than 5 years, depending on the mutated codon<a class="elsevierStyleCrossRefs" href="#bib1">1,67</a> (<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>). At the time of writing, molecular DNA diagnosis in MEN2 has become an important tool to a) confirm clinical and laboratory diagnosis of MTC; b) identify as early as possible mutant RET carriers in premalignant stages of the disease; and c) identify noncarrier family members and rule them out for clinical follow-up.<a class="elsevierStyleCrossRef" href="#bib33">33</a><elsevierMultimedia ident="tbl3"></elsevierMultimedia>MODIFIER GENES IN RET EXPRESSIONTransgenic animal models expressing RET mutation are used to better address the question of MEN2 MTC tumor aggressiveness. Medullary thyroid carcinoma occurs in transgenic lines with analogous pathology to that seen in patients with MEN2. When the transgene codon 634 mutation was introduced into 4 different genetic backgrounds (BALB/c, C57BL/6J, FVB/N and CBA/ca), 65% of all animals developed MTC, showing incomplete penetrance. None of the FVB/N transgenic progeny developed MTC, 14% of transgenic progeny BALB/c, 64% of C57BL/6J, and 98% CBA/ca mice developed thyroid tumors by 10 months of age, indicating that incomplete tumor penetrance could be modulated by genetic background. Furthermore, tumors in the CBA/ca and C57BL/6J mice were significantly larger than those in BALB/c transgenic mice. These results are relevant to human MEN2 disease, because this model system may be used to study genes modifying thyroid tumor penetrance in this dominantly inherited human cancer syndrome.<a class="elsevierStyleCrossRef" href="#bib68">68</a>ROUTINE PROCEDURES IN MOLECULAR RET DIAGNOSISInvestigators working on studies dealing with humans should follow the Helsinque decisions; thus, before collecting blood samples for DNA analysis, projects should be approved by local ethic committees, and patients involved in research projects should sign a written informed consent.For genomic DNA extraction, a salting-out method is indicated since it is a simple, low-cost procedure.<a class="elsevierStyleCrossRef" href="#bib69">69</a> For amplification of genomic DNA, fragments of interest are usually amplified using the polymerase chain reaction (PCR) strategy.<a class="elsevierStyleCrossRef" href="#bib70">70</a> Primers should contain flanking sequences of intronexon boundaries for adequate RET proto-oncogene analysis, and if a laboratory chooses the DGGE (denaturing gradient gel electrophoresis) strategy for screening mutation analysis, primers may also contain a 50bp GC-clamp coupled in one of the sequences.<a class="elsevierStyleCrossRefs" href="#bib71">71–73</a> The presence of adequate amplified sequences are confirmed using runs in 1% agarose gel electrophoresis stained with ethidium bromide. After obtaining PCR products, direct sequencing analysis (the gold-standard method for RET mutation diagnosis) should be performed in all MEN2 index cases. Once the genotype of the RET mutation in the index case is known, it may be used as intrafamilial positive control. For at-risk family members, screening methods may be used. In this latter alternative, it is possible to use DGGE, single-strand conformation polymorphism (SSCP) or restriction enzyme approaches.<a class="elsevierStyleCrossRefs" href="#bib72">72–77</a> The DGGE and SSCP techniques are based on differential migration mobilities in polyacrylamide gel. Thus, applying these techniques, it is possible to discriminate between mutant carriers and noncarriers. Different electrophoretic migration patterns are influenced by denaturant substances, such as urea and formamide (in DGGE) or heteroduplex formation (in SSCP). Particularly when screening large MEN2 families, these methods are very useful; for instance, using DGGE, one might analyze 16 exons in 24 hours. Restriction enzymes may possibly be useful in genetic screening for RET mutations, as mutations create or destroy restriction sites recognizable by endonucleases. However, this method should only be applied to confirm DGGE or SSCP findings, considering that interferences may occur as follows: a) inadequate recognition of restriction site and consequently no defined band in agarose gel electrophoresis or b) incomplete discrimination of amplified sequences with similar base pair sizes.<a class="elsevierStyleCrossRefs" href="#bib77">77,78</a>Using direct genetic sequencing analysis (the gold-standard method), DNA fragments of interest are sequenced by enzymatic or chain termination, as described by Sanger in 1977.<a class="elsevierStyleCrossRef" href="#bib71">71</a> In this technique, each primer must be added separately to sense and missense reaction tubes, with a commercial buffer (Big Dye Terminator Cycle Sequencing, Applied Biosystems, Foster City, USA) and processed in a thermocycler. After the sequencing reaction, samples are purified with isopropanol and ethanol and diluted in blue dextran buffer with deionized formamide. The sequencing products are then denatured at 90 °C for 2 minutes, immediately cooled, and applied into a specific electrophoresis polymer for the DNA sequencer. Using these procedures, good reproducibility is usually obtained, avoiding the need of a confirmation reaction. <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a> illustrates examples of electropherograms showing MEN-2 RET mutations.<elsevierMultimedia ident="fig1"></elsevierMultimedia>CONCLUSIONBefore RET molecular diagnosis was possible, first-degree relatives of MEN2 patients (who have a 50% chance of being carriers) were clinically and biochemically followed up every 12 months for MTC, PHEO, and HPT. Individuals had to be annually evaluated from 6 years of age on. Thus, basal and stimulated calcitonin serum levels were measured in these individuals, as well as serum PTH, calcium, and serum/urinary cathecolamines.<a class="elsevierStyleCrossRefs" href="#bib8">8,22,67</a> The sensitivity of these tests was variable, and as a consequence, MTC was usually diagnosed late. This prolonged follow-up was expensive; individuals at risk were maintained in a stressing condition; survival rates were diminished, and cure was almost never achieved due to late MEN2 diagnosis and high prevalence of lymph node metastases,.<a class="elsevierStyleCrossRefs" href="#bib79">79,80</a>At the time of writing, because almost 95% of affected MEN2 patients harbor a mutation, genetic diagnosis of MEN2 has become a great success story in the management of patients that are RET mutation carriers.<a class="elsevierStyleCrossRefs" href="#bib67">67,81</a> Direct DNA sequencing is of course the gold-standard method for RET mutation analysis and should be performed routinely in all index cases and possibly in all suspected cases. Alternatively, once the presence of a RET mutation is ascertained, screening methods may be used in analyzing family members at risk. Whatever DNA method is used, early RET mutation analysis provides information to clinicians and surgeons allowing them to make adequate surgical decisions. As a consequence of these procedures, mortality rates in MEN2 have dropped from up to 20% in 1993 to 5% currently.<a class="elsevierStyleCrossRef" href="#bib1">1</a> Finally, early RET mutation analysis should be performed in all MTC and PHEO cases, as suggested by the MEN consensus.<a class="elsevierStyleCrossRef" href="#bib1">1</a>" "textoCompletoSecciones" => array:1 [ "secciones" => array:18 [ 0 => array:2 [ "identificador" => "xpalclavsec1585041" "titulo" => "KEYWORDS" ] 1 => array:3 [ "identificador" => "xres1815387" "titulo" => "RESUMO" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "ceabs20" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1585040" "titulo" => "UNITERMOS" ] 3 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 4 => array:2 [ "identificador" => "cesec20" "titulo" => "MOLECULAR MEDICINE" ] 5 => array:2 [ "identificador" => "cesec30" "titulo" => "CLASSIFICATION" ] 6 => array:2 [ "identificador" => "cesec40" "titulo" => "MEDULLARY THYROID CARCINOMA (MTC)" ] 7 => array:2 [ "identificador" => "cesec50" "titulo" => "PHEOCHROMOCYTOMA (PHEO)" ] 8 => array:2 [ "identificador" => "cesec60" "titulo" => "HYPERPARATHYROIDISM (HPT)" ] 9 => array:2 [ "identificador" => "cesec70" "titulo" => "HIRSCHSPRUNG DISEASE (HSCR)" ] 10 => array:2 [ "identificador" => "cesec80" "titulo" => "MOLECULAR ASPECTS" ] 11 => array:3 [ "identificador" => "cesec90" "titulo" => "GENOTYPE-PHENOTYPE CORRELATIONS" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "cesec100" "titulo" => "Multiple endocrine neoplasia type 2A (MEN2A)" ] ] ] 12 => array:3 [ "identificador" => "cesec110" "titulo" => "FAMILIAL MEDULLARY THYROID CARCINOMA" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "cesec120" "titulo" => "(FMTC)" ] 1 => array:2 [ "identificador" => "cesec130" "titulo" => "Multiple endocrine neoplasia type 2B (MEN2B)" ] ] ] 13 => array:2 [ "identificador" => "cesec140" "titulo" => "MODIFIER GENES IN RET EXPRESSION" ] 14 => array:2 [ "identificador" => "cesec150" "titulo" => "ROUTINE PROCEDURES IN MOLECULAR RET DIAGNOSIS" ] 15 => array:2 [ "identificador" => "cesec160" "titulo" => "CONCLUSION" ] 16 => array:2 [ "identificador" => "xack640440" "titulo" => "ACKNOWLEDGEMENTS" ] 17 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2005-07-04" "fechaAceptado" => "2005-11-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1585041" "palabras" => array:8 [ 0 => "Endocrine Neoplasia" 1 => "MEN2" 2 => "RET proto-oncogene" 3 => "Pheochromocytoma" 4 => "Hyperparathyroidism" 5 => "HSCR" 6 => "MTC" 7 => "FMTC" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "UNITERMOS" "identificador" => "xpalclavsec1585040" "palabras" => array:8 [ 0 => "Neoplasia Endócrina" 1 => "NEM2" 2 => "Protooncogene RET" 3 => "Feocromocitoma" 4 => "Hiperparatireoidismo" 5 => "HSCR" 6 => "CMT" 7 => "CMT-F" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia type 2 is still an underdiagnosed, or late-diagnosed condition in many areas of the world. Since 1993, when the first missense RET proto-oncogene (RET) mutations were reported in MEN2, up to 46 different RET-causing disease mutations have been described. Since a strong genotype-phenotype correlation exists for MEN2, the detection of RET mutations has produced a major impact in early recognition and treatment of MTC and MEN2. Presently, RET mutation analysis should be performed for all MEN2 cases and their at-risk familial relatives. Further, prophylactic total thyroidectomy is indicated in all cases harboring activating gametic RET mutations. In most RET mutation carriers, prophylactic total thyroidectomy is indicated at ages as early as a few months to 4 years of age, promoting longer survival and improvement of quality of life or even definitive cure. We discuss the large impact of RET protooncogene analysis on the clinical management of MEN2 and the role of early RET molecular DNA diagnosis in providing clinicians and surgeons with valuable information that enables them to indicate early total thyroidectomy." ] "pt" => array:2 [ "titulo" => "RESUMO" "resumen" => "A neoplasia endócrina múltipla tipo 2 (NEM2) é caracterizada pela ocorrência do carcinoma medular de tireóide (CMT), hiperparatiroidismo primário (HPT) e feocromocitoma (FEO).<a class="elsevierStyleCrossRefs" href="#bib1">1–12</a> Desde 1993, quando as primeiras mutações do tipo missense no proto-oncogene RET (RET), associadas a NEM2 foram identificadas, 46 diferentes mutações causadoras de doenças foram descritas.<a class="elsevierStyleCrossRefs" href="#bib13">13–17</a> Como há uma forte correlação genótipo-fenótipo na NEM2, a detecção de mutações no RET adquiriu grande impacto no tratamento precoce do CMT e NEM2. A NEM2 persiste como uma doença subdiagnosticada e/ou tardiamente diagnosticada em várias áreas geográficas do globo. A análise de mutações do RET deve ser realizada em todas os casos de NEM2 e atualmente, a tireoidectomia total profilática é indicada para todos os indivíduos portadores de mutações no RET.<a class="elsevierStyleCrossRef" href="#bib1">1</a> Para a grande maioria dos portadores de mutações gaméticas ativadoras no RET este procedimento cirúrgico é indicado nos primeiros anos de vida, promovendo melhora na qualidade de vida, aumento da sobrevida ou mesmo levando à cura definitiva.<a class="elsevierStyleCrossRef" href="#bib1">1</a> Discutimos nesta revisão, o impacto da análise do proto-oncogene RET na conduta clínica da neoplasia endócrina múltipla tipo 2. Além disso, o diagnóstico molecular do RET fornece à clínicos e cirurgiões a mais valiosa das informações, permitindo indicação de tireoidectomia total profilática." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2594 "Ancho" => 1542 "Tamanyo" => 374908 ] ] "descripcion" => array:1 [ "en" => "Electropherograms showing five different types of RET mutations in MEN2, using a DNA sequencer (ABI 310 DNA Sequencer - Applied Biosystems, USA)" ] ] 1 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 01" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multiple endocrine neoplasia2A (1): Families with medullary thyroid carcinoma, pheochromocytoma and hyperparatyroidism phenotype \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multiple endocrine neoplasia2A (2): Families with medullary thyroid carcinoma and pheochromocytoma phenotype in at least one at risk relative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multiple endocrine neoplasia2A (3): Families with medullary thyroid carcinoma and hyperparatyroidism phenotype in at least one at risk relative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multiple endocrine neoplasia2B: Families with medullary thyroid carcinoma, associated or not with pheochromocytoma and muscular / skeletal abnormalities and mucosal neuromas \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Familial medullary thyroid carcinoma: Families only with medullary thyroid carcinoma phenotype in at least four at risk relatives \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Others: Families with less than four relatives with medullary thyroid carcinoma, pheochromocytoma and hyperparatyroidism phenotype. In this group are included partially documented families \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Phenotypic classification of MEN2 (Adapted from ref.<a class="elsevierStyleCrossRef" href="#bib1">1,</a><a class="elsevierStyleCrossRef" href="#bib13">13</a>)" ] ] 2 => array:7 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "MEN2A: Multiple endocrine neoplasia type 2A; MEN2B: Multiple endocrine neoplasia type 2B; FMTC: Familial medullary thyroid carcinoma; Ins: Insertion" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Exon \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Affected Codon \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Nucleotides (wild-type → mutant) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Amino acid (wild-type → mutant) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Phenotype \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">MEN2 cases(%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">532, 533, 534 533 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins AGG AGT GTG GGC-TGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins Glu Glu Cys Gly-Cys \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FMTC / HSCR FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">609 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-CGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC / HSCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0-1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-GGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Gly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">611 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-AGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2-3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-CGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TGG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Trp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">618 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-AGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC / HSCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3-5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-CGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-GGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Gly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">620 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC / HSCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6-8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-AGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-CGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-GGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Gly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TGG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Trp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0-1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">634 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-AGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80-90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-CGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Arg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-GGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Gly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Ser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80-90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGC-TGG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys-Trp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">635, 636, 637, 638 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins CG AGC TGT GCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins Thr Ser Cys Ala \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">637, 638, 639 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins TGC CGC ACG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ins Cys Arg Thr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">648 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTC-ATC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Val-Ile \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">768 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GAG-GAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glu-Asp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">790 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TTG-TTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leu-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TTG-TTT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leu-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">791 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TAT-TTT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tyr-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">804 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTG-ATG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Val-Met \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0-1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTG-TTG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Val-Leu \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">883 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GCT-TTT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ala-Phe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">891 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TCG-GCG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ser-Ala \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2A / FMTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">918 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ATG-ACG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Met-Thr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2B / HSCR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3-5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">922 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TCC-TAC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ser-Tyr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEN2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Multiple endocrine neoplasia type 2 (MEN2) genotype-phenotype correlations (Adapted from ref.<a class="elsevierStyleCrossRef" href="#bib13">13</a>)" ] ] 3 => array:7 [ "identificador" => "tbl3" "etiqueta" => "Table 03" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risk 3 level: Highest risk of development of an aggressive and early form of medullary thyroid carcinoma. Children with multiple endocrine neoplasia 2B or mutation carriers in codons 883, 918 or 922, should be submitted to total thyreoidectomy during the first six months of life, preferentially a the first month as microscopic medullary thyroid carcinoma with metastases may occur in the first months of life. Total thyreoidectomy should be performed in association with an extensive ressection of the neck lymph nodes, mainly including central neck lymph nodes. