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Although cholesterol metabolism has been one of the most intensely studied metabolic pathways in humans, for many years the only known primary defect of the cholesterol biosynthetic pathway was mevalonic aciduria, a rare autosomal recessive deficiency of mevalonate kinase associated with developmental delays, craniofacial dysmorphism, and a variety of systemic and metabolic abnormalities (Branched Chain Organic Acidurias). However, in 1993, a second defect of cholesterol synthesis, a deficiency of 7-dehydrocholesterol reductase (DHCR7), was found to be the apparent cause of the RSH/Smith-Lemli-Opitz syndrome (SLOS), a relatively common autosomal-recessive multiple-malformation syndrome. Patients with both mild and severe forms of SLOS had markedly increased levels of 7-dehydrocholesterol (7DHC) and decreased levels of cholesterol. The finding 5 years later of disabling mutations in the DHCR7 gene in patients with SLOS confirmed SLOS as the second defect of cholesterol biosynthesis and the first affecting sterol metabolism per se.

The discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism has led not only to successful treatment of affected patients, but also to the recognition of the important role of cholesterol in vertebrate embryogenesis. Moreover, the discovery at about the same time that cholesterol is directly involved in the hedgehog embryonic signaling pathway suggested an important link between embryogenesis and the abnormal metabolism in SLOS. No less important has been the recognition of the critical role that cholesterol plays in the expression of the abnormal behaviors that characterize SLOS.


Smith-Lemli-Opitz syndrome was first described as a coherent multiple malformation syndrome in 19641 in a report of three patients with a distinctive facial appearance and the common abnormalities of global developmental delays, microcephaly, broad alveolar ridges, hypospadias, a characteristic dermatoglyphic pattern, and severe feeding disorder. A more complete delineation of SLOS was presented in 1969 as the “RSH syndrome,” a non-descriptive acronym of the first letters of the original patients' surnames.2 The description of many new cases of SLOS over the next 20 years expanded the known characteristics of the syndrome to include midline cleft palate, cataracts, postaxial polydactyly, heart defects, and a variety of central nervous system defects (Table 299-1).2-11 Many affected children died in the first year from failure to thrive and infections, but many others survived to adulthood. Somewhat later, several authors described patients with a lethal syndrome that resembled SLOS, so-called “type II SLOS.”12-16 These children had many of the “external” anomalies of SLOS, but died in the newborn period from severe internal malformations, including pulmonary hypoplasia, complex congenital heart disease, renal hypoplasia or agenesis, and Hirschsprung disease. In addition, some 46,XY males had severe hypogenitalism or female-appearing external genitalia. In all informative families, segregation of either form of SLOS was consistent with autosomal recessive inheritance,2,12 and the severity of malformations and degree of mental retardation was usually similar ...

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