metricas
covid
Buscar en
Clinics
Toda la web
Inicio Clinics Tegumentary manifestations of Noonan and Noonan-related syndromes
Journal Information

Statistics

Follow this link to access the full text of the article

CLINICAL SCIENCE
Tegumentary manifestations of Noonan and Noonan-related syndromes
Caio Robledo D'Angioli Costa QuaioI, Tatiana Ferreira de AlmeidaI, Amanda Salem BrasilI,II, Alexandre C. PereiraII, Alexander A.L. JorgeIII, Alexsandra C. MalaquiasIII, Chong Ae KimI, Débora Romeo BertolaI,
Corresponding author
debora.bertola@icr.usp.br

Tel.: 55 11 2661-8671
I Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Instituto da Criança, Genetics Unit, São Paulo/SP, Brazil
II Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Instituto do Coração (INCOR), São Paulo/SP, Brazil
III Faculdade de Medicina da Universidade de São Paulo, Discipline of Endocrinology, Genetics Unit, LIM/25, São Paulo/SP, Brazil
Read
1087
Times
was read the article
336
Total PDF
751
Total HTML
Share statistics
 array:24 [
  "pii" => "S1807593222016398"
  "issn" => "18075932"
  "doi" => "10.6061/clinics/2013(08)03"
  "estado" => "S300"
  "fechaPublicacion" => "2013-08-01"
  "aid" => "1639"
  "copyright" => "CLINICS"
  "copyrightAnyo" => "2013"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
  "subdocumento" => "fla"
  "cita" => "Clinics. 2013;68:1079-83"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1807593222016404"
    "issn" => "18075932"
    "doi" => "10.6061/clinics/2013(08)04"
    "estado" => "S300"
    "fechaPublicacion" => "2013-08-01"
    "aid" => "1640"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "fla"
    "cita" => "Clinics. 2013;68:1084-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">CLINICAL SCIENCE</span>"
      "titulo" => "The level of circulating endothelial progenitor cells may be associated with the occurrence and recurrence of chronic subdural hematoma"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "1084"
          "paginaFinal" => "1088"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Yan Song, Zhitao Wang, Li Liu, Dong Wang, Jianning Zhang"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "Yan"
              "apellidos" => "Song"
            ]
            1 => array:2 [
              "nombre" => "Zhitao"
              "apellidos" => "Wang"
            ]
            2 => array:2 [
              "nombre" => "Li"
              "apellidos" => "Liu"
            ]
            3 => array:2 [
              "nombre" => "Dong"
              "apellidos" => "Wang"
            ]
            4 => array:2 [
              "nombre" => "Jianning"
              "apellidos" => "Zhang"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222016404?idApp=UINPBA00004N"
    "url" => "/18075932/0000006800000008/v1_202212010718/S1807593222016404/v1_202212010718/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1807593222016386"
    "issn" => "18075932"
    "doi" => "10.6061/clinics/2013(08)02"
    "estado" => "S300"
    "fechaPublicacion" => "2013-08-01"
    "aid" => "1638"
    "copyright" => "CLINICS"
    "documento" => "simple-article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "edi"
    "cita" => "Clinics. 2013;68:1077-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:9 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">EDITORIAL</span>"
      "titulo" => "Electronic health records&#58; beyond the digitization of medical files"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "1077"
          "paginaFinal" => "1078"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Sigfrido Burgos C&#225;ceres"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "Sigfrido Burgos"
              "apellidos" => "C&#225;ceres"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222016386?idApp=UINPBA00004N"
    "url" => "/18075932/0000006800000008/v1_202212010718/S1807593222016386/v1_202212010718/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">CLINICAL SCIENCE</span>"
    "titulo" => "Tegumentary manifestations of Noonan and Noonan-related syndromes"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "1079"
        "paginaFinal" => "1083"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Caio Robledo D&#39;Angioli Costa Quaio, Tatiana Ferreira de Almeida, Amanda Salem Brasil, Alexandre C&#46; Pereira, Alexander A&#46;L&#46; Jorge, Alexsandra C&#46; Malaquias, Chong Ae Kim, D&#233;bora Romeo Bertola"
        "autores" => array:8 [
          0 => array:3 [
            "nombre" => "Caio Robledo D&#39;Angioli Costa"
            "apellidos" => "Quaio"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Tatiana Ferreira"
            "apellidos" => "de Almeida"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Amanda Salem"
            "apellidos" => "Brasil"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "aff2"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Alexandre C&#46;"
            "apellidos" => "Pereira"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "aff2"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Alexander A&#46;L&#46;"
            "apellidos" => "Jorge"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">III</span>"
                "identificador" => "aff3"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Alexsandra C&#46;"
            "apellidos" => "Malaquias"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">III</span>"
                "identificador" => "aff3"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "Chong Ae"
            "apellidos" => "Kim"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          7 => array:4 [
            "nombre" => "D&#233;bora Romeo"
            "apellidos" => "Bertola"
            "email" => array:1 [
              0 => "debora.bertola@icr.usp.br"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "&#42;"
                "identificador" => "cor1"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo&#44; Instituto da Crian&#231;a&#44; Genetics Unit&#44; S&#227;o Paulo&#47;SP&#44; Brazil"
            "etiqueta" => "I"
            "identificador" => "aff1"
          ]
          1 => array:3 [
            "entidad" => "Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo&#44; Instituto do Cora&#231;&#227;o &#40;INCOR&#41;&#44; S&#227;o Paulo&#47;SP&#44; Brazil"
            "etiqueta" => "II"
            "identificador" => "aff2"
          ]
          2 => array:3 [
            "entidad" => "Faculdade de Medicina da Universidade de S&#227;o Paulo&#44; Discipline of Endocrinology&#44; Genetics Unit&#44; LIM&#47;25&#44; S&#227;o Paulo&#47;SP&#44; Brazil"
            "etiqueta" => "III"
            "identificador" => "aff3"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "&#42;"
            "correspondencia" => "Tel&#46;&#58; 55 11 2661-8671"
          ]
        ]
      ]
    ]
    "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" => 515
            "Ancho" => 777
            "Tamanyo" => 63094
