Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome

array:24 ["pii" => "S1807593222024012" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)15" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2401" "copyright" => "CLINICS" "copyrightAnyo" => "2012" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "fla" "cita" => "Clinics. 2012;67 Supl 1:85-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S1807593222024024" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)16" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2402" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2012;67 Supl 1:91-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "REVIEW" "titulo" => "Personalized medicine: caught between hope, hype and the real world" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "91" "paginaFinal" => "97" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Marc Dammann, Frank Weber" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Marc" "apellidos" => "Dammann" ] 1 => array:2 [ "nombre" => "Frank" "apellidos" => "Weber" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024024?idApp=UINPBA00004N" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024024/v1_202212010649/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1807593222024000" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)14" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2400" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2012;67 Supl 1:77-84" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "REVIEW" "titulo" => "Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "77" "paginaFinal" => "84" ] ] "contieneResumen" => array:1 [ "en" => 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" => 480 "Ancho" => 559 "Tamanyo" => 32125 ] ] "descripcion" => array:1 [ "en" => "The RET receptor: structure, activation, and oncogenic mutations. (A) Schematic diagram depicting RET tyrosine kinase receptor domains and the location of recurrent oncogenic mutations. The RET protein has a large extracellular domain containing a cysteine-rich region and a series of cadherin homology domains, a transmembrane domain, and an intracellular tyrosine kinase domain. The positions of the most common mutations found in patients with multiple endocrine neoplasia type 2 (MEN 2) are shown. (B) Mechanism of RET activation. Wild-type RET activation requires the dimerization of RET, mediated through formation of a multicomponent complex. RET is activated by binding both a soluble ligand (glial cell-line-derived neurotrophic factor; GDNF) and a non-signaling extracellular co-receptor (GDNF family receptor; GFRα). Upon activation of RET, phosphorylation of multiple intracellular tyrosines leads to stimulation of downstream signaling pathways." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Simona M. Wagner, ShuJun Zhu, Adrian C. Nicolescu, Lois M Mulligan" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Simona M." "apellidos" => "Wagner" ] 1 => array:2 [ "nombre" => "ShuJun" "apellidos" => "Zhu" ] 2 => array:2 [ "nombre" => "Adrian C." "apellidos" => "Nicolescu" ] 3 => array:2 [ "nombre" => "Lois M" "apellidos" => "Mulligan" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024000?idApp=UINPBA00004N" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024000/v1_202212010649/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "CLINICAL SCIENCE" "titulo" => "Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "85" "paginaFinal" => "89" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Nikoletta Lendvai, Miklos Tóth, Zsuzsanna Valkusz, Gabriella Bekő, Nikolette Szücs, Éva Csajbók, Péter Igaz, Balázs Kriszt, Balázs Kovács, Károly Rácz, Attila Patócs" "autores" => array:11 [ 0 => array:3 [ "nombre" => "Nikoletta" "apellidos" => "Lendvai" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 1 => array:3 [ "nombre" => "Miklos" "apellidos" => "Tóth" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 2 => array:3 [ "nombre" => "Zsuzsanna" "apellidos" => "Valkusz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "II" "identificador" => "aff2" ] ] ] 3 => array:3 [ "nombre" => "Gabriella" "apellidos" => "Bekő" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "III" "identificador" => "aff3" ] ] ] 4 => array:3 [ "nombre" => "Nikolette" "apellidos" => "Szücs" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 5 => array:3 [ "nombre" => "Éva" "apellidos" => "Csajbók" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "II" "identificador" => "aff2" ] ] ] 6 => array:3 [ "nombre" => "Péter" "apellidos" => "Igaz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 7 => array:3 [ "nombre" => "Balázs" "apellidos" => "Kriszt" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "IV" "identificador" => "aff4" ] ] ] 8 => array:3 [ "nombre" => "Balázs" "apellidos" => "Kovács" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "IV" "identificador" => "aff4" ] ] ] 9 => array:3 [ "nombre" => "Károly" "apellidos" => "Rácz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 10 => array:4 [ "nombre" => "Attila" "apellidos" => "Patócs" "email" => array:1 [ 0 => "patatt@bel2.sote.hu" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "III" "identificador" => "aff3" ] 1 => array:2 [ "etiqueta" => "V" "identificador" => "aff5" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "2nd Department of Medicine, Semmelweis University, Budapest, Hungary." "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "1st Department of Medicine, University of Szeged, Szeged, Hungary." "etiqueta" => "II" "identificador" => "aff2" ] 2 => array:3 [ "entidad" => "Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary." "etiqueta" => "III" "identificador" => "aff3" ] 3 => array:3 [ "entidad" => "Regional University Center of Excellence in Environmental Industry Based on Natural Resource, Szent Istvan University, Gödöllő, Hungary." "etiqueta" => "IV" "identificador" => "aff4" ] 4 => array:3 [ "entidad" => "Molecular Medicine Research Group, Hungarian Academy of Sciences and 2nd Department of Medicine, Semmelweis University, Budapest, Hungary." "etiqueta" => "V" "identificador" => "aff5" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Tel.: 36 1 266 0926 ext. 55577" ] ] ] ] "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" => 178 "Ancho" => 465 "Tamanyo" => 15377 ] ] "descripcion" => array:1 [ "en" => "(A) Gel electrophoresis of PCR fragments after digestion with BanI for identification of the G12S polymorphism of the SDHD gene by RFLP (L = DNA ladder; C+ = positive control; heterozygote for G12S; C- = negative control; G12 normal, P1–P5 = patients. (B) Chromatograms of exon 1 of the SDHD gene showing the wild type and the heterozygote form of the G12S (GGT12AGT) polymorphism." ] ] ] "textoCompleto" => "INTRODUCTIONThe RET (rearranged during transfection) proto-oncogene located on chromosomal region 10q11.2 consists of 21 exons, and it encodes a receptor tyrosine kinase (<a class="elsevierStyleCrossRef" href="#bib1">1</a>). Germline gain-of-function mutations of the RET proto-oncogene cause multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited disease with an approximate prevalence of 2.5 per 100.000 in the general population (<a class="elsevierStyleCrossRef" href="#bib1">1</a>). MEN2 has three subtypes: i) MEN2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo) and primary hyperparathyroidism; ii) MEN2B, which presents with the most aggressive MTC, pheochromocytoma, neuromas and marfanoid phenotype; and iii) familial MTC (FMTC), the mildest form of MTC. Several important genotype–phenotype associations have been determined; the most commonly affected codon, 634 (nearly 85% of MEN2A cases), frequently associates with Pheo and hyperparathyroidism, whereas mutations of codons 609, 611, 618, and 620 (accounting for 10–15% of MEN2A) usually associate with the milder form of MEN2 (<a class="elsevierStyleCrossRefs" href="#bib1">1–3</a>). However, the phenotypic heterogeneity observed even in members of the same family suggests that other factors, for example genetic modifiers, may influence the clinical manifestation of the disease (<a class="elsevierStyleCrossRefs" href="#bib4">4–7</a>).Hereditary paraganglioma/pheochromocytoma (PGL) syndrome is caused by the germline heterozygous mutations of the SDHx genes (SDHB, SDHC, SDHD, encoding subunits B, C and D, respectively) (<a class="elsevierStyleCrossRefs" href="#bib8">8–10</a>) and the newly identified SDH5 gene (<a class="elsevierStyleCrossRef" href="#bib11">11</a>) and TMEM127. SDHx genes encode subunits of the mitochondrial complex II (succinate dehydrogenase, SDH), an enzyme involved in oxidative phosphorylation and intracellular oxygen sensing and signaling (<a class="elsevierStyleCrossRef" href="#bib12">12</a>).Both MTC and paraganglioma/pheochromocytoma arise from neural crest-derived precursor cells. Accumulation of amino-acid coding polymorphisms (S163P in SDHB, G12S, and H50R in SDHD) has been found among patients with MTC, especially in those with familial tumors (<a class="elsevierStyleCrossRef" href="#bib13">13</a>). In addition, these rare genetic variants have been identified in patients with Cowden-like syndrome (<a class="elsevierStyleCrossRef" href="#bib14">14</a>) and the H50R polymorphism has been described in six members of a family with non-RET-associated C-cell hyperplasia and hypercalcitoninemia (<a class="elsevierStyleCrossRef" href="#bib15">15</a>). These previous data may suggest a possible connection between SDHx polymorphisms and familial MTC and/or C-cell hyperplasia/hypercalcitoninemia; however, the occurrence of the SDHx variants among patients harboring germline RET mutations has not been previously examined. Therefore, the aim of the present study was to investigate whether polymorphisms of the SDHx genes could influence clinical manifestations of the disease in a cohort of subjects harboring RET mutations. In addition, we wanted to determine whether the prevalence of SDHx polymorphisms in patients with sporadic MTC, sporadic Pheo and healthy subjects might be different from that found in RET mutation carriers.PATIENTS AND METHODSWritten informed consent was obtained from all patients and family members who participated in the study. Patients underwent a complete clinical examination, laboratory testing, including serum basal calcitonin measurement [hCalcitonin IRMA kit (Diagnostic Systems Laboratories, Inc., Budapest, Hungary), reference range: male <15 pg/ml, female <10 pg/ml until December 2007; and Liaison (Diasorin SPA, Stillwater, MN, USA), reference value: male <18.9 pg/ml and female <6 pg/ml after January 2008], plasma parathyroid hormone (Elecsys; Roche Diagnostics, Basel, Switzerland), urinary catecholamine metabolites (high pressure liquid chromatography with electrochemical detection), and imaging studies, including cervical ultrasonography, thoracal and abdominal computed tomography (CT), and whole-body metaiodobenzylguanidine scintigraphy (MIBG).Patients with MEN2 syndromeIn total, 77 patients with germline RET proto-oncogene mutations who were members of 21 unrelated families with MEN2 syndrome were identified by genetic screening at our center. Of the 77 patients, 55 had MEN2A (mean age at diagnosis: 33.4±17 years; range: 7–76 years), three had MEN2B (mean age at diagnosis: 15.6±5 years; range: 10–20 years), and 19 had FMTC (mean age at diagnosis: 23.7±16.8 years; range: 2–57 years). The presence of Pheo and MTC were confirmed by histologic examination of surgically removed tumors. Total thyroidectomy was performed in all patients with germline RET mutation in the symptomatic group and was also offered to all individuals from the asymptomatic group.Patients with sporadic MTCThe study included 47 unrelated patients with histologically confirmed MTC evaluated consecutively at the 2nd Department of Medicine, Faculty of Medicine, Semmelweis University between 1998 and 2010. There were 15 men (age, mean ± SD, 44.7±13.3; range: 28–82 years) and 32 women (age, mean ± SD, 47.7±12,3; range: 23–76 years). Pre-operative evaluation included medical history, physical examination, thyroid and abdominal ultrasonography, CT or magnetic resonance imaging (MRI), MIBG-scintigraphy, routine biochemical testing, serum calcitonin measurements, and mutation analysis of exons 10–14 of the RET gene.Patients with apparently sporadic PheoThe study included 48 unrelated patients with histologically confirmed sporadic adrenal pheochromocytomas evaluated consecutively at the 2nd Department of Medicine, Faculty of Medicine, Semmelweis University between 1998 and 2010. There were 16 men (age, mean ± SD, 36±14; range: 13–66 years) and 32 women (age, mean ± S.D, 42±14; range: 19–64 years). Pre-operative evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI, MIBG-scintigraphy, routine biochemical testing, and 24 h urinary catecholamine metabolite determination. The mutation analysis of RET exons 10–14 and the entire VHL, SDHB, and SDHD genes revealed no disease-causing mutations. Patients with confirmed VHL (five patients), SDHB (one patient), or SDHD (one patient) mutations were excluded from the study. Five patients were initially thought to have sporadic pheochromocytoma, but were later identified as having a disease-causing RET mutation and were included in the study as RET mutation carriers. MTC, either by elevated serum calcitonin or by postoperative histology, had been diagnosed in all of these patients. Genetic counseling and genetic screening for all first-degree relatives have been offered.Germline mutation screening of the RET, VHL, SDHB, and SDHD genesGenomic DNA was isolated from peripheral blood using the Roche DNA Isolation Kit (Roche Diagnostics GmbH, Mannheim, Germany) and QIAamp DNA Blood Mini Kit (Qiagen Inc., Valencia, CA, USA) in accordance with the manufacturers' instructions. RET proto-oncogene mutations were detected by direct sequencing as previously reported (<a class="elsevierStyleCrossRef" href="#bib16">16</a>),(<a class="elsevierStyleCrossRef" href="#bib17">17</a>). Mutation analysis of the VHL, SDHB, and SDHD genes in cases of apparently sporadic Pheo were performed by direct sequencing of the entire coding region of the VHL, SDHB, and SDHD genes, as previously reported (<a class="elsevierStyleCrossRef" href="#bib17">17</a>),(<a class="elsevierStyleCrossRef" href="#bib18">18</a>), and large deletion analysis of the VHL, SDHB, SDHC, and SDHD genes performed using multiplex ligation probe amplification (<a class="elsevierStyleCrossRef" href="#bib18">18</a>).Restriction fragment length polymorphism (RFLP) analysis for identification the G12S polymorphism of the SDHD geneThe nucleotide change of G to A, which corresponds to the G12S polymorphism, results in the preservation of the BanI restriction cleavage site. Therefore, digestion with the BanI restriction enzyme (New England BioLabs Inc., Ipswich, MA, USA) for 90 min at 37°C was performed after polymerase chain reaction (PCR) amplification of exon 1 of the SDHD gene for genotyping of RET mutation carriers, sporadic MTC patients, and 100 controls (<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>). Samples from patients with positive results were examined by direct DNA sequencing. The results obtained with both methods were the same in all cases.<elsevierMultimedia ident="fig1"></elsevierMultimedia>Statistical analysisBaseline characteristics were compared using the chi-squared test or Fisher's exact test for qualitative variables, and Student's t test or Mann-Whitney's U test for quantitative variables. The statistical package SPSS 15.0 (SPSS Inc., Chicago, IL, USA) was used and p<0.05 was considered statistically significant.RESULTS AND DISCUSSIONEight of the 55 patients with MEN2A (15.5%) had the G12S variant, whereas it was absent in the MEN2B and FMTC groups. No patient with sporadic MTC and/or sporadic Pheo carried this variant. Among the 100 population-based, healthy control individuals, only one individual carried this variant (prevalence, 1%) (<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>). No association between the G12S polymorphism of the SDHD gene and the incidence of Pheo or hyperparathyroidism in RET mutation carriers was observed, and the age of disease manifestation was similar in G12S carriers and in non-carriers (43±9 versus 40±3 years in probands and 29.6±19.3 versus 32.5±20.5 years in non-carriers). Among probands with RET mutations, carriers of the G12S had higher serum calcitonin levels compared with those who did not carry the SDHD G12S variant (6,864±11,111 versus 1,250±932 pg/ml), but the difference was not significant. Among family members with RET mutations, serum calcitonin levels were similar in G12S carriers and non-carriers 436±876 versus 393±556 pg/ml) (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>).<elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia>The phenotypic heterogeneity seen in families with different RET mutations, the variation of clinical course within families with the same RET mutation, and the results from RET transgenic mouse models suggest a potential role of genetic components in phenotype modulation (<a class="elsevierStyleCrossRef" href="#bib2">2</a>),(<a class="elsevierStyleCrossRef" href="#bib19">19</a>). Polymorphisms of the RET gene have been analyzed as such genetic modifiers, but the results from these studies are conflicting. Robledo et al. showed that two RET variants (G691S and S904S) may modify the age of onset of MTC in family members (<a class="elsevierStyleCrossRef" href="#bib5">5</a>); and Tamanaha et al. reported that two intronic polymorphisms of RET may modify the phenotype in a large family with G533C RET mutation (<a class="elsevierStyleCrossRef" href="#bib7">7</a>), while Baumgartner-Parzer found that the L769L and the IVS14-24 may act as modifiers in some forms of hereditary and sporadic MTC (<a class="elsevierStyleCrossRef" href="#bib20">20</a>). However, Lesueur et al. were unable to replicate this association in a large cohort of 384 members of MEN2 families from four different European populations. This latter study showed that of the several polymorphisms of genes encoding the RET protein, its co-receptors and ligands, only the synonymous polymorphism A432A of the RET gene associated weakly with tumor spectra in patients with MEN2A (<a class="elsevierStyleCrossRef" href="#bib6">6</a>). MEN2-related MTC RET variants have been analyzed as genetic susceptibility factors for the development of sporadic MTC: polymorphisms located in coding regions of RET, G691S, L769L, S836S, and S904S have been shown to be over-represented in patients with sporadic MTC (<a class="elsevierStyleCrossRefs" href="#bib21">21–23</a>) compared with the general population, but others were unable to confirm these associations (<a class="elsevierStyleCrossRef" href="#bib24">24</a>),(<a class="elsevierStyleCrossRef" href="#bib25">25</a>).Germline mutations of SDHx genes encoding subunits of the mitochondrial complex II represent a genetic susceptibility for Pheo/PGL. These tumors are derived from cells of the neural crest, similar to MTC. RET mutations also cause Pheo, again suggesting a link between the genetic background of Pheo and MTC. Therefore, it has been assumed that mutations of these genes may be involved in the pathogenesis of MTC. Lima et al. reported a family with C-cell hyperplasia, a pre-cancerous state of MTC, who were proved to have the H50R variant of the SDHD gene (<a class="elsevierStyleCrossRef" href="#bib15">15</a>). Montani et al. demonstrated an increased frequency of amino acid-coding SDHx polymorphisms in patients with sporadic and familial MTC (<a class="elsevierStyleCrossRef" href="#bib13">13</a>). In addition, a systemic evaluation of genetic variants of the SDHx genes among patients with sporadic MTC showed a significant association between the H50R variant and sporadic MTC in Spanish patients, although this observation was absent in an English cohort (<a class="elsevierStyleCrossRef" href="#bib26">26</a>). Variants of the SDHx genes have been implicated in the pathogenesis of various endocrine and non-endocrine tumors, such as Merkel cell carcinoma, carcinoid, papillary thyroid cancer, and renal cell cancer found in patients with Cowden-like syndrome (<a class="elsevierStyleCrossRef" href="#bib14">14</a>).In the present study, we found that the G12S variant was significantly over-represented among RET mutation carriers compared with sporadic MTC, sporadic Pheo, or control individuals. In our study, this variant occurred mainly in patients with MEN2A, while Montani et al. detected G12S in a patient with MEN2B harboring the M918T mutation of the RET gene (<a class="elsevierStyleCrossRef" href="#bib13">13</a>). Interestingly, the prevalence of alterations of the SDHx genes in patients with RET mutations was similar in our study and the study of Montani et al. (<a class="elsevierStyleCrossRef" href="#bib13">13</a>).The prevalence of the G12S in the general population is between 2.5% and 5% (<a class="elsevierStyleCrossRef" href="#bib27">27</a>) according to the Leiden Open Variation Database (<a href="http://chromium.liacs.nl">http://chromium.liacs.nl</a>) (<a class="elsevierStyleCrossRef" href="#bib28">28</a>), which is somewhat higher than in our control population (1%). This difference may be due to differences in the selection criteria applied for controls. Our control group were evaluated for endocrine dysfunction; none of them had signs or symptoms characteristic of thyroid cancer or Pheo. By contrast, population-based controls, frequently anonymous blood donors, have never been tested for these rare conditions. Alternatively, the difference between the studies in prevalence of G12S can also be attributed to the ethnic background of the different populations tested. Our patients and controls were of Hungarian origin, representing an independent entity among Caucasian populations. More importantly, in our study, the high incidence of the G12S variant among RET carriers, especially in those with the MEN2A phenotype, raised the possibility that this variant may have a role in the phenotypic modulation of the disease. However, we were unable to detect significant differences in the clinical presentation between G12S carriers and non-carriers. Whether this failure was a result of the relatively small size of our patient cohorts remains to be further investigated. Interestingly, Waldmann et al. reported an increased prevalence of intronic SDHB polymorphisms among patients with malignant Pheo compared with patients with benign tumors (<a class="elsevierStyleCrossRef" href="#bib29">29</a>).In conclusion, we found a significantly higher prevalence of the G12S variant of the SDHD gene among germline RET mutation carriers presenting with MEN2A compared with the control group. The high prevalence of the G12S variant in these patients supports its genetic modifier role, but this proposal remains to be established." "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "xpalclavsec1581208" "titulo" => "KEYWORDS" ] 1 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 2 => array:3 [ "identificador" => "cesec20" "titulo" => "PATIENTS AND METHODS" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "cesec30" "titulo" => "Patients with MEN2 syndrome" ] 1 => array:2 [ "identificador" => "cesec40" "titulo" => "Patients with sporadic MTC" ] 2 => array:2 [ "identificador" => "cesec50" "titulo" => "Patients with apparently sporadic Pheo" ] 3 => array:2 [ "identificador" => "cesec60" "titulo" => "Germline mutation screening of the RET, VHL, SDHB, and SDHD genes" ] 4 => array:2 [ "identificador" => "cesec70" "titulo" => "Restriction fragment length polymorphism (RFLP) analysis for identification the G12S polymorphism of the SDHD gene" ] 5 => array:2 [ "identificador" => "cesec80" "titulo" => "Statistical analysis" ] ] ] 3 => array:2 [ "identificador" => "cesec90" "titulo" => "RESULTS AND DISCUSSION" ] 4 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1581208" "palabras" => array:4 [ 0 => "RET proto-oncogene" 1 => "Succinate dehydrogenase subunit D" 2 => "Medullary thyroid cancer" 3 => "Pheochromocytoma" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "resumen" => "OBJECTIVE:To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2. Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome. Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene. METHODS:Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals. Exons 10–16 of the rearranged during transfection proto-oncogene were analyzed by direct DNA sequencing, and all exons of the von Hippel-Lindau, succinate dehydrogenase B, and succinate dehydrogenase subunit D genes were tested by direct DNA sequencing and multiple ligation probe analysis. The G12S polymorphism of the succinate dehydrogenase subunit D gene was determined by restriction fragment length polymorphism. RESULTS:Of the 77 rearranged during transfection mutation carriers, 55 from 16 families had multiple endocrine neoplasia type 2A, three from three families had multiple endocrine neoplasia type 2B, and 19 from two families had familial medullary thyroid carcinoma. Eight of 55 (14.5%) patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, and sporadic pheochromocytoma groups, and its prevalence in controls was 1% (p<0.002 multiple endocrine neoplasia type 2A versus controls). No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed. CONCLUSION:The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "ceabs10" "titulo" => "OBJECTIVE:" ] 1 => array:2 [ "identificador" => "ceabs20" "titulo" => "METHODS:" ] 2 => array:2 [ "identificador" => "ceabs30" "titulo" => "RESULTS:" ] 3 => array:2 [ "identificador" => "ceabs40" "titulo" => "CONCLUSION:" ] ] ] ] "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "No potential conflict of interest was reported. Patócs A was responsible for the statistical analysis and study design, molecular biological analysis, evaluation and collection of clinical data, genetic counseling, and manuscript writing and critical review. Lendvai N has contributed to the statistical analysis and study design, molecular biological analysis, and manuscript writing and critical review. Kovács B and Kriszt B have contributed to the molecular biological analysis and to the manuscript writing and critical review. Tóth M, Szücs N, Csajbók É and Rácz K have contributed to the evaluation and collection of clinical data and to the manuscript writing and critical review. Igaz P has contributed to the evaluation and collection of clinical data, genetic counseling, and manuscript writing and critical review. Bekő G was responsible for the measurement of serum calcitonin levels and to the manuscript writing and critical review." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 178 "Ancho" => 465 "Tamanyo" => 15377 ] ] "descripcion" => array:1 [ "en" => "(A) Gel electrophoresis of PCR fragments after digestion with BanI for identification of the G12S polymorphism of the SDHD gene by RFLP (L = DNA ladder; C+ = positive control; heterozygote for G12S; C- = negative control; G12 normal, P1–P5 = patients. (B) Chromatograms of exon 1 of the SDHD gene showing the wild type and the heterozygote form of the G12S (GGT12AGT) polymorphism." ] ] 1 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "FMTC = familiar medullary thyroid cancer; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MTC = medullary thyroid cancer; Pheo = pheochromocytoma." "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="top" scope="col">MEN2A \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="center" valign="top" scope="col">FMTC \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="center" valign="top" scope="col">MEN2B \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="center" valign="top" scope="col">Spoaradic MTC \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="center" valign="top" scope="col">Spoaradic Pheo \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="center" valign="top" scope="col">Control \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="top">8/55 (15.5%)<a class="elsevierStyleCrossRef" href="#tfn1">∗</a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">0/19 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">0/3 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">0/47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">0/48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">1/100 (1%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tfn1" "etiqueta" => "∗" "nota" => "p<0.002 versus control group." ] ] ] "descripcion" => array:1 [ "en" => "Prevalence of the G12S polymorphism of the SDHD gene among germline RET mutation carriers, patients with sporadic medullary thyroid cancer, patients with sporadic pheochromocytomas, and healthy controls." ] ] 2 => array:7 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "SD = standard deviation; MEN2A = multiple endocrine neoplasia type 2A; MTC = medullary thyroid cancer; Pheo = pheochromocytoma; PHPT = primary hyperparathyroidism." "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="top" scope="col">MEN2A (n = 55) \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="center" valign="top" scope="col">G12S negative \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="center" valign="top" scope="col">G12S positive \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="top">Probands (n = 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="center" valign="top">n = 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="center" valign="top">n = 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="left" valign="top">Age of presentation (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">40.1±9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">43±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="left" valign="top">Prevalence of: \t\t\t\t\t\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="top">MTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">12/13 \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="center" valign="top">3/3 \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="left" valign="top">Pheo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">6/13 \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="center" valign="top">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="left" valign="top">PHPT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">4/13 \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="center" valign="top">1/3 \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="left" valign="top">Serum calcitonin; mean ± SD (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">1,206±932 (13–2400) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">6,864±11,111 (124–19,690) \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="top">Affected family members (n = 39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">n = 34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">n = 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="left" valign="top">Age of presentation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">32.5±19.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">29.6±20.5 \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="left" valign="top">Prevalence of: \t\t\t\t\t\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="top">MTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">22/34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">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="left" valign="top">Pheo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">8/34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">2/5 \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="left" valign="top">PHPT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">4/34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">1/5 \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="left" valign="top">Serum calcitonin mean ± SD (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">393.8±556 (0–1978) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">436.2±876 (0–2000) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical presentation, serum calcitonin concentration and the G12S status of patients with MEN2A." ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "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:7 [ "tituloSerie" => "Nature" "fecha" => "1993" "volumen" => "363" "numero" => "6428" "paginaInicial" => "458" "paginaFinal" => "460" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8099202" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ C Eng \n \t\t\t\t\t\t\t\t """ 1 => """ D Clayton \n \t\t\t\t\t\t\t\t """ 2 => """ I Schuffenecker \n \t\t\t\t\t\t\t\t """ 3 => """ G Lenoir \n \t\t\t\t\t\t\t\t """ 4 => """ G Cote \n \t\t\t\t\t\t\t\t """ 5 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "JAMA" "fecha" => "1996" "volumen" => "276" "numero" => "19" "paginaInicial" => "1575" "paginaFinal" => "1579" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8918855" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene" "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 => """ T Attie \n \t\t\t\t\t\t\t\t """ 3 => """ S Lyonnet \n \t\t\t\t\t\t\t\t """ 4 => """ DJ Marsh \n \t\t\t\t\t\t\t\t """ 5 => """ VJ Hyland \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/hmg/3.12.2163" "Revista" => array:7 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1996" "volumen" => "3" "numero" => "12" "paginaInicial" => "2163" "paginaFinal" => "2167" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7881414" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ S Borrego \n \t\t\t\t\t\t\t\t """ 1 => """ ME Saez \n \t\t\t\t\t\t\t\t """ 2 => """ A Ruiz \n \t\t\t\t\t\t\t\t """ 3 => """ O Gimm \n \t\t\t\t\t\t\t\t """ 4 => """ M López-Alonso \n \t\t\t\t\t\t\t\t """ 5 => """ G Antiñolo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jmg.36.10.771" "Revista" => array:7 [ "tituloSerie" => "J Med Genet" "fecha" => "1999" "volumen" => "36" "numero" => "10" "paginaInicial" => "771" "paginaFinal" => "774" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10528857" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Robledo \n \t\t\t\t\t\t\t\t """ 1 => """ L Gil \n \t\t\t\t\t\t\t\t """ 2 => """ M Pollan \n \t\t\t\t\t\t\t\t """ 3 => """ A Cebrián \n \t\t\t\t\t\t\t\t """ 4 => """ S Ruíz \n \t\t\t\t\t\t\t\t """ 5 => """ M Azañedo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Cancer Res" "fecha" => "2003" "volumen" => "63" "numero" => "8" "paginaInicial" => "1814" "paginaFinal" => "1817" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12702567" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ F Lesueur \n \t\t\t\t\t\t\t\t """ 1 => """ A Cebrian \n \t\t\t\t\t\t\t\t """ 2 => """ M Robledo \n \t\t\t\t\t\t\t\t """ 3 => """ P Niccoli-Sire \n \t\t\t\t\t\t\t\t """ 4 => """ KA Svensson \n \t\t\t\t\t\t\t\t """ 5 => """ S Pinson \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/0008-5472.CAN-05-2995" "Revista" => array:7 [ "tituloSerie" => "Cancer Res" "fecha" => "2006" "volumen" => "66" "numero" => "2" "paginaInicial" => "1177" "paginaFinal" => "1180" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16424056" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation: specific RET variants may modulate age at onset and clinical presentation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ R Tamanaha \n \t\t\t\t\t\t\t\t """ 1 => """ CP Camacho \n \t\t\t\t\t\t\t\t """ 2 => """ AC Pereira \n \t\t\t\t\t\t\t\t """ 3 => """ AM da Silva \n \t\t\t\t\t\t\t\t """ 4 => """ RM Maciel \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" => "10.1111/j.1365-2265.2008.03491.x" "Revista" => array:7 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "2009" "volumen" => "71" "numero" => "1" "paginaInicial" => "56" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19138318" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ D Astuti \n \t\t\t\t\t\t\t\t """ 1 => """ F Latif \n \t\t\t\t\t\t\t\t """ 2 => """ A Dallol \n \t\t\t\t\t\t\t\t """ 3 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 4 => """ F Douglas \n \t\t\t\t\t\t\t\t """ 5 => """ E George \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1086/321282" "Revista" => array:7 [ "tituloSerie" => "Am J Hum Genet" "fecha" => "2001" "volumen" => "69" "numero" => "2" "paginaInicial" => "49" "paginaFinal" => "54" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11404820" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in SDHC cause autosomal