The Smith-Lemli-Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology

The brief history of the Smith-Lemli-Opitz syndrome (SLOS) (MIM 270400) ref lects that of latter 20th century dysmorphology and biochemical and molecul ar genetics: from its first description as a rare but characteristic multip le malformation syndrome known only to a handful of dysmorphologists, to a relatively common Garrodian defect with a complex molecular basis that has captured the attention of researchers and basic scientists from the fields as diverse as embryology, developmental biology, sterol biochemistry, epide miology, and teratology. The discovery of the underlying biochemical defect -deficiency of 3 beta -hydroxysteroid-Delta (7)-reductase (DHCR7), an enzym e catalyzing the last step of cholesterol biosynthesis, and the resultant g eneralized cholesterol deficiency-has led to an explosion of knowledge of t his biochemical pathway and to a paradigm shift in the recognition of metab olic deficiencies as causes of dysmorphic syndromes. Characterization of th e human DHCR7 gene and the identification of mutations in patients with SLO S have revealed a complex picture of molecular heterogeneity and provided i nsights into the structure and function of DHCR7. SLOS is the first metabol ic malformation syndrome with profound effects on the body plan, and its di scovery has paved the way to the discovery of a number of other defects pat hway.