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Infelizmente&#44; n&#227;o h&#225; tratamento eficaz para a doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> M&#233;todos confi&#225;veis para o diagn&#243;stico pr&#233;&#8208;natal s&#227;o&#44; portanto&#44; essenciais para a detec&#231;&#227;o neonatal de IA&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Antes de 2005&#44; nenhum gene candidato para IA havia sido identificado&#44; e o diagn&#243;stico da doen&#231;a dependia de histopatologia em bi&#243;psias intrauterinas da pele fetal entre 19 e 23 semanas&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">4&#8211;6</span></a> Entretanto&#44; como esse m&#233;todo &#233; invasivo e tecnicamente dif&#237;cil&#44; ele aumenta o risco de m&#250;ltiplas complica&#231;&#245;es na gravidez&#46; Portanto&#44; depois que o gene ABCA12 foi identificado como o gene causador da IA&#44; a an&#225;lise da muta&#231;&#227;o do gene ABCA12 pela an&#225;lise do l&#237;quido amni&#243;tico e sangue do cord&#227;o umbilical tornou&#8208;se m&#233;todo eficaz para o diagn&#243;stico pr&#233;&#8208;natal de IA&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">7&#44;8</span></a> No entanto&#44; gr&#225;vidas sem hist&#243;rico familiar ou hist&#243;rico de gravidez com IA muitas vezes optam por n&#227;o realizar a triagem pr&#233;&#8208;natal espec&#237;fica para IA utilizando os m&#233;todos mencionados acima&#46; A ultrassonografia &#40;US&#41;&#44; contudo&#44; como exame n&#227;o invasivo e de baixo custo&#44; parece ser m&#233;todo eficaz para o diagn&#243;stico pr&#233;&#8208;natal de IA&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">No presente estudo&#44; os autores realizaram com sucesso o diagn&#243;stico pr&#233;&#8208;natal utilizando US em 2D combinada com 3D em um feto com IA sem hist&#243;rico familiar&#46; An&#225;lise cromoss&#244;mica por <span class="elsevierStyleItalic">microarray</span> &#40;CMA&#44; do ingl&#234;s <span class="elsevierStyleItalic">chromosomal microarray analysis</span>&#41; e an&#225;lise da sequ&#234;ncia de Sanger foram usadas para identificar anormalidades cromoss&#244;micas fetais e identificar a muta&#231;&#227;o patog&#234;nica do gene ABCA12&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">9&#44;10</span></a> Al&#233;m disso&#44; pesquisando a literatura publicada sobre IA&#44; os autores resumiram as caracter&#237;sticas ultrassonogr&#225;ficas da doen&#231;a&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Fontes de dados</span><p id="par0020" class="elsevierStylePara elsevierViewall">Os dados ultrassonogr&#225;ficos e cl&#237;nicos da paciente foram obtidos do banco de dados m&#233;dico eletr&#244;nico do Second Affiliated Hospital da Dalian Medical University&#46; O dispositivo de diagn&#243;stico por US colorida GE Voluson E8 com frequ&#234;ncia de sonda definida de 2&#44;5 a 5&#44;0<span class="elsevierStyleHsp" style=""></span>MHz foi usado no presente estudo&#46; A an&#225;lise por <span class="elsevierStyleItalic">microarray</span> de microRNA foi processada com um chip de <span class="elsevierStyleItalic">microarray</span> comercial de 750K&#44; e as muta&#231;&#245;es foram detectadas por an&#225;lise de dados da sequ&#234;ncia de Sanger&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Estrat&#233;gia de busca</span><p id="par0025" class="elsevierStylePara elsevierViewall">A estrat&#233;gia de busca no banco de dados MEDLINE&#47;Pubmed utilizou as seguintes palavras&#8208;chave&#58; &#8220;<span class="elsevierStyleItalic">Ichthyosis&#44; Lamellar</span>&#8221; e &#8220;<span class="elsevierStyleItalic">Ultrasonography&#44; Prenatal</span>&#8221; &#91;Mesh&#93;&#44; adaptadas &#224;s demais bases de dados quando necess&#225;rio&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Resultados</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Apresenta&#231;&#227;o do caso</span><p id="par0030" class="elsevierStylePara elsevierViewall">O presente caso descreve uma paciente do sexo feminino&#44; de 40 anos&#44; gesta 1&#44; para 0&#44; que concebeu espontaneamente&#44; sem hist&#243;rico familiar de IA&#46; A m&#227;e negou hist&#243;rico de medica&#231;&#227;o ou infec&#231;&#227;o e hist&#243;rico de exposi&#231;&#227;o ambiental adversa durante a gravidez&#46; Os achados ultrassonogr&#225;ficos no in&#237;cio da gravidez&#44; com 13 semanas&#44; e os achados da US no exame durante o per&#237;odo intermedi&#225;rio da gravidez com 24 <span class="elsevierStyleSup">&#43;3</span> semanas n&#227;o mostraram anormalidades significantes&#59; a translusc&#234;ncia nucal &#40;TN&#41; foi de 2&#44;1<span class="elsevierStyleHsp" style=""></span>mm&#46; Os resultados da triagem pr&#233;&#8208;natal n&#227;o invasiva &#40;NIPS&#44; do ingl&#234;s <span class="elsevierStyleItalic">noninvasive prenatal screening</span>&#41; foram negativos&#46; At&#233; 30 <span class="elsevierStyleSup">&#43;2</span> semanas de gesta&#231;&#227;o&#44; os demais exames pr&#233;&#8208;natais foram normais&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Embora o exame de US no final da gravidez com 30 <span class="elsevierStyleSup">&#43;2</span> semanas n&#227;o tenha sugerido nenhuma anormalidade significante dos indicadores de desenvolvimento &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#44; os autores observaram caracter&#237;sticas ultrassonogr&#225;ficas t&#237;picas&#44; incluindo nariz achatado&#44; descama&#231;&#227;o da pele &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#44;B&#41;&#44; ectr&#243;pio&#44; l&#237;ngua voltada para cima e fenda bucal anormalmente grande &#40;semelhante &#224; boca de peixe&#59; <a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#44;B&#41;&#44; microtia &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41; e &#237;ndice de l&#237;quido amni&#243;tico &#40;AFI&#44; do ingl&#234;s <span class="elsevierStyleItalic">amniotic fluid index</span>&#41; de 340<span class="elsevierStyleHsp" style=""></span>mm&#46; Por outro lado&#44; a avalia&#231;&#227;o por US de outros &#243;rg&#227;os&#44; como c&#233;rebro&#44; cora&#231;&#227;o e rins&#44; foi normal e a imagem de fluxo por Doppler colorido &#40;CDFI&#44; do ingl&#234;s <span class="elsevierStyleItalic">color Doppler flow imaging</span>&#41; indicou aus&#234;ncia de anormalidade &#243;bvia no sinal de fluxo sangu&#237;neo da art&#233;ria cerebral m&#233;dia e da art&#233;ria umbilical&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Para melhor observa&#231;&#227;o&#44; foi realizada reconstru&#231;&#227;o tridimensional &#40;3D&#41; da imagem&#59; os achados foram os seguintes&#58; edema de palmas&#44; m&#227;os cerradas&#44; encurtamento de falanges e metacarpos &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a> A&#8208;C&#41;&#44; p&#233;s tortos &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a> A&#44; B&#41;&#44; test&#237;culos n&#227;o descidos &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 6</a>&#41; e l&#237;quido amni&#243;tico ecog&#234;nico&#46; Ap&#243;s aconselhamento&#44; o casal decidiu interromper a gravidez e foi solicitado o teste gen&#233;tico&#46; A pele do feto estava espessada&#44; com fissuras profundas&#44; difusamente eritematosa em todo o corpo&#44; com apar&#234;ncia de &#8220;armadura&#8221;&#46; O feto apresentava ectr&#243;pio&#44; nariz achatado e pequeno&#46; Foram observadas a abertura da boca e a protrus&#227;o da l&#237;ngua&#46; Al&#233;m disso&#44; os membros eram r&#237;gidos e edematosos&#44; as m&#227;os cerradas&#44; os p&#233;s voltados para dentro e os dedos das m&#227;os e dos p&#233;s eram pequenos&#46; Os test&#237;culos estavam ausentes no saco escrotal&#46; Foi confirmado que o diagn&#243;stico baseado na US pr&#233;&#8208;natal havia sido preciso &#40;<a