SLOS – Smith Lemli Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is a rare, autosomal recessive metabolic congenital disorder caused by biallelic pathogenic variants in DHCR7. First described in 1964, it is considered the first true metabolic syndrome of multiple congenital malformations. The syndrome has a wide clinical spectrum, ranging from mild cases with minimal physical abnormalities and learning issues to severe, life-threatening cases with profound intellectual disability and major congenital malformations.

SLOS is caused by pathogenic variants in the DHCR7 gene located on chromosome 11q13.4 – OMIM ID: 60285

https://www.omim.org/entry/602858?search=DHCR7&highlight=dhcr7

The primary mechanism of SLOS is an abnormality in cholesterol metabolism, resulting from a deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase encoded by DHCR7. This enzyme catalyzes the final step in the synthesis of cholesterol, converting 7-DHC to cholesterol. Pathogenic variants lead to low levels of cholesterol in the blood and the accumulation of the toxic precursor, 7-DHC.

This deficiency impairs cell membrane function and disrupts the signaling pathway of Hedgehog proteins, which are essential for embryonic development, thus leading to the observed malformations. SLOS is inherited in an autosomal recessive manner, meaning an individual must inherit two pathogenic variants (one from each parent) to be affected.

SLOS is a multisystemic disorder. Common features include:

• Neurological & Developmental: Moderate-to-severe intellectual disability, developmental delay, microcephaly (small head size), hypotonia (weak muscle tone), and behavioral issues, including features of autism.
• Growth: Prenatal and postnatal growth restriction (failure to thrive).
• Craniofacial & Skeletal: Distinctive facial features, cleft palate, postaxial polydactyly (extra digits), and characteristic 2-3 syndactyly (fusion of the second and third toes).
• Genitourinary: Common in males and includes underdeveloped external genitalia, hypospadias (abnormal urethral opening), ambiguous genitalia, and renal anomalies like renal agenesis or ureteral duplication.

Other: Congenital heart defects, pulmonary hypoplasia, gastrointestinal issues (e.g., feeding difficulties, Hirschsprung disease), cataracts, and photosensitivity.

SLOS is suspected in infants or children with characteristic features, including:

• Prenatal or postnatal growth restriction
• Microcephaly
• Distinctive facial features
• Genital anomalies (especially in males)
• Syndactyly of toes 2–3
• Hypotonia
• Feeding difficulties
• Developmental delay or intellectual disability
• Congenital heart or kidney defects

Clinical presentation alone is not diagnostic, and clinical diagnosis requires biochemical and/or molecular testing:

Biochemical (Metabolic) Testing (Primary Diagnostic Method). The key diagnostic laboratory test is elevated 7-dehydrocholesterol (7-DHC) measured in plasma, serum, or amniotic fluid. Biochemical testing is typically the first-line diagnostic tool, especially in newborns or prenatally.

Genetic Testing (Definitive Diagnosis). SLOS is confirmed by detecting pathogenic variants in both alleles of the DHCR7 gene. Recommended genetic tests include:

1. DHCR7 single-gene sequencing
2. DHCR7 deletion/duplication analysis (for missing exons or larger structural variants)
3. Whole-exome sequencing (WES) or whole-genome sequencing (WGS) if diagnosis is unclear or phenotype is atypical

Management is multidisciplinary, aiming to treat symptoms and address the underlying metabolic defect.

• Metabolic Treatment: The mainstay of treatment is dietary cholesterol supplementation, which may result in clinical improvement. Oral bile acid therapy may also be considered.
• Therapies: Early intervention and physical, occupational, and speech therapies are vital for developmental support. Melatonin may be used for sleep disturbances.
• Surgical Interventions: Surgery is often required to correct major congenital anomalies such as cleft palate, cardiac defects, and genital malformations.

• Precautions: Extended sun exposure should be avoided due to photosensitivity, and certain psychotropic drugs that elevate 7-DHC should be used with caution.