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Mosaic showing several tegumentary findings of the patients reported in this article&#46; <span class="elsevierStyleBold">A and B&#41;</span> A patient with Noonan syndrome with loose anagen hair and SHOC2 mutation &#40;p&#46;S2G&#41; who presented with thin hair and premature baldness&#59; <span class="elsevierStyleBold">C</span>&#41; a patient with Noonan syndrome and PTPN11 &#40;p&#46;G60A&#41; mutation with premature graying of the hair&#59; <span class="elsevierStyleBold">D&#41;</span> a patient with CFC syndrome &#40;<span class="elsevierStyleItalic">BRAF</span> p&#46;N581D&#41;&#44; sparse eyebrows and follicular hyperkeratosis&#59; <span class="elsevierStyleBold">E&#41;</span> a patient with Noonan syndrome &#40;PTPN11 p&#46;T468 M&#41; who presented with caf&#233;-au-lait spots and prominent pectus excavatum&#59; <span class="elsevierStyleBold">F and G&#41;</span> a patient with Noonan syndrome &#40;KRAS p&#46;K5E&#41;&#44; nasal papillomas and marked plantar creases&#59; 1H&#58; a patient with CFC syndrome &#40;BRAF p&#46;T470P&#41; and plantar hyperkeratosis&#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">Noonan syndrome &#40;NS&#59; Online Mendelian Inheritance in Man &#91;OMIM&#93; 163950&#41; and Noonan-related syndromes &#40;NRS&#41;&#44; such as cardiofaciocutaneous &#40;CFC&#41; syndrome &#40;OMIM 115150&#41;&#44; NS with multiple lentigines &#40;NSML&#93;&#59; OMIM 151100&#41;&#44; Costello syndrome &#40;CS&#59; OMIM 218040&#41;&#44; neurofibromatosis type I &#40;NFI&#59; OMIM 162200&#41;&#44; Legius syndrome &#40;LS&#59; OMIM 611431&#41; and NS with loose anagen hair &#40;NSLAH&#59; OMIM 607721&#41; are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement&#46; These syndromes share common traits&#44; such as craniofacial dysmorphisms&#44; short stature&#44; cardiac malformations&#44; variable cognitive impairment&#44; an increased risk of cancer development and a certain extent of tegumentary involvement &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">These disorders are caused by germline mutations in genes that participate in the rat sarcoma&#47;mitogen-activated protein kinase &#40;RAS&#47;MAPK&#41; pathway&#44; which transduces extracellular growth factor signals into the intracellular environment and plays a role in cell cycle regulation&#44; differentiation&#44; growth and death and affects the inflammatory response &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Although the role of the RAS&#47;MAPK pathway in skin development and functioning is not completely understood&#44; several skin manifestations in individuals with NS and NRS have been described&#44; such as pigmented lesions &#40;caf&#233;-au-lait &#91;CAL&#93; spots&#44; lentigines and melanocytic lesions&#41;&#44; proliferative ectodermal lesions &#40;e&#46;g&#46;&#44; ichthyosiform manifestations&#44; follicular hyperkeratosis&#44; and short&#44; curly and thin hair&#41; and hyperplasia &#40;redundant skin and papillomatous growths&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Several of these skin manifestations are associated with a specific syndromic phenotype&#44; such as lentigines in NSML patients&#44; thin&#44; sparse hair in NSLAH patients and hyperkeratotic skin in CFC syndrome and in NS patients harboring <span class="elsevierStyleItalic">SOS1</span> gene mutations &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; The exact underlying molecular mechanism determining the diverse physiopathological spectrum of lesions&#44; the association of specific tegumentary lesions with specific syndromes and the increased prevalence of tegumentary involvement in groups with mutations in specific genes is still unknown &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#44;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">The exact delineation of the tegumentary findings in each group of patients harboring mutations in different genes&#44; a comprehensive genotype-phenotype correlation in NS and NRS patients and a model of the molecular mechanisms of the diseases all remain to be determined&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with NS or NRS who harbor a confirmed germline mutation in genes of the RAS&#47;MAPK pathway and to unveil certain aspects of the molecular mechanisms underlying ectodermal involvement in NS and NRS patients by comparing the clinical features of patient groups classified by their gene mutations&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><p id="para50" class="elsevierStylePara elsevierViewall">A prospective study that included 41 patients affected by NS or NRS was performed at the Outpatient Clinic of the Genetics Unit of Instituto da Crian&#231;a do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo&#46; The majority of these patients were referred to our unit by pediatric endocrinology and cardiology services&#46; Consensus clinical criteria were used to classify the patients as being affected by NS&#44; NSML or CFC syndrome &#40;<a class="elsevierStyleCrossRefs" href="#bib8">8&#8211;11</a>&#41;&#46; Only one patient&#44; who had tested negative for the previously described gene alterations in other known NS-related genes &#40;<span class="elsevierStyleItalic">PTPN11</span>&#44; <span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">RAF1</span> and <span class="elsevierStyleItalic">KRAS</span>&#41;&#44; was diagnosed with NSLAH by the presence of slow growth&#44; fine hair and a <span class="elsevierStyleItalic">SHOC2</span> gene mutation &#40;p&#46;S2G&#41;&#46; Another patient&#44; who presented with the mutation p&#46;T468M in the <span class="elsevierStyleItalic">PTPN11</span> gene&#44; which is usually associated with NSML&#44; was classified as an NS patient because he lacked lentigines by the age of 21 years&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">The molecular analysis of this cohort included the sequencing of the following genes in all patients&#58; <span class="elsevierStyleItalic">PTPN11</span>&#44; <span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">RAF1</span>&#44; <span class="elsevierStyleItalic">KRAS</span> and <span class="elsevierStyleItalic">SHOC2</span>&#46; Additionally&#44; the <span class="elsevierStyleItalic">BRAF</span> gene was analyzed in patients fulfilling CFC syndrome diagnostic criteria&#46; The p&#46;T470P &#40;<span class="elsevierStyleItalic">BRAF</span> gene&#41; gene alteration was novel&#59; in silico prediction &#40;PolyPhen&#44; SIFT and Mutation Taster&#41; suggested that the mutation damaged the protein structure and affected protein function&#44; indicating the alteration&#39;s pathogenicity&#46; The mutation was a <span class="elsevierStyleItalic">de novo</span> event in the family&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">A standard questionnaire was administered&#44; and a focused physical examination based on a systematic review of clinical records was performed on all patients to verify the presence of the following complaints&#58; xeroderma &#40;the presence of dry skin&#44; indicated by either scaling or cracking of the skin upon clinical examination&#41;&#44; photosensitivity &#40;a subjective impression of greater skin redness following sun exposure&#41;&#44; hair loss &#40;a subjective sensation of thinning of the hair&#41;&#44; lentigines &#40;the presence of &#62;100 lentiginous lesions&#41;&#44; CAL spots &#40;uniformly light brown&#44; sharply defined and usually oval-shaped skin patches&#41;&#44; thin hair&#44; curly hair&#44; sparse eyebrows&#44; a clinical history of recurrent oral ulcers&#44; nevi &#40;at least 100&#41;&#44; hyperpigmentation of the skin &#40;increased pigmentation of the skin compared with other family