class="elsevierStyleCrossRef" href="#fig0035">fig&#46; 7</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Ensaios de microarray cromoss&#244;micos e an&#225;lise da sequ&#234;ncia de Sanger</span><p id="par0045" class="elsevierStylePara elsevierViewall">Os resultados preliminares dos ensaios de <span class="elsevierStyleItalic">microarray</span> cromoss&#244;micos sugeriram que as informa&#231;&#245;es do gen&#243;tipo revelaram perda de heterozigosidade &#40;LOH&#44; do ingl&#234;s <span class="elsevierStyleItalic">loss of heterozigosity</span>&#41; no cromossomo 2 &#40;<a class="elsevierStyleCrossRef" href="#fig0040">fig&#46; 8</a>&#41;&#46; Al&#233;m disso&#44; muta&#231;&#227;o patog&#234;nica no gene <span class="elsevierStyleItalic">ABCA12</span> &#40;ABCA12&#58;c&#46;3785delT&#41; em homozigose foi identificada com base no resultado da an&#225;lise da sequ&#234;ncia de Sanger &#40;<a class="elsevierStyleCrossRef" href="#fig0045">fig&#46; 9</a>&#41;&#46;</p><elsevierMultimedia ident="fig0040"></elsevierMultimedia><elsevierMultimedia ident="fig0045"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pesquisa na literatura</span><p id="par0050" class="elsevierStylePara elsevierViewall">Por meio da pesquisa dos casos publicados&#44; foram identificados 13 casos de IA diagnosticados por US pr&#233;&#8208;natal&#46; Ao integrar caracter&#237;sticas cl&#237;nicas e ultrassonogr&#225;ficas de todos os casos&#44; foi observado que a idade materna oscilou em uma ampla faixa de 27 a 40 anos e que a propor&#231;&#227;o de pacientes com hist&#243;ria familiar foi baixa &#40;3&#47;13&#41;&#46; O in&#237;cio da IA concentrou&#8208;se no terceiro trimestre da gravidez e nenhum dos fetos com IA sobreviveu &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#8211;20</span></a> Os autores analisaram e resumiram 13 caracter&#237;sticas ultrass&#244;nicas t&#237;picas da IA &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#8211;20</span></a> Descama&#231;&#227;o da pele&#44; m&#227;os cerradas e p&#233;s tortos&#44; ectr&#243;pio&#44; nariz achatado&#44; retardo do crescimento fetal&#44; polidr&#226;mnio e l&#237;quido amni&#243;tico ecog&#234;nico s&#227;o as mais frequentes &#40;&#8805; 5&#41;&#46; Al&#233;m disso&#44; como no presente caso&#44; os autores encontraram fetos com IA que apresentavam associa&#231;&#227;o de microtia&#44; encurtamento de falanges e metacarpos&#44; com anomalias genitais &#40;test&#237;culos n&#227;o descidos&#41;&#44; que raramente ou nunca foram mencionados em relatos anteriores&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discuss&#227;o</span><p id="par0055" class="elsevierStylePara elsevierViewall">A IA &#233; genodermatose rara com alta letalidade&#44; n&#227;o havendo tratamento eficaz para a doen&#231;a&#46; Com base nos resultados deste estudo&#44; foi encontrada uma ampla faixa et&#225;ria materna de casos de IA &#40;variando de 27 a 40 anos&#41; e nenhuma anormalidade significante nos exames do primeiro e segundo trimestres&#46; Em virtude de sua raridade e do per&#237;odo de in&#237;cio&#44; a triagem pr&#233;&#8208;natal para IA &#233; extremamente dif&#237;cil&#44; e a maioria das mulheres gr&#225;vidas&#44; especialmente aquelas sem hist&#243;rico familiar&#44; pode facilmente perder o per&#237;odo adequado para realizar exames precisos&#44; como a detec&#231;&#227;o de altera&#231;&#245;es moleculares no l&#237;quido amni&#243;tico e no sangue do cord&#227;o umbilical&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> Entretanto&#44; algumas caracter&#237;sticas ultrassonogr&#225;ficas espec&#237;ficas da IA podem ser detectadas no exame ultrassonogr&#225;fico no final da gravidez &#40;variando de 27 a 34 semanas&#41;&#46; Espera&#8208;se que o uso pr&#233;&#8208;natal da US&#44; em virtude da aus&#234;ncia de radia&#231;&#227;o ionizante&#44; sua conveni&#234;ncia e aplicabilidade cl&#237;nica&#44; seja ferramenta eficaz para a triagem pr&#233;&#8208;natal de IA&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">No presente estudo&#44; os autores resumiram as principais caracter&#237;sticas ultrassonogr&#225;ficas de IA pesquisando a literatura relevante&#44; e os resultados s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#8211;20</span></a> As caracter&#237;sticas com ocorr&#234;ncia em mais de cinco casos foram as seguintes&#58; &#40;1&#41; descama&#231;&#227;o da pele&#59; &#40;2&#41; m&#227;os cerradas e p&#233;s tortos&#59; &#40;3&#41; ectr&#243;pio&#59; &#40;4&#41; nariz achatado&#59; &#40;5&#41; retardo do crescimento fetal&#59; &#40;6&#41; polidr&#226;mnio&#59; &#40;7&#41; l&#237;quido amni&#243;tico ecog&#234;nico&#46; Os autores acreditam que as apresenta&#231;&#245;es ultrassonogr&#225;ficas espec&#237;ficas descritas acima podem estar relacionadas principalmente a altera&#231;&#245;es da pele em fetos com IA&#46; Por exemplo&#44; o espessamento anormal da pele pode limitar o movimento dos membros fetais e afetar o crescimento e desenvolvimento intrauterinos&#46; Como o l&#237;quido amni&#243;tico e a pele fetal apresentam difus&#227;o livre durante a gravidez&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> isso tamb&#233;m parece explicar por que a IA pode causar polidr&#226;mnio&#46; A descama&#231;&#227;o da pele tamb&#233;m &#233; considerada uma das causas do l&#237;quido amni&#243;tico ecog&#234;nico&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">A observa&#231;&#227;o tridimensional permitiu aos autores obter mais informa&#231;&#245;es visuais de imagens estereosc&#243;picas e descobrir as caracter&#237;sticas ultrassonogr&#225;ficas espec&#237;ficas da IA&#46; Al&#233;m disso&#44; a maioria dos casos de IA apresenta polidr&#226;mnio&#44; o que favorece a aquisi&#231;&#227;o de imagens tridimensionais&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> Portanto&#44; os autores declaram que a combina&#231;&#227;o de US em 2D e 3D pode ser de maior utilidade para o diagn&#243;stico pr&#233;&#8208;natal de IA&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">O gene ABCA12&#44; localizado na membrana celular&#44; &#233; um transportador de lip&#237;dios de queratin&#243;citos epid&#233;rmicos e o defeito no ABCA12 leva &#224; quebra da barreira lip&#237;dica da pele&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">8&#44;23</span></a> Os resultados da an&#225;lise de <span class="elsevierStyleItalic">microarray</span> cromoss&#244;mico do presente caso mostraram a perda de heterozigosidade &#40;LOH&#41; no cromossomo 2&#46; A an&#225;lise de sequenciamento do gene ABCA12 identificou uma nova muta&#231;&#227;o &#8208; ABCA12&#58;c&#46;3785delT&#46; A muta&#231;&#227;o ABCA12&#58;c&#46;3785delT &#233; uma muta&#231;&#227;o <span class="elsevierStyleItalic">frameshift</span> e de dele&#231;&#227;o que faz com que a fenilalanina se converta em serina em sua cadeia pept&#237;dica codificadora e gere um c&#243;don de termina&#231;&#227;o prematura na posi&#231;&#227;o 42 do novo frame de leitura&#46; Carregar c&#243;dons de parada prematura pode gerar prote&#237;nas truncadas<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> e induzir um processo de degrada&#231;&#227;o do mRNA chamado decaimento do mRNA mediado por <span class="elsevierStyleItalic">nonsense</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> Essas causas levam &#224; perda de fun&#231;&#227;o da prote&#237;na original &#40;p&#46;Phe1262Serfs&#42;42&#41;&#46; Os achados do presente caso fornecem novas pistas para uma investiga&#231;&#227;o mais aprofundada sobre a patog&#234;nese da IA&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclus&#227;o</span><p id="par0075" class="elsevierStylePara elsevierViewall">A IA tem caracter&#237;sticas ultrassonogr&#225;ficas relativamente espec&#237;ficas&#59; portanto&#44; o exame sistem&#225;tico de mulheres gr&#225;vidas utilizando US em 2D combinado com 3D no terceiro trimestre da gravidez pode reduzir drasticamente a taxa de diagn&#243;sticos n&#227;o realizados ou errados de IA&#46; Al&#233;m disso&#44; uma nova muta&#231;&#227;o patog&#234;nica no gene ABCA12 foi identificada&#44; a qual explicou o poss&#237;vel mecanismo patog&#234;nico&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Suporte financeiro</span><p id="par0080" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Contribui&#231;&#227;o dos autores</span><p id="par0085" class="elsevierStylePara elsevierViewall">Zesi Liu&#58; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Chunli Jing&#58; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflito de interesses</span><p id="par0095" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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    "fechaRecibido" => "2022-08-28"
