Purpose of review: This review covers a group of human malformation syndromes, which are caused by inborn errors of cholesterol synthesis. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation, and mental retardation syndrome that is the prototypical example of this group of disorders. In the 10 years since the biochemical cause of SLOS was identified, other malformation syndromes have been shown to result from defects in this pathway. These include desmosterolosis, lathosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM dysplasia), and some cases of Antley-Bixler syndrome. These disorders represent the first true merging of dysmorphology with biochemical genetics.
Recent findings: Recent studies report the identification of human lathosterolosis patients, indicate that SLOS is a relatively common genetic disorder that may be a major unrecognized cause of fetal loss, suggest that correction of the biochemical defect can improve central nervous system function, and show that perturbed sonic hedgehog signaling due to decreased sterol levels likely underlies some of the malformations in SLOS and lathosterolosis.
Summary: Recognition of the biochemical defect in these syndromes has given insight into the role that cholesterol plays during normal development, into understanding the pathophysiological processes that underlie the clinical problems found in these disorders, and into developing therapeutic interventions.