dominant paraganglioma, type 3" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ S Niemann \n \t\t\t\t\t\t\t\t """ 1 => """ U Muller \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nat Genet" "fecha" => "2000" "volumen" => "26" "numero" => "3" "paginaInicial" => "70" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ BE Baysal \n \t\t\t\t\t\t\t\t """ 1 => """ RE Ferrell \n \t\t\t\t\t\t\t\t """ 2 => """ JE Willett-Brozick \n \t\t\t\t\t\t\t\t """ 3 => """ EC Lawrence \n \t\t\t\t\t\t\t\t """ 4 => """ D Myssiorek \n \t\t\t\t\t\t\t\t """ 5 => """ A Bosch \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.287.5454.848" "Revista" => array:7 [ "tituloSerie" => "Science" "fecha" => "2000" "volumen" => "287" "numero" => "2" "paginaInicial" => "848" "paginaFinal" => "851" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10657297" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ HX Hao \n \t\t\t\t\t\t\t\t """ 1 => """ O Khalimonchuk \n \t\t\t\t\t\t\t\t """ 2 => """ M Schraders \n \t\t\t\t\t\t\t\t """ 3 => """ N Dephoure \n \t\t\t\t\t\t\t\t """ 4 => """ JP Bayley \n \t\t\t\t\t\t\t\t """ 5 => """ H Kunst \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1175689" "Revista" => array:7 [ "tituloSerie" => "Science" "fecha" => "2009" "volumen" => "325" "numero" => "17" "paginaInicial" => "1139" "paginaFinal" => "1142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19628817" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate–ubiquinone oxidoreductase" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ H Hirawake \n \t\t\t\t\t\t\t\t """ 1 => """ M Taniwaki \n \t\t\t\t\t\t\t\t """ 2 => """ A Tamura \n \t\t\t\t\t\t\t\t """ 3 => """ H Amino \n \t\t\t\t\t\t\t\t """ 4 => """ E Tomitsuka \n \t\t\t\t\t\t\t\t """ 5 => """ K Kita \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0005-2728(99)00071-7" "Revista" => array:7 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "1999" "volumen" => "1412" "numero" => "3" "paginaInicial" => "295" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10482792" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Montani \n \t\t\t\t\t\t\t\t """ 1 => """ AM Schmitt \n \t\t\t\t\t\t\t\t """ 2 => """ S Schmid \n \t\t\t\t\t\t\t\t """ 3 => """ T Locher \n \t\t\t\t\t\t\t\t """ 4 => """ P Saremaslani \n \t\t\t\t\t\t\t\t """ 5 => """ PU Heitz \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1677/erc.1.00996" "Revista" => array:7 [ "tituloSerie" => "Endocr Relat Cancer" "fecha" => "2005" "volumen" => "12" "numero" => "4" "paginaInicial" => "1011" "paginaFinal" => "1016" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16322339" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ Y Ni \n \t\t\t\t\t\t\t\t """ 1 => """ KM Zbuk \n \t\t\t\t\t\t\t\t """ 2 => """ T Sadler \n \t\t\t\t\t\t\t\t """ 3 => """ A Patocs \n \t\t\t\t\t\t\t\t """ 4 => """ G Lobo \n \t\t\t\t\t\t\t\t """ 5 => """ E Edelman \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ajhg.2008.07.011" "Revista" => array:7 [ "tituloSerie" => "Am J Hum Genet" "fecha" => "2008" "volumen" => "83" "numero" => "2" "paginaInicial" => "261" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18678321" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ J Lima \n \t\t\t\t\t\t\t\t """ 1 => """ J Teixeira-Gomes \n \t\t\t\t\t\t\t\t """ 2 => """ P Soares \n \t\t\t\t\t\t\t\t """ 3 => """ V Maximo \n \t\t\t\t\t\t\t\t """ 4 => """ M Honavar \n \t\t\t\t\t\t\t\t """ 5 => """ D Williams \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2002-030008" "Revista" => array:7 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2003" "volumen" => "88" "numero" => "10" "paginaInicial" => "4932" "paginaFinal" => "4937" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14557476" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ A Patócs \n \t\t\t\t\t\t\t\t """ 1 => """ Z Valkusz \n \t\t\t\t\t\t\t\t """ 2 => """ P Igaz \n \t\t\t\t\t\t\t\t """ 3 => """ K Balogh \n \t\t\t\t\t\t\t\t """ 4 => """ M Tóth \n \t\t\t\t\t\t\t\t """ 5 => """ I Varga \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1034/j.1399-0004.2003.00044.x" "Revista" => array:7 [ "tituloSerie" => "Clin Genet" "fecha" => "2003" "volumen" => "63" "numero" => "3" "paginaInicial" => "219" "paginaFinal" => "223" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12694233" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and biochemical features of sporadic and hereditary phaeochromocytomas: an analysis of 41 cases investigated in a single endocrine centre" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ A Patócs \n \t\t\t\t\t\t\t\t """ 1 => """ E Karádi \n \t\t\t\t\t\t\t\t """ 2 => """ M Tóth \n \t\t\t\t\t\t\t\t """ 3 => """ I Varga \n \t\t\t\t\t\t\t\t """ 4 => """ N Szücs \n \t\t\t\t\t\t\t\t """ 5 => """ K Balogh \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00008469-200410000-00008" "Revista" => array:7 [ "tituloSerie" => "Eur J Cancer Prev" "fecha" => "2004" "volumen" => "13" "numero" => "5" "paginaInicial" => "403" "paginaFinal" => "409" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15452453" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Gergics \n \t\t\t\t\t\t\t\t """ 1 => """ A Patocs \n \t\t\t\t\t\t\t\t """ 2 => """ M Toth \n \t\t\t\t\t\t\t\t """ 3 => """ P Igaz \n \t\t\t\t\t\t\t\t """ 4 => """ N Szucs \n \t\t\t\t\t\t\t\t """ 5 => """ I Liko \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/EJE-09-0399" "Revista" => array:7 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "2009" "volumen" => "161" "numero" => "3" "paginaInicial" => "495" "paginaFinal" => "502" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19574279" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "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 => """ BA Ponder \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Cancer Res" "fecha" => "2003" "volumen" => "63" "numero" => "16" "paginaInicial" => "4777" "paginaFinal" => "4780" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12941793" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ SM Baumgartner-Parzer \n \t\t\t\t\t\t\t\t """ 1 => """ R Lang \n \t\t\t\t\t\t\t\t """ 2 => """ L Wagner \n \t\t\t\t\t\t\t\t """ 3 => """ G Heinze \n \t\t\t\t\t\t\t\t """ 4 => """ B Niederle \n \t\t\t\t\t\t\t\t """ 5 => """ K Kaserer \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2005-1278" "Revista" => array:7 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2005" "volumen" => "90" "numero" => "11" "paginaInicial" => "6232" "paginaFinal" => "6236" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16118333" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ R Elisei \n \t\t\t\t\t\t\t\t """ 1 => """ B Cosci \n \t\t\t\t\t\t\t\t """ 2 => """ C Romei \n \t\t\t\t\t\t\t\t """ 3 => """ V Bottici \n \t\t\t\t\t\t\t\t """ 4 => """ M Sculli \n \t\t\t\t\t\t\t\t """ 5 => """ R Lari \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2003-031898" "Revista" => array:7 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2004" "volumen" => "89" "numero" => "7" "paginaInicial" => "3579" "paginaFinal" => "3584" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15240649" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET 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 => """ DS Neuberg \n \t\t\t\t\t\t\t\t """ 2 => """ DJ Marsh \n \t\t\t\t\t\t\t\t """ 3 => """ PL Dahia \n \t\t\t\t\t\t\t\t """ 4 => """ C Hoang-Vu \n \t\t\t\t\t\t\t\t """ 5 => """ F Raue \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Oncogene" "fecha" => "1999" "volumen" => "18" "numero" => "6" "paginaInicial" => "23" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ A Cebrian \n \t\t\t\t\t\t\t\t """ 1 => """ F Lesueur \n \t\t\t\t\t\t\t\t """ 2 => """ S Martin \n \t\t\t\t\t\t\t\t """ 3 => """ J Leyland \n \t\t\t\t\t\t\t\t """ 4 => """ S Ahmed \n \t\t\t\t\t\t\t\t """ 5 => """ C Luccarini \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2004-2449" "Revista" => array:7 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2005" "volumen" => "90" "numero" => "11" "paginaInicial" => "6268" "paginaFinal" => "6274" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16091499" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Germline-sequence variants S836S and L769L in the RE arranged during Transfection (RET) proto-oncogene are not associated with predisposition to sporadic medullary carcinoma in the French population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ I Berard \n \t\t\t\t\t\t\t\t """ 1 => """ JL Kraimps \n \t\t\t\t\t\t\t\t """ 2 => """ F Savagner \n \t\t\t\t\t\t\t\t """ 3 => """ A Murat \n \t\t\t\t\t\t\t\t """ 4 => """ K Renaudin \n \t\t\t\t\t\t\t\t """ 5 => """ P Nicolli-Sire \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.0009-9163.2004.00172.x" "Revista" => array:7 [ "tituloSerie" => "Clin Genet" "fecha" => "2004" "volumen" => "65" "numero" => "2" "paginaInicial" => "150" "paginaFinal" => "152" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14984475" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "G691S, L769L and S836S ret proto-oncogene polymorphisms are not associated with higher risk to sporadic medullary thyroid carcinoma in Chilean patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ GN Wohllk \n \t\t\t\t\t\t\t\t """ 1 => """ CE Soto \n \t\t\t\t\t\t\t\t """ 2 => """ AM Bravo \n \t\t\t\t\t\t\t\t """ 3 => """ CP Becker \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Med Chil" "fecha" => "2005" "volumen" => "133" "numero" => "4" "paginaInicial" => "402" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Succinate dehydrogenase D variants do not constitute a risk factor for developing C cell hyperplasia or sporadic medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ A Cascon \n \t\t\t\t\t\t\t\t """ 1 => """ A Cebrian \n \t\t\t\t\t\t\t\t """ 2 => """ M Pollan \n \t\t\t\t\t\t\t\t """ 3 => """ S Ruiz-Llorente \n \t\t\t\t\t\t\t\t """ 4 => """ C Montero-Conde \n \t\t\t\t\t\t\t\t """ 5 => """ R Leton \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2005" "volumen" => "90" "numero" => "4" "paginaInicial" => "30" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "G12S and H50R variations are polymorphisms in the SDHD gene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ A Cascon \n \t\t\t\t\t\t\t\t """ 1 => """ S Ruiz-Llorente \n \t\t\t\t\t\t\t\t """ 2 => """ A Cebrian \n \t\t\t\t\t\t\t\t """ 3 => """ R Leton \n \t\t\t\t\t\t\t\t """ 4 => """ D Telleria \n \t\t\t\t\t\t\t\t """ 5 => """ J Benitez \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/gcc.10212" "Revista" => array:8 [ "tituloSerie" => "Genes Chromosomes Cancer" "fecha" => "2003" "volumen" => "37" "numero" => "2" "paginaInicial" => "220" "paginaFinal" => "221" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12696072" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S014067361830984X" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ PE Taschner \n \t\t\t\t\t\t\t\t """ 1 => """ JC Jansen \n \t\t\t\t\t\t\t\t """ 2 => """ BE Baysal \n \t\t\t\t\t\t\t\t """ 3 => """ A Bosch \n \t\t\t\t\t\t\t\t """ 4 => """ EH Rosenberg \n \t\t\t\t\t\t\t\t """ 5 => """ AH Bröcker-Vriends \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/gcc.1144" "Revista" => array:7 [ "tituloSerie" => "Genes Chromosomes Cancer" "fecha" => "2001" "volumen" => "31" "numero" => "3" "paginaInicial" => "274" "paginaFinal" => "281" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11391798" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ J Waldmann \n \t\t\t\t\t\t\t\t """ 1 => """ P Langer \n \t\t\t\t\t\t\t\t """ 2 => """ N Habbe \n \t\t\t\t\t\t\t\t """ 3 => """ V Fendrich \n \t\t\t\t\t\t\t\t """ 4 => """ A Ramaswamy \n \t\t\t\t\t\t\t\t """ 5 => """ M Rothmund \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12020-009-9178-y" "Revista" => array:7 [ "tituloSerie" => "Endocrine" "fecha" => "2009" "volumen" => "35" "numero" => "3" "paginaInicial" => "347" "paginaFinal" => "355" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19399650" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024012/v1_202212010649/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/00000067000000S1/v1_202212010649/S1807593222024012/v1_202212010649/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024012?idApp=UINPBA00004N"]