    "fechaAceptado" => "2022-09-30"
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            0 => "Ictiose arlequim"
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            2 => "Ultrassonografia pr&#233;&#8208;natal"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A ictiose arlequim &#40;IA&#41; &#233; doen&#231;a de pele rara com letalidade extremamente alta em decorr&#234;ncia da muta&#231;&#227;o do gene ABCA12&#46; Em virtude de sua raridade e do in&#237;cio frequentemente tardio&#44; a triagem pr&#233;&#8208;natal para IA &#233; extremamente dif&#237;cil&#44; e a maioria das gestantes pode facilmente perder o per&#237;odo adequado para realizar exames precisos&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Resumir as caracter&#237;sticas ultrassonogr&#225;ficas da IA para fins de diagn&#243;stico pr&#233;&#8208;natal&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Os autores descrevem um caso de IA sem hist&#243;rico familiar&#44; diagnosticado por meio de ultrassonografia pr&#233;&#8208;natal&#46; As caracter&#237;sticas ultrassonogr&#225;ficas da IA e as caracter&#237;sticas cl&#237;nicas das gestantes foram resumidas por meio de pesquisa na literatura relevante ao longo de quase duas d&#233;cadas&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">As apresenta&#231;&#245;es ultrassonogr&#225;ficas espec&#237;ficas&#44; incluindo descama&#231;&#227;o da pele&#44; m&#227;os cerradas e p&#233;s tortos&#44; ectr&#243;pio&#44; nariz achatado&#44; restri&#231;&#227;o de crescimento fetal&#44; polidr&#226;mnio e l&#237;quido amni&#243;tico ecog&#234;nico podem estar relacionadas especialmente a dist&#250;rbios de pele em fetos com IA&#46; Tamb&#233;m foi identificada nova muta&#231;&#227;o patog&#234;nica do gene ABCA12 e o poss&#237;vel mecanismo patog&#234;nico &#233; explicado&#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">Deve&#8208;se ter cuidado ao resumir as caracter&#237;sticas da doen&#231;a em virtude do pequeno n&#250;mero de casos&#59; os autores enfrentaram a possibilidade de busca incompleta de casos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#245;es</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A IA tem caracter&#237;sticas ultrassonogr&#225;ficas relativamente &#250;nicas&#46; Portanto&#44; a ultrassonografia em 2D combinada com a ultrassonografia em 3D pode ser um m&#233;todo eficaz para o diagn&#243;stico pr&#233;&#8208;natal de IA&#46; Al&#233;m disso&#44; uma nova muta&#231;&#227;o patog&#234;nica do gene ABCA12 pode fornecer pistas importantes para futuras pesquisas sobre a etiologia da IA&#46; Entretanto&#44; os autores consideram que estudos adicionais s&#227;o necess&#225;rios para fornecer mais evid&#234;ncias para o diagn&#243;stico pr&#233;&#8208;natal&#46;</p></span>"
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Ultrassonografia em 3D&#58; punhos cerrados e edema cut&#226;neo&#46; &#40;B&#41; Ultrassonografia em 2D&#58; encurtamento das falanges e metacarpos&#46; &#40;C&#41; Ultrassonografia em 3D&#58; imagem do membro superior do feto</p>"
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          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Apar&#234;ncia do feto abortado com ictiose arlequim foi consistente com o diagn&#243;stico ultrassonogr&#225;fico pr&#233;&#8208;natal</p>"
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          "pt" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Resultado da an&#225;lise cromoss&#244;mica por <span class="elsevierStyleItalic">microarray</span> para o cromossomo 2</p>"
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          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">A an&#225;lise de sequ&#234;ncia realizada no presente caso identificou nova muta&#231;&#227;o patog&#234;nica do gene ABCA12 &#40;ABCA12&#58;c&#46;3785delT&#41;&#44; muta&#231;&#227;o <span class="elsevierStyleItalic">frameshift</span> e de dele&#231;&#227;o que leva a c&#243;don de termina&#231;&#227;o prematura</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" scope="col">Indicadores de desenvolvimento&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Presente caso&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caso 1<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G3P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 2<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 3<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G3P2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resultado materno de IA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 4<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</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">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 5<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</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">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31s&#43;5d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 6<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</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">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G2P1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 7<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 8<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G2P1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 9<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 10<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G5P3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 11<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G3P2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resultado materno de IA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 12<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</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">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Caso 13<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</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">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G2P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30s &#40;primeira vez&#41;&#47;25s &#40;segunda vez&#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">Resultado materno de IA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&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">Presente caso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G1P0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30s&#43;2d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3303799.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas cl&#237;nicas e resultados da gravidez em todos os casos</p>"
        ]
      ]
