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codifica a hamartina&#44; e o <span class="elsevierStyleItalic">TSC2</span> &#40;16p13&#46;3&#41; codifica a tuberina&#46; Sob condi&#231;&#245;es fisiol&#243;gicas&#44; as prote&#237;nas hamartina&#44; tuberina e TBC1D7 &#40;OMIM 612655&#41; formam um complexo citoplasm&#225;tico que suprime o crescimento celular ao inibir o alvo mecan&#237;stico da rapamicina &#40;mTOR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a> A perda de fun&#231;&#227;o bial&#233;lica de <span class="elsevierStyleItalic">TSC1</span> ou <span class="elsevierStyleItalic">TSC2</span> prejudica o efeito inibit&#243;rio na via mTOR causando diferencia&#231;&#227;o e crescimento celular anormais&#44; resultando em les&#245;es hamartomatosas &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">3&#8208;5</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Desde 2012&#44; a presen&#231;a de altera&#231;&#227;o patog&#234;nica no gene <span class="elsevierStyleItalic">TSC1</span> ou <span class="elsevierStyleItalic">TSC2</span> &#233; crit&#233;rio definitivo e suficiente para diagnosticar o CET&#44; independentemente dos achados cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a> Em 2021&#44; o crit&#233;rio diagn&#243;stico gen&#233;tico foi confirmado e a combina&#231;&#227;o de crit&#233;rios cl&#237;nicos que levam a diagn&#243;sticos cl&#237;nicos definitivos ou prov&#225;veis foi mantida &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> Entretanto&#44; houve poucas altera&#231;&#245;es nos crit&#233;rios cl&#237;nicos&#46; M&#250;ltiplos tub&#233;rculos corticais e&#47;ou linhas de migra&#231;&#227;o radial substitu&#237;ram o termo geral displasia cortical como crit&#233;rio maior&#44; e les&#245;es &#243;sseas escler&#243;ticas foram restabelecidas como crit&#233;rio menor &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> Pacientes com diagn&#243;stico definitivo&#44; prov&#225;vel ou suspeito de CET devem ser monitorados por equipe multidisciplinar para identifica&#231;&#227;o precoce de sinais e sintomas&#44; manejo cl&#237;nico e interven&#231;&#227;o terap&#234;utica&#44; resultando em melhores desfechos cl&#237;nicos&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A associa&#231;&#227;o entre gen&#243;tipos e fen&#243;tipos de CET tem sido estudada&#44; destacando&#8208;se as altera&#231;&#245;es no gene <span class="elsevierStyleItalic">TSC2</span> mais frequentemente entre pacientes com relatos anteriores de convuls&#245;es&#44; presen&#231;a de s&#237;ndrome de West &#40;espasmos epil&#233;pticos&#47;infantis com in&#237;cio na primeira inf&#226;ncia associados a hipsarritmia e regress&#227;o do desenvolvimento&#41; e d&#233;ficit cognitivo mais grave&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">2</span></a> Embora as an&#225;lises gen&#243;tipo&#8208;fen&#243;tipo se concentrem nos sinais neurol&#243;gicos e renais&#44; que s&#227;o as principais causas de morbidade e mortalidade&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> os sinais dermatol&#243;gicos s&#227;o uma das apresenta&#231;&#245;es cl&#237;nicas mais precoces e sua detec&#231;&#227;o pode levar &#224; suspeita de CET&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">O CET tem sido frequentemente subdiagnosticado&#44; principalmente em pa&#237;ses em desenvolvimento&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> O aparecimento precoce de alguns sinais cut&#226;neos &#233; altamente sugestivo da doen&#231;a &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; Dada sua import&#226;ncia para o diagn&#243;stico e tratamento dessa doen&#231;a gen&#233;tica neurocut&#226;nea&#44; este estudo teve como objetivo caracterizar as les&#245;es cut&#226;neas de 37 pacientes com diagn&#243;stico cl&#237;nico e gen&#233;tico definitivo de CET&#46; Al&#233;m disso&#44; os pacientes foram classificados de acordo com o gene alterado&#59; em cada categoria gen&#233;tica verificou&#8208;se a frequ&#234;ncia de les&#245;es cut&#226;neas espec&#237;ficas&#46; Nessa coorte de CET&#44; os autores descrevem associa&#231;&#227;o significante entre fibromas ungueais e altera&#231;&#245;es no gene <span class="elsevierStyleItalic">TSC2</span>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pacientes e m&#233;todos</span><p id="par0025" class="elsevierStylePara elsevierViewall">Este estudo observacional&#44; anal&#237;tico e transversal foi realizado no Departamento de Pediatria do Complexo Hospitalar de Cl&#237;nicas da Universidade Federal do Paran&#225; &#40;CHC&#8208;UFPR&#41;&#44; Curitiba&#44; Brasil&#46; O protocolo do estudo foi aprovado pelos Comit&#234;s de &#201;tica em Pesquisa do CHC&#47;UFPR &#40;CAAE n&#176; 67137317&#46;5&#46;0000&#46;0096&#41; e da Universidade de S&#227;o Paulo &#40;CAAE n&#176; 12572913&#46;3&#46;3002&#46;5479 e 48259715&#46;2&#46;3003&#46;5505&#41;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Os pacientes inclu&#237;dos no estudo foram clinicamente diagnosticados com CET de acordo com Northrup et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a> e tinham uma variante patog&#234;nica de DNA previamente identificada por Sanger&#44; amplifica&#231;&#227;o de sonda dependente de liga&#231;&#227;o multiplex &#40;MLPA&#44; do ingl&#234;s <span class="elsevierStyleItalic">multiplex ligation&#8208;dependent probe amplification</span>&#41; ou sequenciamento de pr&#243;xima gera&#231;&#227;o &#40;NGS&#44; do ingl&#234;s <span class="elsevierStyleItalic">next&#8208;generation sequencing</span>&#41; nos genes <span class="elsevierStyleItalic">TSC1</span> &#40;NM&#95;000368&#46;4&#41; ou <span class="elsevierStyleItalic">TSC2</span> &#40;NM&#95;000548&#46;3&#41; na Universidade de S&#227;o Paulo&#44; S&#227;o Paulo&#44; Brasil &#40;dados n&#227;o publicados&#41;&#46; Ap&#243;s a publica&#231;&#227;o dos crit&#233;rios diagn&#243;sticos atualizados&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> os dados foram revisados adequadamente e