members&#41;&#44; cutis marmorata &#40;a reticulated cutaneous vascular pattern with altered color &#40;red or blue&#41;&#44; follicular hyperkeratosis&#44; palmo-plantar hyperkeratosis &#40;the presence of areas of thickening of the skin in the palmar and plantar regions&#41;&#44; markedly increased palmar and plantar creases&#44; keloid scars &#40;excessive growth of scar tissue&#41;&#44; nasal papilloma &#40;cauliflower-like epithelial lesions&#41; and the early onset of gray hair&#46; The presence or absence of subjective clinical signs was based on the clinical impression of the genetic unit team&#44; which is experienced when evaluating patients with NS and NRS&#46; Therefore&#44; the clinical protocol and physical examination were applied using the same clinical criteria for all patients&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">Statistical analyses comparing the between-group differences&#44; which were stratified by age&#44; gender and gene mutation&#44; were performed using Fisher&#39;s exact test with a significance limit of 0&#46;05&#46; The Student&#39;s t-test was used to compare the frequency distribution of tegumentary findings between a group of patients with mutations in <span class="elsevierStyleItalic">PTPN11</span> and a group that comprised the remaining individuals&#46; The samples did not show any deviation related to gender or age&#44; indicating that sample bias was unlikely&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Ethics</span><p id="para90" class="elsevierStylePara elsevierViewall">The local ethics committee &#40;Comiss&#227;o de &#201;tica para An&#225;lise de Projetos de Pesquisa &#91;CAPPesq&#93; do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo - 0843&#47;08 and 0325&#47;10&#41; approved this study&#44; and written informed consent was obtained from all participants&#46;</p></span></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">RESULTS</span><p id="para100" class="elsevierStylePara elsevierViewall">Patients ranged in age from five to 58 years&#44; with a mean age of 20 years and a median age of 17 years&#46; Gender was almost equally distributed &#40;21 females and 20 males&#41;&#46; The cohort was composed of 36 NS patients&#44; two CFC syndrome patients&#44; two NSML patients and one NSLAH patient&#46; The molecular analysis identified 30 patients harboring mutations in <span class="elsevierStyleItalic">PTPN11</span>&#44; five in <span class="elsevierStyleItalic">SOS1</span>&#44; two in <span class="elsevierStyleItalic">BRAF</span>&#44; two in <span class="elsevierStyleItalic">RAF1</span>&#44; one in <span class="elsevierStyleItalic">SHOC2</span> and one in <span class="elsevierStyleItalic">KRAS</span>&#46; Most individuals &#40;34 patients&#44; 83&#37;&#41; were sporadic cases caused by a <span class="elsevierStyleItalic">de novo</span> mutation&#44; whereas familiar aggregation was found in seven patients &#40;three individuals in one family and two individuals in each of two families&#41;&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">The following tegumentary alterations were observed&#44; in order of prevalence&#58; xeroderma &#40;46&#37;&#41;&#44; photosensitivity &#40;29&#37;&#41;&#44; excessive hair loss &#40;24&#37;&#41;&#44; recurrent oral ulcers &#40;22&#37;&#41;&#44; curly hair &#40;29&#37;&#41;&#44; nevi &#40;20&#37;&#41;&#44; follicular hyperkeratosis &#40;17&#37;&#41;&#44; markedly increased palmar and plantar creases &#40;15&#37;&#41;&#44; CAL spots &#40;15&#37;&#41;&#44; sparse eyebrows &#40;12&#37;&#41;&#44; palmo-plantar hyperkeratosis &#40;10&#37;&#41;&#44; lentigines &#40;5&#37;&#41;&#44; keloid scars &#40;5&#37;&#41;&#44; hyperpigmentation of the skin &#40;5&#37;&#41;&#44; nasal papilloma &#40;2&#37;&#41;&#44; the early onset of gray hair &#40;2&#37;&#41;&#44; cutis marmorata &#40;2&#37;&#41; and thin hair &#40;2&#37;&#41;&#46; The great majority of individuals &#40;93&#37;&#41; presented with at least one tegumentary involvement &#40;mean of three&#44; median of two&#44; maximum of nine&#41;&#44; whereas three individuals did not present with any tegumentary involvement&#46; The most relevant clinical characteristics of these patients are summarized in <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a> and shown in <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="fig1"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">The mean number of positive tegumentary findings was highest in the group of patients with CFC syndrome &#40;n &#61; 6 findings&#47;individual&#41;&#44; followed by NSML &#40;n &#61; 5&#41;&#44; NSLAH &#40;n &#61; 4&#41; and NS &#40;n &#61; 2&#41;&#46; When we stratified the patients by the affected gene&#44; the ranking of the mean number of positive tegumentary findings per individual in each group was as follows&#58; <span class="elsevierStyleItalic">KRAS</span> &#40;n &#61; 9 findings&#47;individual&#41;&#44; BRAF &#40;n &#61; 6&#41;&#44; <span class="elsevierStyleItalic">SHOC2</span> &#40;n &#61; 4&#41;&#44; <span class="elsevierStyleItalic">PTPN11</span> &#40;n &#61; 3&#41;&#44; <span class="elsevierStyleItalic">SOS1</span> &#40;n &#61; 2&#41; and <span class="elsevierStyleItalic">RAF1</span> &#40;n &#61; 1&#41;&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">The distribution of the number of tegumentary findings in patients harboring <span class="elsevierStyleItalic">PTPN11</span> mutations &#40;mean &#61; 1&#46;9&#44; standard deviation &#91;SD&#93; &#61; 1&#46;42&#41; compared with patients with mutations in other genes &#40;mean &#61; 3&#46;6&#44; SD &#61; 2&#46;6&#41; showed a significant difference &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;0352&#41;&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">CAL spots were more common in males &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;0471&#41;&#46; Follicular hyperkeratosis was statistically more prevalent in postpubertal &#40;&#62;16 years of age&#41; patients &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;0269&#41;&#46; No patients harboring a <span class="elsevierStyleItalic">PTPN11</span> mutation developed a nevus prior to the age of 11 years in contrast to patients harboring other gene mutations &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;0476&#41;&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">Patients with <span class="elsevierStyleItalic">PTPN11</span> mutations had a lower frequency of follicular hyperkeratosis &#40;3&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 40&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;011&#41; and markedly increased palmar and plantar creases &#40;3&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 40&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;011&#41; and palmar&#47;plantar hyperkeratosis &#40;3&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 30&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;0449&#41; compared with other patients&#46; Comparing the <span class="elsevierStyleItalic">PTPN11</span> patients with the <span class="elsevierStyleItalic">SOS1</span> patients&#44; the <span class="elsevierStyleItalic">PTPN11</span> patients had a lower frequency of follicular hyperkeratosis &#40;3&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 50&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;0326&#41; and