Smith–Lemli–Opitz syndrome: Phenotype, natural history, and epidemiology


  • Małgorzata J.M. Nowaczyk,

    Corresponding author
    • Department of Pathology and Molecular Medicine and Department of Pediatrics, McMaster University McMaster University Medical Centre, Room 3N16, 1200 Main Street West, Hamilton ON, Canada L8S 4J9.
    Search for more papers by this author
    • Dr. Małgorzata Nowaczyk is a pediatric clinical geneticist at McMaster University in Hamilton, Canada. She is an Associate Professor in the Departments of Pediatrics and of Pathology and Molecular Medicine. Dr. Nowaczyk's research interests include disorders of endogenous sterol synthesis, delineation of novel genetic syndromes, and prenatal diagnosis. She is a member of the Canadian College of Medical Geneticists and of the American College of Medical Genetics.

  • Mira B. Irons

    Search for more papers by this author
    • Dr. Mira Irons is the Associate Chief of the Division of Genetics and the Chief of Clinical Programs in the Division of Genetics at Children's Hospital Boston. Dr. Irons is an Associate Professor of Pediatrics at Harvard Medical School. Dr. Irons' research interests include genotype–phenotype correlations and abnormalities of bone in NF1, the long-term effects of cholesterol treatment of children with inborn errors of sterol metabolism, and the impact of chromosome microarray and next generation sequencing in clinical practice. She is Board Certified in Medical Genetics, Biochemical Genetics, and Pediatrics.

  • How to cite this article: Nowaczyk MJM, Irons MB. 2012. Smith–Lemli–Opitz syndrome: Phenotype, natural history, and epidemiology. Am J Med Genet Part C Semin Med Genet 160C: 250–262.


Smith–Lemli–Opitz syndrome (SLOS) is a congenital multiple anomaly/intellectual disability syndrome caused by a deficiency of cholesterol synthesis resulting from a deficiency of 7-dehydrocholesterol (7DHC) reductase encoded by DHCR7. SLOS is inherited in an autosomal recessive pattern. It is characterized by prenatal and postnatal growth retardation, microcephaly, a variable degree of intellectual disability that encompasses normal intelligence to severe intellectual deficiency, and multiple major and minor malformations. External malformations include distinctive facial features, cleft palate, postaxial polydactyly, 2–3 syndactyly of the toes, and underdeveloped external genitalia in males, while internal anomalies may affect every organ system. The clinical spectrum is wide, and rare individuals have been described with normal development and only minor malformations. The clinical diagnosis of SLOS is confirmed by demonstrating an abnormally elevated concentration of the cholesterol precursor, 7DHC, in serum or other tissues, or by the presence of two DHCR7 mutations. The enzymatic deficiency results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the physical and behavioral phenotype of SLOS, the diagnostic approaches, the natural history from the prenatal period to adulthood, and current understanding of the pathophysiology of SLOS. © 2012 Wiley Periodicals, Inc.