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Arquivos de Medicina

versão On-line ISSN 2183-2447

Arq Med v.19 n.1-2 Porto jan. 2005

 

Diagnóstico Pré-Natal de Síndrome de Smith-Lemli-Opitz

 

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

 

Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome

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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REFERÊNCIAS

1 - Smith DW, Lemli L, Opitz JA. A newly recognized syndrome of multiple congenital anomlies. J Pediatr 1964;64:210-7         [ Links ]

2 - Wayne JS, Nakamura LM, Eng B, Hunnisett L, Chitayat D, Costa T, Nowaczyk MJM. Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. J Med Genet 2002;39;e31

3 - Schoen E, Norem C, O’ Keefe J, Krieger R, Walton D, To TT. Maternal Serum Unconjugated Estriol as a Predictor for Smith-Lemli-Opitz Syndrome and Other Fetal Conditions. Obstet & Gynecol 2003;102:167-72

4 - Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen T, Salen G. Defective Cholesterol Biosynthesis Associated with the Smith-Lemli-Opitz syndrome. New Engl J Med 1994;330:107-13

5 - Waterham HR, Wanders RJA. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz. Biochim Biophys Acta 2000;1529:340-56

6 - Seller MJ, Russell J, Tint GS. Unusual Case of Smith-Lemli-Opitz Syndrome “Type II”. Am J Hum Genet 1995;56:265-8

7 - Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down’s syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med 1999;341:461-7.

8 - Kelley RI. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholes-terol in plasma, amniotic fluid and cultured skin fibroblasts. Clin Chim Acta 1995;236:45-58

9 - Connor WE, Lin DS. Placental transfer of cholesterol - 4-14C into rabbit and guinea pig fetus. J Lipid Res 1967;8:558-64

10 - Schmid KE. Endogenous and Exogenous Sources of Cholesterol During Fetal Development. PhD thesis in Pathobiology and Molecular Medicine, University of Cincinnati, 2003

11 - Clayton PT. Disorders of Cholesterol biosynthesis. Arch Dis Child 1998;78:185-189

12 - Goldenberg A, Wolf C, Chevy F, Benachi A, Dumez Y, Munnich A, Cormier-Daire V. Antenatal manifestations of Smith-Lemli-Opitz (RSH) Syndrome : A retrospective Survey of 30 cases. Am J Med Genet 2004;124A:423-6

13 - Kratz LE, Kelley RI. Prenatal diagnosis of the RSH / Smith-Lemli-Opitz syndrome. Am J Med Genet 1999;82:376-81

14 - Angle B, Tint GS, Yacoub OA, Clark AL. Atypical case of Smih-Lemli-Opitz Syndrome: Implications for diagnosis. Am J Med Genet 1998;80:322-6

15 - Canick JA, Abuelo DN, Bradley LA Tint GS. Maternal serum marker levels in two pregnanacies affected with Smith-Lemli-Opitz syndrome. Prenat Diagn 1997;17:187-9

16 - Rossiter JP, Hofman KJ, Kelley RI. Smih-Lemli-Opitz Syndrome: Prenatal Diagnosis by Quantification of Cholesterol Precursors in Amniotic Fluid. Am J Hum Genet 1995;56:272-5

17 - Bick DP, McCorkle D, Stanley WS, Stern HJ, Staszak P, Berkovitz GD et al. Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome in a pregnancy with Low Maternal Serum Oestriol and a Sex-reversed fetus. Prenat Diagn 1999;19:68-71

18 - Abuelo DN, Tint GS, Kelley R, Batta AK, Shefer S, Salen G. Prenatal Detection of the cholesterol Biosynthetic Defect in the Smith-Lemli-Opitz syndrome by the Analysis of Amniotic Fluid Sterols. Am J Med Genet 1995;56:281-5

19 - Dallaire L, Mitchell G, Giguère R, Lefebvre F, Melançon SB, Lambert M. Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid. Prenat Diagn 1995;15:855-8

20 - Linck LM, Hayflick SJ, Lin DS, Battaile KP, Ginat S, Burlingame T, et al. Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol ?7-reductase activity in chorionic villi. Prenat Diagn 2000;20:238-40

21 - Shackleton C, Roitman E, Kratz L, Kelley R. Dehydrooestriol and dehydropregnanetriol are candidate analyse for prenatal diagnosis of Smith-Lemli-Opitz syndrome. Prenat Diagn 2001;21:207-12.

22 - Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE. Mutations in the human sterol ?-7-reduc-tase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet 1998;63:55-62

23 - Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, et al. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet 1998;63:329-38

24 - Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik Y-K, Glossmann H et al. Mutations in the ?-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Natl Acad Sci USA 95:8181-8186

25 - Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, Kraft HG, Moebius FF, Glossmann H et al. Mutational spectrum in the delta 7-sterol reductase gene and genotype-pheno-type correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet 2000;66:402-12

26 - Goldenberg A, Chevy F, Bernard C, Wolf C, Cormier-Daire V. Circonstances cliniques du diagnostique du syndrome deSmith-Lemli-Opitz et tentatives de corrélation phénotypegenótype: à propos de 45 casirconstances cliniques du diagnostique du syndrome de Smith-Lemli-Opitz et tentatives de corr 84 patients with Smith-Lemli-Opit. Arch Pediatr 2003;10:4-10

27 - Bzdúch V, Kozák L, Franvová H, Behúlová D. Prenatal Diagnosis of Smith-Lemli-Opitz syndrome by Mutation Analysis. Am J Med Genet 2000;95:85

28 - Nowaczyk MJM, Farrell SA, Sirkin WL, Velsher L, Krakowiak PA, Waye JS, Porter FD. Smith-Lemli-Opitz (RHS) Syndrome: Holoprosencephaly and Homozygous IVS8-1G_C Genotype Am J Med Genet 2001;103:75-80

29 - Nowaczyk MJM, Garcia DM, Eng B, Waye J. Rapid Molecular Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome. Am J Med Genet 2001;102:287-388

30 - Löffler J, Utermann G, Witsch-Baumgartner M. Molecular prenatal diagnosis of Smith-Lemli-Opitz syndrome is reliable and efficient. Prenat Diagn 2002;22:827-30

31 - Löffler J, Trojovsky A, Casati B, Kroisel PM, Utermann G. Homozygosity for the W151X Stop Mutation in the ?7-sterol Reductase Gene (DHCR7) Causing a Lethal Form of Smith-Lemli-Opitz syndrome: Retrospective Molecular Diagnosis. Am J Med Genet 2000;95:174-7

 

Correspondência:

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

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