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risk 2 level: High risk to present an aggressive form of medullary thyroid carcinoma. Children carrying RET mutation in codons 611, 618, 620 or 634 should be submitted to total surgery before 5 years of age. Total thyreoidectomy should be performed in association with removal of thyroid posterior capsule and dissection of central lymph nodes. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risk 1 level: Moderate risk to develop aggressive forms of medullary thyroid carcinoma. Children carrying mutations in codons 609, 768, 790, 791 804 or 891 should be also submitted to total thyreoidectomy. There are three alternatives related to ages for surgical procedures. First, some authors indicate patients should be operated before age 5, as in risk 2 level. Others suggest 10 years of age as a cut-off for surgical indication. The third alternative is waiting for abnormal basal or stimulated calcitonin values for indicating surgery. Biological behaviors of these tumors are variable, but frequently present a late and indolent evolution. It is worthwhile to note that metastases or death were reported in patients carrying all these genotypes. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Surgical management of multiple endocrine neoplasia2 based on international multiple endocrine neoplasia consensus (Adapted from ref.<a class="elsevierStyleCrossRef" href="#bib1">1</a>)" ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:81 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CONSENSUS: Guideline for diagnosis and therapy of MEN type 1 and type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ ML Brandi \n \t\t\t\t\t\t\t\t """ 1 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ 2 => """ A Angeli \n \t\t\t\t\t\t\t\t """ 3 => """ JP Bilezikian \n \t\t\t\t\t\t\t\t """ 4 => """ P Beck-Peccoz \n \t\t\t\t\t\t\t\t """ 5 => """ C Bordi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.86.12.8070" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "5658" "paginaFinal" => "5671" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11739416" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impact of gene mapping techniques on the management of multiple endocrine neoplasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Trends Endocr Metab" "fecha" => "1991" "volumen" => "2" "paginaInicial" => "19" "paginaFinal" => "25" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular genetics of multiple endocrine neoplasia types 1 and 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ SJ Marx \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nature" "fecha" => "2005" "volumen" => "5" "paginaInicial" => "367" "paginaFinal" => "375" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple Endocrine Neoplasia Type 2: Clinical Aspects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ O Gimm \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "PLMDahia, CEng" "titulo" => "Genetic Disorders of Endocrine Neoplasia" "paginaInicial" => "103" "paginaFinal" => "130" "edicion" => "1st ed." "serieFecha" => "2001" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neoplasias Endocrinas Múltiplas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ 1 => """ NMA Abelin \n \t\t\t\t\t\t\t\t """ 2 => """ MCL Ezabella \n \t\t\t\t\t\t\t\t """ 3 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 4 => """ PM Dahia \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "BLWajchenberg" "titulo" => "Tratado de Endocrinologia Clínica" "paginaInicial" => "943" "paginaFinal" => "964" "edicion" => "1° ed." "serieFecha" => "1992" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple Endocrine Neoplasia Type 2: Molecular Aspects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "PLMDahia, CEng" "titulo" => "Genetic Disorders of Endocrine Neoplasia" "paginaInicial" => "81" "paginaFinal" => "102" "edicion" => "1st ed." "serieFecha" => "2001" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neoplasias Endócrinas Múltiplas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ MCL Ezabella \n \t\t\t\t\t\t\t\t """ 1 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 2 => """ NMA Abelin \n \t\t\t\t\t\t\t\t """ 3 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "GMedeiros-Neto" "titulo" => "Moléstias Hereditárias do Sistema Tireoideano" "paginaInicial" => "225" "paginaFinal" => "242" "edicion" => "1° ed." "serieFecha" => "1996" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET proto-oncogene in the development of human cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ C Eng \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol" "fecha" => "1999" "volumen" => "17" "paginaInicial" => "390" "paginaFinal" => "393" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Specific localization of calcitonin activity in humans’ thyroid glands" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ MA Aliepoulios \n \t\t\t\t\t\t\t\t """ 1 => """ EH Rose \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Calcitonin Proceedings of the Second International Syposium" "paginaInicial" => "295" "paginaFinal" => "300" "edicion" => "2nd ed." "serieFecha" => "1970" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Editorial: RET proto-oncogene mutations and endocrine neoplasia – A story interwined with neuronal crest differentiation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Endocrinology" "fecha" => "1996" "volumen" => "137" "paginaInicial" => "509" "paginaFinal" => "511" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of occult medullary thyroid carcinoma evidenced only by serum calcitonin levels elevations after apparently adequate neck operation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ MA Block \n \t\t\t\t\t\t\t\t """ 1 => """ CE Jackson \n \t\t\t\t\t\t\t\t """ 2 => """ AH Tashjian Jr. \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archsurg.1978.01370160026003" "Revista" => array:6 [ "tituloSerie" => "Arch Surg" "fecha" => "1978" "volumen" => "113" "paginaInicial" => "368" "paginaFinal" => "372" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/637706" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medullary carcinoma of the thyroid gland" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ SA Wells Jr \n \t\t\t\t\t\t\t\t """ 1 => """ C Franz \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s002680010166" "Revista" => array:6 [ "tituloSerie" => "World J Surg" "fecha" => "2000" "volumen" => "24" "paginaInicial" => "952" "paginaFinal" => "956" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10865039" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasias" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ AO Hoff \n \t\t\t\t\t\t\t\t """ 1 => """ GJ Cote \n \t\t\t\t\t\t\t\t """ 2 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.physiol.62.1.377" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Physiol" "fecha" => "2000" "volumen" => "62" "paginaInicial" => "377" "paginaFinal" => "400" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10845096" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cloning and expression of RET proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ M Takahashi \n \t\t\t\t\t\t\t\t """ 1 => """ Y Buma \n \t\t\t\t\t\t\t\t """ 2 => """ Y Iwamoto \n \t\t\t\t\t\t\t\t """ 3 => """ H Ikeda \n \t\t\t\t\t\t\t\t """ 4 => """ H Hiahi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Oncogene" "fecha" => "1988" "volumen" => "3" "paginaInicial" => "571" "paginaFinal" => "578" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3078962" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Isolation of RET proto-oncogene DNA with an amino-terminal signal sequence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ M Takahashi \n \t\t\t\t\t\t\t\t """ 1 => """ Y Buma \n \t\t\t\t\t\t\t\t """ 2 => """ H Hiahi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Oncogene" "fecha" => "1989" "volumen" => "4" "paginaInicial" => "805" "paginaFinal" => "806" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2660074" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structural analysis of the human RET proto-oncogene using exon trapping" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ JB Kwok \n \t\t\t\t\t\t\t\t """ 1 => """ E Gardner \n \t\t\t\t\t\t\t\t """ 2 => """ JP Warner \n \t\t\t\t\t\t\t\t """ 3 => """ BAJ Ponder \n \t\t\t\t\t\t\t\t """ 4 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Oncogene" "fecha" => "1993" "volumen" => "8" "paginaInicial" => "2575" "paginaFinal" => "2582" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8361767" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN2A and FMTC" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 1 => """ C Eng \n \t\t\t\t\t\t\t\t """ 2 => """ CS Healey \n \t\t\t\t\t\t\t\t """ 3 => """ D Calyton \n \t\t\t\t\t\t\t\t """ 4 => """ JBJ Kwok \n \t\t\t\t\t\t\t\t """ 5 => """ E Gardner \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng0194-70" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "1994" "volumen" => "6" "paginaInicial" => "70" "paginaFinal" => "74" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7907913" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ J Hansford \n \t\t\t\t\t\t\t\t """ 1 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jmg.37.11.817" "Revista" => array:6 [ "tituloSerie" => "J Med Genet" "fecha" => "2000" "volumen" => "37" "paginaInicial" => "817" "paginaFinal" => "827" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11073534" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ M Peczkowska \n \t\t\t\t\t\t\t\t """ 1 => """ A Januszewicz \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10689-005-4150-3" "Revista" => array:6 [ "tituloSerie" => "Familial Cancer" "fecha" => "2005" "volumen" => "4" "paginaInicial" => "25" "paginaFinal" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15889224" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ BT Teh \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1046/j.1365-2796.2003.01162.x" "Revista" => array:6 [ "tituloSerie" => "Journal of Internal Medicine" "fecha" => "2003" "volumen" => "253" "paginaInicial" => "588" "paginaFinal" => "589" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12755953" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 1 => """ JB Kwok \n \t\t\t\t\t\t\t\t """ 2 => """ CS Healey \n \t\t\t\t\t\t\t\t """ 3 => """ MJ Elsdon \n \t\t\t\t\t\t\t\t """ 4 => """ C Eng \n \t\t\t\t\t\t\t\t """ 5 => """ E Gardner \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/363458a0" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "1993" "volumen" => "363" "paginaInicial" => "458" "paginaFinal" => "460" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8099202" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in RET proto-oncogene are associated with MEN2A and FMTC" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ H Donnis-Keller \n \t\t\t\t\t\t\t\t """ 1 => """ S Dou \n \t\t\t\t\t\t\t\t """ 2 => """ D Chi \n \t\t\t\t\t\t\t\t """ 3 => """ KM Carlson \n \t\t\t\t\t\t\t\t """ 4 => """ K Toshima \n \t\t\t\t\t\t\t\t """ 5 => """ TC Lairmore \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/hmg/2.7.851" "Revista" => array:6 [ "tituloSerie" => "Hum Molec Genet" "fecha" => "1993" "volumen" => "2" "paginaInicial" => "851" "paginaFinal" => "856" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8103403" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic testing in endocrinology: lessons learned from experience with multiple endocrine neoplasia type 2 (MEN2)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ C Jimenez \n \t\t\t\t\t\t\t\t """ 1 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000527123" "Revista" => array:6 [ "tituloSerie" => "Growth Horm & IGF Res" "fecha" => "2004" "volumen" => "14" "paginaInicial" => "S150" "paginaFinal" => "S157" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36446332" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carcinoma Medular de Tireóide: da Definição às Bases Moleculares" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ PKR Magalhães \n \t\t\t\t\t\t\t\t """ 1 => """ M Castro \n \t\t\t\t\t\t\t\t """ 2 => """ LLK Elias \n \t\t\t\t\t\t\t\t """ 3 => """ LMZ Maciel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "2003" "volumen" => "47" "paginaInicial" => "515" "paginaFinal" => "528" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neoplasia Endócrina Múltipla tipo 2 – Manejo Diagnóstíco e Terapêutico" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ FFR Maia \n \t\t\t\t\t\t\t\t """ 1 => """ HJ Júnior \n \t\t\t\t\t\t\t\t """ 2 => """ LR Araújo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "606" "paginaFinal" => "610" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel 9-base pair in RET exon 8 in familial medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Pigny \n \t\t\t\t\t\t\t\t """ 1 => """ C Bauters \n \t\t\t\t\t\t\t\t """ 2 => """ JL Wemeau \n \t\t\t\t\t\t\t\t """ 3 => """ ML Houcke \n \t\t\t\t\t\t\t\t """ 4 => """ M Crepin \n \t\t\t\t\t\t\t\t """ 5 => """ P Caron \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.84.5.5665" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1999" "volumen" => "84" "paginaInicial" => "1700" "paginaFinal" => "1704" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10323403" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Brauckhoff \n \t\t\t\t\t\t\t\t """ 1 => """ O Gimm \n \t\t\t\t\t\t\t\t """ 2 => """ C L Weiss \n \t\t\t\t\t\t\t\t """ 3 => """ J Ukkat \n \t\t\t\t\t\t\t\t """ 4 => """ C Sekulla \n \t\t\t\t\t\t\t\t """ 5 => """ K Brauckhoff \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00268-004-7637-4" "Revista" => array:6 [ "tituloSerie" => "World J Surg" "fecha" => "2004" "volumen" => "28" "paginaInicial" => "1305" "paginaFinal" => "1311" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15517484" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early detection of medullary thyroid carcinoma in multiple endocrine neoplasia type II" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ MC Ezabella \n \t\t\t\t\t\t\t\t """ 1 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 2 => """ H Bisi \n \t\t\t\t\t\t\t\t """ 3 => """ MO Leite \n \t\t\t\t\t\t\t\t """ 4 => """ A Borelli \n \t\t\t\t\t\t\t\t """ 5 => """ NM Abelin \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo" "fecha" => "1990" "volumen" => "45" "paginaInicial" => "105" "paginaFinal" => "109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1983764" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine type II neoplasm" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ 1 => """ AR Ferraz \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo" "fecha" => "1990" "volumen" => "45" "paginaInicial" => "1" "paginaFinal" => "2" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1983459" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunohistochemistry of medullary thyroid carcinoma and C-cell hyperplasia by an affinity-purified anti-human calcitonin antiserum" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 1 => """ VAF Alves \n \t\t\t\t\t\t\t\t """ 2 => """ CT Kanamura \n \t\t\t\t\t\t\t\t """ 3 => """ MCL Ezabella \n \t\t\t\t\t\t\t\t """ 4 => """ NMA Abelin \n \t\t\t\t\t\t\t\t """ 5 => """ W Nicolau \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1097-0142(19930815)72:4<1356::aid-cncr2820720434>3.0.co;2-0" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "1993" "volumen" => "72" "paginaInicial" => "1356" "paginaFinal" => "1363" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8339225" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "C cell hyperplasia/neoplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ VA Livolsi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.82.1.3707" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1997" "volumen" => "82" "paginaInicial" => "39" "paginaFinal" => "41" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8989229" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inheritable form of medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ A Bachelot \n \t\t\t\t\t\t\t\t """ 1 => """ F Lombardo \n \t\t\t\t\t\t\t\t """ 2 => """ E Baudin \n \t\t\t\t\t\t\t\t """ 3 => """ JM Bidart \n \t\t\t\t\t\t\t\t """ 4 => """ M Schlumberger \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Biochimie" "fecha" => "2002" "volumen" => "89" "paginaInicial" => "61" "paginaFinal" => "66" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tumorigênese Molecular Tiroideana: Implicações Para a Prática Médica" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ RMB Maciel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "381" "paginaFinal" => "390" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ S Leboulleux \n \t\t\t\t\t\t\t\t """ 1 => """ E Baudin \n \t\t\t\t\t\t\t\t """ 2 => """ JP Travagli \n \t\t\t\t\t\t\t\t """ 3 => """ M Schlumberger \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol" "fecha" => "2004" "volumen" => "61" "paginaInicial" => "299" "paginaFinal" => "310" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of RET oncogenic activation in MEN2 inherited cancer syndromes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ S Xing \n \t\t\t\t\t\t\t\t """ 1 => """ PA Smanik \n \t\t\t\t\t\t\t\t """ 2 => """ MJ Oglesbee \n \t\t\t\t\t\t\t\t """ 3 => """ JE Trosko \n \t\t\t\t\t\t\t\t """ 4 => """ EL Mazzaferri \n \t\t\t\t\t\t\t\t """ 5 => """ SM Jhiang \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/endo.137.5.8612479" "Revista" => array:6 [ "tituloSerie" => "Endocrinology" "fecha" => "1996" "volumen" => "137" "paginaInicial" => "1512" "paginaFinal" => "1519" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8612479" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abordagem clínica e laboratorial do bócio uni-nodular sólido: vantagens da determinação da calcitonina sérica por métodos distintos" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ NMA Abelin \n \t\t\t\t\t\t\t\t """ 1 => """ S Gomes \n \t\t\t\t\t\t\t\t """ 2 => """ MT Ivanoff \n \t\t\t\t\t\t\t\t """ 3 => """ MCL Ezabella \n \t\t\t\t\t\t\t\t """ 4 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 5 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "1999" "volumen" => "43" "paginaInicial" => "104" "paginaFinal" => "113" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Calcitonin levels in tissue culture of thyroid medullary carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ RC Martin \n \t\t\t\t\t\t\t\t """ 1 => """ MC Ezabella \n \t\t\t\t\t\t\t\t """ 2 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo" "fecha" => "1985" "volumen" => "40" "paginaInicial" => "220" "paginaFinal" => "222" ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dynamics of calcitonin secretion in tissue culture of medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ RC Martin \n \t\t\t\t\t\t\t\t """ 1 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo" "fecha" => "1989" "volumen" => "44" "paginaInicial" => "36" "paginaFinal" => "39" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2814186" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medullary carcinoma of the thyroid" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ GW Randolph \n \t\t\t\t\t\t\t\t """ 1 => """ D Maniar \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/107327480000700305" "Revista" => array:6 [ "tituloSerie" => "Cancer Control" "fecha" => "2000" "volumen" => "7" "paginaInicial" => "253" "paginaFinal" => "261" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10832112" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ A Machens \n \t\t\t\t\t\t\t\t """ 1 => """ O Gimm \n \t\t\t\t\t\t\t\t """ 2 => """ R Hinze \n \t\t\t\t\t\t\t\t """ 3 => """ W Höppner \n \t\t\t\t\t\t\t\t """ 4 => """ BO Boehm \n \t\t\t\t\t\t\t\t """ 5 => """ H Dralle \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.86.3.7290" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "1104" "paginaFinal" => "1109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11238493" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adrenal medullary disease in multiple endocrine neoplasia type 2. Pheocromocytoma and its precursors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ JA Carney \n \t\t\t\t\t\t\t\t """ 1 => """ GW Sizemore \n \t\t\t\t\t\t\t\t """ 2 => """ SG Sheps \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ajcp/66.2.279" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Pathol" "fecha" => "1976" "volumen" => "66" "paginaInicial" => "279" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/949038" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular and immunohistochemical analysis of P53 in phaeochromocytoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 1 => """ RC Aguiar \n \t\t\t\t\t\t\t\t """ 2 => """ AM Tsanaclis \n \t\t\t\t\t\t\t\t """ 3 => """ I Bendit \n \t\t\t\t\t\t\t\t """ 4 => """ SP Bydlowski \n \t\t\t\t\t\t\t\t """ 5 => """ NM Abelin \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/bjc.1995.487" "Revista" => array:6 [ "tituloSerie" => "Br J Cancer" "fecha" => "1995" "volumen" => "72" "paginaInicial" => "1211" "paginaFinal" => "1213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7577469" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ C Eng \n \t\t\t\t\t\t\t\t """ 1 => """ PA Crossey \n \t\t\t\t\t\t\t\t """ 2 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 3 => """ CS Healey \n \t\t\t\t\t\t\t\t """ 4 => """ C Houghton \n \t\t\t\t\t\t\t\t """ 5 => """ A Prowse \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jmg.32.12.934" "Revista" => array:6 [ "tituloSerie" => "J Med Genet" "fecha" => "1995" "volumen" => "32" "paginaInicial" => "934" "paginaFinal" => "937" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8825918" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deletion analysis of the p16 tumour suppressor gene in phaeochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ RC Aguiar \n \t\t\t\t\t\t\t\t """ 1 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 2 => """ H Sill \n \t\t\t\t\t\t\t\t """ 3 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ 4 => """ JM Goldman \n \t\t\t\t\t\t\t\t """ 5 => """ NC Cross \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "1996" "volumen" => "45" "paginaInicial" => "93" "paginaFinal" => "96" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8796144" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutation analysis of glial cell line-derived neurotrophic factor (GDNF), a ligand for the RET/GDNF receptor alpha complex, in sporadic phaeochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 1 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ 2 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 3 => """ ER Maher \n \t\t\t\t\t\t\t\t """ 4 => """ AB Grossman \n \t\t\t\t\t\t\t\t """ 5 => """ C Eng \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cancer Res" "fecha" => "1997" "volumen" => "57" "paginaInicial" => "310" "paginaFinal" => "313" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9000574" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ EM Duerr \n \t\t\t\t\t\t\t\t """ 1 => """ O Gimm \n \t\t\t\t\t\t\t\t """ 2 => """ DS Neuberg \n \t\t\t\t\t\t\t\t """ 3 => """ JB Kum \n \t\t\t\t\t\t\t\t """ 4 => """ SC Clifford \n \t\t\t\t\t\t\t\t """ 5 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.84.9.5961" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1999" "volumen" => "84" "paginaInicial" => "3207" "paginaFinal" => "3211" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10487688" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET and neuroendocrine tumors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ M Ichihara \n \t\t\t\t\t\t\t\t """ 1 => """ Y Murakumo \n \t\t\t\t\t\t\t\t """ 2 => """ M Takahashi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0304-3835(03)00456-7" "Revista" => array:6 [ "tituloSerie" => "Cancer Letters" "fecha" => "2004" "volumen" => "204" "paginaInicial" => "197" "paginaFinal" => "211" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15013219" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 1 => """ KN Ross \n \t\t\t\t\t\t\t\t """ 2 => """ ME Wright \n \t\t\t\t\t\t\t\t """ 3 => """ CY Hayashida \n \t\t\t\t\t\t\t\t """ 4 => """ S Santagata \n \t\t\t\t\t\t\t\t """ 5 => """ M Barontini \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pgen.0010008" "Revista" => array:6 [ "tituloSerie" => "PLoS Genet" "fecha" => "2005" "volumen" => "1" "paginaInicial" => "72" "paginaFinal" => "80" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16103922" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Surgical management of hyperparathyroidism is patients with multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ KK Herfarth \n \t\t\t\t\t\t\t\t """ 1 => """ D Bartsch \n \t\t\t\t\t\t\t\t """ 2 => """ GM Doherty \n \t\t\t\t\t\t\t\t """ 3 => """ SA Wells \n \t\t\t\t\t\t\t\t """ 4 => """ TC Lairmore \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0039-6060(96)80042-0" "Revista" => array:6 [ "tituloSerie" => "Surgery" "fecha" => "1996" "volumen" => "120" "paginaInicial" => "966" "paginaFinal" => "974" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8957482" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => """ SA Wells Jr \n \t\t\t\t\t\t\t\t """ 1 => """ DD Chi \n \t\t\t\t\t\t\t\t """ 2 => """ Toshimak \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00000658-199409000-00002" "Revista" => array:6 [ "tituloSerie" => "Ann Surg" "fecha" => "1994" "volumen" => "220" "paginaInicial" => "237" "paginaFinal" => "250" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7916559" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis of Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ G Martucciello \n \t\t\t\t\t\t\t\t """ 1 => """ I Ceccherini \n \t\t\t\t\t\t\t\t """ 2 => """ M Lerone \n \t\t\t\t\t\t\t\t """ 3 => """ V Jasonni \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jpsu.2000.7763" "Revista" => array:6 [ "tituloSerie" => "J Pediat Surg" "fecha" => "2000" "volumen" => "35" "paginaInicial" => "1017" "paginaFinal" => "1025" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10917288" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ AB Nunes \n \t\t\t\t\t\t\t\t """ 1 => """ MCL Ezabella \n \t\t\t\t\t\t\t\t """ 2 => """ AC Pereira \n \t\t\t\t\t\t\t\t """ 3 => """ JE Krieger \n \t\t\t\t\t\t\t\t """ 4 => """ SPA Toledo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2002-020345" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2002" "volumen" => "87" "paginaInicial" => "5658" "paginaFinal" => "5661" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12466368" "web" => "Medline" ] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib53" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carcinoma Medular de Tireóide: Aspectos Moleculares, Clínico-Oncológicos e Terapêuticos" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ MK Puñales \n \t\t\t\t\t\t\t\t """ 1 => """ PA Rocha \n \t\t\t\t\t\t\t\t """ 2 => """ JL Gross \n \t\t\t\t\t\t\t\t """ 3 => """ AL Maia \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "2004" "volumen" => "48" "paginaInicial" => "137" "paginaFinal" => "146" ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib54" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia type 2: molecular aspects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000061051" "Revista" => array:6 [ "tituloSerie" => "Front Horm Res" "fecha" => "2001" "volumen" => "28" "paginaInicial" => "81" "paginaFinal" => "102" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11443855" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib55" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and hirschsprung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ F Carlomagno \n \t\t\t\t\t\t\t\t """ 1 => """ RM Melillio \n \t\t\t\t\t\t\t\t """ 2 => """ R Visconti \n \t\t\t\t\t\t\t\t """ 3 => """ G Salvatore \n \t\t\t\t\t\t\t\t """ 4 => """ G De Vita \n \t\t\t\t\t\t\t\t """ 5 => """ G Lupoli \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/endo.139.8.6124" "Revista" => array:6 [ "tituloSerie" => "Endocrinology" "fecha" => "1998" "volumen" => "139" "paginaInicial" => "3613" "paginaFinal" => "3619" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9681515" "web" => "Medline" ] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib56" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Point mutation within the tyrosine kinase domain of the RET protooncogene in multiple endocrine neoplasia type 2B and related sporadic tumours" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ C Eng \n \t\t\t\t\t\t\t\t """ 1 => """ DP Smith \n \t\t\t\t\t\t\t\t """ 2 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 3 => """ MA Nagai \n \t\t\t\t\t\t\t\t """ 4 => """ CS Healey \n \t\t\t\t\t\t\t\t """ 5 => """ MA Ponder \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/hmg/3.2.237" "Revista" => array:6 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1994" "volumen" => "3" "paginaInicial" => "237" "paginaFinal" => "241" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7911697" "web" => "Medline" ] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib57" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET codon 634 mutations in multiple endocrine neoplasia type 2: Variable clinical features and clinical outcome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ MK Puñales \n \t\t\t\t\t\t\t\t """ 1 => """ H Graf \n \t\t\t\t\t\t\t\t """ 2 => """ JL Gross \n \t\t\t\t\t\t\t\t """ 3 => """ AL Maia \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2002-021422" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2003" "volumen" => "88" "paginaInicial" => "2644" "paginaFinal" => "2649" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12788868" "web" => "Medline" ] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib58" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early or prophylatic thyroidectomy in MEN2/FMTC gene carriers: results in 71 thyroidectomized patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Niccoli-Sire \n \t\t\t\t\t\t\t\t """ 1 => """ A Murat \n \t\t\t\t\t\t\t\t """ 2 => """ E Baudin \n \t\t\t\t\t\t\t\t """ 3 => """ J Henry \n \t\t\t\t\t\t\t\t """ 4 => """ C Proye \n \t\t\t\t\t\t\t\t """ 5 => """ J Bigorgne \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/eje.0.1410468" "Revista" => array:6 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "1999" "volumen" => "141" "paginaInicial" => "468" "paginaFinal" => "474" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10576762" "web" => "Medline" ] ] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib59" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rastreamento Genético do Carcinoma Medular de Tireóide: Identificação de Mutações no Protooncogene RET" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ MK Puñales \n \t\t\t\t\t\t\t\t """ 1 => """ H Graf \n \t\t\t\t\t\t\t\t """ 2 => """ JL Gross \n \t\t\t\t\t\t\t\t """ 3 => """ AL Maia \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arq Bras Endocrinol Metab" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "632" "paginaFinal" => "639" ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib60" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Nunes AB. Identificação de mutações do proto-oncogene RET associadas à forma hereditária do carcinoma medular de tireóide. 2001; Tese de Doutoramento, Departamento de Clínica Médica, FMUSP." ] ] ] 60 => array:3 [ "identificador" => "bib61" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ F Lombardo \n \t\t\t\t\t\t\t\t """ 1 => """ E Baudin \n \t\t\t\t\t\t\t\t """ 2 => """ E Chiefari \n \t\t\t\t\t\t\t\t """ 3 => """ F Arturi \n \t\t\t\t\t\t\t\t """ 4 => """ S Bardet \n \t\t\t\t\t\t\t\t """ 5 => """ B Caillou \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.87.4.8403" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2002" "volumen" => "87" "paginaInicial" => "1674" "paginaFinal" => "1680" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11932300" "web" => "Medline" ] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib62" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the RET proto-oncogene in Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Edery \n \t\t\t\t\t\t\t\t """ 1 => """ S Lyonnet \n \t\t\t\t\t\t\t\t """ 2 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 3 => """ A Pelet \n \t\t\t\t\t\t\t\t """ 4 => """ E Dow \n \t\t\t\t\t\t\t\t """ 5 => """ L Abel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/367378a0" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "1994" "volumen" => "367" "paginaInicial" => "378" "paginaFinal" => "380" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8114939" "web" => "Medline" ] ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib63" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ C Eng \n \t\t\t\t\t\t\t\t """ 1 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1098-1004(1997)9:2<97::AID-HUMU1>3.0.CO;2-M" "Revista" => array:6 [ "tituloSerie" => "Hum Mutat" "fecha" => "1997" "volumen" => "9" "paginaInicial" => "97" "paginaFinal" => "109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9067749" "web" => "Medline" ] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib64" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new hot spot for mutations in the ret proto-oncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ I Berndt \n \t\t\t\t\t\t\t\t """ 1 => """ M Reuter \n \t\t\t\t\t\t\t\t """ 2 => """ B Saller \n \t\t\t\t\t\t\t\t """ 3 => """ K Frank-Raue \n \t\t\t\t\t\t\t\t """ 4 => """ P Groth \n \t\t\t\t\t\t\t\t """ 5 => """ M Grubendorf \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.83.3.4619" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1998" "volumen" => "83" "paginaInicial" => "770" "paginaFinal" => "774" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9506724" "web" => "Medline" ] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib65" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel germ-line mutation in RET exon 8 (Gly533Cys) in a large kindred with familial medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ AMA Silva \n \t\t\t\t\t\t\t\t """ 1 => """ RMB Maciel \n \t\t\t\t\t\t\t\t """ 2 => """ MRD Silva \n \t\t\t\t\t\t\t\t """ 3 => """ SRC Toledo \n \t\t\t\t\t\t\t\t """ 4 => """ MB Carvalho \n \t\t\t\t\t\t\t\t """ 5 => """ JM Cerutti \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2003-030997" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2003" "volumen" => "88" "paginaInicial" => "5438" "paginaFinal" => "5443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14602786" "web" => "Medline" ] ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib66" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline dinucleotide mutation in codon 883 of the RET protooncogene in multiple endocrine neoplasia type 2B without codon 918 mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ O Gimm \n \t\t\t\t\t\t\t\t """ 1 => """ DJ Marsh \n \t\t\t\t\t\t\t\t """ 2 => """ SD Andrew \n \t\t\t\t\t\t\t\t """ 3 => """ A Frilling \n \t\t\t\t\t\t\t\t """ 4 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 5 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.82.11.4508" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1997" "volumen" => "82" "paginaInicial" => "3902" "paginaFinal" => "3904" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9360560" "web" => "Medline" ] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib67" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acceptable age for prophylatic surgery in children with multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ T Kahraman \n \t\t\t\t\t\t\t\t """ 1 => """ JWB Groot \n \t\t\t\t\t\t\t\t """ 2 => """ C Rouwe \n \t\t\t\t\t\t\t\t """ 3 => """ RMW Hofstra \n \t\t\t\t\t\t\t\t """ 4 => """ TP Links \n \t\t\t\t\t\t\t\t """ 5 => """ RH Sijmons \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/ejso.2002.1378" "Revista" => array:6 [ "tituloSerie" => "Eur J Surg Oncol" "fecha" => "2002" "volumen" => "29" "paginaInicial" => "331" "paginaFinal" => "335" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12711285" "web" => "Medline" ] ] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib68" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Modulation of medullary thyroid carcinoma penetrance suggests the presence of modifier genes in a RET transgenic mouse model" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ AN Cranston \n \t\t\t\t\t\t\t\t """ 1 => """ BAJ Ponder \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cancer Research" "fecha" => "2003" "volumen" => "63" "paginaInicial" => "4777" "paginaFinal" => "4780" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12941793" "web" => "Medline" ] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib69" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A simple salting out procedure for extracting DNA from human nucleated cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ S Miller \n \t\t\t\t\t\t\t\t """ 1 => """ D Dykes \n \t\t\t\t\t\t\t\t """ 2 => """ H Poleski \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "1988" "volumen" => "16" ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib70" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ RK Saiki \n \t\t\t\t\t\t\t\t """ 1 => """ DH Gelfand \n \t\t\t\t\t\t\t\t """ 2 => """ S Stoffel \n \t\t\t\t\t\t\t\t """ 3 => """ SJ Scharf \n \t\t\t\t\t\t\t\t """ 4 => """ HA Erlich \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.2448875" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "1988" "volumen" => "239" "paginaInicial" => "487" "paginaFinal" => "491" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2448875" "web" => "Medline" ] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib71" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ F Sanger \n \t\t\t\t\t\t\t\t """ 1 => """ AR Coulson \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Mol Biol" "fecha" => "1975" "volumen" => "94" "paginaInicial" => "444" "paginaFinal" => "448" ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib72" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Attachment of a 40-base pair G+C rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ VC Sheffield \n \t\t\t\t\t\t\t\t """ 1 => """ DR Cox \n \t\t\t\t\t\t\t\t """ 2 => """ LS Lerman \n \t\t\t\t\t\t\t\t """ 3 => """ RM Myers \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.86.1.232" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci (USA)" "fecha" => "1989" "volumen" => "86" "paginaInicial" => "232" "paginaFinal" => "236" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2643100" "web" => "Medline" ] ] ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib73" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Denaturing gel electrophoresis to diagnose multiple endocrine neoplasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ RD Blank \n \t\t\t\t\t\t\t\t """ 1 => """ CA Skalr \n \t\t\t\t\t\t\t\t """ 2 => """ ML Martin \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Chem" "fecha" => "1996" "volumen" => "42" "paginaInicial" => "598" "paginaFinal" => "603" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8605678" "web" => "Medline" ] ] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib74" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Update on the profile of multiple endocrine neoplasia type 2A RET mutations: Practical issues and implications for genetic testing" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ RA Decker \n \t\t\t\t\t\t\t\t """ 1 => """ ML Peacock \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Cancer" "fecha" => "1997" "volumen" => "80" "paginaInicial" => "557" "paginaFinal" => "568" ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib75" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improvement of fragment and primer selection for mutation detection by denaturing gradient gel electrophoresis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ Y Wu \n \t\t\t\t\t\t\t\t """ …5 ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "1998" "volumen" => "26" ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib76" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved mutation detection in GC-rich DNA fragments by combined DGGE and CDGE" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/nar/27.15.e9" "Revista" => array:5 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "1999" "volumen" => "27" "paginaInicial" => "e9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib77" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Frediani D. 2002; Rastreamento Gênico através de Enzimas de Restrição na forma Hereditária do Carcinoma Medular de Tireóide. Monografia, Departamento de Clínica Médica, FMUSP." ] ] ] 77 => array:3 [ "identificador" => "bib78" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12864-022-08691-6" "Revista" => array:6 [ "tituloSerie" => "Genomics" "fecha" => "1994" "volumen" => "23" "paginaInicial" => "477" "paginaFinal" => "479" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib79" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia type 2 and the practice of molecular medicine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev in Endocrinol Dis" "fecha" => "2000" "volumen" => "1" "paginaInicial" => "283" "paginaFinal" => "290" ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib80" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular diagnosis of multiple endocrine neoplasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Expert Ver Mol Diagn" "fecha" => "2003" "volumen" => "3" "paginaInicial" => "769" "paginaFinal" => "779" ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib81" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Review of multiple endocrine neoplasia type 2a in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.111.2.e132" "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "2004" "volumen" => "111" "paginaInicial" => "E132" "paginaFinal" => "E140" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack640440" "titulo" => "ACKNOWLEDGEMENTS" "texto" => "We thank Papaiz group for supporting this research, aiming to bring to society a faster, safe, and accurate diagnosis of multiple endocrine neoplasias. We also thank all the staff of the Endocrine Genetics Unit (http://medicina.fm.usp.br/ueg) for the support." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/0000006100000001/v1_202212060829/S1807593222030058/v1_202212060829/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006100000001/v1_202212060829/S1807593222030058/v1_202212060829/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222030058?idApp=UINPBA00004N"]