markedly increased palmar and plantar creases &#40;3&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 75&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;0029&#41;&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">DISCUSSION</span><p id="para160" class="elsevierStylePara elsevierViewall">In the current study&#44; we described the most relevant tegumentary findings in a cohort of 41 patients with a molecularly proven diagnosis of NS or NRS&#46; We found that these tegumentary findings are common in these syndromes&#44; particularly in patients with <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">KRAS</span> and <span class="elsevierStyleItalic">SHOC2</span> mutations&#46; Note that this phenomenon was demonstrated in a sample composed of mostly young individuals&#46; This report is the first comprehensive study in the literature to address tegumentary involvement in NS patients with germline mutations in several genes of the RAS&#47;MAPK pathway&#46; Several of the manifestations reported in this article have not been previously described in the literature&#44; including the frequency of tegumentary involvement in this syndromic group as a whole&#46;</p><p id="para170" class="elsevierStylePara elsevierViewall">The association of CAL spots with male gender is not exclusive to our group of patients because CAL spots are more commonly observed in normal males than in normal females &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46; We also observed that follicular hyperkeratosis and nevi are associated with postpubertal age&#44; which we speculate is because of an accumulation of sun exposure or hormonal influence&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">The RAS&#47;MAPK signaling pathway receives extracellular stimuli from cell surface receptors and acts as a molecular switch in the processes of cell proliferation&#44; differentiation&#44; survival and death &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Several components of this pathway are related to the promotion of epidermal proliferation and may interfere in the epidermal cell state &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; Signal transmission is initiated by the extracellular stimulators &#40;growth factors&#44; hormones and cytokines&#41; that create intracellular docking sites for adaptor molecules activating cell surface receptors&#46; This interaction promotes the activation of RAS GTPases&#44; including the products of <span class="elsevierStyleItalic">KRAS</span>&#44; <span class="elsevierStyleItalic">NRAS</span> and <span class="elsevierStyleItalic">HRAS</span> &#40;monomeric GTPases that use GDP&#47;GTP-regulated molecular switching to control intracellular signal flow&#41;&#44; and&#44; therefore&#44; the interaction and activation of the RAF protein kinase components&#44; including the products of <span class="elsevierStyleItalic">RAF1</span> and <span class="elsevierStyleItalic">BRAF</span>&#44; members of a small family of serine-threonine kinases that function as RAS effectors&#46; Activating the RAF cascade results in the phosphorylation and activation of the final MAPK components &#40;the substrates of the pathway&#41; and&#44; consequently&#44; cellular responses &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#44;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">PTPN11</span> gene encodes SHP2&#44; a cytoplasmic protein tyrosine phosphatase that positively modulates RAS signaling through its interaction with the GRB2&#47;SOS1 complex&#46; SHP2 also exhibits other intricate&#44; contradictory and relatively unknown interactions&#46; <span class="elsevierStyleItalic">SOS1</span> encodes a multidomain product that catalyzes the release of GDP from RAS through a close interaction with GRB2&#46; This event facilitates the conversion of the inactive form of RAS into its active GTP-bound state&#46; The <span class="elsevierStyleItalic">SHOC2</span> gene encodes a protein that positively modulates the RAS-MAPK signal flow &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#44;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; Interestingly&#44; <span class="elsevierStyleItalic">PTPN11</span> is the only studied gene that also functions as a downregulator &#40;unlike <span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">KRAS</span>&#44; <span class="elsevierStyleItalic">RAF1</span> and <span class="elsevierStyleItalic">BRAF</span>&#41; &#40;National Cancer Institute&#44; Pathway Interaction Database&#44; USA&#41;&#46; For example&#44; <span class="elsevierStyleItalic">PTPN11</span> specifically inhibits the GRB2&#47;SOS1 complex in the neuromuscular junction &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">We observed that patients with mutations in genes directly involved in the kinase cascades for cell proliferation &#40;<span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">KRAS</span> and <span class="elsevierStyleItalic">RAF1</span>&#41; have a higher frequency of proliferative skin lesions &#40;hyperkeratosis and marked palmar and plantar creases&#41; compared with patients with mutations in a gene that has a more complex interaction with and modulation of this transduction pathway &#40;<span class="elsevierStyleItalic">PTPN11</span>&#41;&#46; Previous studies have also supported this observation&#46; Hyperkeratosis has been described in patients harboring mutations in those genes&#46; Additionally&#44; patients with mutations in <span class="elsevierStyleItalic">MEK1</span> and <span class="elsevierStyleItalic">MEK2</span>&#44; the final effectors of the MAPK cascade&#44; develop remarkable tegumentary involvement that usually includes hyperkeratosis &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46; Activation of the RAS&#47;MAPK pathway by a contradictory effect of dabrafenib&#44; a <span class="elsevierStyleItalic">BRAF</span> inhibitor used to treat melanoma&#44; induces the proliferation of keratinocytes and predisposes patients to hyperkeratosis &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">Limitations of this study include the descriptive nature of the data and the relatively small sample size for statistical analysis&#44; although a sample size of 41 is considerable for rare genetic disorders&#46; Additionally&#44; several tegumentary findings described here &#40;i&#46;e&#46;&#44; xeroderma and photosensitivity&#41; are either common in the normal population or are diagnosed solely based on patient complaints or the clinical impression of the examiner&#59; therefore&#44; the prevalence of these conditions in our patients may have been inflated&#46; Despite our work to improve the delineation of tegumentary genotype-phenotype correlations in this study&#44; we encourage further investigation in this field&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">A thorough description of dermatological findings has been developed for Costello syndrome&#44; an NRS caused by germline mutations in <span class="elsevierStyleItalic">HRAS</span> &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#46; Costello syndrome patients have a statistically higher frequency of cutaneous papillomas and palmar hyperkeratosis but a lower frequency of sparse eyebrows compared with patients with CFC syndrome &#40;i&#46;e&#46;&#44; harboring mutations