nenhuma altera&#231;&#227;o foi feita&#46; Neste estudo ambispectivo&#44; ap&#243;s a fam&#237;lia fornecer consentimento informado por escrito&#44; os prontu&#225;rios m&#233;dicos foram revisados retrospectivamente&#46; Em seguida&#44; os pacientes foram atendidos prospectivamente pela equipe de Dermatologia Pedi&#225;trica durante mutir&#227;o para o atendimento de pacientes com CET em outubro de 2021 e outubro de 2022&#46; As informa&#231;&#245;es &#40;identifica&#231;&#227;o&#44; idade&#44; datas&#44; resultado do estudo gen&#233;tico e descri&#231;&#227;o das les&#245;es cut&#226;neas&#41; foram registradas e as les&#245;es cl&#237;nicas&#44; fotografadas&#46; Os dados foram analisados estatisticamente no <span class="elsevierStyleItalic">software</span> Excel&#174;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A amostra foi selecionada de maneira n&#227;o probabil&#237;stica e sistem&#225;tica por conveni&#234;ncia&#44; por ordem de agendamento e admiss&#227;o no estudo&#46; As medidas de tend&#234;ncia central e dispers&#227;o foram expressas como m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio padr&#227;o para vari&#225;veis cont&#237;nuas com distribui&#231;&#227;o sim&#233;trica e mediana &#40;intervalo interquartil &#91;IQR&#93;&#41; para aquelas com distribui&#231;&#227;o assim&#233;trica&#46; As vari&#225;veis categ&#243;ricas foram expressas como frequ&#234;ncias absolutas e relativas&#46; O teste n&#227;o param&#233;trico de Mann&#8208;Whitney foi utilizado para estimar a diferen&#231;a entre vari&#225;veis cont&#237;nuas com distribui&#231;&#227;o assim&#233;trica&#44; e os testes exato de Fisher e Qui&#8208;Quadrado de Pearson foram utilizados para estimar a diferen&#231;a entre vari&#225;veis categ&#243;ricas&#46; Todos os testes consideraram n&#237;vel de signific&#226;ncia m&#237;nimo de 5&#37;&#44; erro tipo II de 10&#37; e magnitude do efeito da diferen&#231;a estimada entre genes mutados de quatro vezes&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="par0040" class="elsevierStylePara elsevierViewall">A amostra do estudo incluiu um total de 37 pacientes &#40;36 pacientes n&#227;o aparentados&#41;&#44; com diagn&#243;stico cl&#237;nico e gen&#233;tico definitivo de CET&#44; dos quais 20 &#40;54&#44;1&#37;&#41; eram do g&#234;nero masculino e 17 &#40;45&#44;9&#37;&#41; do feminino&#46; Todos apresentavam pelo menos um sinal dermatol&#243;gico considerado crit&#233;rio diagn&#243;stico de CET &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; Todos os pacientes tiveram a primeira les&#227;o cut&#226;nea antes dos 18 anos&#46; A mediana da idade no momento do diagn&#243;stico de CET foi de 18 meses &#40;IIQ&#58; 8&#8208;60&#41;&#44; e a mediana da idade na avalia&#231;&#227;o dermatol&#243;gica foi de 16 anos &#40;IIQ&#58; 9&#8208;24&#44;5&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Vinte e sete fam&#237;lias souberam informar o primeiro sinal cut&#226;neo identificado no paciente&#46; A mediana da idade de in&#237;cio dos pacientes foi de 3 meses &#40;IIQ&#58; 0&#8208;19&#41;&#44; e a les&#227;o cut&#226;nea mais frequente identificada inicialmente foi a m&#225;cula hipomelan&#243;tica em forma de folha &#40;25&#47;27&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Considerando os pacientes de acordo com o g&#234;nero&#44; n&#227;o foi observada diferen&#231;a nos primeiros sinais cut&#226;neos&#44; idade de in&#237;cio&#44; idade do diagn&#243;stico de CET ou gene mutado &#40;p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">As <a class="elsevierStyleCrossRefs" href="#fig0005">figuras 1 e 2</a> ilustram alguns dos principais achados cut&#226;neos nos pacientes com CET desta coorte&#44; que foram m&#225;culas hipomelan&#243;ticas &#40;92&#44;5&#37;&#41;&#44; angiofibromas &#40;87&#44;5&#37;&#41;&#44; placas cef&#225;licas &#40;80&#37;&#41;&#44; les&#245;es semelhantes a confete &#40;67&#44;5&#37;&#41;&#44; placas de Shagreen &#40;55&#37;&#41;&#44; fibromas ungueais &#40;55&#37;&#41; e fibromas intraorais &#40;25&#37;&#41;&#46; Quando cada les&#227;o cut&#226;nea do CET foi considerada individualmente&#44; n&#227;o houve diferen&#231;a entre os g&#234;neros &#40;p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3A</a>&#41;&#46; O n&#250;mero de angiofibromas tamb&#233;m foi semelhante entre os g&#234;neros &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;31&#41;&#46; Dados coletados de 37 pacientes &#40;mediana de idade de 16 &#91;4&#8208;41&#93; anos&#41; examinados em dois momentos &#40;outubro de 2021 e outubro de 2022&#41; n&#227;o revelaram nenhuma nova les&#227;o cut&#226;nea um ano depois&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Todos os 37 pacientes com CET tiveram DNA avaliado por sequenciamento&#44; incluindo dois irm&#227;os&#46; As 36 altera&#231;&#245;es patog&#234;nicas do DNA foram distribu&#237;das entre o gene <span class="elsevierStyleItalic">TSC1</span> em quatro indiv&#237;duos n&#227;o aparentados &#40;11&#44;1&#37;&#41; e <span class="elsevierStyleItalic">TSC2</span> em 32 &#40;88&#44;9&#37;&#41; pacientes&#44; definindo raz&#227;o de altera&#231;&#227;o TSC2&#58;TSC1 de 8&#58;1&#46; Havia tr&#234;s variantes de <span class="elsevierStyleItalic">frameshift</span> e uma grande dele&#231;&#227;o no <span class="elsevierStyleItalic">TSC1</span>&#46; Os dois irm&#227;os apresentavam altera&#231;&#227;o patog&#234;nica do <span class="elsevierStyleItalic">TSC1</span>&#44; totalizando cinco indiv&#237;duos com altera&#231;&#245;es nesse gene&#46; As altera&#231;&#245;es do <span class="elsevierStyleItalic">TSC2</span> compreenderam sete variantes de <span class="elsevierStyleItalic">frameshift</span>&#44; sete de <span class="elsevierStyleItalic">missense</span> &#250;nico&#44; seis <span class="elsevierStyleItalic">nonsense</span> &#250;nico&#44; tr&#234;s <span class="elsevierStyleItalic">splicing</span> e tr&#234;s variantes de dele&#231;&#227;o <span class="elsevierStyleItalic">in&#8208;frame</span>&#44; al&#233;m