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(A) The pedigrees of proband 1. (B) Photograph and X-ray image of proband 1. Photograph showed massive swelling of left ankle and right knee. X-ray image exhibited osteophytes (bone spurs), overwhelming production of callus and subluxation of the right knee joint. (C) The pedigrees of proband 2. (D) Photograph of proband 2. The photograph showed repeated cracking, infection and shortened fingers resulting from self-mutilating behaviors. (E, F) Sequence electropherograms of the <span class="elsevierStyleItalic">NTRK1</span> mutations identified in probands. (G, H) The corresponding structure of the <span class="elsevierStyleItalic">NTRK1</span> gene and TrkA protein, with the <span class="elsevierStyleItalic">NTRK1</span> mutations reported in this study. 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"documento" => "simple-article" "crossmark" => 1 "subdocumento" => "cor" "cita" => "Med Clin. 2021;157:454-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Miliary tuberculosis complicated with acute respiratory distress syndrome and hemophagocytic lymphohistiocytosis syndrome in an immunocompetent patient" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "454" "paginaFinal" => "455" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tuberculosis miliar complicada con síndrome de distrés respiratorio y linfohistiocitosis hemofagocítica en un paciente inmunocompetente" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Antonio Rosales-Castillo, Miguel Ángel López-Ruz" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Antonio" "apellidos" => "Rosales-Castillo" ] 1 => array:2 [ "nombre" => "Miguel Ángel" "apellidos" => "López-Ruz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S002577532030734X" "doi" => "10.1016/j.medcli.2020.09.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577532030734X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621005349?idApp=UINPBA00004N" "url" => "/23870206/0000015700000009/v1_202111060623/S2387020621005349/v1_202111060623/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020621005350" "issn" => "23870206" "doi" => "10.1016/j.medcle.2020.09.017" "estado" => "S300" "fechaPublicacion" => "2021-11-12" "aid" => "5464" "copyright" => "Elsevier España, S.L.U." 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array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Congenital insensitivity to pain with anhidrosis: A report of two unrelated Chinese families with novel mutations in <span class="elsevierStyleItalic">NTRK1</span> gene" "tieneTextoCompleto" => true "saludo" => "Dear Editor:" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "451" "paginaFinal" => "453" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Yujue Li, Xueyang Tang, Xijie Yu" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Yujue" "apellidos" => "Li" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Xueyang" "apellidos" => "Tang" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] 2 => array:4 [ "nombre" => "Xijie" "apellidos" => "Yu" "email" => array:1 [ 0 => "xijieyu@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of General Practice, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Insensibilidad congénita al dolor con anhidrosis: Estudio de dos familias chinas no relacionadas con nuevas mutaciones en el gen <span class="elsevierStyleItalic">NTRK1</span>" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2054 "Ancho" => 2917 "Tamanyo" => 456525 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The pedigrees, clinical manifestations and <span class="elsevierStyleItalic">NTRK1</span> mutation analysis of the two probands. (A) The pedigrees of proband 1. (B) Photograph and X-ray image of proband 1. Photograph showed massive swelling of left ankle and right knee. X-ray image exhibited osteophytes (bone spurs), overwhelming production of callus and subluxation of the right knee joint. (C) The pedigrees of proband 2. (D) Photograph of proband 2. The photograph showed repeated cracking, infection and shortened fingers resulting from self-mutilating behaviors. (E, F) Sequence electropherograms of the <span class="elsevierStyleItalic">NTRK1</span> mutations identified in probands. (G, H) The corresponding structure of the <span class="elsevierStyleItalic">NTRK1</span> gene and TrkA protein, with the <span class="elsevierStyleItalic">NTRK1</span> mutations reported in this study. Schematic illustrated 17 exons of <span class="elsevierStyleItalic">NTRK1</span> gene, various structural domains of the TrkA protein, and the location of the 3 mutations.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800) or hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is an extremely rare disorder first described by Swanston in 1963.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> It belongs to a group of rare autosomal recessive peripheral sensory neuropathies and characterized by episodes of unexplained fever, anhidrosis, loss of pain sensation, self-mutilating behavior, bone fractures, and moderate to severe intellectual disability, but touch and pressure sensitivity are unimpaired.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Biallelic mutations of the neurotrophic receptor tyrosine kinase 1 (<span class="elsevierStyleItalic">NTRK1</span>) lead to CIPA. NTRK1, also known as tropomyosin-related kinase A (TrkA), is a high-affinity receptor for nerve growth factor (NGF), contributing to the development and differentiation of sympathetic and sensory neurons.