Statistics

CLINICAL SCIENCE

Nikoletta LendvaiI, Miklos TóthI, Zsuzsanna ValkuszII, Gabriella BekőIII, Nikolette SzücsI, Éva CsajbókII, Péter IgazI, Balázs KrisztIV, Balázs KovácsIV, Károly RáczI, Attila PatócsIII,V,

Corresponding author

patatt@bel2.sote.hu

Tel.: 36 1 266 0926 ext. 55577

I 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.

II 1st Department of Medicine, University of Szeged, Szeged, Hungary.

III Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary.

IV Regional University Center of Excellence in Environmental Industry Based on Natural Resource, Szent Istvan University, Gödöllő, Hungary.

V Molecular Medicine Research Group, Hungarian Academy of Sciences and 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.

Read

702

Times
was read the article

318

Total PDF

384

Total HTML

Share statistics

 array:24 [
  "pii" => "S1807593222024012"
  "issn" => "18075932"
  "doi" => "10.6061/clinics/2012(Sup01)15"
  "estado" => "S300"
  "fechaPublicacion" => "2012-04-01"
  "aid" => "2401"
  "copyright" => "CLINICS"
  "copyrightAnyo" => "2012"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
  "subdocumento" => "fla"
  "cita" => "Clinics. 2012;67 Supl 1:85-9"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1807593222024024"
    "issn" => "18075932"
    "doi" => "10.6061/clinics/2012(Sup01)16"
    "estado" => "S300"
    "fechaPublicacion" => "2012-04-01"
    "aid" => "2402"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "rev"
    "cita" => "Clinics. 2012;67 Supl 1:91-7"
    "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">REVIEW</span>"
      "titulo" => "Personalized medicine&#58; caught between hope&#44; hype and the real world"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "91"
          "paginaFinal" => "97"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Marc Dammann, Frank Weber"
          "autores" => array:2 [
            0 => array:2 [
              "nombre" => "Marc"
              "apellidos" => "Dammann"
            ]
            1 => array:2 [
              "nombre" => "Frank"
              "apellidos" => "Weber"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024024?idApp=UINPBA00004N"
    "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024024/v1_202212010649/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1807593222024000"
    "issn" => "18075932"
    "doi" => "10.6061/clinics/2012(Sup01)14"
    "estado" => "S300"
    "fechaPublicacion" => "2012-04-01"
    "aid" => "2400"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "rev"
    "cita" => "Clinics. 2012;67 Supl 1:77-84"
    "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" => "Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "77"
          "paginaFinal" => "84"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => 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" => 480
              "Ancho" => 559
              "Tamanyo" => 32125
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">The RET receptor&#58; structure&#44; activation&#44; and oncogenic mutations&#46; &#40;A&#41; Schematic diagram depicting RET tyrosine kinase receptor domains and the location of recurrent oncogenic mutations&#46; The RET protein has a large extracellular domain containing a cysteine-rich region and a series of cadherin homology domains&#44; a transmembrane domain&#44; and an intracellular tyrosine kinase domain&#46; The positions of the most common mutations found in patients with multiple endocrine neoplasia type 2 &#40;MEN 2&#41; are shown&#46; &#40;B&#41; Mechanism of RET activation&#46; Wild-type RET activation requires the dimerization of RET&#44; mediated through formation of a multicomponent complex&#46; RET is activated by binding both a soluble ligand &#40;glial cell-line-derived neurotrophic factor&#59; GDNF&#41; and a non-signaling extracellular co-receptor &#40;GDNF family receptor&#59; GFR&#945;&#41;&#46; Upon activation of RET&#44; phosphorylation of multiple intracellular tyrosines leads to stimulation of downstream signaling pathways&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Simona M&#46; Wagner, ShuJun Zhu, Adrian C&#46; Nicolescu, Lois M Mulligan"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "Simona M&#46;"
              "apellidos" => "Wagner"
            ]
            1 => array:2 [
              "nombre" => "ShuJun"
              "apellidos" => "Zhu"
            ]
            2 => array:2 [
              "nombre" => "Adrian C&#46;"
              "apellidos" => "Nicolescu"
            ]
            3 => array:2 [
              "nombre" => "Lois M"
              "apellidos" => "Mulligan"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024000?idApp=UINPBA00004N"
    "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024000/v1_202212010649/en/main.assets"
  ]
  "en" => array:17 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">CLINICAL SCIENCE</span>"
    "titulo" => "Over-representation of the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene in patients with MEN2A syndrome"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "85"
        "paginaFinal" => "89"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Nikoletta Lendvai, Miklos T&#243;th, Zsuzsanna Valkusz, Gabriella Bek&#337;, Nikolette Sz&#252;cs, &#201;va Csajb&#243;k, P&#233;ter Igaz, Bal&#225;zs Kriszt, Bal&#225;zs Kov&#225;cs, K&#225;roly R&#225;cz, Attila Pat&#243;cs"
        "autores" => array:11 [
          0 => array:3 [
            "nombre" => "Nikoletta"
            "apellidos" => "Lendvai"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Miklos"
            "apellidos" => "T&#243;th"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Zsuzsanna"
            "apellidos" => "Valkusz"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "aff2"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Gabriella"
            "apellidos" => "Bek&#337;"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">III</span>"
                "identificador" => "aff3"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Nikolette"
            "apellidos" => "Sz&#252;cs"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "&#201;va"
            "apellidos" => "Csajb&#243;k"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "aff2"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "P&#233;ter"
            "apellidos" => "Igaz"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          7 => array:3 [
            "nombre" => "Bal&#225;zs"
            "apellidos" => "Kriszt"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">IV</span>"
                "identificador" => "aff4"
              ]
            ]
          ]
          8 => array:3 [
            "nombre" => "Bal&#225;zs"
            "apellidos" => "Kov&#225;cs"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">IV</span>"
                "identificador" => "aff4"
              ]
            ]
          ]
          9 => array:3 [
            "nombre" => "K&#225;roly"
            "apellidos" => "R&#225;cz"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          10 => array:4 [
            "nombre" => "Attila"
            "apellidos" => "Pat&#243;cs"
            "email" => array:1 [
              0 => "patatt@bel2.sote.hu"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">III</span>"
                "identificador" => "aff3"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">V</span>"
                "identificador" => "aff5"
              ]
              2 => array:2 [
                "etiqueta" => "&#42;"
                "identificador" => "cor1"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:5 [
          0 => array:3 [
            "entidad" => "2nd Department of Medicine&#44; Semmelweis University&#44; Budapest&#44; Hungary&#46;"
            "etiqueta" => "I"
            "identificador" => "aff1"
          ]
          1 => array:3 [
            "entidad" => "1st Department of Medicine&#44; University of Szeged&#44; Szeged&#44; Hungary&#46;"
            "etiqueta" => "II"
            "identificador" => "aff2"
          ]
          2 => array:3 [
            "entidad" => "Department of Laboratory Medicine&#44; Semmelweis University&#44; Budapest&#44; Hungary&#46;"
            "etiqueta" => "III"
            "identificador" => "aff3"
          ]
          3 => array:3 [
            "entidad" => "Regional University Center of Excellence in Environmental Industry Based on Natural Resource&#44; Szent Istvan University&#44; G&#246;d&#246;ll&#337;&#44; Hungary&#46;"
            "etiqueta" => "IV"
            "identificador" => "aff4"
          ]
          4 => array:3 [
            "entidad" => "Molecular Medicine Research Group&#44; Hungarian Academy of Sciences and 2nd Department of Medicine&#44; Semmelweis University&#44; Budapest&#44; Hungary&#46;"
            "etiqueta" => "V"
            "identificador" => "aff5"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "&#42;"
            "correspondencia" => "Tel&#46;&#58; 36 1 266 0926 ext&#46; 55577"
          ]
        ]
      ]
    ]
    "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" => 178
            "Ancho" => 465
            "Tamanyo" => 15377
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Gel electrophoresis of PCR fragments after digestion with <span class="elsevierStyleItalic">Ban</span>I for identification of the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene by RFLP &#40;L &#61; DNA ladder&#59; C&#43; &#61; positive control&#59; heterozygote for G12S&#59; C- &#61; negative control&#59; G12 normal&#44; P1&#8211;P5 &#61; patients&#46; &#40;B&#41; Chromatograms of exon 1 of the <span class="elsevierStyleItalic">SDHD</span> gene showing the wild type and the heterozygote form of the G12S &#40;GGT12AGT&#41; polymorphism&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">RET</span> &#40;<span class="elsevierStyleItalic">rearranged during transfection</span>&#41; proto-oncogene located on chromosomal region 10q11&#46;2 consists of 21 exons&#44; and it encodes a receptor tyrosine kinase &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; Germline gain-of-function mutations of the <span class="elsevierStyleItalic">RET</span> proto-oncogene cause multiple endocrine neoplasia type 2 &#40;MEN2&#41;&#44; an autosomal dominantly inherited disease with an approximate prevalence of 2&#46;5 per 100&#46;000 in the general population &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; MEN2 has three subtypes&#58; i&#41; MEN2A&#44; characterized by medullary thyroid carcinoma &#40;MTC&#41;&#44; pheochromocytoma &#40;Pheo&#41; and primary hyperparathyroidism&#59; ii&#41; MEN2B&#44; which presents with the most aggressive MTC&#44; pheochromocytoma&#44; neuromas and marfanoid phenotype&#59; and iii&#41; familial MTC &#40;FMTC&#41;&#44; the mildest form of MTC&#46; Several important genotype&#8211;phenotype associations have been determined&#59; the most commonly affected codon&#44; 634 &#40;nearly 85&#37; of MEN2A cases&#41;&#44; frequently associates with Pheo and hyperparathyroidism&#44; whereas mutations of codons 609&#44; 611&#44; 618&#44; and 620 &#40;accounting for 10&#8211;15&#37; of MEN2A&#41; usually associate with the milder form of MEN2 &#40;<a class="elsevierStyleCrossRefs" href="#bib1">1&#8211;3</a>&#41;&#46; However&#44; the phenotypic heterogeneity observed even in members of the same family suggests that other factors&#44; for example genetic modifiers&#44; may influence the clinical manifestation of the disease &#40;<a class="elsevierStyleCrossRefs" href="#bib4">4&#8211;7</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Hereditary paraganglioma&#47;pheochromocytoma &#40;PGL&#41; syndrome is caused by the germline heterozygous mutations of the <span class="elsevierStyleItalic">SDHx</span> genes &#40;<span class="elsevierStyleItalic">SDHB&#44; SDHC&#44; SDHD</span>&#44; encoding subunits B&#44; C and D&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRefs" href="#bib8">8&#8211;10</a>&#41; and the newly identified <span class="elsevierStyleItalic">SDH5</span> gene &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41; and <span class="elsevierStyleItalic">TMEM127</span>&#46; <span class="elsevierStyleItalic">SDHx</span> genes encode subunits of the mitochondrial complex II &#40;succinate dehydrogenase&#44; SDH&#41;&#44; an enzyme involved in oxidative phosphorylation and intracellular oxygen sensing and signaling &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Both MTC and paraganglioma&#47;pheochromocytoma arise from neural crest-derived precursor cells&#46; Accumulation of amino-acid coding polymorphisms &#40;S163P in <span class="elsevierStyleItalic">SDHB&#44;</span> G12S&#44; and H50R in <span class="elsevierStyleItalic">SDHD</span>&#41; has been found among patients with MTC&#44; especially in those with familial tumors &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; In addition&#44; these rare genetic variants have been identified in patients with Cowden-like syndrome &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41; and the H50R polymorphism has been described in six members of a family with non-<span class="elsevierStyleItalic">RET</span>-associated C-cell hyperplasia and hypercalcitoninemia &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; These previous data may suggest a possible connection between <span class="elsevierStyleItalic">SDHx</span> polymorphisms and familial MTC and&#47;or C-cell hyperplasia&#47;hypercalcitoninemia&#59; however&#44; the occurrence of the <span class="elsevierStyleItalic">SDHx</span> variants among patients harboring germline <span class="elsevierStyleItalic">RET</span> mutations has not been previously examined&#46; Therefore&#44; the aim of the present study was to investigate whether polymorphisms of the <span class="elsevierStyleItalic">SDHx</span> genes could influence clinical manifestations of the disease in a cohort of subjects harboring <span class="elsevierStyleItalic">RET</span> mutations&#46; In addition&#44; we wanted to determine whether the prevalence of <span class="elsevierStyleItalic">SDHx</span> polymorphisms in patients with sporadic MTC&#44; sporadic Pheo and healthy subjects might be different from that found in <span class="elsevierStyleItalic">RET</span> mutation carriers&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">PATIENTS AND METHODS</span><p id="para40" class="elsevierStylePara elsevierViewall">Written informed consent was obtained from all patients and family members who participated in the study&#46; Patients underwent a complete clinical examination&#44; laboratory testing&#44; including serum basal calcitonin measurement &#91;hCalcitonin IRMA kit &#40;Diagnostic Systems Laboratories&#44; Inc&#46;&#44; Budapest&#44; Hungary&#41;&#44; reference range&#58; male &#60;15 pg&#47;ml&#44; female &#60;10 pg&#47;ml until December 2007&#59; and Liaison &#40;Diasorin SPA&#44; Stillwater&#44; MN&#44; USA&#41;&#44; reference value&#58; male &#60;18&#46;9 pg&#47;ml and female &#60;6 pg&#47;ml after January 2008&#93;&#44; plasma parathyroid hormone &#40;Elecsys&#59; Roche Diagnostics&#44; Basel&#44; Switzerland&#41;&#44; urinary catecholamine metabolites &#40;high pressure liquid chromatography with electrochemical detection&#41;&#44; and imaging studies&#44; including cervical ultrasonography&#44; thoracal and abdominal computed tomography &#40;CT&#41;&#44; and whole-body metaiodobenzylguanidine scintigraphy &#40;MIBG&#41;&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Patients with MEN2 syndrome</span><p id="para50" class="elsevierStylePara elsevierViewall">In total&#44; 77 patients with germline <span class="elsevierStyleItalic">RET</span> proto-oncogene mutations who were members of 21 unrelated families with MEN2 syndrome were identified by genetic screening at our center&#46; Of the 77 patients&#44; 55 had MEN2A &#40;mean age at diagnosis&#58; 33&#46;4&#177;17 years&#59; range&#58; 7&#8211;76 years&#41;&#44; three had MEN2B &#40;mean age at diagnosis&#58; 15&#46;6&#177;5 years&#59; range&#58; 10&#8211;20 years&#41;&#44; and 19 had FMTC &#40;mean age at diagnosis&#58; 23&#46;7&#177;16&#46;8 years&#59; range&#58; 2&#8211;57 years&#41;&#46; The presence of Pheo and MTC were confirmed by histologic examination of surgically removed tumors&#46; Total thyroidectomy was performed in all patients with germline <span class="elsevierStyleItalic">RET</span> mutation in the symptomatic group and was also offered to all individuals from the asymptomatic group&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Patients with sporadic MTC</span><p id="para60" class="elsevierStylePara elsevierViewall">The study included 47 unrelated patients with histologically confirmed MTC evaluated consecutively at the 2nd Department of Medicine&#44; Faculty of Medicine&#44; Semmelweis University between 1998 and 2010&#46; There were 15 men &#40;age&#44; mean &#177; SD&#44; 44&#46;7&#177;13&#46;3&#59; range&#58; 28&#8211;82 years&#41; and 32 women &#40;age&#44; mean &#177; SD&#44; 47&#46;7&#177;12&#44;3&#59; range&#58; 23&#8211;76 years&#41;&#46; Pre-operative evaluation included medical history&#44; physical examination&#44; thyroid and abdominal ultrasonography&#44; CT or magnetic resonance imaging &#40;MRI&#41;&#44; MIBG-scintigraphy&#44; routine biochemical testing&#44; serum calcitonin