in <span class="elsevierStyleItalic">BRAF</span>&#41;&#46; Although our study did not include patients with Costello syndrome or any patients with <span class="elsevierStyleItalic">HRAS</span> mutations&#44; one patient with a <span class="elsevierStyleItalic">KRAS</span> mutation presented with nasal papilloma and other characteristics that overlap with the characteristics observed in Costello syndrome&#44; such as distal hyperextensibility&#44; marked palmar creases and facial dysmorphisms &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46; As this patient presented with several tegumentary findings and was the only one harboring a <span class="elsevierStyleItalic">KRAS</span> mutation&#44; we may have overestimated the prevalence of skin abnormalities in patients with this gene mutation&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">Cutaneous manifestations in patients with <span class="elsevierStyleItalic">BRAF</span> mutations &#40;i&#46;e&#46;&#44; mainly patients with CFC syndrome&#41; have also been reported&#44; with a high frequency of melanocytic nevi&#44; hyperkeratosis of the palms and soles &#40;typically developed in pressure areas&#41; and follicular hyperkeratosis &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">Tegumentary involvement in NS and NRS patients was common&#44; even in a sample composed of mostly young individuals&#46; Therefore&#44; an active search for cutaneous involvement in NS and NRS patients and the addition of dermatologists to the multidisciplinary team required to assist these patients is necessary for optimal follow-up treatment&#46; Clinicians must keep in mind that several of these skin lesions could have a late onset and thus hinder a straight genotype-phenotype correlation&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">AUTHOR CONTRIBUTIONS</span><p id="para250" class="elsevierStylePara elsevierViewall">Quaio CR&#44; Almeida TF&#44; AAL Jorge&#44; AC Malaquias&#44; Kim CA and Bertola DR designed the study and were responsible for the patient data collection&#44; manuscript writing and review&#46; Almeida TF was also responsible for the statistical analysis&#46; Brasil AS and Pereira AC performed the molecular analysis and reviewed the manuscript&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:8 [
        0 => array:2 [
          "identificador" => "xpalclavsec1581268"
          "titulo" => "KEYWORDS"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Ethics"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec40"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec50"
          "titulo" => "DISCUSSION"
        ]
        5 => array:2 [
          "identificador" => "cesec60"
          "titulo" => "AUTHOR CONTRIBUTIONS"
        ]
        6 => array:2 [
          "identificador" => "xack638811"
          "titulo" => "ACKNOWLEDGMENTS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-02-27"
    "fechaAceptado" => "2013-03-24"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1581268"
          "palabras" => array:4 [
            0 => "Noonan"
            1 => "Skin"
            2 => "Tegument"
            3 => "Tegumentary"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES</span><p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement&#46; The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS</span><p id="spara40" class="elsevierStyleSimplePara elsevierViewall">A standard questionnaire was administered&#46; A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations&#46; The molecular analysis of this cohort included sequencing of the following genes in all patients&#58; <span class="elsevierStyleItalic">PTPN1</span>&#44; <span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">RAF1</span>&#44; <span class="elsevierStyleItalic">KRAS</span>&#44; <span class="elsevierStyleItalic">SHOC2</span> and <span class="elsevierStyleItalic">BRAF</span>&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS</span><p id="spara50" class="elsevierStyleSimplePara elsevierViewall">The most frequent tegumentary alterations were xeroderma &#40;46&#37;&#41;&#44; photosensitivity &#40;29&#37;&#41;&#44; excessive hair loss &#40;24&#37;&#41;&#44; recurrent oral ulcers &#40;22&#37;&#41;&#44; curly hair &#40;20&#37;&#41;&#44; nevi &#40;17&#37;&#41;&#44; markedly increased palmar and plantar creases &#40;12&#37;&#41;&#44; follicular hyperkeratosis &#40;12&#37;&#41;&#44; palmoplantar hyperkeratosis &#40;10&#37;&#41;&#44; caf&#233;-au-lait spots &#40;10&#37;&#41; and sparse eyebrows &#40;7&#37;&#41;&#46; Patients with mutations in <span class="elsevierStyleItalic">PTPN11</span> had lower frequencies of palmar and plantar creases and palmar&#47;plantar hyperkeratosis compared with the other patients&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades &#40;<span class="elsevierStyleItalic">SOS1</span>&#44; <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">KRAS</span> and <span class="elsevierStyleItalic">RAF1</span>&#41; had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades &#40;<span class="elsevierStyleItalic">PTPN11</span>&#41;&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "ceabs10"
            "titulo" => "OBJECTIVES"
          ]
          1 => array:2 [
            "identificador" => "ceabs20"
            "titulo" => "METHODS"
          ]
          2 => array:2 [
            "identificador" => "ceabs30"
            "titulo" => "RESULTS"
          ]
          3 => array:2 [
            "identificador" => "ceabs40"
            "titulo" => "CONCLUSIONS"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 515
            "Ancho" => 777
            "Tamanyo" => 63094
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Mosaic showing several tegumentary findings of the patients reported in this article&#46; <span class="elsevierStyleBold">A and B&#41;</span> A patient with Noonan syndrome with loose anagen hair and SHOC2 mutation &#40;p&#46;S2G&#41; who presented with thin hair and premature baldness&#59; <span class="elsevierStyleBold">C</span>&#41; a patient with Noonan syndrome and PTPN11 &#40;p&#46;G60A&#41; mutation with premature graying of the hair&#59; <span class="elsevierStyleBold">D&#41;</span> a patient with CFC syndrome &#40;<span class="elsevierStyleItalic">BRAF</span> p&#46;N581D&#41;&#44; sparse eyebrows and follicular hyperkeratosis&#59; <span class="elsevierStyleBold">E&#41;</span> a patient with Noonan syndrome &#40;PTPN11 p&#46;T468 M&#41; who presented with caf&#233;-au-lait spots and prominent pectus excavatum&#59; <span class="elsevierStyleBold">F and G&#41;</span> a patient with Noonan syndrome &#40;KRAS p&#46;K5E&#41;&#44; nasal papillomas and marked plantar creases&#59; 1H&#58; a patient with CFC syndrome &#40;BRAF p&#46;T470P&#41; and plantar hyperkeratosis&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="TFN01t01" class="elsevierStyleSimplePara elsevierViewall">Xe&#58; xeroderma&#44; P&#58; photosensitivity&#44; HL&#58; excessive hair loss&#44; OU&#58; recurrent oral ulcers&#44; CH&#58; curly hair&#44; N&#58; nevus&#44; Cr&#58; markedly increased palmar and plantar creases&#44; FH&#58; follicular hyperkeratosis&#44; PH&#58; palmo-plantar hyperkeratosis&#44; CAL&#58; caf&#233;-au-lait spots&#44; SE&#58; sparse eyebrows&#44; Le&#58; lentigines&#44; Ke&#58; keloid scars&#44; HS&#58; hyperpigmentation of the