Smith-Lemli-Opitz syndrome (SLOS)

Smith-Lemli-Opitz syndrome presents across a broad clinical spectrum. The severe form features prenatal and postnatal growth restriction, microcephaly, characteristic facial features, and moderate-to-severe intellectual disability. Major and minor malformations include cleft palate (40-50%), abnormal gingivae, congenital heart defects (50%), hypospadias and/or cryptorchidism (50% of males), ambiguous genitalia or failure of masculinisation in 46,XY individuals (20-25%), postaxial polydactyly (25-50%), 2-3 toe syndactyly (>99%), renal anomalies (25%), and cataract (20%). Hypotonia and UVA-mediated photosensitivity are common. Milder presentations may show only subtle facial dysmorphism, hypotonia, 2-3 toe syndactyly, and minimal or no intellectual disability. Clinical variability is substantial even within families, with affected siblings showing differing degrees of involvement. Onset is prenatal or congenital; in severe forms, multisystem malformations and growth restriction may be detected in utero. The severity of multisystem involvement correlates inversely with serum cholesterol concentration.

The estimated incidence is approximately 1:40,000 live births (GeneReviews, 2020). A carrier frequency of 2.83 % has been reported in representative Czech and Hungarian population cohorts.

Smith-Lemli-Opitz syndrome is caused by biallelic germline pathogenic variants in DHCR7. The gene (locus 11q13.4) encodes 7-dehydrocholesterol reductase (3β-hydroxysteroid-Δ7-reductase), the enzyme catalysing the terminal step of cholesterol biosynthesis. Loss-of-function variants reduce enzyme activity and disrupt conversion of 7-dehydrocholesterol to cholesterol, leading to accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol with concomitantly reduced cholesterol levels.

Smith-Lemli-Opitz syndrome is inherited in an autosomal recessive manner. Each pregnancy of two heterozygous parents carries a 25% risk of an affected child, a 50% risk of a heterozygous carrier, and a 25% chance of an unaffected non-carrier. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis of Smith-Lemli-Opitz syndrome is established biochemically by elevated serum 7-dehydrocholesterol (7-DHC) concentration with low or low-normal serum cholesterol. Identification of biallelic pathogenic variants in DHCR7 supports the diagnosis at the molecular level. No formal clinical consensus diagnostic criteria have been established.

Main differential diagnoses include:

• Squalene synthase deficiency: cholesterol-biosynthesis defect with overlapping multisystem features; biochemically distinguished by normal 7-DHC and elevated farnesol; FDFT1.
• Desmosterolosis: shares ambiguous genitalia, cleft palate, microcephaly; distinguished by anomalous pulmonary venous drainage and osteosclerosis; DHCR24.
• Lathosterolosis: shares cleft palate, 2-3 toe syndactyly, microcephaly; distinguished by hepatic steatosis and haematologic anomalies; SC5D.

• Confirming the clinical diagnosis at the molecular level provides certainty about the underlying genetic cause and concludes the diagnostic process.
• Providing the prerequisite for targeted medical care, specifically enabling condition-specific surveillance and individualised clinical management, which is determined by the treating physicians in consultation with the affected individual.
• Testing of at-risk family members is possible once the familial pathogenic variants have been identified.

• Nowaczyk MJM, Wassif CA. Smith-Lemli-Opitz Syndrome. 1998 Nov 13 [Updated 2020 Jan 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301322. Available from:
• Kovács E, Szűcs Z, Horňák M, Kubíček D, Weisová K, Veselá K, et al. Prevalence of Smith-Lemli-Opitz Syndrome Carriers and the Spectrum of DHCR7 Pathogenic Variants in Representative Czech and Hungarian Population Cohorts. Genes. 2026;17(2). doi: 10.3390/genes17020164. PMID: . PMCID: PMC12940480.
• Barbitoff YA, Khmelkova DN, Pomerantseva EA, Slepchenkov AV, Zubashenko NA, Mironova IV, et al. Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 7452 exome samples. National science review. 2024;11(10):nwae326. doi: 10.1093/nsr/nwae326. PMID: . PMCID: PMC11533896.
• Hannah WB, Drumm ML, Nykamp K, Pramparo T, Steiner RD, Schrodi SJ. Using genomic databases to determine the frequency and population-based heterogeneity of autosomal recessive conditions. Genetics in medicine open. 2024;2:101881. doi: 10.1016/j.gimo.2024.101881. PMID: . PMCID: PMC11613865.