measurements&#44; and mutation analysis of exons 10&#8211;14 of the <span class="elsevierStyleItalic">RET</span> gene&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Patients with apparently sporadic Pheo</span><p id="para70" class="elsevierStylePara elsevierViewall">The study included 48 unrelated patients with histologically confirmed sporadic adrenal pheochromocytomas evaluated consecutively at the 2nd Department of Medicine&#44; Faculty of Medicine&#44; Semmelweis University between 1998 and 2010&#46; There were 16 men &#40;age&#44; mean &#177; SD&#44; 36&#177;14&#59; range&#58; 13&#8211;66 years&#41; and 32 women &#40;age&#44; mean &#177; S&#46;D&#44; 42&#177;14&#59; range&#58; 19&#8211;64 years&#41;&#46; Pre-operative evaluation included medical history&#44; physical examination&#44; abdominal ultrasonography&#44; CT or MRI&#44; MIBG-scintigraphy&#44; routine biochemical testing&#44; and 24 h urinary catecholamine metabolite determination&#46; The mutation analysis of <span class="elsevierStyleItalic">RET</span> exons 10&#8211;14 and the entire <span class="elsevierStyleItalic">VHL</span>&#44; <span class="elsevierStyleItalic">SDHB&#44;</span> and <span class="elsevierStyleItalic">SDHD</span> genes revealed no disease-causing mutations&#46; Patients with confirmed <span class="elsevierStyleItalic">VHL</span> &#40;five patients&#41;&#44; <span class="elsevierStyleItalic">SDHB</span> &#40;one patient&#41;&#44; or <span class="elsevierStyleItalic">SDHD</span> &#40;one patient&#41; mutations were excluded from the study&#46; Five patients were initially thought to have sporadic pheochromocytoma&#44; but were later identified as having a disease-causing <span class="elsevierStyleItalic">RET</span> mutation and were included in the study as <span class="elsevierStyleItalic">RET</span> mutation carriers&#46; MTC&#44; either by elevated serum calcitonin or by postoperative histology&#44; had been diagnosed in all of these patients&#46; Genetic counseling and genetic screening for all first-degree relatives have been offered&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Germline mutation screening of the RET&#44; <span class="elsevierStyleItalic">VHL&#44; SDHB&#44;</span> and <span class="elsevierStyleItalic">SDHD</span> genes</span><p id="para80" class="elsevierStylePara elsevierViewall">Genomic DNA was isolated from peripheral blood using the Roche DNA Isolation Kit &#40;Roche Diagnostics GmbH&#44; Mannheim&#44; Germany&#41; and QIAamp DNA Blood Mini Kit &#40;Qiagen Inc&#46;&#44; Valencia&#44; CA&#44; USA&#41; in accordance with the manufacturers&#39; instructions&#46; <span class="elsevierStyleItalic">RET</span> proto-oncogene mutations were detected by direct sequencing as previously reported &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46; Mutation analysis of the <span class="elsevierStyleItalic">VHL&#44; SDHB&#44;</span> and <span class="elsevierStyleItalic">SDHD</span> genes in cases of apparently sporadic Pheo were performed by direct sequencing of the entire coding region of the <span class="elsevierStyleItalic">VHL&#44; SDHB&#44;</span> and <span class="elsevierStyleItalic">SDHD</span> genes&#44; as previously reported &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#44; and large deletion analysis of the <span class="elsevierStyleItalic">VHL&#44; SDHB&#44; SDHC&#44;</span> and <span class="elsevierStyleItalic">SDHD</span> genes performed using multiplex ligation probe amplification &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Restriction fragment length polymorphism &#40;RFLP&#41; analysis for identification the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene</span><p id="para90" class="elsevierStylePara elsevierViewall">The nucleotide change of G to A&#44; which corresponds to the G12S polymorphism&#44; results in the preservation of the <span class="elsevierStyleItalic">Ban</span>I restriction cleavage site&#46; Therefore&#44; digestion with the <span class="elsevierStyleItalic">Ban</span>I restriction enzyme &#40;New England BioLabs Inc&#46;&#44; Ipswich&#44; MA&#44; USA&#41; for 90 min at 37&#176;C was performed after polymerase chain reaction &#40;PCR&#41; amplification of exon 1 of the <span class="elsevierStyleItalic">SDHD</span> gene for genotyping of <span class="elsevierStyleItalic">RET</span> mutation carriers&#44; sporadic MTC patients&#44; and 100 controls &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46; Samples from patients with positive results were examined by direct DNA sequencing&#46; The results obtained with both methods were the same in all cases&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Statistical analysis</span><p id="para100" class="elsevierStylePara elsevierViewall">Baseline characteristics were compared using the chi-squared test or Fisher&#39;s exact test for qualitative variables&#44; and Student&#39;s t test or Mann-Whitney&#39;s U test for quantitative variables&#46; The statistical package SPSS 15&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; was used and <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">RESULTS AND DISCUSSION</span><p id="para110" class="elsevierStylePara elsevierViewall">Eight of the 55 patients with MEN2A &#40;15&#46;5&#37;&#41; had the G12S variant&#44; whereas it was absent in the MEN2B and FMTC groups&#46; No patient with sporadic MTC and&#47;or sporadic Pheo carried this variant&#46; Among the 100 population-based&#44; healthy control individuals&#44; only one individual carried this variant &#40;prevalence&#44; 1&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46; No association between the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene and the incidence of Pheo or hyperparathyroidism in <span class="elsevierStyleItalic">RET</span> mutation carriers was observed&#44; and the age of disease manifestation was similar in G12S carriers and in non-carriers &#40;43&#177;9 versus 40&#177;3 years in probands and 29&#46;6&#177;19&#46;3 versus 32&#46;5&#177;20&#46;5 years in non-carriers&#41;&#46; Among probands with <span class="elsevierStyleItalic">RET</span> mutations&#44; carriers of the G12S had higher serum calcitonin levels compared with those who did not carry the <span class="elsevierStyleItalic">SDHD</span> G12S variant &#40;6&#44;864&#177;11&#44;111 versus 1&#44;250&#177;932 pg&#47;ml&#41;&#44; but the difference was not significant&#46; Among family members with <span class="elsevierStyleItalic">RET</span> mutations&#44; serum calcitonin levels were similar in G12S carriers and non-carriers 436&#177;876 versus 393&#177;556 pg&#47;ml&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">The phenotypic heterogeneity seen in families with different <span class="elsevierStyleItalic">RET</span> mutations&#44; the variation of clinical course within families with the same <span class="elsevierStyleItalic">RET</span> mutation&#44; and the results from <span class="elsevierStyleItalic">RET</span> transgenic mouse models suggest a potential role of genetic components in phenotype modulation &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41;&#46; Polymorphisms of the <span class="elsevierStyleItalic">RET</span> gene have been analyzed as such genetic modifiers&#44; but the results from these studies are conflicting&#46; Robledo et al&#46; showed that two <span class="elsevierStyleItalic">RET</span> variants &#40;G691S and S904S&#41; may modify the age of onset of MTC in family members &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#59; and Tamanaha et al&#46; reported that two intronic polymorphisms of <span class="elsevierStyleItalic">RET</span> may modify the phenotype in a large family with G533C <span class="elsevierStyleItalic">RET</span> mutation &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#44; while Baumgartner-Parzer found that the L769L and the IVS14-24 may act as modifiers in some forms of hereditary and sporadic MTC &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; However&#44; Lesueur et al&#46; were unable to replicate this association in a large cohort of 384 members of MEN2 families from four different European populations&#46; This latter study showed that of the several polymorphisms of genes encoding the RET protein&#44; its co-receptors and ligands&#44; only the synonymous polymorphism A432A of the <span class="elsevierStyleItalic">RET</span> gene associated weakly with tumor spectra in patients with MEN2A &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; MEN2-related MTC <span class="elsevierStyleItalic">RET</span> variants have been analyzed as genetic susceptibility factors for the development of sporadic MTC&#58; polymorphisms located in coding regions of <span class="elsevierStyleItalic">RET&#44;</span> G691S&#44; L769L&#44; S836S&#44; and S904S have been shown to be over-represented in patients with sporadic MTC &#40;<a class="elsevierStyleCrossRefs" href="#bib21">21&#8211;23</a>&#41; compared with the general population&#44; but others were unable to confirm these associations &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">Germline mutations of <span class="elsevierStyleItalic">SDHx</span> genes encoding subunits of the mitochondrial complex II represent a genetic susceptibility for Pheo&#47;PGL&#46; These tumors are derived from cells of the neural crest&#44; similar to MTC&#46; <span class="elsevierStyleItalic">RET</span> mutations also cause Pheo&#44; again suggesting a link between the genetic background of Pheo and MTC&#46; Therefore&#44; it has been assumed that mutations of these genes may be involved in the pathogenesis of MTC&#46; Lima et al&#46; reported a family with C-cell hyperplasia&#44; a pre-cancerous state of MTC&#44; who were proved to have the H50R variant of the <span class="elsevierStyleItalic">SDHD</span> gene &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; Montani et al&#46; demonstrated an increased frequency of amino acid-coding <span class="elsevierStyleItalic">SDHx</span> polymorphisms in patients with sporadic and familial MTC &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; In addition&#44; a systemic evaluation of genetic variants of the <span class="elsevierStyleItalic">SDHx</span> genes among patients with sporadic MTC showed a significant association between the H50R variant and sporadic MTC in Spanish patients&#44; although this observation was absent in an English cohort &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; Variants of the <span class="elsevierStyleItalic">SDHx</span> genes have been implicated in the pathogenesis of various endocrine and non-endocrine tumors&#44; such as Merkel cell carcinoma&#44; carcinoid&#44; papillary thyroid cancer&#44; and renal cell cancer found in patients with Cowden-like syndrome &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">In the present study&#44; we found that the G12S variant was significantly over-represented among <span class="elsevierStyleItalic">RET</span> mutation carriers compared with sporadic MTC&#44; sporadic Pheo&#44; or control individuals&#46; In our study&#44; this variant occurred mainly in patients with MEN2A&#44; while Montani et al&#46; detected G12S in a patient with MEN2B harboring the M918T mutation of the <span class="elsevierStyleItalic">RET</span> gene &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Interestingly&#44; the prevalence of alterations of the <span class="elsevierStyleItalic">SDHx</span> genes in patients with <span class="elsevierStyleItalic">RET</span> mutations was similar in our study and the study of Montani et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">The prevalence of the G12S in the general population is between 2&#46;5&#37; and 5&#37; &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41; according to the Leiden Open Variation Database &#40;<a href="http://chromium.liacs.nl">http&#58;&#47;&#47;chromium&#46;liacs&#46;nl</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&#44; which is somewhat higher than in our control population &#40;1&#37;&#41;&#46; This difference may be due to differences in the selection criteria applied for controls&#46; Our control group were evaluated for endocrine dysfunction&#59; none of them had signs or symptoms characteristic of thyroid cancer or Pheo&#46; By contrast&#44; population-based controls&#44; frequently anonymous blood donors&#44; have never been tested for these rare conditions&#46; Alternatively&#44; the difference between the studies in prevalence of G12S can also be attributed to the ethnic background of the different populations tested&#46; Our patients and controls were of Hungarian origin&#44; representing an independent entity among Caucasian populations&#46; More importantly&#44; in our study&#44; the high incidence of the G12S variant among <span class="elsevierStyleItalic">RET</span> carriers&#44; especially in those with the MEN2A phenotype&#44; raised the possibility that this variant may have a role in the phenotypic modulation of the disease&#46; However&#44; we were unable to detect significant differences in the clinical presentation between G12S carriers and non-carriers&#46; Whether this failure was a result of the relatively small size of our patient cohorts remains to be further investigated&#46; Interestingly&#44; Waldmann et al&#46; reported an increased prevalence of intronic <span class="elsevierStyleItalic">SDHB</span> polymorphisms among patients with malignant Pheo compared with patients with benign tumors &#40;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#41;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">In conclusion&#44; we found a significantly higher prevalence of the G12S variant of the <span class="elsevierStyleItalic">SDHD</span> gene among germline <span class="elsevierStyleItalic">RET</span> mutation carriers presenting with MEN2A compared with the control group&#46; The high prevalence of the G12S variant in these patients supports its genetic modifier role&#44; but this proposal remains to be established&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:5 [
        0 => array:2 [
          "identificador" => "xpalclavsec1581208"
          "titulo" => "KEYWORDS"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "PATIENTS AND METHODS"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Patients with MEN2 syndrome"
            ]
            1 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "Patients with sporadic MTC"
            ]
            2 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "Patients with apparently sporadic Pheo"
            ]
            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Germline mutation screening of the RET&#44; VHL&#44; SDHB&#44; and SDHD genes"
            ]
            4 => array:2 [
              "identificador" => "cesec70"
              "titulo" => "Restriction fragment length polymorphism &#40;RFLP&#41; analysis for identification the G12S polymorphism of the SDHD gene"
            ]
            5 => array:2 [
              "identificador" => "cesec80"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec90"
          "titulo" => "RESULTS AND DISCUSSION"
        ]
        4 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1581208"
          "palabras" => array:4 [
            0 => "<span class="elsevierStyleItalic">RET</span> proto-oncogene"
            1 => "Succinate dehydrogenase subunit D"
            2 => "Medullary thyroid cancer"
            3 => "Pheochromocytoma"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2&#46; Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma&#47;pheochromocytoma syndrome&#46; Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the <span class="elsevierStyleItalic">rearranged during transfection</span> proto-oncogene&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 <span class="elsevierStyleItalic">rearranged during transfection</span> mutation carriers&#44; 47 patients with sporadic medullary thyroid cancer&#44; 48 patients with sporadic Pheo&#44; and 100 healthy individuals&#46; Exons 10&#8211;16 of the <span class="elsevierStyleItalic">rearranged during transfection</span> proto-oncogene were analyzed by direct DNA sequencing&#44; and all exons of the von Hippel-Lindau&#44; succinate dehydrogenase <span class="elsevierStyleItalic">B&#44;</span> and succinate dehydrogenase subunit <span class="elsevierStyleItalic">D</span> genes were tested by direct DNA sequencing and multiple ligation probe analysis&#46; The G12S polymorphism of the succinate dehydrogenase subunit <span class="elsevierStyleItalic">D</span> gene was determined by restriction fragment length polymorphism&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Of the 77 <span class="elsevierStyleItalic">rearranged during transfection</span> mutation carriers&#44; 55 from 16 families had multiple endocrine neoplasia type 2A&#44; three from three families had multiple endocrine neoplasia type 2B&#44; and 19 from two families had familial medullary thyroid carcinoma&#46; Eight of 55 &#40;14&#46;5&#37;&#41; patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B&#44; familial medullary thyroid carcinoma&#44; sporadic medullary thyroid carcinoma&#44; and sporadic pheochromocytoma groups&#44; and its prevalence in controls was 1&#37; &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;002 multiple endocrine neoplasia type 2A versus controls&#41;&#46; No associations between G12S and age of manifestation&#44; incidence of pheochromocytoma or hyperparathyroidism&#44; or level of serum calcitonin were observed&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier&#44; but this proposal remains to be established&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "ceabs10"
