The Smith-Lemli-Opitz syndrome

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is one of the archetypical multiple congenital malformation syndromes. The recent discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism have led to important new treatment possibilities for aVected patients. Moreover, the recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its eVects on the expression of homeobox genes, has provided an explanation for the abnormal morphogenesis in the syndrome. The well known role of cholesterol in the formation of steroid hormones has also provided a possible explanation for the abnormal behavioural characteristics of SLOS. (J Med Genet 2000;37:321-335)

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

“…Persistent cloaca has been associated with chromosome 7p rearrangements (18). Furthermore, mutations that disrupt a single gene can cause this malformation: homozygous mutations in the gene DHCR7 cause persistent cloaca in combination with renal aplasia/hypoplasia/ectopia as part of the Smith-Lemli-Opitz syndrome (19), and a heterozygous de-novo missense mutation in the cytoplasmic domain of UPIIIA (human chromosome 22q13.31), a gene expressed in the normal human embryonic urogenital sinus, was found in a girl who had persistent cloaca as well as renal adysplasia (20).…”

Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations

“…[2][3][4] The syndrome is reportedly common in the Czech Republic and Slovakia and is rare or absent in nonCaucasian populations. SLOS is the prototype of a severe human malformation syndrome which is caused by an inborn error of metabolism.…”

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

“…Individuals with this syndrome have mutations in 3β-hydroxysterol Δ 7 -reductase (DHCR7) and convert minimal to no 7-dehydrocholesterol to cholesterol, depending on the type of mutation [4,5]. The deficiency of cholesterol can lead to a wide range of congenital defects, ranging from the mild (minor physical abnormality with behavioral and learning disabilities) to the severe (lethal with multiple major congenital anomalies) [6,7]. Not surprising, the severity of the syndrome is correlated with circulating sterol concentrations [8].…”