First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency)

In Smith-Lemli-Opitz syndrome (SLOs), 7-dehydrocholesterol (7-DHC) accumulates because there is a block in the pathway for synthesis of cholesterol via 7-DHC. Prenatal diagnosis of SLOs has been achieved by analysis of 7-DHC in amniotic fluid obtained at 16-18 wk from pregnancies at risk. The purpose of this study was to investigate 7-DHC and cholesterol concentrations in chorionic villus (CV) samples with a view to performing first trimester prenatal diagnosis. Using a sensitive gas chromatography-mass spectrometry assay it was possible to detect 7-DHC in CV samples obtained as early as 7 wk of gestation. The ratio of 7-DHC to cholesterol in placental tissue was shown to be relatively constant over the gestational period of 7-18 wk. We therefore proceeded to analyze the 7-DHC/cholesterol ratio in CV samples taken at 10-12 wk of gestation from three pregnancies at risk for SLOs. The results were as follows: patient A, 1.10 × 10-3; patient B, 1.80 × 10-3; patient C, 0.091; control range for CVS(8-12 wk), 3.10 × 10-4 to 1.62 × 10-3 (mean ± 2SD; n = 5). The fetus of patient C was diagnosed as affected by SLOs, and the parents requested termination. Analysis of cultured skin fibroblasts confirmed the diagnosis. Pregnancies A and B were diagnosed unaffected, and this was confirmed first by amniocentesis and then by the birth of normal infants at term. We conclude that synthesis of cholesterol via 7-DHC is occurring in the placenta and/or fetus at 10 wk of gestation and that prenatal diagnosis by CV biopsy is possible.