de tr&#234;s grandes dele&#231;&#245;es e uma grande duplica&#231;&#227;o&#46; Uma variante <span class="elsevierStyleItalic">nonsense</span> do <span class="elsevierStyleItalic">TSC2</span> foi encontrada em tr&#234;s pacientes n&#227;o aparentados&#44; totalizando 32 pacientes com altera&#231;&#245;es no <span class="elsevierStyleItalic">TSC2</span>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">As frequ&#234;ncias de altera&#231;&#245;es patog&#234;nicas nos genes <span class="elsevierStyleItalic">TSC1</span> e <span class="elsevierStyleItalic">TSC2</span> foram semelhantes entre os g&#234;neros &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;34&#41;&#46; A idade de in&#237;cio da les&#227;o cut&#226;nea e a idade do diagn&#243;stico de CET estavam dispon&#237;veis para cinco e 22 pacientes com altera&#231;&#245;es patog&#234;nicas no DNA dos genes <span class="elsevierStyleItalic">TSC1</span> e <span class="elsevierStyleItalic">TSC2</span>&#44; respectivamente&#46; N&#227;o houve diferen&#231;as significantes entre os grupos de pacientes com genes alterados distintos&#44; quando as compara&#231;&#245;es foram feitas para idade no aparecimento da primeira les&#227;o cut&#226;nea&#44; no diagn&#243;stico de CET ou tipo da primeira les&#227;o cut&#226;nea &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#59; p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Os fibromas ungueais foram mais frequentes entre os pacientes com altera&#231;&#227;o gen&#233;tica no <span class="elsevierStyleItalic">TSC2</span> do que no <span class="elsevierStyleItalic">TSC1</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3B</a>&#59; 65&#44;6&#37; <span class="elsevierStyleItalic">vs</span>&#46; 20&#44;0&#37;&#44; para <span class="elsevierStyleItalic">TSC2</span><span class="elsevierStyleItalic">vs</span>&#46; <span class="elsevierStyleItalic">TSC1</span>&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;07&#41;&#46; As raz&#245;es de chances &#40;<span class="elsevierStyleItalic">odds ratio</span>&#41; estimadas para les&#245;es cut&#226;neas espec&#237;ficas revelaram um aumento de dez vezes para fibroma ungueal quando uma altera&#231;&#227;o patog&#234;nica de <span class="elsevierStyleItalic">TSC2</span> estava presente &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4A</a>&#59; raz&#227;o de chances<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#44;50&#59; intervalo de confian&#231;a de 95&#37;&#58; 1&#44;12&#8208;67&#44;21&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41;&#46; O n&#250;mero de angiofibromas por paciente foi semelhante entre pacientes portadores de altera&#231;&#227;o patog&#234;nica em diferentes genes &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3B</a>&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;64&#41; e variou de zero a cinco &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4B</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discuss&#227;o</span><p id="par0070" class="elsevierStylePara elsevierViewall">As les&#245;es cut&#226;neas associadas ao CET devem ser reconhecidas pelos cl&#237;nicos gerais e pediatras&#44; pois s&#227;o comumente os primeiros sinais percept&#237;veis dessa doen&#231;a e compreendem quatro dos 11 crit&#233;rios maiores e tr&#234;s dos sete crit&#233;rios menores para o diagn&#243;stico cl&#237;nico de CET &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; O diagn&#243;stico precoce &#233; importante para o acompanhamento longitudinal e o in&#237;cio do tratamento adequado&#44; limitando o crescimento das les&#245;es e a morbidade relacionada&#46; Os inibidores de mTOR receberam aprova&#231;&#227;o cl&#237;nica como terapia oral para les&#245;es espec&#237;ficas de TSC&#44; como por exemplo o everolimus para tratar astrocitoma subependim&#225;rio de c&#233;lulas gigantes&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> angiomiolipoma renal&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a> e como tratamento adjuvante de convuls&#245;es de in&#237;cio parcial do CET&#59;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a> e sirolimus &#40;rapamicina&#41; para linfangioleiomiomatose&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a> Em estudos cl&#237;nicos&#44; o sirolimus t&#243;pico diminuiu os angiofibromas&#44; as m&#225;culas hipomelan&#243;ticas e as placas cef&#225;licas e &#233; bem tolerado por crian&#231;as&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">12&#8208;14</span></a> Portanto&#44; as les&#245;es cut&#226;neas do CET n&#227;o s&#227;o importantes apenas para o diagn&#243;stico da doen&#231;a&#44; mas podem ser tratadas de maneira eficaz atrav&#233;s da hiperativa&#231;&#227;o do mTOR&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Em nossa coorte de 37 pacientes com diagn&#243;stico cl&#237;nico e gen&#233;tico definitivo de CET&#44; os sinais cut&#226;neos iniciais mais comuns foram m&#225;culas hipomelan&#243;ticas&#44; que tamb&#233;m foram a apresenta&#231;&#227;o dermatol&#243;gica mais frequente &#40;92&#44;5&#37;&#41;&#46; M&#225;culas hipomelan&#243;ticas ocorrem em aproximadamente 90&#37; dos pacientes e t&#234;m in&#237;cio geralmente ao nascimento ou na primeira inf&#226;ncia&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> como observado &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27 casos informados&#59; idade m&#233;dia de 3 meses&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; Outros primeiros sinais cut&#226;neos menos observados foram les&#245;es em confete&#44; placas fibrosas cef&#225;licas ou intraorais &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; Entre os beb&#234;s de 1 m&#234;s de vida com pelo menos um sinal sugestivo de CET&#44; as m&#225;culas hipomelan&#243;ticas foram a causa da suspeita diagn&#243;stica em 31&#37; deles&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> Em pacientes com at&#233; 4 meses de vida&#44; m&#225;culas hipomelan&#243;ticas foram o sinal inicial em 