Prenatal diagnosis of Smith-Lemli-Opitz syndrome via an abnormal maternal serum screen

Abstract

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder which results from a defect in cholesterol biosynthesis. The finding of elevated levels of cholesterol precursors is diagnostic of SLO. There have been few reported cases of the prenatal diagnosis of SLO in the presence of a non-contributory family history. Abnormal triple screen, sex discrepancy, and polydactyly led to such a diagnosis in this case.L.M. was a 29 year old G2 P1 ABO who presented at 17.1 weeks gestation due to a positive maternal serum triple screen which estimated a midtrimester risk for fetal trisomy 18 of 1/15. The triple screen was reported as follows: MSAFP 0.44 MOM; ESTRIOL 0.43 MOM; HCG 0.35 MOM at 16.1 weeks. The couple opted for amniocentesis which resulted in a normal 46,XY karyotype. Due to a suspicion of early IUGR, a repeat ultrasound examination was performed at 20.1 weeks gestation, revealing a discrepancy between observed fetal sex and karyotype, post-axial polydactyly of both feet and the left hand, and growth lag. A repeat amniocentesis was performed to confirm fetal sex. L.M. was counseled regarding the sonographic and biochemical evidence that was suggestive of SLO. She elected to terminate the pregnancy. Amniotic fluid analysis subsequently revealed that 7-dehydrocholesterol (7-DHC) was greater than 800-fold increased in comparison to control; conversion of ergosterol to brassicasterol (estimating 7-DHC reductase activity) was 0.5% in fetal fibroblasts (control 15-35%, n=2), verifying SLO. Features consistent with SLO reported on autopsy included ambiguous genitalia with micropenis, severe hypospadias, and bifid scrotum. There was left hand post-axial polydactyly, bilateral post-axial polydactyly of the feet, and partial syndactyly of the second and third toes bilaterally. Facial dysmorphia included a broad nasal tip and anteverted nares, broad maxillary alveolar ridges, with a high arched hard palate and a soft palate cleft.This case demonstrates a possible role for triple screen, particularly uE3 analysis, in the detection of fetuses at risk for SLO.