skin&#44; NP&#58; nasal papilloma&#44; GH&#58; the early onset of gray hair&#44; CM&#58; cutis marmorata&#44; TH&#58; thin hair&#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">Syndrome&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">Gene&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">Mutation&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">Clinical characteristics&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">NS</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">PTPN11&nbsp;\t\t\t\t\t\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">p&#46;G60A&nbsp;\t\t\t\t\t\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 yo Male &#40;OU&#59; N&#59; CAL&#59; GH&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;Y62D&nbsp;\t\t\t\t\t\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">24 yo Male &#40;Xe&#59; N&#59; CAL&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;Y63C&nbsp;\t\t\t\t\t\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">9 yo Male &#40;P&#59; PH&#59; FH&#41; &#124; 9 yo Female &#40;Xe&#59; OU&#41; I 11 yo Male &#40;Xe&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;Q79R&nbsp;\t\t\t\t\t\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">23 yo Female &#40;CM&#41; &#124; 19 yo Male &#40;Xe&#59; P&#59; OU&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;D106A&nbsp;\t\t\t\t\t\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">10 yo Female &#40;SE&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;I282V&nbsp;\t\t\t\t\t\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 yo Male &#40;Xe&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;F285S&nbsp;\t\t\t\t\t\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">33 yo Female &#40;Xe&#59; P&#59; HL&#59; Cr&#59; FH&#59; CH&#59; SE&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;N308D&nbsp;\t\t\t\t\t\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"><span class="elsevierStyleBold">13 yo Female</span> &#124; 17 yo Female &#40;CH&#59; FH&#41; &#124; 22 yo Male &#40;Xe&#59; P&#59; OU&#59; CH&#41; &#124; 56 yo Male &#40;HL&#41; &#124; 11 yo Female &#40;Xe&#59; P&#59; OU&#41; &#124; 12 yo Male &#40;N&#41; &#124; 21 yo Female &#40;Xe&#59; HL&#41; &#124; 5 yo Female &#40;CH&#59; SE&#41; &#124; 20 yo Male &#40;Xe&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;N308S&nbsp;\t\t\t\t\t\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"><span class="elsevierStyleBold">29 yo Male</span> &#124; <span class="elsevierStyleBold">56 yo Female</span> &#124; 16 yo Female &#40;HL&#59; Ke&#41; &#124; 32 yo Female &#40;CH&#59; P&#59; N&#41; &#124; 15 yo Female &#40;HL&#59; N&#59; Ke&#41; &#124; 11 yo Male &#40;Xe&#59; CH&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;T468M&nbsp;\t\t\t\t\t\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">21 yo Male &#40;N&#59; CAL&#59; Cr&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;M504V&nbsp;\t\t\t\t\t\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 yo Male &#40;P&#59; OU&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;Q510P&nbsp;\t\t\t\t\t\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 yo Male &#40;CH&#59; CAL&#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="" 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="center" valign="top">RAF1&nbsp;\t\t\t\t\t\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">p&#46;P235S&nbsp;\t\t\t\t\t\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 yo Female &#40;PH&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;S257K&nbsp;\t\t\t\t\t\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 yo Male &#40;N&#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="" 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="center" valign="top">SOS1&nbsp;\t\t\t\t\t\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">p&#46;M269T&nbsp;\t\t\t\t\t\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">27 yo Male &#40;Xe&#59; P&#59; CH&#59; Cr&#59; FH&#59; HS&#41; &#124; 58 yo Female &#40;Xe&#59; HL&#41; &#124; 7 yo Male &#40;Cr&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;R552G&nbsp;\t\t\t\t\t\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">28 yo Female &#40;P&#59; Cr&#59; FH&#59; CH&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;R552S&nbsp;\t\t\t\t\t\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">13 yo Male &#40;CAL&#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="" 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="center" valign="top"><span class="elsevierStyleItalic">KRAS</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">p&#46;K5E&nbsp;\t\t\t\t\t\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">24 yo Female &#40;Xe&#59; HL&#59; OU&#59; CH&#59; Cr&#59; FH&#59; HS&#59; NP&#59; Ly&#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">CFC</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"><span class="elsevierStyleItalic">BRAF</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">p&#46;N581D&nbsp;\t\t\t\t\t\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">17 yo Female &#40;Xe&#59; P&#59; CH&#59; FH&#59; PH&#59; SE&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">p&#46;T470P&nbsp;\t\t\t\t\t\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">9 yo Female &#40;Xe&#59; HL&#59; CH&#59; N&#59; PH&#59; SE&#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">NSML</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"><span class="elsevierStyleItalic">PTPN11</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">p&#46;Y279C&nbsp;\t\t\t\t\t\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">31 yo Female &#40;Xe&#59; P&#59; CAL&#59; Le&#41; &#124; 18 yo Female &#40;Xe&#59; P&#59; HL&#59; OU&#59; Le&#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">NSLAH</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"><span class="elsevierStyleItalic">SHOC2</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">p&#46;S2G&nbsp;\t\t\t\t\t\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">40yo Male &#40;Xe&#59; HL&#59; OU&#59; TH&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Genetic and clinical profiles of the 41 patients diagnosed with Noonan syndrome and Noonan-related syndromes&#46; The syndrome column shows the clinical diagnosis of the patients&#59; the gene column contains each gene&#59; the mutation column contains the pathogenic alteration in the product of the genes&#59; and the clinical characteristics column shows the most relevant clinical features of each patient&#44; including age and gender&#44; and tegumentary involvement is in brackets&#46; Note that patients with no tegumentary involvement are indicated in bold&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:18 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Noonan syndrome and clinically related disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              M Tartaglia \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              BD Gelb \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Zenker \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Best Pract Res Clin Endocrinol Metab"
                        "fecha" => "2011"
                        "volumen" => "25"
                        "numero" => "1"
                        "paginaInicial" => "161"