Statistics

REVIEW

Sergio Pereira de Almeida Toledo, Marcelo Augusto Cortina Gonçalves dos Santos Rodrigo de Almeida Toledo, Delmar Muniz Lourenço Júnior

Genetic Endocrinology Unit (LIM-25), Internal Medicine Department, São Paulo University Medical School, São Paulo/SP, Brazil

Read

1180

Times
was read the article

310

Total PDF

870

Total HTML

Share statistics

 array:24 [
  "pii" => "S1807593222030058"
  "issn" => "18075932"
  "doi" => "10.1590/S1807-59322006000100011"
  "estado" => "S300"
  "fechaPublicacion" => "2006-02-01"
  "aid" => "3005"
  "copyright" => "CLINICS"
  "copyrightAnyo" => "2006"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
  "subdocumento" => "rev"
  "cita" => "Clinics. 2006;61:59-70"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S180759322203006X"
    "issn" => "18075932"
    "doi" => "10.1590/S1807-59322006000100012"
    "estado" => "S300"
    "fechaPublicacion" => "2006-02-01"
    "aid" => "3006"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "rev"
    "cita" => "Clinics. 2006;61:71-6"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>"
      "titulo" => "SEPSIS&#58; EMERGING ROLE OF NITRIC OXIDE AND SELECTINS"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "pt"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "71"
          "paginaFinal" => "76"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "pt" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig1"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 696
              "Ancho" => 992
              "Tamanyo" => 84949
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Role of selections and excessive nitric oxide in sepsis-related tissue injury&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Abhijit Chandra<span class="elsevierStyleSup">a</span>, Perenlei Enkhbaatar<span class="elsevierStyleSup">b</span>, Yoshimitshu Nakano<span class="elsevierStyleSup">b</span>, Lillian D Traber<span class="elsevierStyleSup">b</span>, Daniel L&#46; Traber<span class="elsevierStyleSup">b</span>"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "Abhijit"
              "apellidos" => "Chandra<span class="elsevierStyleSup">a</span>"
            ]
            1 => array:2 [
              "nombre" => "Perenlei"
              "apellidos" => "Enkhbaatar<span class="elsevierStyleSup">b</span>"
            ]
            2 => array:2 [
              "nombre" => "Yoshimitshu"
              "apellidos" => "Nakano<span class="elsevierStyleSup">b</span>"
            ]
            3 => array:2 [
              "nombre" => "Lillian D"
              "apellidos" => "Traber<span class="elsevierStyleSup">b</span>"
            ]
            4 => array:2 [
              "nombre" => "Daniel L&#46;"
              "apellidos" => "Traber<span class="elsevierStyleSup">b</span>"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S180759322203006X?idApp=UINPBA00004N"
    "url" => "/18075932/0000006100000001/v1_202212060829/S180759322203006X/v1_202212060829/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1807593222030046"
    "issn" => "18075932"
    "doi" => "10.1590/S1807-59322006000100010"
    "estado" => "S300"
    "fechaPublicacion" => "2006-02-01"
    "aid" => "3004"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "fla"
    "cita" => "Clinics. 2006;61:53-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">ORIGINAL RESEARCH</span>"
      "titulo" => "DOES ENDOTHELIAL DYSFUNCTION CORRELATE BETTER WITH WAIST-TO-HIP RATIO THAN WITH BODY MASS INDEX OR WAIST CIRCUMFERENCE AMONG OBESE PATIENTS&#63;"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "pt"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "53"
          "paginaFinal" => "58"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "pt" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Nivaldo Ribeiro Villela, Luiz Guilherme Kraemer Aguiar, Luciana Bahia, Daniel Bottino, Eliete Bouskela"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "Nivaldo Ribeiro"
              "apellidos" => "Villela"
            ]
            1 => array:2 [
              "nombre" => "Luiz Guilherme Kraemer"
              "apellidos" => "Aguiar"
            ]
            2 => array:2 [
              "nombre" => "Luciana"
              "apellidos" => "Bahia"
            ]
            3 => array:2 [
              "nombre" => "Daniel"
              "apellidos" => "Bottino"
            ]
            4 => array:2 [
              "nombre" => "Eliete"
              "apellidos" => "Bouskela"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222030046?idApp=UINPBA00004N"
    "url" => "/18075932/0000006100000001/v1_202212060829/S1807593222030046/v1_202212060829/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>"
    "titulo" => "IMPACT OF RET PROTO-ONCOGENE ANALYSIS ON THE CLINICAL MANAGEMENT OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "59"
        "paginaFinal" => "70"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "Sergio Pereira de Almeida Toledo, Marcelo Augusto Cortina Gon&#231;alves dos Santos Rodrigo de Almeida Toledo, Delmar Muniz Louren&#231;o J&#250;nior"
        "autores" => array:3 [
          0 => array:2 [
            "nombre" => "Sergio Pereira"
            "apellidos" => "de Almeida Toledo"
          ]
          1 => array:3 [
            "nombre" => "Marcelo Augusto Cortina Gon&#231;alves dos Santos Rodrigo"
            "apellidos" => "de Almeida Toledo"
            "email" => array:1 [
              0 => "cortina_marcelo@hotmail.com"
            ]
          ]
          2 => array:2 [
            "nombre" => "Delmar Muniz Louren&#231;o"
            "apellidos" => "J&#250;nior"
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Genetic Endocrinology Unit &#40;LIM-25&#41;&#44; Internal Medicine Department&#44; S&#227;o Paulo University Medical School&#44; S&#227;o Paulo&#47;SP&#44; Brazil"
            "identificador" => "aff1"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2594
            "Ancho" => 1542
            "Tamanyo" => 374908
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Electropherograms showing five different types of <span class="elsevierStyleItalic">RET</span> mutations in MEN2&#44; using a DNA sequencer &#40;ABI 310 DNA Sequencer - Applied Biosystems&#44; USA&#41;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Multiple endocrine neoplasia type 2 &#40;MEN2&#41; is associated with the occurrence of 3 inherited endocrine tumors&#58; medullary thyroid carcinoma &#40;MTC&#41;&#44; primary hyperparathyroidism &#40;HPT&#41;&#44; and pheochromocytoma &#40;PHEO&#41;&#46; Multiple endocrine neoplasia type 2 is transmitted by an autosomal dominant gene&#44; which imposes the need of genetic screening of all family members at risk having inherited a predisposition to this condition&#46; The 3 neoplasias involved are derived from neural crest cells&#44; such as C thyroid cells&#44; parathyroid oxyphilic and chief cells&#44; and chromaffin cells of the adrenal medulla&#46; Sympathetic&#44; parasympathetic&#44; and enteric ganglia and the urogenital tract have been also reported as expressing high levels of several hormonal and nonhormonal substances produced by the affected glands&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#8211;13&#44;18&#8211;20</span></a></p><p id="para20" class="elsevierStylePara elsevierViewall">Despite all efforts performed towards the management of MEN2&#44; this condition is still an underdiagnosed&#44; or late-diagnosed disease in many areas of the world&#46; Presently&#44; molecular DNA diagnosis to identify <span class="elsevierStyleItalic">RET</span> mutations is mandatory for all MEN2 cases and for their relatives at risk for a predisposition to MEN2&#46; This diagnostic procedure is turning out to be a fundamental tool in early MEN2 diagnosis&#44; enabling correct therapeutic surgical management&#46;<a class="elsevierStyleCrossRef" href="#bib12"><span class="elsevierStyleSup">12</span></a></p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">MOLECULAR MEDICINE</span><p id="para30" class="elsevierStylePara elsevierViewall">In 1986&#44; with the identification of DNA polymorphisms in chromosome 10 in large MEN2 genealogies&#44; the study of the RET proto-oncogene gained further interest&#46;<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10</span></a> Transfection DNA studies of several MTC tumors revealed important foci of proliferation in NIH-3T3 cells&#44; represented by the presence of different genetic DNA sequences&#46;<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10</span></a> Among these sequences&#44; one &#8211; <span class="elsevierStyleItalic">RET</span> &#40;rearranged during transfection&#41; &#8211; was present in all tumor specimens&#46; Soon afterwards&#44; the <span class="elsevierStyleItalic">RET</span> sequence was localized in the chromosome band 10q11&#46;2&#46;<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10&#44;</span></a><a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13&#8211;15</span></a> The <span class="elsevierStyleItalic">RET</span> gene has 60 kb of the human genome spread through 21 exons&#44; with 60 to 287 base pairs &#40;bp&#41;&#44; having a 24 kb intron between the first and second exons and encoding a protein of approximately 1&#44;100 amino acids&#46;<a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13&#44;16</span></a> In 1993&#44; Mulligan et al and Donnis-Keller et al &#40;1993&#41; identified the first missense mutations in the <span class="elsevierStyleItalic">RET</span> extracellular <span class="elsevierStyleItalic">RET</span>domain in patients with MTC and MEN2&#46;<a class="elsevierStyleCrossRefs" href="#bib21"><span class="elsevierStyleSup">21&#44;22</span></a></p><p id="para40" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RET</span> is the only gene that has been associated with MEN2&#44; and gametic mutation in this proto-oncogene has been extensively studied&#46; Management of MEN2 using DNA sequencing information represents an excellent example of how molecular DNA diagnosis may improve clinical management&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;3&#44;6&#44;8&#44;13&#44;23</span></a></p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">CLASSIFICATION</span><p id="para50" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a> summarizes the accepted classification of MEN2&#44; as suggested by the international consensus on MEN&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> This classification is based on clinical pictures of affected MEN2 patients&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para60" class="elsevierStylePara elsevierViewall">Thyroid cancer is a relatively rare event comprising 0&#46;6&#37; and 1&#46;6&#37; of all carcinomas affecting men and women&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib24"><span class="elsevierStyleSup">24</span></a> Medullary thyroid carcinoma comprises 10&#37; of all thyroid cancers&#44; presenting as sporadic &#40;75&#37;&#41; or inherited &#40;25&#37;&#41; forms&#46; Multiple endocrine neoplasia type 2 has an estimated prevalence of 1 in 30&#44;000 individuals&#44; and more than 90&#37; of <span class="elsevierStyleItalic">RET</span> carriers will develop MTC&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;8&#44;25</span></a> The international consensus on MEN estimates that 95&#37; of MEN2 patients have a detectable <span class="elsevierStyleItalic">RET</span> mutation&#46; Mutations in exons 10&#44; 11&#44; and 16 are present in 90&#37; to 95&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p><p id="para70" class="elsevierStylePara elsevierViewall">Multiple endocrine neoplasia type 2A comprises 75&#37; of all MEN2 cases&#46; In MEN2A&#44; MTC is prevalent in almost 100&#37; of patients&#44; whereas PHEO &#40;50&#37;&#41; and HPT &#40;20&#37;&#8211;30&#37;&#41; are less frequently expressed&#46; The mean age of clinical diagnosis of MEN2A is 20 to 40 years&#44; but this should soon decrease&#44; as new young <span class="elsevierStyleItalic">RET</span> mutation carriers are recognized and treated earlier in life&#46;<a class="elsevierStyleCrossRef" href="#bib8"><span class="elsevierStyleSup">8</span></a></p><p id="para80" class="elsevierStylePara elsevierViewall">The familial form of MTC &#40;FMTC&#41; comprises 20&#37; of all MEN2 cases&#44; and it is characterized by the presence of MTC in the absence of both PHEO and HPT&#44; both in index cases and affected family members&#46; Usually in FMTC&#44; MTC tends to present less aggressive behavior and better prognosis than in MEN2A or MEN2B&#46;<a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13&#44;26</span></a></p><p id="para90" class="elsevierStylePara elsevierViewall">Five percent &#40;5&#37;&#41; of MEN2 cases have the phenotype of MEN2B&#44; the most aggressive form of MTC&#46; This form is characterized by the association of MTC&#44; PHEO&#44; marfanoid habitus&#44; and mucosal neuromas &#40;lips&#44; tongue&#44; eyebrows&#44; and intestinal tract&#41;&#44; whereas the presence of HPT is very rare&#46;<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a> Medullary thyroid carcinoma in MEN2B usually appears very early&#44; usually before 12 months of age&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;27</span></a></p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MEDULLARY THYROID CARCINOMA &#40;MTC&#41;</span><p id="para100" class="elsevierStylePara elsevierViewall">Affected families usually have several members with MTC&#46;<a class="elsevierStyleCrossRef" href="#bib8"><span class="elsevierStyleSup">8</span></a> Ever since molecular diagnosis has been performed&#44; increasing incidences and prevalences of inherited forms of MTC have been reported&#46; Familial forms of MTC are constitutive events that lead to bilateral&#44; multicentric thyroid cancer&#46; Among several bioactive substances secreted by thyroid C cells&#44; calcitonin is the most representative and the best tumor marker for MTC&#46;<a class="elsevierStyleCrossRefs" href="#bib4"><span class="elsevierStyleSup">4&#44;9</span></a></p><p id="para110" class="elsevierStylePara elsevierViewall">Thyroid C-cell hyperplasia is usually the earlier histologic abnormality in MTC and represents a premalignant stage&#46; It initially occurs as small foci&#44; progressing to nodular diffuse hyperplasias that may evolve to focal and finally to metastatic MTC&#46;<a class="elsevierStyleCrossRefs" href="#bib28"><span class="elsevierStyleSup">28&#8211;32</span></a> The usual clinical presentation of MTC is a solitary thyroid nodule&#46;<a class="elsevierStyleCrossRefs" href="#bib28"><span class="elsevierStyleSup">28&#8211;32</span></a> At the stage of palpable thyroid nodules&#44; MTC measures at least 1 cm&#44; and 50&#37; of patients already have local neck lymph node metastases and more rarely lung&#44; liver&#44; and bone metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib33"><span class="elsevierStyleSup">33&#44;34</span></a> It has been suggested that routine calcitonin measurements should be performed in all patients with solid thyroid nodules&#44; since this procedure would permit presurgical diagnosis of the sporadic form of MTC as well as in familial MTC index cases&#44; permitting the establishment of an adequate surgical plan&#46;<a class="elsevierStyleCrossRefs" href="#bib35"><span class="elsevierStyleSup">35&#44;36</span></a> Fine-needle biopsy followed by immunocytochemistry for calcitonin is also helpful for the presurgical diagnosis of MTC&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;11&#44;12&#44;37&#8211;40</span></a> Total thyroidectomy associated with extensive resection of neck lymph nodes is the only effective treatment for MTC&#44; as the tumor is usually resistant to iodo-&#44; chemo-&#44; and radiotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;11&#44;12</span></a> In early diagnosed cases&#44; C-cell hyperplasia is predominant&#44; and neck lymph node resection may be less massive&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;11&#44;12</span></a></p><p id="para120" class="elsevierStylePara elsevierViewall">Genetic sequencing of MTC has resulted in dramatically lower mortality rates&#46; Before Genetic sequencing was available&#44; mortality rates for MEN2 were up to 20&#37;&#44; whereas after <span class="elsevierStyleItalic">RET</span> mutation analysis&#44; mortality has been as low as 5&#37; in some samples&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">PHEOCHROMOCYTOMA &#40;PHEO&#41;</span><p id="para130" class="elsevierStylePara elsevierViewall">Five to fifteen percent of all PHEOs are associated with MEN2&#44; and most of them &#40;90&#37;&#41; are benign&#46; Pheochromocytomas associated with MEN2 are usually located on the adrenals &#40;90&#37;&#41;&#44; but extra-adrenal cases have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> Most tumors &#40;50&#37;&#8211;80&#37;&#41; are bilateral&#46; Patients with PHEO&#47;MEN2 present a pretumoral stage characterized by nodular or diffuse hyperplasia of chromaffin adrenal cells&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;41&#8211;48</span></a> The diagnosis of PHEO is usually accomplished after the recognition of MTC &#40;40&#37;&#8211;50&#37;&#41;&#59; however&#44; it may occur before or synchronously with MTC diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;41</span></a> Thus&#44; RET analysis should be considered in all PHEO cases&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p><p id="para140" class="elsevierStylePara elsevierViewall">Notably&#44; the possibility of an undiagnosed PHEO must be ruled out in all MTC patients before surgery to avoid the intrasurgical risk of an adrenal hypertensive crisis&#46; Since a contralateral tumor may appear many years after the first diagnosis&#44; PHEO&#47;MEN2 patients need long-term follow-up&#46; Image studies with MIBG &#40;metaiodobenzylguanidine&#41; and serum&#47;urinary measurements of catecholamines are useful in this task&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;41</span></a></p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">HYPERPARATHYROIDISM &#40;HPT&#41;</span><p id="para150" class="elsevierStylePara elsevierViewall">Hyperparathyroidism associated with MEN2 &#40;HPT&#47;MEN2&#41; results from a hyperplastic process of parathyroid chief cells involving the 4 parathyroid glands&#46; In most HPT&#47;MEN2 cases &#40;68&#37;&#41;&#44; associated adenomas have been also reported&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;49</span></a> Primary HPT associated with MEN2 is a mild disease presenting slightly elevated concentrations of PTH and calcium&#46; Several measurements may be needed to enable the biochemical diagnosis of HPT&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> In early-diagnosed MEN2 cases&#44; HPT tends to be asymptomatic&#46; Late-diagnosed cases are usually symptomatic&#44; and renal stones are usually reported as the first clinical symptom&#46; Osteoporosis may occur in such cases&#46; During neck surgery for MTC in MEN2 cases&#44; enlarged parathyroid glands are frequently found&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p><p id="para160" class="elsevierStylePara elsevierViewall">Two surgical approaches have been used for HPT in MEN2&#46; In the first approach&#44; the 4 parathyroid glands are removed and half of a gland is implanted in the nondominant forearm&#46; In the other approach&#44; 3 1&#47;2 glands are removed&#46; Postsurgical euparathyroidism is less often achieved in HPT&#47;MEN2 than in sporadic primary HPT&#44; and its recurrence rate may be high&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;49</span></a> When HPT is present&#44; parathyroidectomy and total thyroidectomy are usually performed during the same surgical stage&#46;<a class="elsevierStyleCrossRef" href="#bib50"><span class="elsevierStyleSup">50</span></a></p><p id="para170" class="elsevierStylePara elsevierViewall">Prior to 1993&#44; i&#46;e&#46;&#44; before the advent of genetic analysis for <span class="elsevierStyleItalic">RET&#44;</span> all individuals at risk for MTC&#44; PHEO&#44; and HPT underwent annual screening &#40;from 6 years of age&#41;&#46; This procedure usually included measurements of basal and stimulated calcitonin&#44; serum and urinary catecholamines&#44; calcium&#44; and PTH&#46; <span class="elsevierStyleItalic">RET</span> genetic analysis is indicated for all patients with MTC or PHEO&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> In apparently sporadic HPT&#44; in the absence of other clinical suspicion for hereditary MEN2&#44; analysis for <span class="elsevierStyleItalic">RET</span> is not usually performed&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">HIRSCHSPRUNG DISEASE &#40;HSCR&#41;</span><p id="para180" class="elsevierStylePara elsevierViewall">A nonendocrine entity such as congenital megacolon or Hirschsprung disease &#40;HSCR&#41; has been described in association with gametic inactivating <span class="elsevierStyleItalic">RET</span> mutations and MEN2 cases&#46; This disorder is due to an embryonic defect in the enteric nervous system&#46; In HSCR associated with MEN2&#44; myenteric and submucosal plexi are affected in extensive areas of the distal enteric tube&#46; Most patients present with intestinal obstruction and constipation&#46; Colectomy is frequently performed at early ages in order to correct intestinal transit&#46;<a class="elsevierStyleCrossRefs" href="#bib31"><span class="elsevierStyleSup">31&#44;51</span></a></p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">MOLECULAR ASPECTS</span><p id="para190" class="elsevierStylePara elsevierViewall">The RET proto-oncogene encodes for a tyrosine kinase cell membrane receptor&#46; The extracellular domain of this protein is rich in cysteine residues&#44; and it is encoded by the first 10 exons of <span class="elsevierStyleItalic">RET&#46;</span> Exon 11 encodes for the transmembrane domain&#44; and the 2 intracellular domains of the protein are encoded by 10 other exons&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;36&#44;52&#44;53</span></a></p><p id="para200" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">RET</span> extracellular domain includes coding for a cadherin-binding site that is important in intercellular signaling&#46; Extracellular cysteines play an important role in receptor dimerization&#46; At least 10 <span class="elsevierStyleItalic">RET</span> isoforms have been reported as result of 5&#8217; and 3&#8217; splicing of exon 21&#59; however&#44; their physiological function still partially unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;36&#44;53</span></a></p><p id="para210" class="elsevierStylePara elsevierViewall">The protein encoded by <span class="elsevierStyleItalic">RET</span> plays an important role in embryologic migration and development of neural crest-derived cells&#44; such as thyroid C cells&#44; chromaffin adrenal cells&#44; sympathetic&#44; parasympathetic&#44; and enteric ganglia cells&#44; as well as in urogenital tract&#46;<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a> The RET protooncogene is also expressed in parathyroid cells derived from branchial arches&#46; Binding proteins such as GDNF &#40;glial cell line-derived neurotrophic factor&#41; and its receptor&#44; GFR&#945;-1 &#40;GDNF family receptor alpha one&#41; interact with the RET-encoded extracellular protein&#44; promoting