Clinical Guidance

Although no strong correlation exists between phenotype and location or type of RPS6KA3 pathogenic variant, individuals with certain missense pathogenic variants may tend to have milder disease expression . suggested that truncating variants, either in or upstream from the N-terminal kinase domain, may cause a particular susceptibility to stimulus-induced drop attacks (SIDAs). However, the finding of an affected female with SIDAs who had a heterozygous pathogenic variant in the region encoding the C-terminal kinase domain of the protein would argue against this correlation .

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care .

Suggestive Findings

RPS6KA3-ID should be suspected in a proband with the following suggestive clinical findings, imaging findings, and family history.

Clinical Findings

Males. All individuals have developmental delay/ intellectual disability, typically delayed development, with speech more severely affected than motor skills, and moderate-to-severe intellectual disability. Other findings in some individuals:

• Neurologic features

• Hypotonia

• Stimulus-induced drop attacks

• Progressive spasticity/paraplegia

• Seizures

• Musculoskeletal features

• Kyphoscoliosis of childhood onset that is often progressive

• Pectus carinatum and/or excavatum

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Differential Diagnosis

Individuals with phenotypic findings suggestive of Coffin-Lowry syndrome (the more severe end of the RPS6KA3-related intellectual disability phenotypic continuum). See .

Table 3.

Disorders of Interest in the Differential Diagnosis of Coffin-Lowry Syndrome

Gene/ Genetic Mechanism | Disorder | MOI | Clinical Characteristics/ Comment

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Management Guidelines

No clinical practice guidelines for RPS6KA3-related intellectual disability (RPS6KA3-ID) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with RPS6KA3-ID, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with RPS6KA3-Related Intellectual Disability

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Clinical Guidance

Care should be taken to avoid specific stimuli that are known to trigger SIDAs in a given individual. Physical activity may be limited due to valvular disease as recommended by a cardiologist.

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Recommended Surveillance for Individuals with RPS6KA3-Related Intellectual Disability

Source: GeneReviews — "RPS6KA3-Related Intellectual Disability"