35&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> O presente estudo n&#227;o avaliou sinais n&#227;o dermatol&#243;gicos&#46; Ele confirma que&#44; entre as les&#245;es cut&#226;neas&#44; as m&#225;culas hipomelan&#243;ticas s&#227;o o primeiro sinal mais frequente em pacientes com CET &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Os angiofibromas faciais foram a segunda les&#227;o mais frequente &#40;87&#44;5&#37;&#41;&#44; seguidos pelas placas cef&#225;licas &#40;80&#37;&#41;&#46; A ocorr&#234;ncia geral estimada de angiofibroma &#40;75&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> aumenta na segunda d&#233;cada de vida&#44; ap&#243;s a puberdade&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> Assim&#44; a frequ&#234;ncia dos angiofibromas depende da m&#233;dia de idade dos pacientes no momento da admiss&#227;o na coorte&#46; As placas de Shagreen s&#227;o geralmente observadas a partir da primeira d&#233;cada de vida&#44; mais comumente a partir dos 5 anos&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">5&#44;16</span></a> em frequ&#234;ncia &#40;50&#37;&#41; semelhante &#224; observada pelos autores do presente estudo &#40;55&#37;&#41;&#46; Les&#245;es semelhantes a confete foram detectadas em 67&#44;5&#37; dos pacientes&#46; Em geral&#44; come&#231;am na primeira d&#233;cada de vida&#44; mas t&#234;m utilidade limitada como crit&#233;rio diagn&#243;stico em adultos&#44; pois podem se desenvolver como consequ&#234;ncia de exposi&#231;&#227;o solar cr&#244;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> Uma hist&#243;ria de in&#237;cio na primeira inf&#226;ncia &#233; sugestiva de CET&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">5</span></a> Os fibromas intraorais ocorrem em 20&#8208;50&#37; dos pacientes&#44; mais frequentemente em adultos do que em crian&#231;as&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> Essas les&#245;es foram detectadas em 10 pacientes desta coorte com CET &#40;25&#37;&#41;&#46; A distribui&#231;&#227;o das les&#245;es cut&#226;neas n&#227;o foi diferente entre os g&#234;neros &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; Os fibromas gengivais foram identificados com mais frequ&#234;ncia no g&#234;nero masculino do que no feminino&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">A m&#233;dia de idade ao diagn&#243;stico foi de 18 meses na presente amostra&#44; 15 meses depois da m&#233;dia de idade na detec&#231;&#227;o do primeiro sinal cut&#226;neo e mais tarde do que a m&#233;dia de idade ao diagn&#243;stico em outro estudo recente &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>86&#59; seis meses&#41; que adotou os mesmos crit&#233;rios diagn&#243;sticos&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a> Nesse estudo alem&#227;o&#44; o rabdomioma card&#237;aco&#44; um crit&#233;rio cl&#237;nico maior de CET &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#44; detectado por imagens fetais pr&#233;&#8208;natais&#44; contribuiu para o diagn&#243;stico precoce da doen&#231;a em 22&#37; dos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> Parece que os pacientes da presente coorte brasileira t&#234;m acesso heterog&#234;neo a exames de imagem fetais e dependem mais comumente de hospitais terci&#225;rios de refer&#234;ncia para o estabelecimento do diagn&#243;stico de CET&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">O teste gen&#233;tico &#233; &#250;til para confirmar o diagn&#243;stico de CET&#44; particularmente em casos clinicamente desafiadores em est&#225;gios iniciais&#46; Nessa an&#225;lise&#44; as variantes patog&#234;nicas de <span class="elsevierStyleItalic">TSC1</span> e <span class="elsevierStyleItalic">TSC2</span> foram observadas em 13&#44;5&#37; &#40;5&#47;37&#41; e 86&#44;5&#37; &#40;32&#47;37&#41; dos pacientes&#44; respectivamente&#44; razoavelmente acima da propor&#231;&#227;o observada em outros estudos&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">17&#8208;21</span></a> A predomin&#226;ncia de altera&#231;&#245;es gen&#233;ticas patog&#234;nicas do <span class="elsevierStyleItalic">TSC2</span>&#44; oito vezes mais comuns que as variantes patog&#234;nicas do <span class="elsevierStyleItalic">TSC1</span>&#44; foi observada predominantemente no g&#234;nero feminino &#40;oito vezes no g&#234;nero feminino e 3&#44;4 vezes no masculino&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; A chance de muta&#231;&#227;o no <span class="elsevierStyleItalic">TSC2</span> foi 10 vezes maior na presen&#231;a de fibromas ungueais&#44; embora esses dados devam ser vistos com cautela em virtude do amplo intervalo de confian&#231;a associado ao pequeno n&#250;mero de casos com muta&#231;&#227;o no <span class="elsevierStyleItalic">TSC1</span>&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Um fen&#243;tipo neurol&#243;gico mais grave pode estar associado &#224; muta&#231;&#227;o no <span class="elsevierStyleItalic">TSC2</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">17&#8208;21</span></a> enquanto as les&#245;es cut&#226;neas e a associa&#231;&#227;o genot&#237;pica parecem ser mais vari&#225;veis entre os estudos&#44; exceto para angiofibromas faciais&#46; O banco de dados de hist&#243;ria natural do TSC revelou associa&#231;&#227;o significante entre a muta&#231;&#227;o do <span class="elsevierStyleItalic">TSC2</span> e angiofibromas&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">22</span></a> O grau m&#233;dio de angiofibroma facial parece ser maior em pacientes com altera&#231;&#227;o de <span class="elsevierStyleItalic">TSC2</span> do que de <span class="elsevierStyleItalic">TSC1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> N&#227;o foi observada diferen&#231;a no n&#250;mero de angiofibromas&#44; o que pode ser devido ao pequeno n&#250;mero de pacientes com muta&#231;&#227;o no <span class="elsevierStyleItalic">TSC1</span>&#44; embora pare&#231;a haver tend&#234;ncia ao aumento do n&#250;mero de angiofibromas na presen&#231;a de muta&#231;&#227;o no