cell survival of central and peripheral neurons&#46; The RET protooncogene also plays an essential role in renal and enteric neural development&#46;<a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13&#44;54&#44;55</span></a></p><p id="para220" class="elsevierStylePara elsevierViewall">Once coupled&#44; ligands and their respective receptors give rise to a ligand-receptor complex that promotes RET receptor monomer dimerization through disulfite bonds&#46; Intracellular tyrosine residues are self-phosphorylated&#46; This process is followed by a complex signaling pathway in which mitotic-activating protein kinases &#40;MAPKs&#41; amplify signaling pathways to cell nuclei&#44; promoting cell mobility and survival&#46;<a class="elsevierStyleCrossRefs" href="#bib6"><span class="elsevierStyleSup">6&#44;35&#44;56</span></a></p><p id="para230" class="elsevierStylePara elsevierViewall">The same dimerization process occurs independently of ligand binding when activating <span class="elsevierStyleItalic">RET</span> germline mutations &#40;constitutive mutation&#41; are present in the RET extracellular domain&#44; favoring the development of the neoplastic phenotypes&#46; <span class="elsevierStyleItalic">RET</span> mutations encode for the intracellular protein that leads to disturbances in the substrate catalytic core affinity&#44; favoring the appearance of the neoplastic process&#46;<a class="elsevierStyleCrossRefs" href="#bib6"><span class="elsevierStyleSup">6&#44;35&#44;56</span></a></p><p id="para240" class="elsevierStylePara elsevierViewall">Biochemical and transfection studies of tyrosine kinase have revealed differential RET expressions at the cell membrane level&#46; Thus&#44; cysteine residues next to the 5&#8217; region &#40;such as mutant codons 609 and 611&#41; present lower protein expression compared to codon 634 mutations&#44; located next to the transmembrane domain&#46; The potency of cell neoplastic transformation of codon 634 <span class="elsevierStyleItalic">RET</span> mutations is clearly higher than that occurring in codons 609 and 611&#46; This finding may be due to modulation of expression of mature RET-encoded protein receptors at the cell membrane&#44; where most of the RET-encoded protein expression occurs&#46;<a class="elsevierStyleCrossRefs" href="#bib56"><span class="elsevierStyleSup">56&#44;57</span></a> Thus&#44; most patients with MEN2 who harbor <span class="elsevierStyleItalic">RET</span> 634 mutations will have thyroid&#44; adrenal&#44; and parathyroid tumors&#44; whereas patients with 609 or 611 mutations will present only thyroid cancer&#46; Further&#44; tissue-specific sensitivity may also be modulated by codon-specific <span class="elsevierStyleItalic">RET</span> mutations&#46; Tissue sensitivity is therefore high in thyroid tissue&#44; intermediate in the adrenals&#44; and low in parathyroid glands&#46;<a class="elsevierStyleCrossRef" href="#bib3"><span class="elsevierStyleSup">3</span></a> These observations may also explain why activating <span class="elsevierStyleItalic">RET</span> mutations are usually associated with MEN2&#44; whereas inactivating <span class="elsevierStyleItalic">RET</span> mutations are associated with HSCR&#46; Mutations in codons 618 and 620 usually result in RET-encoded receptor amounts sufficient to transform thyroid and possibly adrenal cells&#44; but insufficient to produce disturbances in normal intestinal gangliogenesis&#46; Hirschsprung disease may be considered a polygenic disease&#44; because <span class="elsevierStyleItalic">RET&#44;</span> GDNF&#44; endothelin receptor-2 genes&#44; and genes located at 9q31 and 22q11 bands are involved&#46;<a class="elsevierStyleCrossRefs" href="#bib6"><span class="elsevierStyleSup">6&#44;8</span></a></p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">GENOTYPE-PHENOTYPE CORRELATIONS</span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Multiple endocrine neoplasia type 2A &#40;MEN2A&#41;</span><p id="para250" class="elsevierStylePara elsevierViewall">The genotype-phenotype correlations in MEN2 are summarized in <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#46; The vast majority of MEN2A cases &#40;98&#37;&#41; harbors a missense <span class="elsevierStyleItalic">RET</span> mutation&#44; primarily in exon 10 and 11 and in codons 609&#44; 611&#44; 618&#44; 620&#44; 630&#44; and 634&#44; which comprise a small 25-amino-acid domain&#46;<a class="elsevierStyleCrossRef" href="#bib3"><span class="elsevierStyleSup">3</span></a> Rarely&#44; small insertions in codons 635 and 637 have been reported&#46; Codon 634 is involved in 85&#37; of MEN2A mutations&#59; 52&#37; of them have a Cys634Arg mutation&#44; and 26&#37; present the Cys634Tyr mutation&#46; Further&#44; MTC tumor aggressiveness induced by these 2 mutations differ&#58; metastases tend to be more frequent and early in Cys634Arg cases&#44; as compared to Cys634Tyr cases&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;13&#44;58&#44;59</span></a></p><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para260" class="elsevierStylePara elsevierViewall">In relatives of patients presenting an increased incidence of HPT and the absence of PHEO&#44; a 12 bp duplication was found between codons 634 and 635&#44; corresponding to 4 amino acids and co-segregated with a Cys634Arg mutation&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;13</span></a> Recently&#44; Nunes et al&#44; of our laboratory&#44; described a case with double <span class="elsevierStyleItalic">RET</span> mutations &#40;Val648Ile&#47;Cys634Arg&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib52"><span class="elsevierStyleSup">52&#44;60</span></a> In this family&#44; 2 siblings were Val648Ile carriers and so far have presented neither clinical nor biochemical abnormalities compatible with MEN2A&#46; The other 2 affected siblings presented the usual Cys634Arg <span class="elsevierStyleItalic">RET</span> mutation and early classical MTC presentation&#46; The father presented a rare phenotype of MEN2A associated with an ectopic ACTH-producing PHEO&#46; He was an obligatory carrier of the double <span class="elsevierStyleItalic">RET</span> mutation&#46; The MEN2A in this specific case had a relatively mild presentation&#46;<a class="elsevierStyleCrossRefs" href="#bib52"><span class="elsevierStyleSup">52&#44;60</span></a></p><p id="para270" class="elsevierStylePara elsevierViewall">Mutations in the <span class="elsevierStyleItalic">RET</span> intracellular protein receptor domain <span class="elsevierStyleItalic">RET</span> in codons 790 and 804 are rarely associated with MEN2A&#46; Mutations associated with codon 804 are frequent in FMTC&#46; In most of these cases&#44; thyroid tumor tends to present a late onset&#44; slow course&#44; and low aggressiveness&#44; when compared to phenotypes presenting <span class="elsevierStyleItalic">RET</span> extracellular-domain mutations&#46; These patients may exhibit incomplete neoplastic transformation induced by the 804 mutation&#59; however&#44; aggressive MTC tumors and even death due to MTC have been reported in cases harboring codon 804 mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;61</span></a></p><p id="para280" class="elsevierStylePara elsevierViewall">Hirschsprung disease has been described in association with MEN2A or FMTC cases that are associated with mutations primarily in codons 609&#44; 611&#44; 618&#44; and 620&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;62&#44;63</span></a></p></span></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">FAMILIAL MEDULLARY THYROID CARCINOMA</span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">&#40;FMTC&#41;</span><p id="para290" class="elsevierStylePara elsevierViewall">Most FMTC cases &#40;85&#37;&#41; present <span class="elsevierStyleItalic">RET</span> mutations in exons 10 and 11&#46; The Cys618Ser genotype is found in 33&#37; of cases&#59; the Cys634Tyr genotype is found in 30&#37; cases&#59; whereas&#44; the Cys634Arg genotype is rarely associated with this phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;8</span></a> Mutations in codons 609&#44; 611&#44; and 620 and those of Glu768Asp&#44; Val804Leu&#44; and Val804Met occurring in tyrosine kinase domains are accepted to be related to FMTC&#44; even though they may also occur in MEN2A&#46; Other mutations in <span class="elsevierStyleItalic">RET</span> tyrosine kinase domains&#44; such as in codons 790&#44; 791&#44; and 891&#44; have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;8&#44;57</span></a></p><p id="para300" class="elsevierStylePara elsevierViewall">Less frequently&#44; hot spots and mutations&#44; such as those in codons 630&#44; 790&#44; 791&#44; 891&#44; and a 12 bp duplication between codons 634 and 635&#44; have been reported in FMTC families&#44; associated with an indolent form of MTC&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;64</span></a></p><p id="para310" class="elsevierStylePara elsevierViewall">Additionally&#44; a 9 bp duplication in <span class="elsevierStyleItalic">RET</span> exon 8 creating a new cysteine residue in the extracellular portion of the RET protein receptor was reported in a FMTC family&#44; possibly associated with HSCR&#46; The affected case did not present germline mutations in exons 10&#44; 11&#44; 13&#44; 14&#44; or 15 or somatic mutations in exons 11&#44; 13&#44; 15&#44; and 16&#44; suggesting the neoplastic activity of this mutation&#46;<a class="elsevierStyleCrossRef" href="#bib26"><span class="elsevierStyleSup">26</span></a></p><p id="para320" class="elsevierStylePara elsevierViewall">Recently&#44; a new exon 8&#44; Gly533Cys <span class="elsevierStyleItalic">RET</span> mutation was reported in 76 FMTC carriers belonging to a family of Spanish extraction in which 229 individuals were at risk&#46;<a class="elsevierStyleCrossRef" href="#bib65"><span class="elsevierStyleSup">65</span></a></p></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">Multiple endocrine neoplasia type 2B &#40;MEN2B&#41;</span><p id="para330" class="elsevierStylePara elsevierViewall">A <span class="elsevierStyleItalic">RET</span> intracellular tyrosine kinase domain mutation&#44; Met918Thr&#44; has been reported in 95&#37; of MEN2B cases&#46;<a class="elsevierStyleCrossRef" href="#bib56"><span class="elsevierStyleSup">56</span></a> In 4 families with MEN2B from Germany&#44; United Kingdom&#44; and Australia&#44; an Ala883Phe substitution in exon 15 was described&#44; comprising 4&#37; of all MEN2B phenotypes reported to date&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;13&#44;56</span></a> Some rare mutations have been described&#44; such as Ser922Tyr and a double mutation in codon 804 and Tyr806Cys occurring in the same allele&#44; which was detected in a patient with MEN2B&#46;<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a></p><p id="para340" class="elsevierStylePara elsevierViewall">Genotype-phenotype correlations in MEN2 have a major and immediate impact in clinical medicine&#44; since genetic testing may differentiate <span class="elsevierStyleItalic">RET</span> carriers from noncarriers&#46; <span class="elsevierStyleItalic">RET</span> carriers should undergo total thyroidectomy at ages that depend on the mutated codon&#44;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;67</span></a> following the MEN consensus &#40;<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46; Conversely&#44; noncarriers of the <span class="elsevierStyleItalic">RET</span> mutation should be excluded from annual clinical follow-up&#44; an expensive and stressing procedure for patients&#46; In skillful surgical hands&#44; the risks of neck surgery are minimal even in children&#46; False positives in genetic testing are exceedingly low&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;10</span></a> All these data have generated an international consensus on MEN regarding which MTC patients should undergo surgery at ages preferably less than 5 years&#44; depending on the mutated codon<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#44;67</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46; At the time of writing&#44; molecular DNA diagnosis in MEN2 has become an important tool to a&#41; confirm clinical and laboratory diagnosis of MTC&#59; b&#41; identify as early as possible mutant <span class="elsevierStyleItalic">RET</span> carriers in premalignant stages of the disease&#59; and c&#41; identify noncarrier family members and rule them out for clinical follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib33"><span class="elsevierStyleSup">33</span></a></p><elsevierMultimedia ident="tbl3"></elsevierMultimedia></span></span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">MODIFIER GENES IN <span class="elsevierStyleItalic">RET</span> EXPRESSION</span><p id="para350" class="elsevierStylePara elsevierViewall">Transgenic animal models expressing <span class="elsevierStyleItalic">RET</span> mutation are used to better address the question of MEN2 MTC tumor aggressiveness&#46; Medullary thyroid carcinoma occurs in transgenic lines with analogous pathology to that seen in patients with MEN2&#46; When the transgene codon 634 mutation was introduced into 4 different genetic backgrounds &#40;BALB&#47;c&#44; C57BL&#47;6J&#44; FVB&#47;N and CBA&#47;ca&#41;&#44; 65&#37; of all animals developed MTC&#44; showing incomplete penetrance&#46; None of the FVB&#47;N transgenic progeny developed MTC&#44; 14&#37; of transgenic progeny BALB&#47;c&#44; 64&#37; of C57BL&#47;6J&#44; and 98&#37; CBA&#47;ca mice developed thyroid tumors by 10 months of age&#44; indicating that incomplete tumor penetrance could be modulated by genetic background&#46; Furthermore&#44; tumors in the CBA&#47;ca and C57BL&#47;6J mice were significantly larger than those in BALB&#47;c transgenic mice&#46; These results are relevant to human MEN2 disease&#44; because this model system may be used to study genes modifying thyroid tumor penetrance in this dominantly inherited human cancer syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib68"><span class="elsevierStyleSup">68</span></a></p></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">ROUTINE PROCEDURES IN MOLECULAR <span class="elsevierStyleItalic">RET</span> DIAGNOSIS</span><p id="para360" class="elsevierStylePara elsevierViewall">Investigators working on studies dealing with humans should follow the Helsinque decisions&#59; thus&#44; before collecting blood samples for DNA analysis&#44; projects should be approved by local ethic committees&#44; and patients involved in research projects should sign a written informed consent&#46;</p><p id="para370" class="elsevierStylePara elsevierViewall">For genomic DNA extraction&#44; a salting-out method is indicated since it is a simple&#44; low-cost procedure&#46;<a class="elsevierStyleCrossRef" href="#bib69"><span class="elsevierStyleSup">69</span></a> For amplification of genomic DNA&#44; fragments of interest are usually amplified using the polymerase chain reaction &#40;PCR&#41; strategy&#46;<a class="elsevierStyleCrossRef" href="#bib70"><span class="elsevierStyleSup">70</span></a> Primers should contain flanking sequences of intronexon boundaries for adequate RET proto-oncogene analysis&#44; and if a laboratory chooses the DGGE &#40;denaturing gradient gel electrophoresis&#41; strategy for screening mutation analysis&#44; primers may also contain a 50bp GC-clamp coupled in one of the sequences&#46;<a class="elsevierStyleCrossRefs" href="#bib71"><span class="elsevierStyleSup">71&#8211;73</span></a> The presence of adequate amplified sequences are confirmed using runs in 1&#37; agarose gel electrophoresis stained with ethidium bromide&#46; After obtaining PCR products&#44; direct sequencing analysis &#40;the gold-standard method for <span class="elsevierStyleItalic">RET</span> mutation diagnosis&#41; should be performed in all MEN2 index cases&#46; Once the genotype of the <span class="elsevierStyleItalic">RET</span> mutation in the index case is known&#44; it may be used as intrafamilial positive control&#46; For at-risk family members&#44; screening methods may be used&#46; In this latter alternative&#44; it is possible to use DGGE&#44; single-strand conformation polymorphism &#40;SSCP&#41; or restriction enzyme approaches&#46;<a class="elsevierStyleCrossRefs" href="#bib72"><span class="elsevierStyleSup">72&#8211;77</span></a> The DGGE and SSCP techniques are based on differential migration mobilities in polyacrylamide gel&#46; Thus&#44; applying these techniques&#44; it is possible to discriminate between mutant carriers and noncarriers&#46; Different electrophoretic migration patterns are influenced by denaturant substances&#44; such as urea and formamide &#40;in DGGE&#41; or heteroduplex formation &#40;in SSCP&#41;&#46; Particularly when screening large MEN2 families&#44; these methods are very useful&#59; for instance&#44; using DGGE&#44; one might analyze 16 exons in 24 hours&#46; Restriction enzymes may possibly be useful in genetic screening for <span class="elsevierStyleItalic">RET</span> mutations&#44; as mutations create or destroy restriction sites recognizable by endonucleases&#46; However&#44; this method should only be applied to confirm DGGE or SSCP findings&#44; considering that interferences may occur as follows&#58; a&#41; inadequate recognition of restriction site and consequently no defined band in agarose gel electrophoresis or b&#41; incomplete discrimination of amplified sequences with similar base pair sizes&#46;<a class="elsevierStyleCrossRefs" href="#bib77"><span class="elsevierStyleSup">77&#44;78</span></a></p><p id="para380" class="elsevierStylePara elsevierViewall">Using direct genetic sequencing analysis &#40;the gold-standard method&#41;&#44; DNA fragments of interest are sequenced by enzymatic or chain termination&#44; as described by Sanger in 1977&#46;<a class="elsevierStyleCrossRef" href="#bib71"><span class="elsevierStyleSup">71</span></a> In this technique&#44; each primer must be added separately to sense and missense reaction tubes&#44; with a commercial buffer &#40;Big Dye Terminator Cycle Sequencing&#44; Applied Biosystems&#44; Foster City&#44; USA&#41; and processed in a thermocycler&#46; After the sequencing reaction&#44; samples are purified with isopropanol and ethanol and diluted in blue dextran buffer with deionized formamide&#46; The sequencing products are then denatured at 90 &#176;C for 2 minutes&#44; immediately cooled&#44; and applied into a specific electrophoresis polymer for the DNA sequencer&#46; Using these procedures&#44; good reproducibility is usually obtained&#44; avoiding the need of a confirmation reaction&#46; <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a> illustrates examples of electropherograms showing MEN-2 <span class="elsevierStyleItalic">RET</span> mutations&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">CONCLUSION</span><p id="para390" class="elsevierStylePara elsevierViewall">Before <span class="elsevierStyleItalic">RET</span> molecular diagnosis was possible&#44; first-degree relatives of MEN2 patients &#40;who have a 50&#37; chance of being carriers&#41; were clinically and biochemically followed up every 12 months for MTC&#44; PHEO&#44; and HPT&#46; Individuals had to be annually evaluated from 6 years of age on&#46; Thus&#44; basal and stimulated calcitonin serum levels were measured in these individuals&#44; as well as serum PTH&#44; calcium&#44; and serum&#47;urinary cathecolamines&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;22&#44;67</span></a> The sensitivity of these tests was variable&#44; and as a consequence&#44; MTC was usually diagnosed late&#46; This prolonged follow-up was expensive&#59; individuals at risk were maintained in a stressing condition&#59; survival rates were diminished&#44; and cure was almost never achieved due to late MEN2 diagnosis and high prevalence of lymph node metastases&#44;&#46;<a class="elsevierStyleCrossRefs" href="#bib79"><span class="elsevierStyleSup">79&#44;80</span></a></p><p id="para400" class="elsevierStylePara elsevierViewall">At the time of writing&#44; because almost 95&#37; of affected MEN2 patients harbor a mutation&#44; genetic diagnosis of MEN2 has become a great success story in the management of patients that are <span class="elsevierStyleItalic">RET</span> mutation carriers&#46;<a class="elsevierStyleCrossRefs" href="#bib67"><span class="elsevierStyleSup">67&#44;81</span></a> Direct DNA sequencing is of course the gold-standard method for <span class="elsevierStyleItalic">RET</span> mutation analysis and should be performed routinely in all index cases and possibly in all suspected cases&#46; Alternatively&#44; once the presence of a <span class="elsevierStyleItalic">RET</span> mutation is ascertained&#44; screening methods may be used in analyzing family members at risk&#46; Whatever DNA method is used&#44; early <span class="elsevierStyleItalic">RET</span> mutation analysis provides information to clinicians and surgeons allowing them to make adequate surgical decisions&#46; As a consequence of these procedures&#44; mortality rates in MEN2 have dropped from up to 20&#37; in 1993 to 5&#37; currently&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> Finally&#44; early <span class="elsevierStyleItalic">RET</span> mutation analysis should be performed in all MTC and PHEO cases&#44; as suggested by the MEN consensus&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a></p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:18 [
        0 => array:2 [
          "identificador" => "xpalclavsec1585041"
          "titulo" => "KEYWORDS"
        ]
        1 => array:3 [
          "identificador" => "xres1815387"
          "titulo" => "RESUMO"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "ceabs20"
            ]
          ]
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1585040"
          "titulo" => "UNITERMOS"
        ]
        3 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        4 => array:2 [
          "identificador" => "cesec20"
          "titulo" => "MOLECULAR MEDICINE"
        ]
        5 => array:2 [
          "identificador" => "cesec30"
          "titulo" => "CLASSIFICATION"
        ]
        6 => array:2 [
          "identificador" => "cesec40"
          "titulo" => "MEDULLARY THYROID CARCINOMA &#40;MTC&#41;"
        ]
        7 => array:2 [
          "identificador" => "cesec50"
          "titulo" => "PHEOCHROMOCYTOMA &#40;PHEO&#41;"
        ]
        8 => array:2 [
          "identificador" => "cesec60"
          "titulo" => "HYPERPARATHYROIDISM &#40;HPT&#41;"
        ]
        9 => array:2 [
          "identificador" => "cesec70"
          "titulo" => "HIRSCHSPRUNG DISEASE &#40;HSCR&#41;"
        ]
        10 => array:2 [
          "identificador" => "cesec80"
          "titulo" => "MOLECULAR ASPECTS"
        ]
        11 => array:3 [
          "identificador" => "cesec90"
          "titulo" => "GENOTYPE-PHENOTYPE CORRELATIONS"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "cesec100"
              "titulo" => "Multiple endocrine neoplasia type 2A &#40;MEN2A&#41;"
            ]
          ]
        ]
        12 => array:3 [
          "identificador" => "cesec110"
          "titulo" => "FAMILIAL MEDULLARY THYROID CARCINOMA"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "cesec120"
              "titulo" => "&#40;FMTC&#41;"
            ]
            1 => array:2 [