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">NTRK1</span> (MIM #191315) gene, the only recognized causative gene of CIPA, in the 1q21-q22 chromosome region contains 17 exons and 16 introns, which encodes 796 amino acids.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Due to the recessive mode of inheritance, the pathogenic genes of CIPA patients are all homozygous or compound heterozygous. To date, over 110 mutations associated with CIPA according to Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/) have been reported in patients and families with CIPA. These mutations, including missense or nonsense mutations, spliced site mutations, deletions or insertions, affect the domains of extracellular binding site and the intracellular signal transduction, causing abnormal function of the TrkA protein.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In this study, we described the clinical and genetic findings of two Han boys with CIPA in two unrelated Chinese families. We identified 3 different <span class="elsevierStyleItalic">NTRK1</span> mutations (c.851-33T>A, c.1354+1G>T and c.7C>T), and two of them (c.1354+1G>T and c.7C>T) had not been reported previously. The identification of the novel mutations of <span class="elsevierStyleItalic">NTRK1</span> gene suggests that the advent of high throughput next-generation sequencing (NGS) has accelerated the identification of new genetic causative variations.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case report</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Family 1</span><p id="par0020" class="elsevierStylePara elsevierViewall">Proband 1, a 13-year-old boy, was the second child in family 1 and born after 36 weeks of gestation with a birth weight of 2750<span class="elsevierStyleHsp" style=""></span>g (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). As the first symptom of CIPA, the boy developed recurrent episodes of fever with unknown causes at about one year old. The boy was insensitive to pain and accompanied with anhidrosis. The boy presented with recurrent, painless bone fractures and chronic ankle swelling since the age of 5 years. He underwent surgery for fracture of the right radius at about 5 years old, but the fracture healing was delayed. He suffered from recurrent chronic ankle swelling of left knee joint, left ankle joint and right knee joint without any known traumas after 6 years old, and was diagnosed with Charcot's arthritis. His parents were non-consanguineous, and neither of his parents nor his elder sister showed any symptoms.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Physical examination revealed severe trophic changes (dryness, hyperkeratosis and fissuring) in the skin of distal limbs. His right forearm was deformed due to malunion of fracture. He presented with tumorous swellings of the right knee and left ankle, and restricted articular movement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Except for insensitive to pain and temperature, his sensations of touch, vibration and joint position were normal. Radiographs of his upper and lower extremities showed multiple healed fractures, dislocation of joints and arthritis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Fortunately, he did not show obvious symptoms of self-mutilation, mental retardation or delayed development. His grades were average in the class. Tumorlike swellings of multiple joints and bone signs of Charcot neuropathy were developed in adolescence, together with a history of recurrent painless bone fractures and fever with anhidrosis, led to a clinical suspicion of CIPA.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Family 2</span><p id="par0030" class="elsevierStylePara elsevierViewall">Proband 2, a 11-year-old boy, was the second child in family 2 and born at full-term with unclear birth weight and body length (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C). He presented with recurrent episodes of unexplained fever within the first year after birth. He was prone to catch a fever in high temperature condition, so he avoided going out in hot summer. At the age of about 3 years, he began to chew his fingers and bit off the tip of his tongue (self-mutilation). He presented with insensitivity to painful stimuli, which was similar to his elder brother. In addition, he presented with recurrent fractures, joint dislocation and arthritis. After a slight fall at the age of 9 years, he had a fracture of his left femur with a delayed fracture healing. His parents were non-consanguineous. His mother was healthy, while his father died in a traffic accident.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Clinically, his skin was thickened and dry, and he was insensitive to pain with impaired sensations of pinprick and temperature. The self-mutilating behaviors were identified by the damage to the fingertips after repeated finger biting (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D). A skeletal survey displayed severe anomalies of bilateral hip joints with subluxated joints, destroyed articular surfaces and a mixture of sclerosis, massive osteophytosis and bone fragmentation. The patient had no mental retardation or development delay. Based on these findings CIPA was diagnosed.