gene <span class="elsevierStyleItalic">TSC2</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4A</a>&#41;&#46; Em outro estudo&#44; crian&#231;as de 2 anos com muta&#231;&#227;o no gene <span class="elsevierStyleItalic">TSC1</span> apresentaram menos m&#225;culas hipomelan&#243;ticas e angiofibromas faciais do que aquelas com altera&#231;&#227;o gen&#233;tica no <span class="elsevierStyleItalic">TSC2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a> Por outro lado&#44; placas de Shagreen foram observadas com mais frequ&#234;ncia em pacientes com altera&#231;&#227;o no gene <span class="elsevierStyleItalic">TSC1</span> do que no <span class="elsevierStyleItalic">TSC2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> Entre 38 pacientes com CET com pelo menos um sinal cut&#226;neo&#44; o exame dermatol&#243;gico por si s&#243; foi suficiente para estabelecer o diagn&#243;stico definitivo da doen&#231;a em 34 deles&#44; demonstrando a import&#226;ncia do reconhecimento precoce das les&#245;es cut&#226;neas&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">24&#44;25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">A presente coorte de CET de um centro cl&#237;nico de refer&#234;ncia no sul do Brasil revela a associa&#231;&#227;o entre fibromas ungueais e altera&#231;&#227;o gen&#233;tica do gene <span class="elsevierStyleItalic">TSC2</span>&#46; Uma limita&#231;&#227;o do estudo &#233; o pequeno tamanho amostral e o n&#250;mero limitado de pacientes com variantes patog&#234;nicas do <span class="elsevierStyleItalic">TSC1</span>&#46; Mais estudos s&#227;o necess&#225;rios para avaliar a associa&#231;&#227;o da apresenta&#231;&#227;o dermatol&#243;gica do CET com o gen&#243;tipo&#46; Foi confirmada a import&#226;ncia da detec&#231;&#227;o de les&#245;es cut&#226;neas para identifica&#231;&#227;o precoce do CET&#46; Os m&#233;dicos devem estar cientes das poss&#237;veis les&#245;es mucocut&#226;neas do CET&#44; sua expressividade vari&#225;vel e da hist&#243;ria natural da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Suporte financeiro</span><p id="par0105" class="elsevierStylePara elsevierViewall">Essa pesquisa recebeu suporte financeiro dos subs&#237;dios 2013&#47;08028&#8208;1 e 2019&#47;10868&#8208;4<span class="elsevierStyleHsp" style=""></span>da Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo &#40;FAPESP&#41; e CAPES &#40;Processo&#58; 88881&#46;132401&#47;2016&#8208;01&#59; Brasil&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Contribui&#231;&#227;o dos autores</span><p id="par0110" class="elsevierStylePara elsevierViewall">Beatriz Azevedo Nunes&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Ana Karolina Ferreira Gon&#231;alves Romano&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Mariana Aparecida Pasa Morgan&#58; Concep&#231;&#227;o e planejamento do estudo&#59; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Alice Andrade Gon&#231;alves&#58; Obten&#231;&#227;o de dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">La&#237;s Faria Masulk Cardozo&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o de dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Luiz Gustavo Dufner de Almeida&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Luciana Amaral Haddad&#58; Concep&#231;&#227;o e planejamento do estudo&#59; An&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Ana Chrystina de Souza Crippa&#58; Concep&#231;&#227;o e planejamento do estudo&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Sergio Antonio Antoniuk&#58; Concep&#231;&#227;o e planejamento do estudo&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Kerstin Taniguchi Abagge&#58; Concep&#231;&#227;o e planejamento do estudo&#59; An&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#59; e aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflito de interesses</span><p id="par0160" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O complexo da esclerose tuberosa &#40;CET&#41; &#233; s&#237;ndrome neurocut&#226;nea multissist&#234;mica com fen&#243;tipos variados&#46; A atualiza&#231;&#227;o recente dos crit&#233;rios diagn&#243;sticos do CET reafirmou o crit&#233;rio diagn&#243;stico gen&#233;tico definido como o achado de uma altera&#231;&#227;o patog&#234;nica no DNA nos genes <span class="elsevierStyleItalic">TSC1</span> ou <span class="elsevierStyleItalic">TSC2</span>&#46; A atualiza&#231;&#227;o tamb&#233;m modificou ligeiramente os crit&#233;rios diagn&#243;sticos cl&#237;nicos finais&#46; Les&#245;es cut&#226;neas associadas ao CET na inf&#226;ncia s&#227;o sinais cl&#237;nicos importantes para selecionar indiv&#237;duos com poss&#237;vel CET para seguimento cl&#237;nico mais detalhado e testes gen&#233;ticos&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Aumentar o conhecimento dos crit&#233;rios diagn&#243;sticos atualizados do CET&#59; avaliar a frequ&#234;ncia de les&#245;es cut&#226;neas em pacientes com CET&#44; bem como a primeira apresenta&#231;&#227;o dermatol&#243;gica&#59; e associar os achados &#224;s altera&#231;&#245;es do <span class="elsevierStyleItalic">TSC1</span> ou <span class="elsevierStyleItalic">TSC2</span>&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Estudo observacional transversal&#46; Os dados cl&#237;nicos e gen&#233;ticos foram coletados retrospectivamente de 37 pacientes com CET em hospital universit&#225;rio brasileiro&#46; Pacientes com sinais cut&#226;neos foram examinados e avaliados prospectivamente por 12 meses&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">As les&#245;es cut&#226;neas mais precoces foram m&#225;culas hipomelan&#243;ticas&#59; que juntamente com os angiofibromas tamb&#233;m foram as les&#245;es dermatol&#243;gicas mais frequentes&#46; A raz&#227;o total de altera&#231;&#245;es patog&#234;nicas no DNA entre os genes <span class="elsevierStyleItalic">TSC2</span> e <span class="elsevierStyleItalic">TSC1</span> foi de 8&#58;1&#46; A frequ&#234;ncia de uma variante patog&#234;nica do <span