            "titulo" => "OBJECTIVE&#58;"
          ]
          1 => array:2 [
            "identificador" => "ceabs20"
            "titulo" => "METHODS&#58;"
          ]
          2 => array:2 [
            "identificador" => "ceabs30"
            "titulo" => "RESULTS&#58;"
          ]
          3 => array:2 [
            "identificador" => "ceabs40"
            "titulo" => "CONCLUSION&#58;"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">No potential conflict of interest was reported&#46;</p> <p class="elsevierStyleNotepara" id="cenpara30">Pat&#243;cs A was responsible for the statistical analysis and study design&#44; molecular biological analysis&#44; evaluation and collection of clinical data&#44; genetic counseling&#44; and manuscript writing and critical review&#46; Lendvai N has contributed to the statistical analysis and study design&#44; molecular biological analysis&#44; and manuscript writing and critical review&#46; Kov&#225;cs B and Kriszt B have contributed to the molecular biological analysis and to the manuscript writing and critical review&#46; T&#243;th M&#44; Sz&#252;cs N&#44; Csajb&#243;k &#201; and R&#225;cz K have contributed to the evaluation and collection of clinical data and to the manuscript writing and critical review&#46; Igaz P has contributed to the evaluation and collection of clinical data&#44; genetic counseling&#44; and manuscript writing and critical review&#46; Bek&#337; G was responsible for the measurement of serum calcitonin levels and to the manuscript writing and critical review&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 178
            "Ancho" => 465
            "Tamanyo" => 15377
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Gel electrophoresis of PCR fragments after digestion with <span class="elsevierStyleItalic">Ban</span>I for identification of the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene by RFLP &#40;L &#61; DNA ladder&#59; C&#43; &#61; positive control&#59; heterozygote for G12S&#59; C- &#61; negative control&#59; G12 normal&#44; P1&#8211;P5 &#61; patients&#46; &#40;B&#41; Chromatograms of exon 1 of the <span class="elsevierStyleItalic">SDHD</span> gene showing the wild type and the heterozygote form of the G12S &#40;GGT12AGT&#41; polymorphism&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">FMTC &#61; familiar medullary thyroid cancer&#59; MEN2A &#61; multiple endocrine neoplasia type 2A&#59; MEN2B &#61; multiple endocrine neoplasia type 2B&#59; MTC &#61; medullary thyroid cancer&#59; Pheo &#61; pheochromocytoma&#46;</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="top" scope="col">MEN2A&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="center" valign="top" scope="col">FMTC&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="center" valign="top" scope="col">MEN2B&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="center" valign="top" scope="col">Spoaradic MTC&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="center" valign="top" scope="col">Spoaradic Pheo&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="center" valign="top" scope="col">Control&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="top">8&#47;55 &#40;15&#46;5&#37;&#41;<a class="elsevierStyleCrossRef" href="#tfn1">&#8727;</a>&#41;&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="center" valign="top">0&#47;19 &#40;0&#37;&#41;&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="center" valign="top">0&#47;3 &#40;0&#37;&#41;&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="center" valign="top">0&#47;47&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="center" valign="top">0&#47;48&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="center" valign="top">1&#47;100 &#40;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tfn1"
              "etiqueta" => "&#8727;"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara10"><span class="elsevierStyleItalic">p</span>&#60;0&#46;002 versus control group&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Prevalence of the G12S polymorphism of the <span class="elsevierStyleItalic">SDHD</span> gene among germline <span class="elsevierStyleItalic">RET</span> mutation carriers&#44; patients with sporadic medullary thyroid cancer&#44; patients with sporadic pheochromocytomas&#44; and healthy controls&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">SD &#61; standard deviation&#59; MEN2A &#61; multiple endocrine neoplasia type 2A&#59; MTC &#61; medullary thyroid cancer&#59; Pheo &#61; pheochromocytoma&#59; PHPT &#61; primary hyperparathyroidism&#46;</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="top" scope="col">MEN2A &#40;n &#61; 55&#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="center" valign="top" scope="col">G12S negative&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="center" valign="top" scope="col">G12S positive&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="top"><span class="elsevierStyleBold">Probands &#40;n &#61; 16&#41;</span>&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="center" valign="top">n &#61; 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="center" valign="top">n &#61; 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="left" valign="top">Age of presentation &#40;years&#41;&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="center" valign="top">40&#46;1&#177;9&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="center" valign="top">43&#177;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="left" valign="top">Prevalence of&#58;&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="top">MTC&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="center" valign="top">12&#47;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="center" valign="top">3&#47;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="left" valign="top">Pheo&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="center" valign="top">6&#47;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="center" valign="top">2&#47;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="left" valign="top">PHPT&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="center" valign="top">4&#47;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="center" valign="top">1&#47;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="left" valign="top">Serum calcitonin&#59; mean &#177; SD &#40;range&#41;&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="center" valign="top">1&#44;206&#177;932 &#40;13&#8211;2400&#41;&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="center" valign="top">6&#44;864&#177;11&#44;111 &#40;124&#8211;19&#44;690&#41;&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="top"><span class="elsevierStyleBold">Affected family members &#40;n &#61; 39&#41;</span>&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="center" valign="top">n &#61; 34&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="center" valign="top">n &#61; 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="left" valign="top">Age of presentation&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="center" valign="top">32&#46;5&#177;19&#46;3&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="center" valign="top">29&#46;6&#177;20&#46;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="left" valign="top">Prevalence of&#58;&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="top">MTC&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="center" valign="top">22&#47;34&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="center" valign="top">3&#47;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="left" valign="top">Pheo&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="center" valign="top">8&#47;34&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="center" valign="top">2&#47;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="left" valign="top">PHPT&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="center" valign="top">4&#47;34&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="center" valign="top">1&#47;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="left" valign="top">Serum calcitonin mean &#177; SD &#40;range&#41;&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="center" valign="top">393&#46;8&#177;556 &#40;0&#8211;1978&#41;&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="center" valign="top">436&#46;2&#177;876 &#40;0&#8211;2000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Clinical presentation&#44; serum calcitonin concentration and the G12S status of patients with MEN2A&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:29 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "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:7 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1993"
                        "volumen" => "363"
                        "numero" => "6428"
                        "paginaInicial" => "458"
                        "paginaFinal" => "460"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8099202"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2&#46; International RET mutation consortium analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              C Eng \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              D Clayton \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              I Schuffenecker \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              G Lenoir \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              G Cote \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              RF Gagel \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1996"
                        "volumen" => "276"
                        "numero" => "19"
                        "paginaInicial" => "1575"
                        "paginaFinal" => "1579"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8918855"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene"
                      "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 => """
                              T Attie \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              S Lyonnet \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              DJ Marsh \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              VJ Hyland \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/hmg/3.12.2163"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hum Mol Genet"
                        "fecha" => "1996"
                        "volumen" => "3"
                        "numero" => "12"
                        "paginaInicial" => "2163"
                        "paginaFinal" => "2167"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7881414"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              S Borrego \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              ME Saez \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Ruiz \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              O Gimm \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M L&#243;pez-Alonso \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              G Anti&#241;olo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jmg.36.10.771"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Med Genet"
                        "fecha" => "1999"
                        "volumen" => "36"
                        "numero" => "10"
                        "paginaInicial" => "771"
                        "paginaFinal" => "774"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10528857"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms G691S&#47;S904S of RET as genetic modifiers of MEN 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              M Robledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              L Gil \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Pollan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Cebri&#225;n \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              S Ru&#237;z \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              M Aza&#241;edo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "2003"
                        "volumen" => "63"
                        "numero" => "8"
                        "paginaInicial" => "1814"
                        "paginaFinal" => "1817"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12702567"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              F Lesueur \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Cebrian \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Robledo \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              P Niccoli-Sire \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              KA Svensson \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              S Pinson \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/0008-5472.CAN-05-2995"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "2006"
                        "volumen" => "66"
                        "numero" => "2"
                        "paginaInicial" => "1177"
                        "paginaFinal" => "1180"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16424056"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation&#58; specific RET variants may modulate age at onset and clinical presentation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              R Tamanaha \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CP Camacho \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AC Pereira \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              AM da Silva \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              RM Maciel \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" => "10.1111/j.1365-2265.2008.03491.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
                        "fecha" => "2009"
                        "volumen" => "71"
                        "numero" => "1"
                        "paginaInicial" => "56"
                        "paginaFinal" => "64"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19138318"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              D Astuti \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              F Latif \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Dallol \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              F Douglas \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              E George \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/321282"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Hum Genet"
                        "fecha" => "2001"
                        "volumen" => "69"
                        "numero" => "2"
                        "paginaInicial" => "49"
                        "paginaFinal" => "54"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11404820"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in SDHC cause autosomal dominant paraganglioma&#44; type 3"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              S Niemann \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              U Muller \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Genet"
                        "fecha" => "2000"
                        "volumen" => "26"
                        "numero" => "3"
                        "paginaInicial" => "70"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in SDHD&#44; a mitochondrial complex II gene&#44; in hereditary paraganglioma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              BE Baysal \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              RE Ferrell \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JE Willett-Brozick \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              EC Lawrence \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              D Myssiorek \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              A Bosch \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.287.5454.848"
                      "Revista" => array:7 [
                        "tituloSerie" => "Science"
                        "fecha" => "2000"
                        "volumen" => "287"
                        "numero" => "2"
                        "paginaInicial" => "848"
                        "paginaFinal" => "851"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10657297"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">SDH5</span>&#44; a gene required for flavination of succinate dehydrogenase&#44; is mutated in paraganglioma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              HX Hao \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              O Khalimonchuk \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Schraders \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              N Dephoure \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              JP Bayley \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              H Kunst \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.1175689"