      11 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Os s&#237;mbolos &#8220;&#43;&#8221; ou &#8220;&#8208;&#8221; representam caracter&#237;sticas ultrassonogr&#225;ficas de presen&#231;a ou aus&#234;ncia&#44; respectivamente&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Achados ultrassonogr&#225;ficos&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">Ectr&#243;pio&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">M&#227;os cerradas e p&#233;s tortos&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">Descama&#231;&#227;o da pele&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">Nariz achatado&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">Retardo do crescimento fetal&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">Polidr&#226;mnio&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">Caso 1<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 2<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 3<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 4<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 5<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 6<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 7<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 8<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 9<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 10<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 11<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 12<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 13<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Presente caso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3303797.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Achados ultrassonogr&#225;ficos&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">L&#237;quido amni&#243;tico ecog&#234;nico&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">&#8216;Boca de peixe&#8217;&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">Macroglossia&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">Edema subcut&#226;neo&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">Micrognatia&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">Microcefalia&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">Cord&#227;o umbilical curto&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">Caso 1<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 2<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 3<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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">Caso 4<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 5<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 6<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 7<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 8<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 9<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 10<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 11<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 12<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</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">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Caso 13<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Presente caso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&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">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Treze caracter&#237;sticas ultrassonogr&#225;ficas t&#237;picas de IA nos casos publicados</p>"
        ]
      ]
    ]
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      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
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            0 => array:3 [
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              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetically transmitted&#44; generalized disorders of cornification"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;L&#46; Williams"
                            1 => "P&#46;M&#46; Elias"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "The ichthyoses&#46; Dermatol Clin&#46;"
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                        "paginaFinal" => "178"
                        "link" => array:1 [
                          0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Treatment of harlequin ichthyosis with acitretin"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46; Arjona-Aguilera"
                            1 => "C&#46; Albarr&#225;n-Planelles"
                            2 => "D&#46; Jim&#233;nez-Gallo"
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                    0 => array:2 [
                      "doi" => "10.1016/j.ad.2015.03.003"
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                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
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                        "volumen" => "106"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25917960"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Harlequin ichthyosis&#58; a medico legal case report &#38; review of literature with peculiar findings in autopsy"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                    0 => array:2 [
                      "doi" => "10.1016/j.jflm.2012.02.019"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Forensic Leg Med&#46;"
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                        "volumen" => "19"
                        "paginaInicial" => "352"
                        "paginaFinal" => "354"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity"
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                          "etal" => true
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                            3 => "Y&#46; Yamanaka"
                            4 => "J&#46;R&#46; McMillan"
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                    0 => array:2 [
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                        "tituloSerie" => "J Invest Dermatol&#46;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
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                            2 => "D&#46;M&#46; Main"
                            3 => "C&#46;E&#46; Otto"
                            4 => "K&#46;A&#46; Holbrook"
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                      "doi" => "10.1111/1523-1747.ep12371764"
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                        "tituloSerie" => "J Invest Dermatol&#46;"
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                        "paginaInicial" => "210"
                        "paginaFinal" => "213"
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                0 => array:2 [
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                      "titulo" => "Prenatal diagnosis of harlequin ichthyosis by fetal skin biopsy&#59; report of two cases"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46; Suzumori"
                            1 => "T&#46; Kanzaki"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pd.1970110707"
                      "Revista" => array:6 [
                        "tituloSerie" => "Prenat Diagn&#46;"
                        "fecha" => "1991"
                        "volumen" => "11"
                        "paginaInicial" => "451"
                        "paginaFinal" => "457"
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                          0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Akiyama"
                            1 => "Y&#46; Sugiyama-Nakagiri"
                            2 => "K&#46; Sakai"
                            3 => "J&#46;R&#46; McMillan"
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Achados ultrassonográficos bidimensionais e tridimensionais da ictiose arlequim: relato de caso e revisão da literatura
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Zesi Liua, Chunli Jingb,
Autor para correspondência
tg980927@126.com

