Smith-Lemli-Opitz syndrome (SLOS) is characterized, depending on the severity, by a wide range of symptoms with signs of dysmorphia (microcephaly, "midline defect," microretrognathia, low-set ears, blepharoptosis, postaxial polydactyly), psychomotor retardation, short stature, and malformations such as heart defects and cleft lip and/or palate. Affected boys may also be conspicuous for genital malformations (e.g., hypospadias). The molecular cause is found in a disturbance of the last step in the synthesis pathway of cholesterol, resulting in the accumulation of 7-dehydrocholesterol (and its isomer 8-dehydrocholesterol). Since conventional enzymatic cholesterol determination cannot differentiate cholesterol from 7-dehydrocholesterol, biochemical detection of SLOS is performed by gas chromatography/mass spectrometry. An elevated 7-dehydrocholesterol/cholesterol ratio is indicative of SLOS.
The inheritance of SLOS follows an autosomal recessive pattern. The prevalence is 1:10,000 to 1:30,000. Pathogenic variants in the DHCR7 gene, which codes for the enzyme 7-dehydrocholesterol reductase, lead to loss of enzyme activity and thus to failure of the last step in cholesterol synthesis. The most common causative variant (c.964-1G>C) is located in intron 8 of the DHCR7 gene. It can be detected in about 30% of all patients. Types of variants and loci in the gene influence the severity of SLOS. However, a clear genotype-phenotype correlation does not always exist, so that patients with the same variants may be affected to different degrees. Therefore, other factors that influence the phenotype are discussed. A 2004 study demonstrated a correlation between maternal ApoE genotype and severity in patients with SLOS.
Nowaczyk M.J.M. 2013, GeneReviews® [Internet] / Corso et al. 2011, Clin Chem Lab Med 12:2039 / DeBarber et al. 2011, Expert Rev Mol Med 13:e24 / Yu et Patel 2005, Clin Genet 68:383 / Witsch-Baumgartner et al. 2004, J Med Genet 41:577