Snyder-Robinson Syndrome

Excerpt

Clinical characteristics: Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by facial dysmorphism, asthenic build, progressive kyphoscoliosis, early-onset osteoporosis, and seizures. To date, only affected males have been reported. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to mild-to-profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year. Seizure onset varies but typically occurs in early childhood. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma. Rare findings may include nonspecific kidney manifestations.

Diagnosis/testing: The diagnosis of SRS is established in a male proband with a hemizygous loss-of-function SMS pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational support; treatment of seizures per neurologist; calcium supplementation has slightly improved bone mineral density in a few individuals; standard management of kyphoscoliosis and contractures by orthopedics; standard surgical treatment by craniofacial team for those with cleft palate; treatment of genitourinary and kidney manifestations per urologist and/or nephrologist; develop transitional care plan in adolescence; social work and family support.

Surveillance: Monitor developmental progress and educational needs at each visit; monitor those with seizures as clinically indicated; clinical examination and DXA scans to evaluate for progression of osteoporosis and investigate for factures if medically indicated; while receiving calcium supplementation, individuals should be evaluated regularly for ectopic calcification by endocrinologist; clinical examinations for kyphoscoliosis and assessment of mobility and self-help skills at each visit; monitor for nephrocalcinosis and renal cysts and kidney function per nephrologist, considering creatine levels in the context of low muscle mass; assess family needs at each visit.

Agents/circumstances to avoid: Assess the risk vs benefit of medications associated with increased osteoporosis (e.g., anticonvulsants), particularly when alternative treatments are limited.

Genetic counseling: SRS is inherited in an X-linked manner. If the mother of the proband has an SMS pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (to date, features of SRS have not been observed in heterozygous females). Affected males are not known to reproduce. The risk to other family members of a male proband depends on the status of the proband's mother: if the mother has the SMS pathogenic variant, the maternal aunts and maternal cousins of the proband may be at risk of having an SMS pathogenic variant. Once an SMS pathogenic variant is identified in an affected family member, carrier testing for at-risk female relatives and prenatal/preimplantation genetic testing are possible.