                      "Revista" => array:7 [
                        "tituloSerie" => "Science"
                        "fecha" => "2009"
                        "volumen" => "325"
                        "numero" => "17"
                        "paginaInicial" => "1139"
                        "paginaFinal" => "1142"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19628817"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of the human SDHD gene encoding the small subunit of cytochrome b &#40;cybS&#41; in mitochondrial succinate&#8211;ubiquinone oxidoreductase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              H Hirawake \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              M Taniwaki \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Tamura \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              H Amino \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              E Tomitsuka \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              K Kita \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0005-2728(99)00071-7"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "1999"
                        "volumen" => "1412"
                        "numero" => "3"
                        "paginaInicial" => "295"
                        "paginaFinal" => "300"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10482792"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              M Montani \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AM Schmitt \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              S Schmid \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              T Locher \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              P Saremaslani \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              PU Heitz \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1677/erc.1.00996"
                      "Revista" => array:7 [
                        "tituloSerie" => "Endocr Relat Cancer"
                        "fecha" => "2005"
                        "volumen" => "12"
                        "numero" => "4"
                        "paginaInicial" => "1011"
                        "paginaFinal" => "1016"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16322339"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              Y Ni \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              KM Zbuk \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              T Sadler \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Patocs \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              G Lobo \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              E Edelman \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ajhg.2008.07.011"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Hum Genet"
                        "fecha" => "2008"
                        "volumen" => "83"
                        "numero" => "2"
                        "paginaInicial" => "261"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18678321"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              J Lima \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J Teixeira-Gomes \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              P Soares \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              V Maximo \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M Honavar \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              D Williams \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2002-030008"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "numero" => "10"
                        "paginaInicial" => "4932"
                        "paginaFinal" => "4937"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14557476"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Pat&#243;cs \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              Z Valkusz \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              P Igaz \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              K Balogh \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M T&#243;th \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              I Varga \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1034/j.1399-0004.2003.00044.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Genet"
                        "fecha" => "2003"
                        "volumen" => "63"
                        "numero" => "3"
                        "paginaInicial" => "219"
                        "paginaFinal" => "223"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12694233"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and biochemical features of sporadic and hereditary phaeochromocytomas&#58; an analysis of 41 cases investigated in a single endocrine centre"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Pat&#243;cs \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Kar&#225;di \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M T&#243;th \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              I Varga \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              N Sz&#252;cs \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              K Balogh \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/00008469-200410000-00008"
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur J Cancer Prev"
                        "fecha" => "2004"
                        "volumen" => "13"
                        "numero" => "5"
                        "paginaInicial" => "403"
                        "paginaFinal" => "409"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15452453"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              P Gergics \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Patocs \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Toth \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              P Igaz \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              N Szucs \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              I Liko \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/EJE-09-0399"
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "2009"
                        "volumen" => "161"
                        "numero" => "3"
                        "paginaInicial" => "495"
                        "paginaFinal" => "502"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19574279"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "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 => """
                              BA Ponder \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "2003"
                        "volumen" => "63"
                        "numero" => "16"
                        "paginaInicial" => "4777"
                        "paginaFinal" => "4780"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12941793"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in exon 13 and intron 14 of the RET protooncogene&#58; genetic modifiers of medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              SM Baumgartner-Parzer \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              R Lang \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              L Wagner \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              G Heinze \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              B Niederle \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              K Kaserer \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2005-1278"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2005"
                        "volumen" => "90"
                        "numero" => "11"
                        "paginaInicial" => "6232"
                        "paginaFinal" => "6236"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16118333"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "RET exon 11 &#40;G691S&#41; polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              R Elisei \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              B Cosci \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              C Romei \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              V Bottici \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              M Sculli \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              R Lari \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2003-031898"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2004"
                        "volumen" => "89"
                        "numero" => "7"
                        "paginaInicial" => "3579"
                        "paginaFinal" => "3584"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15240649"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET 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 => """
                              DS Neuberg \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              DJ Marsh \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              PL Dahia \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Hoang-Vu \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              F Raue \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Oncogene"
                        "fecha" => "1999"
                        "volumen" => "18"
                        "numero" => "6"
                        "paginaInicial" => "23"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in the initiators of RET &#40;rearranged during transfection&#41; signaling pathway and susceptibility to sporadic medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Cebrian \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              F Lesueur \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              S Martin \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              J Leyland \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              S Ahmed \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              C Luccarini \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2004-2449"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2005"
                        "volumen" => "90"
                        "numero" => "11"
                        "paginaInicial" => "6268"
                        "paginaFinal" => "6274"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16091499"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Germline-sequence variants S836S and L769L in the RE arranged during Transfection &#40;RET&#41; proto-oncogene are not associated with predisposition to sporadic medullary carcinoma in the French population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              I Berard \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JL Kraimps \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              F Savagner \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Murat \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              K Renaudin \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              P Nicolli-Sire \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.0009-9163.2004.00172.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Genet"
                        "fecha" => "2004"
                        "volumen" => "65"
                        "numero" => "2"
                        "paginaInicial" => "150"
                        "paginaFinal" => "152"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14984475"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "G691S&#44; L769L and S836S ret proto-oncogene polymorphisms are not associated with higher risk to sporadic medullary thyroid carcinoma in Chilean patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              GN Wohllk \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CE Soto \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AM Bravo \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CP Becker \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Med Chil"
                        "fecha" => "2005"
                        "volumen" => "133"
                        "numero" => "4"
                        "paginaInicial" => "402"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Succinate dehydrogenase D variants do not constitute a risk factor for developing C cell hyperplasia or sporadic medullary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Cascon \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Cebrian \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Pollan \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              S Ruiz-Llorente \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Montero-Conde \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              R Leton \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2005"
                        "volumen" => "90"
                        "numero" => "4"
                        "paginaInicial" => "30"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "G12S and H50R variations are polymorphisms in the SDHD gene"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Cascon \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              S Ruiz-Llorente \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Cebrian \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              R Leton \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              D Telleria \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              J Benitez \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/gcc.10212"
                      "Revista" => array:8 [
                        "tituloSerie" => "Genes Chromosomes Cancer"
                        "fecha" => "2003"
                        "volumen" => "37"
                        "numero" => "2"
                        "paginaInicial" => "220"
                        "paginaFinal" => "221"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12696072"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S014067361830984X"
                          "estado" => "S300"
                          "issn" => "01406736"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              PE Taschner \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JC Jansen \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              BE Baysal \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Bosch \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              EH Rosenberg \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              AH Br&#246;cker-Vriends \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/gcc.1144"
                      "Revista" => array:7 [
                        "tituloSerie" => "Genes Chromosomes Cancer"
                        "fecha" => "2001"
                        "volumen" => "31"
                        "numero" => "3"
                        "paginaInicial" => "274"
                        "paginaFinal" => "281"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11391798"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations and polymorphisms in the SDHB&#44; SDHD&#44; VHL&#44; and RET genes in sporadic and familial pheochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              J Waldmann \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              P Langer \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              N Habbe \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              V Fendrich \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              A Ramaswamy \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              M Rothmund \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12020-009-9178-y"
                      "Revista" => array:7 [
                        "tituloSerie" => "Endocrine"
                        "fecha" => "2009"
                        "volumen" => "35"
                        "numero" => "3"
                        "paginaInicial" => "347"
                        "paginaFinal" => "355"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19399650"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222024012/v1_202212010649/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/18075932/00000067000000S1/v1_202212010649/S1807593222024012/v1_202212010649/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222024012?idApp=UINPBA00004N"
]

Article information

ISSN: 18075932
Original language: English

DOI:10.6061/clinics/2012(Sup01)15

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	2	6
2024 October	23	22	45
2024 September	29	19	48
2024 August	43	25	68
2024 July	31	17	48
2024 June	36	7	43
2024 May	13	9	22
2024 April	15	21	36
2024 March	37	14	51
2024 February	40	21	61
2024 January	10	13	23
2023 December	14	18	32
2023 November	16	23	39
2023 October	16	37	53
2023 September	16	27	43
2023 August	7	8	15
2023 July	13	20	33
2023 June	12	9	21
2023 May	5	4	9
2023 April	2	0	2
2023 February	0	1	1
2023 January	2	1	3

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter