Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- SLOs:
-
Smith-Lemli-Opitz syndrome
- 7-DHC:
-
7-dehydrocholesterol
- CV:
-
chorionic villus
References
Smith DW, Lemli L, Opitz JM 1964 A newly recognised syndrome of multiple congenital anomalies. J Pediatr 64: 210–217.
Curry CJR, Carey JC, Holland JS 1987 Smith-Lemli-Opitz syndrome-type II. Am J Med Genet 26: 45–57.
Opitz JM, Penchaszadeh VB, Holt MC, Spano LM 1987 Smith-Lemli-Opitz (RSH) syndrome bibliography. Am J Med Genet 28: 745–750.
Chasalow FI, Blethen SL, Taysi K 1985 Possible abnormalities of steroid excretion in children with Smith-Lemli-Opitz syndrome and their parents. Steroids 46: 827–843.
Tint GS, Irons M, Elias ER 1994 Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330: 107–113.
McGaughran JM, Clayton PT, Mills KA, Rimmer S, Moore L, Donnai D 1995 Prenatal diagnosis of Smith-Lemli-Opitz syndrome. Am J Med Genet 56: 269–271.
Abuelo DN, Canick JA, Kelley RI, Irons M, Tint GS, Salen G, Batta AK 1994 Prenatal diagnosis of Smith-Lemli-Opitz syndrome by detection of the cholesterol biosynthetic defect in amniotic fluid. (Cholesterol Metabolism in the RHS/Smith-Lemli-Opitz Syndrome: Summary of an NIHCD Conference. ) Am J Med Genet 50: 326–338.
Beatty TH, Kwiterowich PO, Khoury MJ, White S, Bachorik PS, Smith HH, Sniderman A 1986 Genetic analysis of plasma sitosterol, apoprotein B and lipoproteins in a large Amish pedigree with sitosterolaemia. Am J Hum Genet 38: 492–504.
Ishikawa TT, Macgee J, Morrison JA, Glueck CJ 1974 Quantitative analysis of cholesterol in 5 to 20 l of plasma. J Lipid Res 15: 286–291.
Clayton PT, Bowron A, Mills KA, Casteels M, Milla P 1993 Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 105: 1806–1813.
Chevalier F 1967 Dynamics of cholesterol in rats studied by the isotopic equilibrium method. Adv Lipid Res 5: 209–239.
Carr BR Simpson ER 1982 Cholesterol synthesis in human fetal tissues. J Clin Endocrinol Metab 55: 447–452.
Axelson M 1991 Occurrence of isomeric dehydrocholesterols in human plasma. J Lipid Res 32: 1441–1448.
Acknowledgements
The authors thank Dr. Davies, Regional Cytogenetics Unit, Bristol, for help with collection of the 14-18-wk placental samples, and John Rainer and Elisabeth Young of the enzyme laboratory at the Institute of Child Health for help with cell culture procedures and the dissection of the chorionic villus samples. We also thank Asprey Plc. for the donation of the gas chromatography-mass spectrometry equipment.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mills, K., Mandel, H., Montemagno, R. et al. First Trimester Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome(7-Dehydrocholesterol Reductase Deficiency). Pediatr Res 39, 816–819 (1996). https://doi.org/10.1203/00006450-199605000-00012
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199605000-00012
This article is cited by
-
Relation between biomarkers and clinical severity in patients with Smith–Lemli–Opitz syndrome
European Journal of Pediatrics (2013)
-
Congenital cataract and multisystem disorders
Eye (1999)