Autor para correspondência.
a Departamento de Ginecologia e Obstetrícia, The First Affiliated Hospital Dalian Medical University, Dalian, China
b Departamento de Ultrassonografia em Ginecologia e Obstetrícia, The Second Affiliated Hospital Dalian Medical University, Dalian, China
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Tabela 1. Medidas ultrassonográficas dos parâmetros de desenvolvimento
Tabela 2. Características clínicas e resultados da gravidez em todos os casos
Tabela 3. Treze características ultrassonográficas típicas de IA nos casos publicados
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Resumo
Fundamentos

A ictiose arlequim (IA) é doença de pele rara com letalidade extremamente alta em decorrência da mutação do gene ABCA12. Em virtude de sua raridade e do início frequentemente tardio, a triagem pré‐natal para IA é extremamente difícil, e a maioria das gestantes pode facilmente perder o período adequado para realizar exames precisos.

Objetivo

Resumir as características ultrassonográficas da IA para fins de diagnóstico pré‐natal.

Métodos

Os autores descrevem um caso de IA sem histórico familiar, diagnosticado por meio de ultrassonografia pré‐natal. As características ultrassonográficas da IA e as características clínicas das gestantes foram resumidas por meio de pesquisa na literatura relevante ao longo de quase duas décadas.

Resultados

As apresentações ultrassonográficas específicas, incluindo descamação da pele, mãos cerradas e pés tortos, ectrópio, nariz achatado, restrição de crescimento fetal, polidrâmnio e líquido amniótico ecogênico podem estar relacionadas especialmente a distúrbios de pele em fetos com IA. Também foi identificada nova mutação patogênica do gene ABCA12 e o possível mecanismo patogênico é explicado.

Limitações do estudo

Deve‐se ter cuidado ao resumir as características da doença em virtude do pequeno número de casos; os autores enfrentaram a possibilidade de busca incompleta de casos.

Conclusões

A IA tem características ultrassonográficas relativamente únicas. Portanto, a ultrassonografia em 2D combinada com a ultrassonografia em 3D pode ser um método eficaz para o diagnóstico pré‐natal de IA. Além disso, uma nova mutação patogênica do gene ABCA12 pode fornecer pistas importantes para futuras pesquisas sobre a etiologia da IA. Entretanto, os autores consideram que estudos adicionais são necessários para fornecer mais evidências para o diagnóstico pré‐natal.

