Maria Luís Cardoso*, Ana Maria Fortuna*, Sérgio Castedo†, Margarida Martins‡, Nuno Montenegro§, Cornelis JakobsII, Peter Clayton**, Laura Vilarinho*

*Instituto de Genética Médica Jacinto de Magalhães, Porto; †GDPN-Genética Médica e Diagnóstico Pré-Natal, Porto;

‡Serviço de Obstetrícia , Hospital Pedro Hispano, Matosinhos; §Departamento de Ginecologia e Obstetrícia, Hospitalde São João, Porto; IIMetabolic Unit, Departement of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands; **Biochemistry Unit, Institute of Child Health, England

A síndrome de Smith-Lemli-Opitz (SLO) é uma síndrome polimalformativa de natureza metabólica e transmissão autossómica recessiva, caracterizada por um padrão de dismorfias faciais minor, anomalias congénitas de vários órgãos, atraso de crescimento e atraso mental. É causada por um defeito da enzima 7-dehidrocolesterol reductase, responsável pelo último passo da via metabólica da síntese do colesterol. A síndrome de Smith-Lemli-Opitz caracteriza-se por níveis diminuídos de colesterol e concentrações altas do seu precursor 7-dehidrocolesterol. Os autores relatam o caso de uma gravidez com rastreio pré-natal integrado positivo para trissomia 21 e níveis séricos de estriol não conjugado particularmente baixos. O cariótipo fetal revelou uma constituição cromossómica 46,XY. Ecograficamente havia a registar uma translucência da nuca aumentada às 11 semanas de gestação e, às 18 semanas ambiguidade genital, encurtamento dos fémures, cardiopatia lábio leporino e atraso de crescimento intra-uterino. A suspeita bioquímica e ecográfica de síndrome de Smith-Lemli-Opitz foi confirmada pela demonstração de níveis baixos de colesterol e níveis altos de 7-dehidrocolesterol e 8-dehidrocolesterol no líquido amniótico. Após interrupção médica da gravidez às 20 semanas, foi realizada a análise mutacional do gene DHCR7 em DNA extraído de tecidos fetais, a qual demonstrou homozigotia para a mutação comum IVS81G>C associada a fenótipos graves. Os autores fazem também uma revisão da literatura respeitante ao diagnóstico pré-natal de síndrome de Smith-Lemli-Opitz.

Palavras-chave: Síndrome Smith-Lemli-Opitz, estriol, 7-dehidrocolesterol, colesterol, DHCR7, diagnóstico pré-natal, translucência da nuca, ambiguidade sexual, IVS81G>C

The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive polimalformative metabolic syndrome, characterized by a recognizable pattern of minor facial anomalies, congenital anomalies of many organs, failure to thrive, and mental retardation. It is caused by a defect in the enzyme 7-dehydrocholesterol reductase, which is responsible for the last step of cholesterol biosynthesis pathway. The Smith-Lemli-Opitz syndrome is characterized by low plasma cholesterol levels and elevated concentrations of the cholesterol precursor 7-dehydrocholesterol. We report on a pregnancy with a positive integrated prenatal screening test for Down’s syndrome, with unusually low maternal serum levels of unconjugated oestriol (uE3). An increased nuchal translucency was noted in the 11 weeks’ scan. The fetal karyotype revealed a normal 46,XY karyotype. Detailed ultrasound scan at 18 weeks revealed ambiguous genitalia, short femur length, cleft lip heart defect and intrauterine growth retardation. Based on these findings and the maternal serum levels of uE3 prenatal diagnosis, SLO was suspected and later confirmed by the demonstration of low levels of cholesterol and high levels of 7-dehydrocholesterol and 8-dehydrocholesterol in a stored frozen sample of amniotic fluid. Pregnancy was terminated at 20 weeks and the mutational analysis of DHCR7 gene on DNA obtained from foetal tissues revealed homozygosity for the common Caucasian mutation IVS81G>C associated with SLO severe phenotypes. The state of the art on prenatal diagnosis of Smith-Lemli-Opitz syndrome is reviewed.

Key-words: Smith-Lemli-Opitz syndrome, oestriol, 7-dehydrocholesterol, cholesterol, DHCR7, prenatal diagnosis, nuchal translucency, ambiguous genitalia, IVS81G>C

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Dr.ª Maria Luís Cardoso

Unidade de Biologia Clínica

Instituto de Genática Mádica Jacinto Magalhães

Praça Pedro Nunes, 88 4099-028 Porto

e-mail: mluiscardoso@gm.min-saude.pt