                        "paginaFinal" => "179"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of Ras signaling in lupus T lymphocytes&#58; Biology and pathogenesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              A Mor \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              MR Philips \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MH Pillinger \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Immunology"
                        "fecha" => "2007"
                        "volumen" => "125"
                        "numero" => "3"
                        "paginaInicial" => "215"
                        "paginaFinal" => "223"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of Ras in lymphocytes&#58; get a GRP"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              JC Stone \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1042/BST0340858"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochem Soc Trans"
                        "fecha" => "2006"
                        "volumen" => "34"
                        "numero" => "Pt 5"
                        "paginaInicial" => "858"
                        "paginaFinal" => "861"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17052215"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rasopathies&#58; developmental disorders that predispose to cancer and skin manifestations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              A Hern&#225;ndez-Mart&#237;n \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Torrelo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ad.2011.02.010"
                      "Revista" => array:7 [
                        "tituloSerie" => "Actas Dermosifiliogr"
                        "fecha" => "2011"
                        "volumen" => "102"
                        "numero" => "6"
                        "paginaInicial" => "402"
                        "paginaFinal" => "416"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21536246"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dermatological phenotype in Costello syndrome&#58; consequences of Ras dysregulation in development"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              DH Siegel \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JA Mann \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AL Krol \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              KA Rauen \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2011.10744.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2012 Mar"
                        "volumen" => "166"
                        "numero" => "3"
                        "paginaInicial" => "601"
                        "paginaFinal" => "607"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22098123"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              DH Siegel \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J McKenzie \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              IJ Frieden \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              KA Rauen \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "2011"
                        "volumen" => "164"
                        "paginaInicial" => "521"
                        "paginaFinal" => "529"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardio-facio-cutaneous syndrome&#58; does genotype predict phenotype"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              JE Allanson \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              G Anner&#233;n \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              Y Aoki \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CM Armour \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              ML Bondeson \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              H Cave \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med Genet C Semin Med Genet"
                        "fecha" => "2011"
                        "volumen" => "157"
                        "numero" => "2"
                        "paginaInicial" => "129"
                        "paginaFinal" => "135"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and molecular studies in a large Dutch family with Noonan syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              I van der Burgt \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Berends \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              E Lommen \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              S van Beersum \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              B Hamel \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              E Mariman \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajmg.1320530213"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Med Genet"
                        "fecha" => "1994"
                        "volumen" => "53"
                        "numero" => "2"
                        "paginaInicial" => "187"
                        "paginaFinal" => "191"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7856646"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multiple lentigines syndrome&#46; Case report and review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              DA Voron \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              HH Hatfield \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              RK Kalkhoff \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0002-9343(76)90764-6"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "1976"
                        "volumen" => "60"
                        "numero" => "3"
                        "paginaInicial" => "447"
                        "paginaFinal" => "456"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1258892"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CFC index for the diagnosis of cardiofaciocutaneous syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              MI Kavamura \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CA Peres \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MM Alchorne \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              D Brunoni \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajmg.10681"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Med Genet"
                        "fecha" => "2002"
                        "volumen" => "112"
                        "numero" => "1"
                        "paginaInicial" => "12"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12239713"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The cardiofaciocutaneous syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              A Roberts \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J Allanson \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              SK Jadico \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MI Kavamura \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              J Noonan \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              JM Opitz \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jmg.2006.042796"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Med Genet"
                        "fecha" => "2006"
                        "volumen" => "43"
                        "numero" => "11"
