Atypical case of Smith-Lemli-Opitz syndrome: Implications for diagnosis

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder compris ed of recognizable facial abnormalities, growth retardation, and multiple c ongenital anomalies, commonly involving genitalia, second and third toe syn dactyly, and cleft palate. The condition is associated with hypocholesterol emia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from defi cient activity of the enzyme 7-dehydrocholesterol reductase. The clinical s pectrum of SLO ranges from individuals with mental retardation and minor an omalies to those with major structural defects and early or even prenatal l ethality. Low maternal serum unconjugated estriol (uE3) levels and a variet y of fetal ultrasound anomalies have been identified in affected pregnancie s, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal ante natal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype, The infant died at birth. A t autopsy the infant had hydrops, unusual face, cleft palate, genital abnor malities, Dandy-Walker malformation, and absence of toe syndactyly, Tests p erformed on cultured skin fibroblasts showed elevated levels of 7DHC and ab normalities of cholesterol biosynthesis characteristic of the metabolic def ect that causes SLO. The atypical findings of hydrops, uncharacteristic fac ial appearance, and absence of toe syndactyly in this case additionally ill ustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal f etal ultrasound findings in the presence of a normal karyotype lends additi onal support for consideration of prenatal biochemical testing for SLO in p regnancies with these findings, including pregnancies not previously known to be at risk. Am. J, Med. Genet, 80:322-326, 1998. (C) 1998 Wiley-Liss, In c.