Palavras‐chave:
Ictiose arlequim
Ultrassonografia
Ultrassonografia pré‐natal
Texto Completo
Introdução

A ictiose arlequim (IA) é doença genética autossômica recessiva rara (prevalência de 1/300.000‐1/1.000.000) com alta taxa de mortalidade.1,2 Fetos com IA podem desenvolver alterações cutâneas graves durante o desenvolvimento, incluindo grandes e espessas escamas em forma de placas cobrindo todo o corpo, eclábio, ectrópio grave e orelhas achatadas, e progressão tardia para eritrodermia esfoliativa grave. Insuficiência respiratória, perda de líquido e calor, infecções de pele e distúrbios metabólicos eletrolíticos são as principais razões para o mau prognóstico da IA. Infelizmente, não há tratamento eficaz para a doença.3 Métodos confiáveis para o diagnóstico pré‐natal são, portanto, essenciais para a detecção neonatal de IA.

Antes de 2005, nenhum gene candidato para IA havia sido identificado, e o diagnóstico da doença dependia de histopatologia em biópsias intrauterinas da pele fetal entre 19 e 23 semanas.4–6 Entretanto, como esse método é invasivo e tecnicamente difícil, ele aumenta o risco de múltiplas complicações na gravidez. Portanto, depois que o gene ABCA12 foi identificado como o gene causador da IA, a análise da mutação do gene ABCA12 pela análise do líquido amniótico e sangue do cordão umbilical tornou‐se método eficaz para o diagnóstico pré‐natal de IA.7,8 No entanto, grávidas sem histórico familiar ou histórico de gravidez com IA muitas vezes optam por não realizar a triagem pré‐natal específica para IA utilizando os métodos mencionados acima. A ultrassonografia (US), contudo, como exame não invasivo e de baixo custo, parece ser método eficaz para o diagnóstico pré‐natal de IA.

No presente estudo, os autores realizaram com sucesso o diagnóstico pré‐natal utilizando US em 2D combinada com 3D em um feto com IA sem histórico familiar. Análise cromossômica por microarray (CMA, do inglês chromosomal microarray analysis) e análise da sequência de Sanger foram usadas para identificar anormalidades cromossômicas fetais e identificar a mutação patogênica do gene ABCA12.9,10 Além disso, pesquisando a literatura publicada sobre IA, os autores resumiram as características ultrassonográficas da doença.

MétodosFontes de dados

Os dados ultrassonográficos e clínicos da paciente foram obtidos do banco de dados médico eletrônico do Second Affiliated Hospital da Dalian Medical University. O dispositivo de diagnóstico por US colorida GE Voluson E8 com frequência de sonda definida de 2,5 a 5,0MHz foi usado no presente estudo. A análise por microarray de microRNA foi processada com um chip de microarray comercial de 750K, e as mutações foram detectadas por análise de dados da sequência de Sanger.

Estratégia de busca

A estratégia de busca no banco de dados MEDLINE/Pubmed utilizou as seguintes palavras‐chave: “Ichthyosis, Lamellar” e “Ultrasonography, Prenatal” [Mesh], adaptadas às demais bases de dados quando necessário.

ResultadosApresentação do caso

O presente caso descreve uma paciente do sexo feminino, de 40 anos, gesta 1, para 0, que concebeu espontaneamente, sem histórico familiar de IA. A mãe negou histórico de medicação ou infecção e histórico de exposição ambiental adversa durante a gravidez. Os achados ultrassonográficos no início da gravidez, com 13 semanas, e os achados da US no exame durante o período intermediário da gravidez com 24 +3 semanas não mostraram anormalidades significantes; a transluscência nucal (TN) foi de 2,1mm. Os resultados da triagem pré‐natal não invasiva (NIPS, do inglês noninvasive prenatal screening) foram negativos. Até 30 +2 semanas de gestação, os demais exames pré‐natais foram normais.

Embora o exame de US no final da gravidez com 30 +2 semanas não tenha sugerido nenhuma anormalidade significante dos indicadores de desenvolvimento (tabela 1), os autores observaram características ultrassonográficas típicas, incluindo nariz achatado, descamação da pele (fig. 1A,B), ectrópio, língua voltada para cima e fenda bucal anormalmente grande (semelhante à boca de peixe; fig. 2A,B), microtia (fig. 3) e índice de líquido amniótico (AFI, do inglês amniotic fluid index) de 340mm. Por outro lado, a avaliação por US de outros órgãos, como cérebro, coração e rins, foi normal e a imagem de fluxo por Doppler colorido (CDFI, do inglês color Doppler flow imaging) indicou ausência de anormalidade óbvia no sinal de fluxo sanguíneo da artéria cerebral média e da artéria umbilical.

Tabela 1.

Medidas ultrassonográficas dos parâmetros de desenvolvimento

Indicadores de desenvolvimento  DBP  PC  CA  CF  CU  PFE  SGE 
Presente caso  75 mm  277 mm  252 mm  54 mm  49 mm  1373±200 g  29+5sem 

DBP, diâmetro biparietal; PC, perímetro cefálico; CA, circunferência abdominal; CF, comprimento do fêmur; CU, comprimento do úmero; PFE, peso fetal estimado; SGE, semana gestacional estimada.

Figura 1.

(A) Ultrassonografia em 2D: a face fetal mostra curva plana e hipoplasia nasal (seta) no corte sagital mediano. (B) Ultrassonografia em 2D: aspecto anormal da pele, em flocos (seta)

(0.11MB).
Figura 2.

(A) Ultrassonografia em 3D: imagem da face do feto. (B) Ultrassonografia em 3D: edema palpebral e ectrópio (seta preta); nariz hipoplásico (seta branca); eclábio e protusão anterior da língua (seta azul)

(0.1MB).
Figura 3.