                        "paginaInicial" => "833"
                        "paginaFinal" => "842"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16825433"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of skin disease among school children and adolescents in a Student Health Service Center in Hong Kong"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              WK Fung \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              KK Lo \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1525-1470.2000.01841.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Pediatr Dermatol"
                        "fecha" => "2000"
                        "volumen" => "17"
                        "numero" => "6"
                        "paginaInicial" => "440"
                        "paginaFinal" => "446"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11123774"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The RAS&#47;MAPK syndromes&#58; novel roles of the RAS pathway in human genetic disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              Y Aoki \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              T Niihori \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              Y Narumi \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              S Kure \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              Y Matsubara \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/humu.20748"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hum Mutat"
                        "fecha" => "2008"
                        "volumen" => "29"
                        "numero" => "8"
                        "paginaInicial" => "992"
                        "paginaFinal" => "1006"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18470943"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gab1 and SHP-2 promote Ras&#47;MAPK regulation of epidermal growth and differentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              T Cai \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              K Nishida \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              T Hirano \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              PA Khavari \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cell Biol"
                        "fecha" => "2002"
                        "volumen" => "159"
                        "numero" => "1"
                        "paginaInicial" => "103"
                        "paginaFinal" => "112"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The molecular functions of Shp2 in the Ras&#47;Mitogen-activated protein kinase &#40;ERK1&#47;2&#41; pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              M Dance \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Montagner \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JP Salles \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              A Yart \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              P Raynal \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cellsig.2007.10.002"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cell Signal"
                        "fecha" => "2008"
                        "volumen" => "20"
                        "numero" => "3"
                        "paginaInicial" => "453"
                        "paginaFinal" => "459"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17993263"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              M Tanowitz \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J Si \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              DH Yu \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              GS Feng \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              L Mei \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci"
                        "fecha" => "1999"
                        "volumen" => "19"
                        "numero" => "21"
                        "paginaInicial" => "9426"
                        "paginaFinal" => "9435"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of BRAF inhibitor-induced hyperkeratosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              JE Battley \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              E Lenihan \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              HP Redmond \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              M Murphy \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              DG Power \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/0284186X.2012.716165"
                      "Revista" => array:7 [
                        "tituloSerie" => "Acta Oncol"
                        "fecha" => "2013"
                        "volumen" => "52"
                        "numero" => "4"
                        "paginaInicial" => "874"
                        "paginaFinal" => "876"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22998476"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Further evidence of genetic heterogeneity in Costello syndrome&#58; involvement of the KRAS gene"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              DR Bertola \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AC Pereira \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              AS Brasil \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              LM Albano \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              CA Kim \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              JE Krieger \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10038-007-0146-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hum Genet"
                        "fecha" => "2007"
                        "volumen" => "52"
                        "numero" => "6"
                        "paginaInicial" => "521"
                        "paginaFinal" => "526"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17468812"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack638811"
        "titulo" => "ACKNOWLEDGMENTS"
        "texto" => "<p id="para260" class="elsevierStylePara elsevierViewall">This study was supported by FAPESP&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/18075932/0000006800000008/v1_202212010718/S1807593222016398/v1_202212010718/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006800000008/v1_202212010718/S1807593222016398/v1_202212010718/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222016398?idApp=UINPBA00004N"
]
Article information
ISSN: 18075932
Original language: English
The statistics are updated each day
Year/Month Html Pdf Total
2024 November 6 3 9
2024 October 44 37 81
2024 September 48 19 67
2024 August 36 15 51
2024 July 21 22 43
2024 June 20 22 42
2024 May 30 12 42
2024 April 22 14 36
2024 March 25 12 37
2024 February 35 20 55
2024 January 42 10 52
2023 December 32 21 53
2023 November 31 21 52
2023 October 47 24 71
2023 September 45 27 72
2023 August 33 12 45
2023 July 39 19 58
2023 June 37 9 46
2023 May 55 2 57
2023 April 41 2 43
2023 March 27 1 28
2023 February 14 1 15
2023 January 6 4 10
2022 December 15 7 22
Show all

Follow this link to access the full text of the article

es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos