Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes 7-dehydrocholesterol reductase, the final enzyme in the cholesterol pathway.

Impaired conversion of 7-dehydrocholesterol (7-DHC) to cholesterol causes low cholesterol and accumulation of 7-DHC, which impairs hedgehog signalling and brain development, and forms toxic oxysterols.

The carrier frequency is about 1 in 30 to 70 in Europeans, and the incidence is about 1 in 20,000 to 60,000 (lower in Africans and Asians).

• Characteristic facies: microcephaly, bitemporal narrowing, ptosis, epicanthal folds, short upturned nose with anteverted nares, micrognathia, and low set ears
• Syndactyly of the second and third toes (the classic finding, in over 95%), postaxial polydactyly, and short thumbs
• Genital anomalies in 46,XY males (hypospadias to complete sex reversal with female external genitalia), cryptorchidism, and normal female genitalia in 46,XX
• Cleft palate, congenital heart defects (AVSD, PDA, VSD), pyloric stenosis, Hirschsprung disease, and renal anomalies
• Feeding difficulty, failure to thrive, irritability, photosensitivity, and sleep disturbance
• Intellectual disability (usually moderate to severe), autism features, self-injurious behaviour, hyperactivity, and seizures
• Severe cases (type II) can be lethal in the neonatal period with multiple malformations; hypocholesterolaemia contributes to adrenal insufficiency during stress

1. Plasma 7-dehydrocholesterol (markedly elevated; the diagnostic test, measured by GC-MS or LC-MS), with low or normal total cholesterol (cholesterol can be normal in mild cases, so cholesterol alone does not exclude).
2. DHCR7 gene sequencing and deletion analysis to confirm and for family testing.
3. Prenatal diagnosis by elevated 7-DHC in amniotic fluid or DHCR7 testing in CVS; low maternal unconjugated oestriol on second trimester screening may be a clue.
4. Evaluate for echocardiography, renal ultrasound, ophthalmology (cataract), audiology, brain MRI, and adrenal function.

• Dietary cholesterol supplementation: egg yolk, cream, liver, or purified cholesterol 40 to 300 mg/kg/day (typically 50 to 150 mg/kg/day in divided doses with meals); improves growth, irritability, photosensitivity and infections, with a limited effect on neurological outcomes. Monitor plasma cholesterol and 7-DHC levels (aim for reduction in 7-DHC) and liver function; consider a fat soluble vitamin supplement.
• Simvastatin 0.5 to 1 mg/kg/day (reduces 7-DHC synthesis) is used by some experts in addition to cholesterol, with caution and monitoring of creatine kinase and liver enzymes; evidence is limited.
• Stress dose hydrocortisone cover (30 to 50 mg/m2/day) during acute illness, surgery or anaesthesia, since adrenal insufficiency is common; confirm with ACTH stimulation test.
• Photoprotection: sunscreen and protective clothing.
• Antioxidants (vitamin E) may reduce oxysterol toxicity.
• Feeding: gastrostomy, antireflux treatment, and management of constipation.
• Surgery: palate repair, hypospadias repair and orchidopexy; sex of rearing in 46,XY with female genitalia requires multidisciplinary discussion.
• Cardiac, ophthalmic and renal management as per lesion.
• Behaviour: behavioural therapy, melatonin, SSRIs, and risperidone as needed.
• Genetic counselling: 25% recurrence risk; prenatal diagnosis and preimplantation testing options.