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A importância dos estudos genéticos no diagnóstico de Síndrome de Prader-Willi : a propósito de um caso clínico
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Resumo(s)
A Síndrome de Prader-Willi (SPW) é uma doença genética com características fenotípicas específicas, acompanhada de alterações endocrinológicas, comportamentais e do neurodesenvolvimento. Afeta igualmente ambos os géneros e a incidência estimada é de 1 em 15.000-25.000 nados vivos.
A SPW resulta de perda de expressão da região cromossómica 15q11.2-q13, herdada do pai. Esta perda de expressão pode ser causada por diferentes mecanismos. Na maioria dos casos (70%) é devida uma microdeleção da região cromossómica 15q11.2-q13 herdada do pai. Pode ocorrer também por dissomia uniparental materna (25%) e mais raramente por defeitos de imprinting. O teste de metilação do ADN permite detetar em 99% dos casos a perda de expressão do locus 15q11.2-q13 paterno. Análises adicionais permitem em cada caso definir o mecanismo associado.
À nascença manifesta-se sobretudo por hipotonia neonatal grave com dificuldades de alimentação e se associado a um fenótipo sugestivo é critério suficiente para iniciar estudo genético. Este fenótipo é definido por dolicocefalia, face e testa estreitas, olhos em forma de amêndoa, boca pequena com o lábio superior fino e cantos da boca virados para baixo. Com o crescimento, surge hiperfagia com obesidade central acompanhada de atraso no neurodesenvolvimento.
Atualmente, a única terapêutica disponível é a hormona do crescimento (HC) recombinante, diminuindo algumas comorbilidades associadas à doença, nomeadamente o excesso de peso, alterações cognitivas e comportamentais. Estão em investigação novos fármacos e métodos cirúrgicos com o objetivo de tratar as comorbilidades e melhorar a qualidade de vida destes doentes.
Apresenta-se um caso clínico de uma criança ex-pretermo de 26 semanas em que apesar de forte suspeita clínica para o diagnóstico de SPW, o estudo genético inicial (FISH) foi negativo. Após realização do teste de metilação de ADN, confirmou-se o diagnóstico de SPW, e posteriormente o subtipo de dissomia uniparental materna.
Prader-Willi Syndrome (PWS) is a genetic disease with specific phenotypic characteristics, associated with endocrinal, behavioral and neurodevelopmental. It affects both genders equally and its estimated prevalence is 1 in 15.000-25.000 births. PWS is caused by the absence or loss of expression of chromosome 15q11.2-q13 genes inherited from the father. This anomaly can occur through different mechanisms. Most cases (70%) are due to a microdeletion in 15q11.2-q13 locus. It can also be caused by maternal uniparental disomy (25%) and more rarely by imprinting defects. The DNA methylation test identifies the absent expression of paternal 15q11.2-q13 locus, detecting 99% of PWS cases. More genetic tests are required to find the specific genetic mechanism. At birth, the major characteristic of PWS is severe neonatal hypotonia with feeding problems, which if associated with a specific phenotype is enough to start a genetic study. This phenotype is defined by a dolichocephalic head, forehead and face narrowed, almond-shaped eyes, small mouth and thin upper lip and downturned mouth. As the child grows hyperphagia with central obesity accompanied by a neurodevelopmental delay occurs. Currently, recombinant growth hormone is the only therapeutic method available, reducing some of PWS comorbidities, such as overweight, cognitive impairment and behavioral alterations. Some studies are being held to find new pharmacologic and surgical methods, with the goal of treating these comorbidities and improving the quality of life of these patients. This case report describes an ex-premature newborn of 26 weeks with a strong clinical suspicion of PWS. Nevertheless, his first genetic test (FISH) was negative. The diagnosis of PWS was confirmed months later with a DNA methylation test, and afterwards the uniparental disomy subtype was confirmed.
Prader-Willi Syndrome (PWS) is a genetic disease with specific phenotypic characteristics, associated with endocrinal, behavioral and neurodevelopmental. It affects both genders equally and its estimated prevalence is 1 in 15.000-25.000 births. PWS is caused by the absence or loss of expression of chromosome 15q11.2-q13 genes inherited from the father. This anomaly can occur through different mechanisms. Most cases (70%) are due to a microdeletion in 15q11.2-q13 locus. It can also be caused by maternal uniparental disomy (25%) and more rarely by imprinting defects. The DNA methylation test identifies the absent expression of paternal 15q11.2-q13 locus, detecting 99% of PWS cases. More genetic tests are required to find the specific genetic mechanism. At birth, the major characteristic of PWS is severe neonatal hypotonia with feeding problems, which if associated with a specific phenotype is enough to start a genetic study. This phenotype is defined by a dolichocephalic head, forehead and face narrowed, almond-shaped eyes, small mouth and thin upper lip and downturned mouth. As the child grows hyperphagia with central obesity accompanied by a neurodevelopmental delay occurs. Currently, recombinant growth hormone is the only therapeutic method available, reducing some of PWS comorbidities, such as overweight, cognitive impairment and behavioral alterations. Some studies are being held to find new pharmacologic and surgical methods, with the goal of treating these comorbidities and improving the quality of life of these patients. This case report describes an ex-premature newborn of 26 weeks with a strong clinical suspicion of PWS. Nevertheless, his first genetic test (FISH) was negative. The diagnosis of PWS was confirmed months later with a DNA methylation test, and afterwards the uniparental disomy subtype was confirmed.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2018
Palavras-chave
Síndrome de Prader-Willi Estudos genéticos Hipotonia neonatal Prematuridade Pediatria