Ultrassonografia em 2D: microtia (seta)

(0.08MB).

Para melhor observação, foi realizada reconstrução tridimensional (3D) da imagem; os achados foram os seguintes: edema de palmas, mãos cerradas, encurtamento de falanges e metacarpos (fig. 4 A‐C), pés tortos (fig. 5 A, B), testículos não descidos (fig. 6) e líquido amniótico ecogênico. Após aconselhamento, o casal decidiu interromper a gravidez e foi solicitado o teste genético. A pele do feto estava espessada, com fissuras profundas, difusamente eritematosa em todo o corpo, com aparência de “armadura”. O feto apresentava ectrópio, nariz achatado e pequeno. Foram observadas a abertura da boca e a protrusão da língua. Além disso, os membros eram rígidos e edematosos, as mãos cerradas, os pés voltados para dentro e os dedos das mãos e dos pés eram pequenos. Os testículos estavam ausentes no saco escrotal. Foi confirmado que o diagnóstico baseado na US pré‐natal havia sido preciso (fig. 7).

Figura 4.

(A) Ultrassonografia em 3D: punhos cerrados e edema cutâneo. (B) Ultrassonografia em 2D: encurtamento das falanges e metacarpos. (C) Ultrassonografia em 3D: imagem do membro superior do feto

(0.11MB).
Figura 5.

(A) Ultrassonografia em 2D: imagem do pé direito do feto. (B) Ultrassonografia em 3D: edema do pé e pés tortos

(0.15MB).
Figura 6.

Ultrassonografia em 3D: ausência de testículos no saco escrotal

(0.06MB).
Figura 7.

Aparência do feto abortado com ictiose arlequim foi consistente com o diagnóstico ultrassonográfico pré‐natal

(0.07MB).
Ensaios de microarray cromossômicos e análise da sequência de Sanger

Os resultados preliminares dos ensaios de microarray cromossômicos sugeriram que as informações do genótipo revelaram perda de heterozigosidade (LOH, do inglês loss of heterozigosity) no cromossomo 2 (fig. 8). Além disso, mutação patogênica no gene ABCA12 (ABCA12:c.3785delT) em homozigose foi identificada com base no resultado da análise da sequência de Sanger (fig. 9).

Figura 8.

Resultado da análise cromossômica por microarray para o cromossomo 2

(0.75MB).
Figura 9.

A análise de sequência realizada no presente caso identificou nova mutação patogênica do gene ABCA12 (ABCA12:c.3785delT), mutação frameshift e de deleção que leva a códon de terminação prematura

(0.04MB).
Pesquisa na literatura

Por meio da pesquisa dos casos publicados, foram identificados 13 casos de IA diagnosticados por US pré‐natal. Ao integrar características clínicas e ultrassonográficas de todos os casos, foi observado que a idade materna oscilou em uma ampla faixa de 27 a 40 anos e que a proporção de pacientes com história familiar foi baixa (3/13). O início da IA concentrou‐se no terceiro trimestre da gravidez e nenhum dos fetos com IA sobreviveu (tabela 2).11–20 Os autores analisaram e resumiram 13 características ultrassônicas típicas da IA (tabela 3).11–20 Descamação da pele, mãos cerradas e pés tortos, ectrópio, nariz achatado, retardo do crescimento fetal, polidrâmnio e líquido amniótico ecogênico são as mais frequentes (≥ 5). Além disso, como no presente caso, os autores encontraram fetos com IA que apresentavam associação de microtia, encurtamento de falanges e metacarpos, com anomalias genitais (testículos não descidos), que raramente ou nunca foram mencionados em relatos anteriores.

Tabela 2.

Características clínicas e resultados da gravidez em todos os casos

ID  Idade  Gestações  Semana gestacional da ultrassonografia  História familiar ou resultado materno de IA  Resultados da gravidez 
Caso 111  31  G3P0  31s  Não  Morte 
Caso 211  28  G1P0  30s  Não  Morte 
Caso 312  ‐  G3P2  ‐  Resultado materno de IA  Morte 
Caso 413  35  G1P0  31s  Não  Morte 
Caso 514  34  G1P0  31s+5d  Não  Morte 
Caso 615  27  G2P1  27s  Não  Morte 
Caso 716  ‐  ‐  ‐  ‐  Morte 
Caso 817  ‐  G2P1  ‐  ‐  Morte 
Caso 918  ‐  G1P0  34s  Não  Morte 
Caso 1018  30  G5P3  33s  Não  Morte 
Caso 1118  27  G3P2  27s  Resultado materno de IA  Morte 
Caso 1219  34  G1P0  32s  Não  Morte 
Caso 1320  32  G2P0  30s (primeira vez)/25s (segunda vez)  Resultado materno de IA  Morte 
Presente caso  40  G1P0  30s+2d  Não  Morte 

O símbolo “‐” indica dados anteriormente não mencionados na literatura.

IA, ictiose arlequim.

Tabela 3.