class="elsevierStyleItalic">TSC2</span> foi dez vezes maior na presen&#231;a de fibromas ungueais&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Amostra pequena e n&#250;mero limitado de pacientes com variantes patog&#234;nicas do <span class="elsevierStyleItalic">TSC1</span>&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Os m&#233;dicos devem ter conhecimento sobre os crit&#233;rios diagn&#243;sticos atualizados do CET&#46; Os pacientes devem ser monitorados por equipe multidisciplinar e tratados adequadamente&#46; A detec&#231;&#227;o precoce de les&#245;es cut&#226;neas &#233; importante para o diagn&#243;stico de CET&#46; &#201; descrita associa&#231;&#227;o significante entre altera&#231;&#245;es patog&#234;nicas do gene <span class="elsevierStyleItalic">TSC2</span> e fibromas ungueais&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Como citar este artigo&#58; Nunes BA&#44; Romano AKFG&#44; Morgan MAP&#44; Gon&#231;alves AA&#44; Cardozo LFM&#44; de Almeida LGD&#44; et al&#46; A dermatological assessment of pediatric patients with tuberous sclerosis complex &#40;TSC&#41;&#46; An Bras Dermatol&#46; 2024&#59;99&#58;662&#8211;9&#46;</p>"
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        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Trabalho realizado no Complexo Hospitalar de Cl&#237;nicas&#44; Universidade Federal do Paran&#225;&#44; Curitiba&#44; PR&#44; Brasil&#46;</p>"
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          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#8208;B&#41; M&#225;culas hipomelan&#243;ticas no abdme &#40;A&#41; e placa de Shagreen no dorso de paciente adolescente &#40;B&#41;&#46;</p>"
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          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#8208;B&#41; Les&#245;es em confete &#40;<span class="elsevierStyleItalic">setas</span>&#41; na regi&#227;o anterior da t&#237;bia &#40;A&#41; e fibromas ungueais no 4&#176; e 5&#176; quirod&#225;ctilos de paciente adulto &#40;B&#41;&#46;</p>"
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          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribui&#231;&#227;o de frequ&#234;ncia das les&#245;es cut&#226;neas por g&#234;nero &#40;A&#41; e gene mutado &#40;B&#41;&#46; &#40;A&#41; Teste exato de Fisher&#58; m&#225;culas hipomelan&#243;ticas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;23&#59; angiofibromas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;00&#59; placas cef&#225;licas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;70&#59; les&#245;es em confete&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;50&#59; fibromas ungueais&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;53&#59; placas de Shagreen&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;33&#59; fibromas intraorais&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;73&#46; &#40;B&#41; Teste exato de Fisher&#58; m&#225;culas hipomelan&#243;ticas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;44&#59; angiofibromas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;00&#59; placas cef&#225;licas&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;61&#59; les&#245;es em confete&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;18&#59; fibromas ungueais&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;07&#59; placas de Shagreen&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;42&#59; fibromas intraorais&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;00&#46;</p>"
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        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Angiofibromas por gene mutado &#40;A&#41; e <span class="elsevierStyleItalic">odds ratio</span> de les&#245;es cut&#226;neas de CET para a muta&#231;&#227;o TSC2 &#40;B&#41;&#46; &#40;A&#41; Teste Qui&#8208;Quadrado de Pearson&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;64&#46; &#40;B&#41; Fibromas ungueais&#58; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#44;50&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">OR</span>&#44; <span class="elsevierStyleItalic">odds ratio</span>&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Os termos sublinhados correspondem a crit&#233;rios atualizados&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t">M&#225;culas hipomelan&#243;ticas &#40;&#8805; 3&#44; com pelo menos 5 mm de di&#226;metro&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Les&#245;es em confete&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Angiofibromas faciais &#40;&#8805; 3&#41; ou placa fibrosa cef&#225;lica&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Depress&#245;es no esmalte dent&#225;rio &#40;&#8805; 3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibromas ungueais &#40;&#8805; 2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Fibromas intraorais &#40;&#8805; 2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Placas de Shagreen&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Mancha acr&#244;mica na retina&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Hamartomas m&#250;ltiplos na retina&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">M&#250;ltiplos cistos renais&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleUnderline">M&#250;ltiplos tub&#233;rculos corticais e&#47;ou linhas de migra&#231;&#227;o radial</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Hamartomas n&#227;o renais&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">N&#243;dulos subependim&#225;rios &#40;&#8805; 2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleUnderline">Les&#245;es &#243;sseas escler&#243;ticas</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Astrocitoma subependim&#225;rio de c&#233;lulas gigantes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Rabdomioma card&#237;aco&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Linfangioleiomiomatose<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">A combina&#231;&#227;o desses dois crit&#233;rios principais sem outras caracter&#237;sticas n&#227;o permite um diagn&#243;stico definitivo&#46;</p> <p class="elsevierStyleNotepara" id="npar0010"><span class="elsevierStyleUnderline">Diagn&#243;stico cl&#237;nico definitivo de CET&#58;</span> dois crit&#233;rios maiores ou um crit&#233;rio maior mais dois ou mais crit&#233;rios menores&#46;</p> <p class="elsevierStyleNotepara" id="npar0015"><span class="elsevierStyleUnderline">Poss&#237;vel diagn&#243;stico cl&#237;nico de CET</span>&#58; um crit&#233;rio maior ou pelo menos dois crit&#233;rios menores&#46;</p>"