              "identificador" => "cesec130"
              "titulo" => "Multiple endocrine neoplasia type 2B &#40;MEN2B&#41;"
            ]
          ]
        ]
        13 => array:2 [
          "identificador" => "cesec140"
          "titulo" => "MODIFIER GENES IN RET EXPRESSION"
        ]
        14 => array:2 [
          "identificador" => "cesec150"
          "titulo" => "ROUTINE PROCEDURES IN MOLECULAR RET DIAGNOSIS"
        ]
        15 => array:2 [
          "identificador" => "cesec160"
          "titulo" => "CONCLUSION"
        ]
        16 => array:2 [
          "identificador" => "xack640440"
          "titulo" => "ACKNOWLEDGEMENTS"
        ]
        17 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2005-07-04"
    "fechaAceptado" => "2005-11-11"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1585041"
          "palabras" => array:8 [
            0 => "Endocrine Neoplasia"
            1 => "MEN2"
            2 => "RET proto-oncogene"
            3 => "Pheochromocytoma"
            4 => "Hyperparathyroidism"
            5 => "HSCR"
            6 => "MTC"
            7 => "FMTC"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "UNITERMOS"
          "identificador" => "xpalclavsec1585040"
          "palabras" => array:8 [
            0 => "Neoplasia End&#243;crina"
            1 => "NEM2"
            2 => "Protooncogene RET"
            3 => "Feocromocitoma"
            4 => "Hiperparatireoidismo"
            5 => "HSCR"
            6 => "CMT"
            7 => "CMT-F"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:1 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Multiple endocrine neoplasia type 2 &#40;MEN2&#41; is an autosomal dominant disease characterized by the presence of medullary thyroid carcinoma&#44; primary hyperparathyroidism&#44; and pheochromocytoma&#46; Multiple endocrine neoplasia type 2 is still an underdiagnosed&#44; or late-diagnosed condition in many areas of the world&#46; Since 1993&#44; when the first missense RET proto-oncogene &#40;<span class="elsevierStyleItalic">RET</span>&#41; mutations were reported in MEN2&#44; up to 46 different RET-causing disease mutations have been described&#46; Since a strong genotype-phenotype correlation exists for MEN2&#44; the detection of <span class="elsevierStyleItalic">RET</span> mutations has produced a major impact in early recognition and treatment of MTC and MEN2&#46; Presently&#44; <span class="elsevierStyleItalic">RET</span> mutation analysis should be performed for all MEN2 cases and their at-risk familial relatives&#46; Further&#44; prophylactic total thyroidectomy is indicated in all cases harboring activating gametic <span class="elsevierStyleItalic">RET</span> mutations&#46; In most <span class="elsevierStyleItalic">RET</span> mutation carriers&#44; prophylactic total thyroidectomy is indicated at ages as early as a few months to 4 years of age&#44; promoting longer survival and improvement of quality of life or even definitive cure&#46; We discuss the large impact of <span class="elsevierStyleItalic">RET</span> protooncogene analysis on the clinical management of MEN2 and the role of early <span class="elsevierStyleItalic">RET</span> molecular DNA diagnosis in providing clinicians and surgeons with valuable information that enables them to indicate early total thyroidectomy&#46;</p></span>"
      ]
      "pt" => array:2 [
        "titulo" => "RESUMO"
        "resumen" => "<span id="ceabs20" class="elsevierStyleSection elsevierViewall"><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">A neoplasia end&#243;crina m&#250;ltipla tipo 2 &#40;NEM2&#41; &#233; caracterizada pela ocorr&#234;ncia do carcinoma medular de tire&#243;ide &#40;CMT&#41;&#44; hiperparatiroidismo prim&#225;rio &#40;HPT&#41; e feocromocitoma &#40;FEO&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1"><span class="elsevierStyleSup">1&#8211;12</span></a> Desde 1993&#44; quando as primeiras muta&#231;&#245;es do tipo <span class="elsevierStyleItalic">missense</span> no proto-oncogene RET &#40;<span class="elsevierStyleItalic">RET</span>&#41;&#44; associadas a NEM2 foram identificadas&#44; 46 diferentes muta&#231;&#245;es causadoras de doen&#231;as foram descritas&#46;<a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13&#8211;17</span></a> Como h&#225; uma forte correla&#231;&#227;o gen&#243;tipo-fen&#243;tipo na NEM2&#44; a detec&#231;&#227;o de muta&#231;&#245;es no <span class="elsevierStyleItalic">RET</span> adquiriu grande impacto no tratamento precoce do CMT e NEM2&#46; A NEM2 persiste como uma doen&#231;a subdiagnosticada e&#47;ou tardiamente diagnosticada em v&#225;rias &#225;reas geogr&#225;ficas do globo&#46; A an&#225;lise de muta&#231;&#245;es do <span class="elsevierStyleItalic">RET</span> deve ser realizada em todas os casos de NEM2 e atualmente&#44; a tireoidectomia total profil&#225;tica &#233; indicada para todos os indiv&#237;duos portadores de muta&#231;&#245;es no <span class="elsevierStyleItalic">RET&#46;</span><a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> Para a grande maioria dos portadores de muta&#231;&#245;es gam&#233;ticas ativadoras no <span class="elsevierStyleItalic">RET</span> este procedimento cir&#250;rgico &#233; indicado nos primeiros anos de vida&#44; promovendo melhora na qualidade de vida&#44; aumento da sobrevida ou mesmo levando &#224; cura definitiva&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> Discutimos nesta revis&#227;o&#44; o impacto da an&#225;lise do proto-oncogene RET na conduta cl&#237;nica da neoplasia end&#243;crina m&#250;ltipla tipo 2&#46; Al&#233;m disso&#44; o diagn&#243;stico molecular do <span class="elsevierStyleItalic">RET</span> fornece &#224; cl&#237;nicos e cirurgi&#245;es a mais valiosa das informa&#231;&#245;es&#44; permitindo indica&#231;&#227;o de tireoidectomia total profil&#225;tica&#46;</p></span>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2594
            "Ancho" => 1542
            "Tamanyo" => 374908
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Electropherograms showing five different types of <span class="elsevierStyleItalic">RET</span> mutations in MEN2&#44; using a DNA sequencer &#40;ABI 310 DNA Sequencer - Applied Biosystems&#44; USA&#41;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 01"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Multiple endocrine neoplasia2A &#40;1&#41;&#58;</span> Families with medullary thyroid carcinoma&#44; pheochromocytoma and hyperparatyroidism phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Multiple endocrine neoplasia2A &#40;2&#41;&#58;</span> Families with medullary thyroid carcinoma and pheochromocytoma phenotype in at least one at risk relative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Multiple endocrine neoplasia2A &#40;3&#41;&#58;</span> Families with medullary thyroid carcinoma and hyperparatyroidism phenotype in at least one at risk relative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Multiple endocrine neoplasia2B&#58;</span> Families with medullary thyroid carcinoma&#44; associated or not with pheochromocytoma and muscular &#47; skeletal abnormalities and mucosal neuromas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Familial medullary thyroid carcinoma&#58;</span> Families only with medullary thyroid carcinoma phenotype in at least four at risk relatives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Others&#58;</span> Families with less than four relatives with medullary thyroid carcinoma&#44; pheochromocytoma and hyperparatyroidism phenotype&#46; In this group are included partially documented families&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Phenotypic classification of MEN2 &#40;Adapted from ref&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1&#44;</span></a><a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a>&#41;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">MEN2A&#58; Multiple endocrine neoplasia type 2A&#59; MEN2B&#58; Multiple endocrine neoplasia type 2B&#59; FMTC&#58; Familial medullary thyroid carcinoma&#59; Ins&#58; Insertion</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Exon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Affected Codon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Nucleotides &#40;wild-type &#8594; mutant&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Amino acid &#40;wild-type &#8594; mutant&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">MEN2 cases&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">532&#44; 533&#44; 534 533&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins AGG AGT GTG GGC-TGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins Glu Glu Cys Gly-Cys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FMTC &#47; HSCR FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">609&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-CGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC &#47; HSCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-GGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Gly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">611&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-AGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-CGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TGG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Trp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">618&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-AGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC &#47; HSCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3-5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-CGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-GGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Gly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">620&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC &#47; HSCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6-8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-AGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-CGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-GGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Gly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TGG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Trp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">630&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">634&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-AGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80-90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-CGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Arg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-GGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Gly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Ser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80-90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGC-TGG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cys-Trp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">635&#44; 636&#44; 637&#44; 638&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins CG AGC TGT GCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins Thr Ser Cys Ala&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">637&#44; 638&#44; 639&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins TGC CGC ACG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ins Cys Arg Thr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">648&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GTC-ATC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Val-Ile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">768&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GAG-GAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glu-Asp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">790&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TTG-TTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leu-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TTG-TTT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leu-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">791&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TAT-TTT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tyr-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">804&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GTG-ATG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Val-Met&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GTG-TTG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Val-Leu&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">883&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GCT-TTT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ala-Phe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">891&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TCG-GCG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ser-Ala&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2A &#47; FMTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">918&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ATG-ACG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Met-Thr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2B &#47; HSCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3-5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">922&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TCC-TAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ser-Tyr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MEN2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Multiple endocrine neoplasia type 2 &#40;MEN2&#41; genotype-phenotype correlations &#40;Adapted from ref&#46;<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a>&#41;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 03"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Risk 3 level&#58;</span> Highest risk of development of an aggressive and early form of medullary thyroid carcinoma&#46; Children with multiple endocrine neoplasia 2B or mutation carriers in codons 883&#44; 918 or 922&#44; should be submitted to total thyreoidectomy during the first six months of life&#44; preferentially a the first month as microscopic medullary thyroid carcinoma with metastases may occur in the first months of life&#46; Total thyreoidectomy should be performed in association with an extensive ressection of the neck lymph nodes&#44; mainly including central neck lymph nodes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Risk 2 level&#58;</span> High risk to present an aggressive form of medullary thyroid carcinoma&#46; Children carrying <span class="elsevierStyleItalic">RET</span> mutation in codons 611&#44; 618&#44; 620 or 634 should be submitted to total surgery before 5 years of age&#46; Total thyreoidectomy should be performed in association with removal of thyroid posterior capsule and dissection of central lymph nodes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Risk 1 level&#58;</span> Moderate risk to develop aggressive forms of medullary thyroid carcinoma&#46; Children carrying mutations in codons 609&#44; 768&#44; 790&#44; 791 804 or 891 should be also submitted to total thyreoidectomy&#46; There are three alternatives related to ages for surgical procedures&#46; First&#44; some authors indicate patients should be operated before age 5&#44; as in risk 2 level&#46; Others suggest 10 years of age as a cut-off for surgical indication&#46; The third alternative is waiting for abnormal basal or stimulated calcitonin values for indicating surgery&#46; Biological behaviors of these tumors are variable&#44; but frequently present a late and indolent evolution&#46; It is worthwhile to note that metastases or death were reported in patients carrying all these genotypes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Surgical management of multiple endocrine neoplasia2 based on international multiple endocrine neoplasia consensus &#40;Adapted from ref&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a>&#41;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:81 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CONSENSUS&#58; Guideline for diagnosis and therapy of MEN type 1 and type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              ML Brandi \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Angeli \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JP Bilezikian \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              P Beck-Peccoz \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              C Bordi \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.86.12.8070"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2001"
                        "volumen" => "86"
                        "paginaInicial" => "5658"
                        "paginaFinal" => "5671"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11739416"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The impact of gene mapping techniques on the management of multiple endocrine neoplasia type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Trends Endocr Metab"
                        "fecha" => "1991"
                        "volumen" => "2"
                        "paginaInicial" => "19"
                        "paginaFinal" => "25"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular genetics of multiple endocrine neoplasia types 1 and 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              SJ Marx \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2005"
                        "volumen" => "5"
                        "paginaInicial" => "367"
                        "paginaFinal" => "375"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple Endocrine Neoplasia Type 2&#58; Clinical Aspects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "PLMDahia, CEng"
                        "titulo" => "Genetic Disorders of Endocrine Neoplasia"
                        "paginaInicial" => "103"
                        "paginaFinal" => "130"
                        "edicion" => "1st ed&#46;"
                        "serieFecha" => "2001"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoplasias Endocrinas M&#250;ltiplas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              NMA Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MCL Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              PM Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "BLWajchenberg"
                        "titulo" => "Tratado de Endocrinologia Cl&#237;nica"
                        "paginaInicial" => "943"
                        "paginaFinal" => "964"
                        "edicion" => "1&#176; ed&#46;"
                        "serieFecha" => "1992"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple Endocrine Neoplasia Type 2&#58; Molecular Aspects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "PLMDahia, CEng"
                        "titulo" => "Genetic Disorders of Endocrine Neoplasia"
                        "paginaInicial" => "81"
                        "paginaFinal" => "102"
                        "edicion" => "1st ed&#46;"
                        "serieFecha" => "2001"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoplasias End&#243;crinas M&#250;ltiplas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              MCL Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              NMA Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "GMedeiros-Neto"
                        "titulo" => "Mol&#233;stias Heredit&#225;rias do Sistema Tireoideano"
                        "paginaInicial" => "225"
                        "paginaFinal" => "242"
                        "edicion" => "1&#176; ed&#46;"
                        "serieFecha" => "1996"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "RET proto-oncogene in the development of human cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1999"
                        "volumen" => "17"
                        "paginaInicial" => "390"
                        "paginaFinal" => "393"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Specific localization of calcitonin activity in humans&#8217; thyroid glands"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              MA Aliepoulios \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              EH Rose \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "Calcitonin Proceedings of the Second International Syposium"
                        "paginaInicial" => "295"
                        "paginaFinal" => "300"
                        "edicion" => "2nd ed&#46;"
                        "serieFecha" => "1970"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Editorial&#58; RET proto-oncogene mutations and endocrine neoplasia &#8211; A story interwined with neuronal crest differentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "1996"
                        "volumen" => "137"
                        "paginaInicial" => "509"
                        "paginaFinal" => "511"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of occult medullary thyroid carcinoma evidenced only by serum calcitonin levels elevations after apparently adequate neck operation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              MA Block \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CE Jackson \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AH Tashjian Jr&#46; \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archsurg.1978.01370160026003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Surg"
                        "fecha" => "1978"
                        "volumen" => "113"
                        "paginaInicial" => "368"
                        "paginaFinal" => "372"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/637706"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medullary carcinoma of the thyroid gland"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              SA Wells Jr \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              C Franz \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s002680010166"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Surg"
                        "fecha" => "2000"
                        "volumen" => "24"
                        "paginaInicial" => "952"
                        "paginaFinal" => "956"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10865039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasias"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              AO Hoff \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              GJ Cote \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev.physiol.62.1.377"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Physiol"
                        "fecha" => "2000"
                        "volumen" => "62"
                        "paginaInicial" => "377"
                        "paginaFinal" => "400"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10845096"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cloning and expression of RET proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              M Takahashi \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              Y Buma \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              Y Iwamoto \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              H Ikeda \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              H Hiahi \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncogene"
                        "fecha" => "1988"