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Mutation analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">According to the analysis of NGS, proband 1 had compound heterozygous <span class="elsevierStyleItalic">NTRK1</span> mutations (c.851-33T>A and c.1354+1G>T), while his parents were carriers of one heterozygous mutation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E). The elder sister of proband 1 neither carried any mutated genes nor had the performance of CIPA. Proband 2 was also heterozygous for the <span class="elsevierStyleItalic">NTRK1</span> mutations [c.851-33T>A and c.7C>T (p.R3*,794)] inherited from her carrier parents. The elder brother of proband 2 carried same mutated genes and had the similar symptoms of CIPA. A total of three mutations in <span class="elsevierStyleItalic">NTRK1</span> gene were confirmed in these two families, including c.7C>T (p.R3*,794) nonsense mutation in exon 1, c.851-33T>A splice mutation in intron 7 and c.1354+1G>T splice mutation in intron 11. Two of them were novel mutations [c.7C>T (p.R3*,794) and c.1354+1G>T].</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">The initial symptom of the two probands was unexplained recurrent fever with anhidrosis. The skeletal disorders occurred during childhood, including recurrent fractures, joint dislocations and osteoarthritis. Progressive joint destruction with massive formation of callus and bone spurs (osteophytosis) was developed in adolescence. The two probands with CIPA carried <span class="elsevierStyleItalic">NTRK1</span> gene mutations (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>G). A compound heterozygote of a reported c.851-33T>A splice mutation in intron 7 and a novel c.1354+1 G>T splice mutation in intron 11 of <span class="elsevierStyleItalic">NTRK1</span> gene was found by NGS analysis in proband 1 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E). Proband 2 was also caused by a compound heterozygote with the same c.851-33T>A mutation and a novel c.7C>T (p.R3*,794) nonsense mutation in exon 1 of <span class="elsevierStyleItalic">NTRK1</span> gene (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>F).</p><p id="par0050" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">NTRK1</span> gene, encoding TrkA protein, was originally discovered as an oncogene and isolated from human colon carcinoma cells in 1986.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> As a transmembrane signal-transducing protein, the TrkA protein is divided into three parts: the extracellular binding region, the nonspecific transmembrane region and the intracellular activating region (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>H). The TrkA protein binds to NGF and activates intracellular signal transduction pathways.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> The NGF-TrkA system regulates the growth and development of peripheral and central neurons, maintains the survival of neurons. In addition, autonomic sympathetic postganglionic neurons responsible for the processes of sweating, pain, inflammation and itch are also regulated by NGF. The mutations of <span class="elsevierStyleItalic">NTRK1</span> impair the structure and/or expression of TrkA protein and affect the signal transduction of NGF, thereby promoting the apoptosis of nerve axon and restraining the development of sensory neurons. The c.851-33C>T mutation was common in patients without mental retardation, so this mutation might be a “mild” mutation of CIPA.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> The c.1354+1 G>T mutation and c.7C>T mutation have not been reported in the literatures nor in the HGMD. The c.1354+1 G>T mutation is a kind of classical splice mutation, which leads to abnormal cut and splicing of mRNA during transcription process and the production of mutant TrkA protein. The c.7C>T mutation generates a premature stop codon in exon 1 of <span class="elsevierStyleItalic">NTRK1</span> gene and leads to a null (non-sense) allele.</p><p id="par0055" class="elsevierStylePara elsevierViewall">There is no effective treatment for patients with CIPA, and it requires a multidisciplinary approach. Temperature control is important in newborns with CIPA and physical cooling should be taken in time in cases of high fever. The common complications of CIPA are bone disorders, including recurrent fractures, arthritis, and joint dislocation. Therapeutic approaches of fractures are conservative treatment of closed reduction and cast immobilization, and even surgical repair. It is necessary to educate the parents to protect the patient from repeated and unperceived minor traumas. In addition, clinicians need to increase the understanding of CIPA to diagnose and treat the disease earlier, thereby improving the rate of survival and quality of life of the patients. The identification of <span class="elsevierStyleItalic">NTRK1</span> mutations is significant and helpful for genetic counseling, prenatal diagnosis and treatment of the disease. In addition, our study has impressed clinicians with features and pathogenesis of CIPA, which is conducive to early identification and diagnosis of patients with CIPA.