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  • Updated 05.05.2023
  • Released 11.28.1994
  • Expires For CME 05.05.2026

Smith-Lemli-Opitz syndrome



Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation syndrome that is associated with intellectual disability. The primary defect is the deficiency of 7-dehydrocholesterol reductase. This leads to an accumulation of 7- and 8-dehydrocholesterol and a lack of cholesterol. The latter is mainly involved in embryonic development. The distinctive malformations observed are characteristic facial features (such as anteverted nares), hypospadias, and 2-3 toe syndactyly. There is significant phenotypic variation in expressivity, and individuals have been described with normal development and only minor malformations. The incidence of Smith-Lemli-Opitz syndrome is about 1:15,000 to 1:60,000. Pathogenic mutations are maintained in the Leiden Open Variation database with links to possible modifier genes. There are still very limited studies about cholesterol therapies and improvement of phenotype by HMG-CoA-reductase inhibitors such as simvastatin.

Key points

• Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic malformation and intellectual disability syndrome due to cholesterol deficiency.

• Mutation spectra are known in a variety of different populations, and pathogenic variants are maintained in the Leiden Open Variation database, HGMD, and in ClinVar).

• There is a large spectrum of phenotype variability. This is due in part to the type of mutations in the DHCR7 gene, the genotype present in the individual, and modifying factors, such as the maternal apo E genotype.

• Smith-Lemli-Opitz syndrome is primarily diagnosed by clinical presentation, including typical malformations, 2-3 toe syndactyly, and elevated 7-dehydrocholesterol.

• There is no curative therapy for Smith-Lemli-Opitz syndrome presently.

• Studies confirm that neuroleptic medications (eg, aripiprazole and cariprazine) lead to an elevation of 7-dehydrocholesterol in the brain of offspring and, hence, should be avoided during pregnancy (36; 37).

Historical note and terminology

In the 1960s, Smith-Lemli-Opitz syndrome (SLOS) was first described in three male patients by the pediatricians David W Smith, Luc Lemli, and John Opitz of the University of Wisconsin, U.S. (101). The syndrome was initially named RSH, a nondescriptive acronym of the first letters of the original patients’ surnames. It was a clinical description of patients who all had microcephaly and hypogonadism.

Thirty years later, Tint and colleagues published their measurements of neutral sterols in the plasma of five patients with Smith-Lemli-Opitz syndrome and found abnormally low concentrations of cholesterol but greater than 1000-fold increases in the level of 7-dehydrocholesterol, the immediate precursor of cholesterol in the Kandutsch-Russell pathway for biosynthesis of cholesterol (42; 110). This step in the biosynthesis of cholesterol is catalyzed by the delta 7-dehydrocholesterol reductase (96). Subsequently, the underlying DHCR7 gene was identified and cloned in 1998 (75).

More than 550 DHCR7 mutations have been described so far in individuals with Smith-Lemli-Opitz syndrome (see LOVD, HGMD, and ClinVar) (116; 119; 23; 122; 124; 131; 84; 130; 118). All patients with elevated levels of 7-dehydrocholesterol were shown to be compound heterozygous for two DHCR7 mutations or homozygous (personal communication).

Comparison between the clinical phenotype described by severity scores (63) and the corresponding biochemical data and their genotypes demonstrates a clear genotype-phenotype correlation (124). Possible phenotypic modifiers may include the maternal apo E genotype (123). The maternal apo E2 genotypes have been associated with a severe Smith-Lemli-Opitz syndrome phenotype, whereas apo E genotypes without the E2 allele have been associated with a milder phenotype. Another modifier of Smith-Lemli-Opitz syndrome associated with viability of patients with Smith-Lemli-Opitz syndrome is the maternal ABCA1 genotype (64), but the size of HDL particles may also influence the maternal transport of cholesterol to the fetus (44).

The HUGO Gene Nomenclature Committee symbol is DHCR7. The genomic sequence source is NG_012655.2. The transcript reference sequence now used for nomenclature of mutations in the DHCR7 gene is NM_001360.3 (MANE transcript) and LRG_340_t1 (see and

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