                        "volumen" => "3"
                        "paginaInicial" => "571"
                        "paginaFinal" => "578"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3078962"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Isolation of RET proto-oncogene DNA with an amino-terminal signal sequence"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              M Takahashi \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              Y Buma \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              H Hiahi \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncogene"
                        "fecha" => "1989"
                        "volumen" => "4"
                        "paginaInicial" => "805"
                        "paginaFinal" => "806"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2660074"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structural analysis of the human RET proto-oncogene using exon trapping"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              JB Kwok \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Gardner \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JP Warner \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              BAJ Ponder \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncogene"
                        "fecha" => "1993"
                        "volumen" => "8"
                        "paginaInicial" => "2575"
                        "paginaFinal" => "2582"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8361767"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN2A and FMTC"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              CS Healey \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              D Calyton \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              JBJ Kwok \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              E Gardner \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ng0194-70"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Genet"
                        "fecha" => "1994"
                        "volumen" => "6"
                        "paginaInicial" => "70"
                        "paginaFinal" => "74"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7907913"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia type 2 and <span class="elsevierStyleItalic">RET</span>&#58; from neoplasia to neurogenesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              J Hansford \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jmg.37.11.817"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Med Genet"
                        "fecha" => "2000"
                        "volumen" => "37"
                        "paginaInicial" => "817"
                        "paginaFinal" => "827"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11073534"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              M Peczkowska \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Januszewicz \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10689-005-4150-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Familial Cancer"
                        "fecha" => "2005"
                        "volumen" => "4"
                        "paginaInicial" => "25"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15889224"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              BT Teh \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1365-2796.2003.01162.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Journal of Internal Medicine"
                        "fecha" => "2003"
                        "volumen" => "253"
                        "paginaInicial" => "588"
                        "paginaFinal" => "589"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12755953"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JB Kwok \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              CS Healey \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MJ Elsdon \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              E Gardner \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/363458a0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1993"
                        "volumen" => "363"
                        "paginaInicial" => "458"
                        "paginaFinal" => "460"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8099202"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in RET proto-oncogene are associated with MEN2A and FMTC"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              H Donnis-Keller \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              S Dou \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              D Chi \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              KM Carlson \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              K Toshima \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              TC Lairmore \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/hmg/2.7.851"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Molec Genet"
                        "fecha" => "1993"
                        "volumen" => "2"
                        "paginaInicial" => "851"
                        "paginaFinal" => "856"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8103403"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic testing in endocrinology&#58; lessons learned from experience with multiple endocrine neoplasia type 2 &#40;MEN2&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              C Jimenez \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000527123"
                      "Revista" => array:6 [
                        "tituloSerie" => "Growth Horm &#38; IGF Res"
                        "fecha" => "2004"
                        "volumen" => "14"
                        "paginaInicial" => "S150"
                        "paginaFinal" => "S157"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36446332"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Carcinoma Medular de Tire&#243;ide&#58; da Defini&#231;&#227;o &#224;s Bases Moleculares"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              PKR Magalh&#227;es \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              M Castro \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LLK Elias \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              LMZ Maciel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "47"
                        "paginaInicial" => "515"
                        "paginaFinal" => "528"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoplasia End&#243;crina M&#250;ltipla tipo 2 &#8211; Manejo Diagn&#243;st&#237;co e Terap&#234;utico"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              FFR Maia \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              HJ J&#250;nior \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LR Ara&#250;jo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "606"
                        "paginaFinal" => "610"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel 9-base pair in RET exon 8 in familial medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              P Pigny \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              C Bauters \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JL Wemeau \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              ML Houcke \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M Crepin \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              P Caron \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.84.5.5665"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1999"
                        "volumen" => "84"
                        "paginaInicial" => "1700"
                        "paginaFinal" => "1704"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10323403"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation&#58; clinical manifestation and course in early and late onset disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              M Brauckhoff \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              C L Weiss \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              J Ukkat \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Sekulla \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              K Brauckhoff \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00268-004-7637-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Surg"
                        "fecha" => "2004"
                        "volumen" => "28"
                        "paginaInicial" => "1305"
                        "paginaFinal" => "1311"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15517484"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early detection of medullary thyroid carcinoma in multiple endocrine neoplasia type II"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              MC Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              H Bisi \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MO Leite \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              A Borelli \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              NM Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo"
                        "fecha" => "1990"
                        "volumen" => "45"
                        "paginaInicial" => "105"
                        "paginaFinal" => "109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1983764"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine type II neoplasm"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AR Ferraz \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo"
                        "fecha" => "1990"
                        "volumen" => "45"
                        "paginaInicial" => "1"
                        "paginaFinal" => "2"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1983459"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunohistochemistry of medullary thyroid carcinoma and C-cell hyperplasia by an affinity-purified anti-human calcitonin antiserum"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              VAF Alves \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              CT Kanamura \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MCL Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              NMA Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              W Nicolau \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/1097-0142(19930815)72:4<1356::aid-cncr2820720434>3.0.co;2-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "1993"
                        "volumen" => "72"
                        "paginaInicial" => "1356"
                        "paginaFinal" => "1363"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8339225"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "C cell hyperplasia&#47;neoplasia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              VA Livolsi \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.82.1.3707"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1997"
                        "volumen" => "82"
                        "paginaInicial" => "39"
                        "paginaFinal" => "41"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8989229"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inheritable form of medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              A Bachelot \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              F Lombardo \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              E Baudin \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JM Bidart \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M Schlumberger \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Biochimie"
                        "fecha" => "2002"
                        "volumen" => "89"
                        "paginaInicial" => "61"
                        "paginaFinal" => "66"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tumorig&#234;nese Molecular Tiroideana&#58; Implica&#231;&#245;es Para a Pr&#225;tica M&#233;dica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              RMB Maciel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "381"
                        "paginaFinal" => "390"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              S Leboulleux \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Baudin \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JP Travagli \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              M Schlumberger \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Endocrinol"
                        "fecha" => "2004"
                        "volumen" => "61"
                        "paginaInicial" => "299"
                        "paginaFinal" => "310"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of RET oncogenic activation in MEN2 inherited cancer syndromes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              S Xing \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              PA Smanik \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MJ Oglesbee \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JE Trosko \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              EL Mazzaferri \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              SM Jhiang \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/endo.137.5.8612479"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "1996"
                        "volumen" => "137"
                        "paginaInicial" => "1512"
                        "paginaFinal" => "1519"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8612479"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Abordagem cl&#237;nica e laboratorial do b&#243;cio uni-nodular s&#243;lido&#58; vantagens da determina&#231;&#227;o da calcitonina s&#233;rica por m&#233;todos distintos"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              NMA Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              S Gomes \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MT Ivanoff \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MCL Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "1999"
                        "volumen" => "43"
                        "paginaInicial" => "104"
                        "paginaFinal" => "113"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Calcitonin levels in tissue culture of thyroid medullary carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              RC Martin \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              MC Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo"
                        "fecha" => "1985"
                        "volumen" => "40"
                        "paginaInicial" => "220"
                        "paginaFinal" => "222"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dynamics of calcitonin secretion in tissue culture of medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              RC Martin \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Hosp Clin Fac Med Sao Paulo"
                        "fecha" => "1989"
                        "volumen" => "44"
                        "paginaInicial" => "36"
                        "paginaFinal" => "39"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2814186"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medullary carcinoma of the thyroid"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              GW Randolph \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              D Maniar \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/107327480000700305"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Control"
                        "fecha" => "2000"
                        "volumen" => "7"
                        "paginaInicial" => "253"
                        "paginaFinal" => "261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10832112"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genotype-phenotype correlations in hereditary medullary thyroid carcinoma&#58; oncological features and biochemical properties"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              A Machens \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              R Hinze \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              W H&#246;ppner \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              BO Boehm \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              H Dralle \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.86.3.7290"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2001"
                        "volumen" => "86"
                        "paginaInicial" => "1104"
                        "paginaFinal" => "1109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11238493"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adrenal medullary disease in multiple endocrine neoplasia type 2&#46; Pheocromocytoma and its precursors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              JA Carney \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              GW Sizemore \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              SG Sheps \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ajcp/66.2.279"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Clin Pathol"
                        "fecha" => "1976"
                        "volumen" => "66"
                        "paginaInicial" => "279"
                        "paginaFinal" => "290"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/949038"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular and immunohistochemical analysis of P53 in phaeochromocytoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RC Aguiar \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AM Tsanaclis \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              I Bendit \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              SP Bydlowski \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              NM Abelin \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/bjc.1995.487"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Cancer"
                        "fecha" => "1995"
                        "volumen" => "72"
                        "paginaInicial" => "1211"
                        "paginaFinal" => "1213"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7577469"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              PA Crossey \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CS Healey \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Houghton \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              A Prowse \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jmg.32.12.934"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Med Genet"
                        "fecha" => "1995"
                        "volumen" => "32"
                        "paginaInicial" => "934"
                        "paginaFinal" => "937"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8825918"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Deletion analysis of the p16 tumour suppressor gene in phaeochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              RC Aguiar \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              H Sill \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              JM Goldman \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              NC Cross \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
                        "fecha" => "1996"
                        "volumen" => "45"
                        "paginaInicial" => "93"
                        "paginaFinal" => "96"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8796144"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutation analysis of glial cell line-derived neurotrophic factor &#40;GDNF&#41;&#44; a ligand for the RET&#47;GDNF receptor alpha complex&#44; in sporadic phaeochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              ER Maher \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              AB Grossman \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "1997"
                        "volumen" => "57"
                        "paginaInicial" => "310"
                        "paginaFinal" => "313"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9000574"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              EM Duerr \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              DS Neuberg \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JB Kum \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              SC Clifford \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.84.9.5961"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1999"
                        "volumen" => "84"
                        "paginaInicial" => "3207"
                        "paginaFinal" => "3211"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10487688"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "RET and neuroendocrine tumors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              M Ichihara \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              Y Murakumo \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Takahashi \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0304-3835(03)00456-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Letters"
                        "fecha" => "2004"
                        "volumen" => "204"
                        "paginaInicial" => "197"
                        "paginaFinal" => "211"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15013219"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              KN Ross \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              ME Wright \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CY Hayashida \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              S Santagata \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              M Barontini \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pgen.0010008"
                      "Revista" => array:6 [
                        "tituloSerie" => "PLoS Genet"
                        "fecha" => "2005"
                        "volumen" => "1"
                        "paginaInicial" => "72"
                        "paginaFinal" => "80"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16103922"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Surgical management of hyperparathyroidism is patients with multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              KK Herfarth \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              D Bartsch \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              GM Doherty \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              SA Wells \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              TC Lairmore \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0039-6060(96)80042-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Surgery"
                        "fecha" => "1996"
                        "volumen" => "120"
