Smith-Lemli-Opitz syndrome

Martina Witsch-Baumgartner PhD (Dr. Witsch-Baumgartner of the Medical University of Innsbruck has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire and Vtesse.)
Originally released November 28, 1994; last updated October 20, 2016; expires October 20, 2019

This article includes discussion of Smith-Lemli-Opitz syndrome, Smith-Lemli-Opitz syndrome type I, Smith-Lemli-Opitz syndrome type II, RSH syndrome, SLO syndrome, and SLOS. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation 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 to 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. The mutations in the HUGO Gene Nomenclature Committee database show some population specificity. Pathogenic mutations are maintained in the Leiden Open Variation database with links to possible modifier genes and their maternal genotypes. 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.

 

• 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.

Historical note and terminology

Fifty years ago, Smith-Lemli-Opitz syndrome (SLOS) was first described in 3 male patients by the pediatricians David W Smith, Luc Lemli, and John Opitz of the University of Wisconsin, U.S. (Smith et al 1964). 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 hypogenitalism.

Thirty years later, Tint and colleagues published their measurements of neutral sterols in the plasma of 5 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 (Irons et al 1993; Tint et al 1994). This step in the biosynthesis of cholesterol is catalyzed by the delta 7-dehydrocholesterol reductase (Shefer et al 1995). Subsequently, the underlying DHCR7 gene was identified and cloned in 1998 (Moebius et al 1998).

More than 150 DHCR7 mutations have been described so far in more than 250 individuals with Smith-Lemli-Opitz syndrome (Wassif et al 1998; Waterham et al 1998; DeBrasi et al 1999; Witsch-Baumgartner et al 2000; Witsch-Baumgartner et al 2001; Yu et al 2000; Patrono et al 2002; Yu and Patel 2005; Waterham and Hennekam 2012). All patients with elevated levels of 7-dehydrocholesterol were shown to be compound heterozygous for 2 DHCR7 mutations (personal communication).

Comparison between the clinical phenotype described by severity scores (Kratz and Kelley 1999) and the corresponding biochemical data and their genotypes demonstrates a clear genotype-phenotype correlation (Witsch-Baumgartner et al 2001). Possible phenotypic modifiers may include the maternal apo E genotype (Witsch-Baumgartner et al 2004). 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 Smith-Lemli-Opitz syndrome patients is ABCA1 (Lanthaler et al 2013), but the size of HDL particles may also influence the maternal transport of cholesterol to the fetus (Jenkins et al 2008).

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_001360.2 and LRG_340_t1 (see http://www.lrg-sequence.org/).

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