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          "pt" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Crit&#233;rios maiores e menores para o diagn&#243;stico cl&#237;nico de CET de acordo com Northrup et al&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a></p>"
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                  <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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Idade e les&#227;o cut&#226;nea</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Feminino&#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Masculino&#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#91;Mediana &#40;IIQ&#41;&#59; n &#40;&#37;&#41;&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#91;Mediana &#40;IIQ&#41;&#59; n &#40;&#37;&#41;&#93;&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediana da idade no in&#237;cio dos primeiros sinais cut&#226;neos &#40;meses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;0 &#40;0&#8208;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;0 &#40;0&#8208;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;92<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediana da idade no diagn&#243;stico de CET &#40;meses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#44;0 &#40;12&#8208;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#44;0 &#40;7&#8208;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primeiros sinais cut&#226;neos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#225;cula hipomelan&#243;tica em folha&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;92&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;92&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;00<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#227;o em confete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;15&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;22<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placa fibrosa cef&#225;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;14&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;7&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;00<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placa fibrosa intraoral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;7&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;48<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gene que abriga a altera&#231;&#227;o patog&#234;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TSC1</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;20&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;5&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;34<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TSC2</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;80&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;94&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Idade na detec&#231;&#227;o da primeira les&#227;o cut&#226;nea&#44; diagn&#243;stico de CET e primeiros sinais cut&#226;neos de acordo com o g&#234;nero</p>"
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                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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Idade&#44; diagn&#243;stico e n&#250;mero de sinais cut&#226;neos</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">TSC1</span> &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">TSC2</span> &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#91;Mediana &#40;IIQ&#41;&#59; n&#160;&#40;&#37;&#41;&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#91;Mediana &#40;IIQ&#41;&#59; n&#160;&#40;&#37;&#41;&#93;&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idade e les&#227;o cut&#226;nea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediana da idade no in&#237;cio dos primeiros sinais cut&#226;neos &#40;meses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0 &#40;0&#8208;18&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;5 &#40;0&#8208;19&#41;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;39<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediana da idade no diagn&#243;stico de CET &#40;meses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#44;0 &#40;15&#8208;57&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#44;0 &#40;8&#8208;60&#41;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;80<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#250;mero de sinais cut&#226;neos observados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#225;cula hipomelan&#243;tica em folha&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;96&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;25<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Angiofibromas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;100&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;100&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;00<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placa fibrosa cef&#225;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;81&#44;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;00<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#227;o em confete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;60&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23 &#40;71&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;62<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placas de Shagreen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;56&#44;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;62<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibromas ungueais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;20&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;65&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;13<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibromas intraorais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;20&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;25&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;00<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Teste Exato de Fisher&#46;</p>"
