RPS6KA3-Related Intellectual Disability

Clinical characteristics: The phenotypic spectrum associated with RPS6KA3 pathogenic variants is a continuum. Coffin-Lowry syndrome (CLS) classically manifests in males with developmental delay, intellectual disability, neurologic manifestations (hypotonia, stimulus-induced drop attacks, spastic paraparesis, and seizures), musculoskeletal manifestations (kyphoscoliosis and pectus deformity), and characteristic craniofacial and hand findings. Dental issues, sensorineural hearing loss, and obstructive sleep apnea also occur. The milder end of the continuum in males includes neurodevelopmental disabilities with or without less pronounced multisystem involvement. Heterozygous females often exhibit clinical manifestations that can be consistent with clinically defined CLS but are typically less severe than those seen in affected males. Developmental delay and intellectual disability comprise the core phenotypic findings, and quality of life and prognosis are variably affected by the presence and severity of neurologic and musculoskeletal involvement.

Diagnosis/testing: The diagnosis of RPS6KA3-related intellectual disability (RPS6KA3-ID) is established in a male proband with suggestive findings and a hemizygous pathogenic variant in RPS6KA3 identified by molecular genetic testing. The diagnosis is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in RPS6KA3 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for RPS6KA3-ID. Supportive multidisciplinary care to improve quality of life, optimize function, and reduce complications may include specialists in clinical genetics and pediatrics as well as allied health professionals in development, neurology, orthopedics, cardiology, dentistry, audiology, and sleep medicine. Management includes developmental and educational support, anti-seizure medications, cardiologic care, correction of hearing impairment, and treatment of sleep apnea. Stimulus-induced drop attacks can be disabling and respond variably to pharmacologic treatment, necessitating avoidance of triggering stimuli and protection from falls. Orthopedic intervention for spine deformities is particularly important, as progressive kyphoscoliosis can compromise both neurologic function (leading to spastic paraplegia) and respiratory function. The potential for difficulty with respiratory management due to spine deformity, obesity, or other factors should be considered prior to procedures requiring anesthesia or sedation.

Surveillance: To monitor disease progression, optimize functional abilities and communication skills, and address emerging disease manifestations, regular evaluations by the treating multidisciplinary specialists as well as assessments of developmental and educational needs are recommended.

Genetic counseling: RPS6KA3-ID is inherited in an X-linked manner. Approximately two thirds of pathogenic variants associated with CLS arise de novo, while the remainder are inherited. Similar data are lacking for persons with clinical manifestations at the milder end of the RPS6KA3-ID continuum. If the mother of an affected male or female proband is known to have a pathogenic variant in RPS6KA3, each of the proband's male sibs has a 50% chance of being hemizygous for the variant and clinically affected, while each of the proband's female sibs has a 50% chance of being heterozygous for the variant and at high risk to exhibit at least some manifestations of the disorder. Once the RPS6KA3 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal/preimplantation genetic testing are possible.