Treze características ultrassonográficas típicas de IA nos casos publicados

Achados ultrassonográficos  Ectrópio  Mãos cerradas e pés tortos  Descamação da pele  Nariz achatado  Retardo do crescimento fetal  Polidrâmnio 
Caso 111  ‐  ‐ 
Caso 211  ‐  ‐ 
Caso 312  ‐ 
Caso 413  ‐  ‐ 
Caso 514  ‐ 
Caso 615  ‐  ‐ 
Caso 716  ‐  ‐  ‐ 
Caso 817  ‐  ‐  ‐  ‐  ‐ 
Caso 918  ‐ 
Caso 1018  ‐ 
Caso 1118  ‐ 
Caso 1219  ‐  ‐ 
Caso 1320  ‐  ‐  ‐ 
Presente caso  ‐ 
Total  12  11  11  10 
Achados ultrassonográficos  Líquido amniótico ecogênico  ‘Boca de peixe’  Macroglossia  Edema subcutâneo  Micrognatia  Microcefalia  Cordão umbilical curto 
Caso 111  ‐  ‐  ‐  ‐  ‐ 
Caso 211  ‐  ‐  ‐  ‐  ‐ 
Caso 312  ‐  ‐  ‐  ‐  ‐ 
Caso 413  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 514  ‐ 
Caso 615  ‐  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 716  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 817  ‐  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 918  ‐  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 1018  ‐  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 1118  ‐  ‐  ‐  ‐  ‐  ‐  ‐ 
Caso 1219  ‐  ‐  ‐  ‐  ‐ 
Caso 1320  ‐  ‐  ‐  ‐  ‐  ‐ 
Presente caso  ‐  ‐  ‐ 
Total 

Os símbolos “+” ou “‐” representam características ultrassonográficas de presença ou ausência, respectivamente.

Discussão

A IA é genodermatose rara com alta letalidade, não havendo tratamento eficaz para a doença. Com base nos resultados deste estudo, foi encontrada uma ampla faixa etária materna de casos de IA (variando de 27 a 40 anos) e nenhuma anormalidade significante nos exames do primeiro e segundo trimestres. Em virtude de sua raridade e do período de início, a triagem pré‐natal para IA é extremamente difícil, e a maioria das mulheres grávidas, especialmente aquelas sem histórico familiar, pode facilmente perder o período adequado para realizar exames precisos, como a detecção de alterações moleculares no líquido amniótico e no sangue do cordão umbilical.11 Entretanto, algumas características ultrassonográficas específicas da IA podem ser detectadas no exame ultrassonográfico no final da gravidez (variando de 27 a 34 semanas). Espera‐se que o uso pré‐natal da US, em virtude da ausência de radiação ionizante, sua conveniência e aplicabilidade clínica, seja ferramenta eficaz para a triagem pré‐natal de IA.

No presente estudo, os autores resumiram as principais características ultrassonográficas de IA pesquisando a literatura relevante, e os resultados são apresentados na tabela 3.11–20 As características com ocorrência em mais de cinco casos foram as seguintes: (1) descamação da pele; (2) mãos cerradas e pés tortos; (3) ectrópio; (4) nariz achatado; (5) retardo do crescimento fetal; (6) polidrâmnio; (7) líquido amniótico ecogênico. Os autores acreditam que as apresentações ultrassonográficas específicas descritas acima podem estar relacionadas principalmente a alterações da pele em fetos com IA. Por exemplo, o espessamento anormal da pele pode limitar o movimento dos membros fetais e afetar o crescimento e desenvolvimento intrauterinos. Como o líquido amniótico e a pele fetal apresentam difusão livre durante a gravidez,21 isso também parece explicar por que a IA pode causar polidrâmnio. A descamação da pele também é considerada uma das causas do líquido amniótico ecogênico.

A observação tridimensional permitiu aos autores obter mais informações visuais de imagens estereoscópicas e descobrir as características ultrassonográficas específicas da IA. Além disso, a maioria dos casos de IA apresenta polidrâmnio, o que favorece a aquisição de imagens tridimensionais.22 Portanto, os autores declaram que a combinação de US em 2D e 3D pode ser de maior utilidade para o diagnóstico pré‐natal de IA.

O gene ABCA12, localizado na membrana celular, é um transportador de lipídios de queratinócitos epidérmicos e o defeito no ABCA12 leva à quebra da barreira lipídica da pele.8,23 Os resultados da análise de microarray cromossômico do presente caso mostraram a perda de heterozigosidade (LOH) no cromossomo 2. A análise de sequenciamento do gene ABCA12 identificou uma nova mutação ‐ ABCA12:c.3785delT. A mutação ABCA12:c.3785delT é uma mutação frameshift e de deleção que faz com que a fenilalanina se converta em serina em sua cadeia peptídica codificadora e gere um códon de terminação prematura na posição 42 do novo frame de leitura. Carregar códons de parada prematura pode gerar proteínas truncadas24 e induzir um processo de degradação do mRNA chamado decaimento do mRNA mediado por nonsense.25 Essas causas levam à perda de função da proteína original (p.Phe1262Serfs*42). Os achados do presente caso fornecem novas pistas para uma investigação mais aprofundada sobre a patogênese da IA.

Conclusão

A IA tem características ultrassonográficas relativamente específicas; portanto, o exame sistemático de mulheres grávidas utilizando US em 2D combinado com 3D no terceiro trimestre da gravidez pode reduzir drasticamente a taxa de diagnósticos não realizados ou errados de IA. Além disso, uma nova mutação patogênica no gene ABCA12 foi identificada, a qual explicou o possível mecanismo patogênico.

Suporte financeiro

Nenhum.

Contribuição dos autores

Zesi Liu: Aprovação da versão final do manuscrito; revisão crítica da literatura; participação efetiva na orientação da pesquisa; elaboração e redação do manuscrito; concepção e planejamento do estudo.

Chunli Jing: Aprovação da versão final do manuscrito; participação efetiva na orientação da pesquisa; obtenção, análise e interpretação dos dados; revisão crítica do manuscrito; concepção e planejamento do estudo.

Conflito de interesses

Nenhum.

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Como citar este artigo: Liu Z, Jing C. Two‐ and three‐dimensional sonographic findings of harlequin ichthyosis: case report and literature review. An Bras Dermatol. 2023;98:806–13.

Trabalho realizado no The Second Affiliated Hospital, Dalian Medical University Dalian, Dalian, China.

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