Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology

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.