                        "paginaInicial" => "966"
                        "paginaFinal" => "974"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8957482"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => """
                              SA Wells Jr \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              DD Chi \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              Toshimak \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/00000658-199409000-00002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Surg"
                        "fecha" => "1994"
                        "volumen" => "220"
                        "paginaInicial" => "237"
                        "paginaFinal" => "250"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7916559"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib51"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathogenesis of Hirschsprung&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              G Martucciello \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              I Ceccherini \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Lerone \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              V Jasonni \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jpsu.2000.7763"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediat Surg"
                        "fecha" => "2000"
                        "volumen" => "35"
                        "paginaInicial" => "1017"
                        "paginaFinal" => "1025"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10917288"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib52"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              AB Nunes \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              MCL Ezabella \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AC Pereira \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JE Krieger \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              SPA Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2002-020345"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "87"
                        "paginaInicial" => "5658"
                        "paginaFinal" => "5661"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12466368"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib53"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Carcinoma Medular de Tire&#243;ide&#58; Aspectos Moleculares&#44; Cl&#237;nico-Oncol&#243;gicos e Terap&#234;uticos"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              MK Pu&#241;ales \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              PA Rocha \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JL Gross \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              AL Maia \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "2004"
                        "volumen" => "48"
                        "paginaInicial" => "137"
                        "paginaFinal" => "146"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib54"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia type 2&#58; molecular aspects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000061051"
                      "Revista" => array:6 [
                        "tituloSerie" => "Front Horm Res"
                        "fecha" => "2001"
                        "volumen" => "28"
                        "paginaInicial" => "81"
                        "paginaFinal" => "102"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11443855"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib55"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and hirschsprung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              F Carlomagno \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RM Melillio \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              R Visconti \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              G Salvatore \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              G De Vita \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              G Lupoli \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/endo.139.8.6124"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "1998"
                        "volumen" => "139"
                        "paginaInicial" => "3613"
                        "paginaFinal" => "3619"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9681515"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib56"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Point mutation within the tyrosine kinase domain of the RET protooncogene in multiple endocrine neoplasia type 2B and related sporadic tumours"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              DP Smith \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MA Nagai \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              CS Healey \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              MA Ponder \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/hmg/3.2.237"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Mol Genet"
                        "fecha" => "1994"
                        "volumen" => "3"
                        "paginaInicial" => "237"
                        "paginaFinal" => "241"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7911697"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib57"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "RET codon 634 mutations in multiple endocrine neoplasia type 2&#58; Variable clinical features and clinical outcome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              MK Pu&#241;ales \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              H Graf \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JL Gross \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              AL Maia \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2002-021422"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "paginaInicial" => "2644"
                        "paginaFinal" => "2649"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12788868"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib58"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early or prophylatic thyroidectomy in MEN2&#47;FMTC gene carriers&#58; results in 71 thyroidectomized patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              P Niccoli-Sire \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Murat \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              E Baudin \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              J Henry \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Proye \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              J Bigorgne \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/eje.0.1410468"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "1999"
                        "volumen" => "141"
                        "paginaInicial" => "468"
                        "paginaFinal" => "474"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10576762"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib59"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rastreamento Gen&#233;tico do Carcinoma Medular de Tire&#243;ide&#58; Identifica&#231;&#227;o de Muta&#231;&#245;es no Protooncogene RET"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              MK Pu&#241;ales \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              H Graf \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JL Gross \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              AL Maia \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "632"
                        "paginaFinal" => "639"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib60"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Nunes AB&#46; Identifica&#231;&#227;o de muta&#231;&#245;es do proto-oncogene RET associadas &#224; forma heredit&#225;ria do carcinoma medular de tire&#243;ide&#46; 2001&#59; Tese de Doutoramento&#44; Departamento de Cl&#237;nica M&#233;dica&#44; FMUSP&#46;"
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib61"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Familial medullary thyroid carcinoma&#58; clinical variability and low aggressiveness associated with RET mutation at codon 804"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              F Lombardo \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Baudin \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              E Chiefari \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              F Arturi \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              S Bardet \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              B Caillou \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.87.4.8403"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "87"
                        "paginaInicial" => "1674"
                        "paginaFinal" => "1680"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11932300"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib62"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations of the RET proto-oncogene in Hirschsprung&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              P Edery \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              S Lyonnet \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Pelet \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              E Dow \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              L Abel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/367378a0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1994"
                        "volumen" => "367"
                        "paginaInicial" => "378"
                        "paginaFinal" => "380"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8114939"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib63"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes&#44; related sporadic tumours&#44; and hirschsprung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/(SICI)1098-1004(1997)9:2<97::AID-HUMU1>3.0.CO;2-M"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Mutat"
                        "fecha" => "1997"
                        "volumen" => "9"
                        "paginaInicial" => "97"
                        "paginaFinal" => "109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9067749"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib64"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A new hot spot for mutations in the ret proto-oncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              I Berndt \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              M Reuter \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              B Saller \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              K Frank-Raue \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              P Groth \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              M Grubendorf \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.83.3.4619"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1998"
                        "volumen" => "83"
                        "paginaInicial" => "770"
                        "paginaFinal" => "774"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9506724"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib65"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel germ-line mutation in RET exon 8 &#40;Gly533Cys&#41; in a large kindred with familial medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              AMA Silva \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RMB Maciel \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MRD Silva \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              SRC Toledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              MB Carvalho \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              JM Cerutti \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2003-030997"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "paginaInicial" => "5438"
                        "paginaFinal" => "5443"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14602786"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib66"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germline dinucleotide mutation in codon 883 of the RET protooncogene in multiple endocrine neoplasia type 2B without codon 918 mutation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              DJ Marsh \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              SD Andrew \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Frilling \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              LM Mulligan \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.82.11.4508"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1997"
                        "volumen" => "82"
                        "paginaInicial" => "3902"
                        "paginaFinal" => "3904"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9360560"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib67"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acceptable age for prophylatic surgery in children with multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              T Kahraman \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JWB Groot \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              C Rouwe \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              RMW Hofstra \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              TP Links \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              RH Sijmons \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/ejso.2002.1378"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Surg Oncol"
                        "fecha" => "2002"
                        "volumen" => "29"
                        "paginaInicial" => "331"
                        "paginaFinal" => "335"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12711285"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib68"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Modulation of medullary thyroid carcinoma penetrance suggests the presence of modifier genes in a <span class="elsevierStyleItalic">RET</span> transgenic mouse model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              AN Cranston \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              BAJ Ponder \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Research"
                        "fecha" => "2003"
                        "volumen" => "63"
                        "paginaInicial" => "4777"
                        "paginaFinal" => "4780"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12941793"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib69"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A simple salting out procedure for extracting DNA from human nucleated cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              S Miller \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              D Dykes \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              H Poleski \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Nucleic Acids Res"
                        "fecha" => "1988"
                        "volumen" => "16"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib70"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              RK Saiki \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              DH Gelfand \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              S Stoffel \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              SJ Scharf \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              HA Erlich \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.2448875"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1988"
                        "volumen" => "239"
                        "paginaInicial" => "487"
                        "paginaFinal" => "491"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2448875"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib71"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              F Sanger \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AR Coulson \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Mol Biol"
                        "fecha" => "1975"
                        "volumen" => "94"
                        "paginaInicial" => "444"
                        "paginaFinal" => "448"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib72"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Attachment of a 40-base pair G&#43;C rich sequence &#40;GC-clamp&#41; to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              VC Sheffield \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              DR Cox \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              LS Lerman \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              RM Myers \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.86.1.232"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci &#40;USA&#41;"
                        "fecha" => "1989"
                        "volumen" => "86"
                        "paginaInicial" => "232"
                        "paginaFinal" => "236"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2643100"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib73"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Denaturing gel electrophoresis to diagnose multiple endocrine neoplasia type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              RD Blank \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CA Skalr \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              ML Martin \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chem"
                        "fecha" => "1996"
                        "volumen" => "42"
                        "paginaInicial" => "598"
                        "paginaFinal" => "603"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8605678"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib74"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Update on the profile of multiple endocrine neoplasia type 2A RET mutations&#58; Practical issues and implications for genetic testing"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              RA Decker \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              ML Peacock \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "1997"
                        "volumen" => "80"
                        "paginaInicial" => "557"
                        "paginaFinal" => "568"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib75"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improvement of fragment and primer selection for mutation detection by denaturing gradient gel electrophoresis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              Y Wu \n
                              \t\t\t\t\t\t\t\t
                              """
                             …5
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Nucleic Acids Res"
                        "fecha" => "1998"
                        "volumen" => "26"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib76"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved mutation detection in GC-rich DNA fragments by combined DGGE and CDGE"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/nar/27.15.e9"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nucleic Acids Res"
                        "fecha" => "1999"
                        "volumen" => "27"
                        "paginaInicial" => "e9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib77"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Frediani D&#46; 2002&#59; Rastreamento G&#234;nico atrav&#233;s de Enzimas de Restri&#231;&#227;o na forma Heredit&#225;ria do Carcinoma Medular de Tire&#243;ide&#46; Monografia&#44; Departamento de Cl&#237;nica M&#233;dica&#44; FMUSP&#46;"
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib78"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12864-022-08691-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genomics"
                        "fecha" => "1994"
                        "volumen" => "23"
                        "paginaInicial" => "477"
                        "paginaFinal" => "479"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib79"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple endocrine neoplasia type 2 and the practice of molecular medicine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev in Endocrinol Dis"
                        "fecha" => "2000"
                        "volumen" => "1"
                        "paginaInicial" => "283"
                        "paginaFinal" => "290"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib80"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular diagnosis of multiple endocrine neoplasia type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Expert Ver Mol Diagn"
                        "fecha" => "2003"
                        "volumen" => "3"
                        "paginaInicial" => "769"
                        "paginaFinal" => "779"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib81"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Review of multiple endocrine neoplasia type 2a in children&#58; therapeutic results of early thyroidectomy and prognostic value of codon analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1542/peds.111.2.e132"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "2004"
                        "volumen" => "111"
                        "paginaInicial" => "E132"
                        "paginaFinal" => "E140"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack640440"
        "titulo" => "ACKNOWLEDGEMENTS"
        "texto" => "<p id="para410" class="elsevierStylePara elsevierViewall">We thank Papaiz group for supporting this research&#44; aiming to bring to society a faster&#44; safe&#44; and accurate diagnosis of multiple endocrine neoplasias&#46; We also thank all the staff of the Endocrine Genetics Unit &#40;http&#58;&#47;&#47;medicina&#46;fm&#46;usp&#46;br&#47;ueg&#41; for the support&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/18075932/0000006100000001/v1_202212060829/S1807593222030058/v1_202212060829/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006100000001/v1_202212060829/S1807593222030058/v1_202212060829/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222030058?idApp=UINPBA00004N"
]

Article information

ISSN: 18075932
Original language: English

DOI:10.1590/S1807-59322006000100011

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	0	8
2024 October	41	34	75
2024 September	71	36	107
2024 August	71	16	87
2024 July	69	21	90
2024 June	55	11	66
2024 May	56	11	67
2024 April	42	9	51
2024 March	34	15	49
2024 February	24	10	34
2024 January	26	13	39
2023 December	23	18	41
2023 November	16	24	40
2023 October	22	21	43
2023 September	28	24	52
2023 August	21	8	29
2023 July	18	17	35
2023 June	45	12	57
2023 May	57	4	61
2023 April	55	2	57
2023 March	55	2	57
2023 February	16	1	17
2023 January	4	0	4
2022 December	13	1	14

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter