Lathosterolosis

Clinical characteristics: Lathosterolosis is characterized by global developmental delays, intellectual disability, microcephaly, characteristic facial features (bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia), cataracts, digit anomalies (postaxial polydactyly, toe syndactyly), and liver disease. The severity of liver disease can range from asymptomatic elevation of liver enzymes to cirrhosis and liver failure.

Diagnosis/testing: The diagnosis of lathosterolosis is established in a proband by identification of elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic variants in SC5D by molecular genetic testing.

Management: Treatment of manifestations: Potential targeted therapies include simvastatin (the safety and/or efficacy of simvastatin has not been proven in lathosterolosis) and liver transplantation. Supportive care includes developmental and educational support; treatment of cataracts per ophthalmologist; treatment of digit anomalies per orthopedist; management of liver disease per hepatologist; treatment of genitourinary anomalies per nephrologist and/or urologist; social work support and care coordination as needed.

Surveillance: Assess developmental milestones at each visit throughout childhood; neuropsychological testing and quality of life assessments as needed; annual ophthalmology evaluation; liver enzymes at each visit; liver imaging including ultrasound and FibroScan^® every six months or per hepatologist; plasma sterol profile before initiating simvastatin and every one to two months while on therapy.

Agents/circumstances to avoid: Medications and chemicals that are hepatotoxic.

Evaluation of relatives at risk: It is appropriate to clarify the status of at-risk relatives of an affected individual to identify as early as possible those who would benefit from initiation of potential treatment, surveillance, and awareness of agents and circumstances to avoid.

Genetic counseling: Lathosterolosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SC5D pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SC5D pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for relatives at risk, prenatal testing, and preimplantation genetic testing are possible.