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          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Idade na detec&#231;&#227;o da primeira les&#227;o cut&#226;nea&#44; diagn&#243;stico de CET e sinais cut&#226;neos totais de acordo com o gene que abriga a altera&#231;&#227;o patog&#234;nica</p>"
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      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:26 [
            0 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "International Tuberous Sclerosis Complex Consensus Group&#46; Tuberous sclerosis complex surveillance and management&#58; recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;A&#46; Krueger"
                            1 => "H&#46; Northrup"
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                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pediatrneurol.2013.08.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Neurol&#46;"
                        "fecha" => "2013"
                        "volumen" => "49"
                        "paginaInicial" => "255"
                        "paginaFinal" => "265"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24053983"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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            1 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Esclerose Tuberosa&#58; diagn&#243;stico&#44; seguimento e tratamento"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;S&#46; Santalha"
                            1 => "I&#46; Carrilho"
                            2 => "T&#46; Temudo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Pediatr Port&#46;"
                        "fecha" => "2013"
                        "volumen" => "44"
                        "paginaInicial" => "82"
                        "paginaFinal" => "89"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Northrup"
                            1 => "M&#46;E&#46; Aronow"
                            2 => "E&#46;M&#46; Bebin"
                            3 => "J&#46; Bissler"
                            4 => "T&#46;N&#46; Darling"
                            5 => "P&#46;J&#46; de Vries"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pediatrneurol.2021.07.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Neurol&#46;"
                        "fecha" => "2021"
                        "volumen" => "123"
                        "paginaInicial" => "50"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34399110"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "International Tuberous Sclerosis Complex Consensus Group&#46; Tuberous sclerosis complex diagnostic criteria update&#58; recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Northrup"
                            1 => "D&#46;A&#46; Krueger"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Pediatr Neurol&#46;"
                        "fecha" => "2013"
                        "volumen" => "49"
                        "paginaInicial" => "243"
                        "paginaFinal" => "254"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genotype&#47;phenotype correlations in tuberous sclerosis complex"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "P&#46; Curatolo"
                            1 => "R&#46; Moavero"
                            2 => "D&#46; Roberto"
                            3 => "F&#46; Graziola"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.spen.2015.10.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Pediatr Neurol&#46;"
                        "fecha" => "2015"
                        "volumen" => "22"
                        "paginaInicial" => "259"
                        "paginaFinal" => "273"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26706013"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence of tuberous sclerosis and age at first diagnosis&#58; new data and emerging trends from a national&#44; prospective surveillance study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Ebrahimi-Fakhari"
                            1 => "L&#46;L&#46; Mann"
                            2 => "M&#46; Poryo"
                            3 => "N&#46; Graf"
                            4 => "R&#46; von Kries"
                            5 => "B&#46; Heinrich"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13023-018-0870-y"
                      "Revista" => array:5 [
                        "tituloSerie" => "Orphanet J Rare Dis&#46;"
                        "fecha" => "2018"
                        "volumen" => "13"
                        "paginaInicial" => "117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30016967"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early diagnosis of tuberous sclerosis complex&#58; a race against time&#46; How to make the diagnosis before seizures&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; S&#322;owi&#324;ska"
                            1 => "S&#46; J&#243;&#378;wiak"
                            2 => "A&#46; Peron"
                            3 => "J&#46; Borkowska"
                            4 => "D&#46; Chmielewski"
                            5 => "K&#46; Sadowski"
                          ]
                        ]
                      ]
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