(RSH) syndrome - Wiley Online Library

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Alice Goldenberg,1 Claude Wolf,2 Françoise Chevy,2 Alexandra Benachi,3. Yves Dumez,3 Arnold Munnich,1 and Valérie Cormier-Daire1*. 1Department of ...
American Journal of Medical Genetics 124A:423– 426 (2004)

Research Review Antenatal Manifestations of Smith-Lemli-Opitz (RSH) Syndrome: A Retrospective Survey of 30 Cases Alice Goldenberg,1 Claude Wolf,2 Franc¸oise Chevy,2 Alexandra Benachi,3 Yves Dumez,3 Arnold Munnich,1 and Vale´rie Cormier-Daire1* 1

Department of Medical Genetics, Hoˆ pital Necker-Enfants-Malades, Paris, France Laboratory of Mass spectrometry, Hoˆ pital Saint-Antoine, Paris, France 3 Department of Obstetrics, Hoˆ pital Necker-Enfants-Malades, Paris, France 2

Smith-Lemli-Opitz (SLO) syndrome or RSH syndrome is an autosomal recessive multiple malformation, and mental retardation syndrome ascribed to 7-dehydrocholesterol reductase deficiency, and usually diagnosed in the early postnatal period. Reviewing a series of 30 cases of SLO, we have investigated the variable antenatal expression of the disorder. Intrauterine growth retardation (IUGR) was the most frequent detectable trait (20/30). IUGR was either isolated (9/20) or associated with at least one other anomaly (11/20), including nuchal edema, renal, cardiac, cerebral malformations, genital anomalies, or polydactyly. In this last group, 3/11 presented with multiple malformations (3 anomalies). In 5/30 cases, isolated nuchal edema (3/30), and isolated cardiac (1/30) or renal malformations (1/30) were the only detectable anomalies. Ultrasound findings were considered normal in 5/ 30 cases and were abnormal in 25/30 cases (83%), but early detection of multiple malformations was rare (3/30, 10%). We suggest giving consideration to a more systematic sterol analysis when dealing with IUGR, especially when associated anomalies are detected. ß 2003 Wiley-Liss, Inc. KEY WORDS: Smith-Lemli-Opitz syndrome; RSH syndrome; antenatal manifestations;

intrauterine growth retardation; sterol analysis

INTRODUCTION Smith-Lemli-Opitz or RSH syndrome (SLO) is an autosomal recessive multiple congenital malformation and mental retardation syndrome [Smith et al., 1964], ascribed to 7-dehydrocholesterol reductase deficiency in the cholesterol biosynthesis pathway [Irons et al., 1993; Tint et al., 1994]. Clinical expression in affected individuals includes minor facial and limb anomalies (syndactyly of the 2nd and 3rd digits), abnormal genitalia, growth failure, microcephaly, and severe psychomotor retardation [Irons et al., 1994; Ryan et al., 1998]. Prenatal diagnosis based on sterol measurement on chorionic villi or amniotic fluid is feasible and highly reliable [Abuelo et al., 1995; Mills et al., 1996; Sharp et al., 1997; Iron and Tint, 1998; Tint et al., 1998]. Since most of our patients expressed the disorder in the early postnatal period, we investigated the variable antenatal expression of SLO, and have addressed the question of whether this diagnosis could have been considered earlier based on the ultrasound survey of the pregnancy. Reviewing a series of 30 confirmed cases, we report here on the spectrum and frequency of antenatal manifestation of the disease, and suggest that a careful oriented ultrasound survey should help improve early diagnosis of SLO. METHODS

*Correspondence to: Vale´rie Cormier-Daire, Department of Medical Genetics, Hoˆpital Necker-Enfants-Malades, 149, rue de Se`vres, 75043 Paris cedex 15, France. E-mail: [email protected] Received 17 September 2002; Accepted 27 May 2003 DOI 10.1002/ajmg.a.20448

ß 2003 Wiley-Liss, Inc.

Thirty cases of biochemically confirmed SLO originating from 20 maternity hospitals were included in the study. All SLO fetuses and infants diagnosed between January 1994 and December 2000 with an available antenatal survey were included in the study. Among the 30 cases, 5 were prenatally diagnosed because of an affected sib (cases 2, 3, 7, 10, 19). Although they were known to have a 25% recurrence risk, they

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were included since the first ultrasound study (10– 13 weeks) was available on all, and the second ultrasound study (20–22 weeks) was also available on two of the subsequent fetuses. Five other cases were diagnosed prenatally because of the detection of malformations (cases 5, 6, 14, 17, 23). The 20 remaining cases were diagnosed postnatally. Biochemical tests were based on gas chromatography–mass spectrometry and performed in the same laboratory of the Hoˆpital Saint Antoine (Paris). Ten of 30 cases were diagnosed antenatally on chorionic villi (1/10), amniotic fluid (7/10), or cord blood (2/10), and 20/ 30 were diagnosed postnatally on plasma sampling. The prenatal survey included three systematic prenatal ultrasound surveys during the first (10–13 weeks), second (20–22 weeks), and third trimesters (30– 34 weeks) as performed in France in routine pregnancy surveillance. The first ultrasound survey included nuchal translucency measurement and was performed in all 30 cases. Three affected fetuses belonging to atrisk families were terminated before 20 weeks of gestation. The second ultrasound survey (bidimensional morphologic examination) was performed in 27 cases as routine examination. At this stage, when an anomaly was suspected, the cases were referred to a fetal medicine center for high level sonographic studies. Two pregnancies in at-risk families were terminated at 21 weeks of gestation, and five were terminated between 23 and 28 weeks of gestation based on prenatal findings. A last ultrasound survey was performed in the remaining 20 cases. Severity score was applied as proposed by Kelley and Hennekam [2000] in the 25 cases on whom precise clinical data were available (Table I). RESULTS Table I summarizes the prenatal findings in all 30 cases, and Table II the postnatal or postmortem observations in the 27 cases of SLO with, at least the first two ultrasound surveys available. Intrauterine growth retardation (IUGR) was the most frequent finding in our series (20). IUGR was detected at 20–22 weeks (6/20, 30%) or 30–34 weeks of pregnancy (14/20, 70%), and was variable in severity (