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Funding</span><p id="par0060" class="elsevierStylePara elsevierViewall">This work was supported by grants from the <span class="elsevierStyleGrantSponsor" id="gs1">National Natural Science Foundation of China</span> (No. <span class="elsevierStyleGrantNumber" refid="gs1">81770875</span>), the <span class="elsevierStyleGrantSponsor" id="gs2">Sichuan University</span> (No. <span class="elsevierStyleGrantNumber" refid="gs2">2018SCUH0093</span>), and the <span class="elsevierStyleGrantSponsor" id="gs3">1.3.5 Project for Disciplines of Excellence of West China Hospital</span> (No. <span class="elsevierStyleGrantNumber" refid="gs3">2020HXFH008</span>, <span class="elsevierStyleGrantNumber" refid="gs3">ZYJC18003</span>).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Case report" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Family 1" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Family 2" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Mutation analysis" ] ] ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 3 => array:2 [ "identificador" => "xack566054" "titulo" => "Acknowledgments" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">These authors contributed equally to this work.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2054 "Ancho" => 2917 "Tamanyo" => 456525 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The pedigrees, clinical manifestations and <span class="elsevierStyleItalic">NTRK1</span> mutation analysis of the two probands. (A) The pedigrees of proband 1. (B) Photograph and X-ray image of proband 1. Photograph showed massive swelling of left ankle and right knee. X-ray image exhibited osteophytes (bone spurs), overwhelming production of callus and subluxation of the right knee joint. (C) The pedigrees of proband 2. (D) Photograph of proband 2. The photograph showed repeated cracking, infection and shortened fingers resulting from self-mutilating behaviors. (E, F) Sequence electropherograms of the <span class="elsevierStyleItalic">NTRK1</span> mutations identified in probands. (G, H) The corresponding structure of the <span class="elsevierStyleItalic">NTRK1</span> gene and TrkA protein, with the <span class="elsevierStyleItalic">NTRK1</span> mutations reported in this study. Schematic illustrated 17 exons of <span class="elsevierStyleItalic">NTRK1</span> gene, various structural domains of the TrkA protein, and the location of the 3 mutations.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital insensitivity to pain with anhydrosis. A unique syndrome in two male siblings" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.G. Swanson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archneur.1963.00460030083008" "Revista" => array:6 [ "tituloSerie" => "Arch Neurol" "fecha" => "1963" "volumen" => "8" "paginaInicial" => "299" "paginaFinal" => "306" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13979626" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital insensitivity to pain with anhidrosis syndrome: a series from Jordan" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Masri" 1 => "M. Shboul" 2 => "A. Khasawneh" 3 => "R. Jadallah" 4 => "A. ALmustafa" 5 => "N. Escande-Beillard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.clineuro.2019.105636" "Revista" => array:6 [ "tituloSerie" => "Clin Neurol Neurosurg" "fecha" => "2020" "volumen" => "189" "paginaInicial" => "105636" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31841741" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S2352301819300347" "estado" => "S300" "issn" => "23523018" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of a novel mutation of the NTRK1 gene in patients with congenital insensitivity to pain with anhidrosis (CIPA)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "W.B. Wang" 1 => "Y.J. Cao" 2 => "S.S. Lyu" 3 => "R.T. Zuo" 4 => "Z.L. Zhang" 5 => "Q.L. Kang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.gene.2018.09.009" "Revista" => array:6 [ "tituloSerie" => "Gene" "fecha" => "2018" "volumen" => "679" "paginaInicial" => "253" "paginaFinal" => "259" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30201336" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.S. Nam" 1 => "W. Li" 2 => "S. Yoon" 3 => "G.H. Eom" 4 => "M.K. Kim" 5 => "S.T. Jung" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jns.12205" "Revista" => array:6 [ "tituloSerie" => "J Peripher Nerv Syst" "fecha" => "2017" "volumen" => "22" "paginaInicial" => "92" "paginaFinal" => "99" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28177573" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D. Martin-Zanca" 1 => "S.H. Hughes" 2 => "M. Barbacid" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/319743a0" "Revista" => array:7 [ "tituloSerie" => "Nature" "fecha" => "1986" "volumen" => "319" "paginaInicial" => "743" "paginaFinal" => "748" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2869410" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S2468125316301819" "estado" => "S300" "issn" => "24681253" ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack566054" "titulo" => "Acknowledgments" "texto" => "<p id="par0065" class="elsevierStylePara elsevierViewall">We thank the patients and their families for their participation in this study.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015700000009/v1_202111060623/S2387020621005507/v1_202111060623/en/main.assets" "Apartado" => array:4 [ "identificador" => "43311" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015700000009/v1_202111060623/S2387020621005507/v1_202111060623/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621005507?idApp=UINPBA00004N" ]
