Penetrance

The majority of the reported pathogenic variants are confirmed de novo. Parental results were not available for all reported cases. There is one report of reduced penetrance. A proband with developmental delay (speech and social) and normal head circumference had a maternally transmitted PPP2R5D pathogenic variant c.1321CT (p.Arg441Ter). His mother had similar cognitive issues and facial features shared with her son, including thick eyebrows, drooping eyelids, shallow orbits, blunt nasal tip, and thick, prominent vermilion of the upper and lower lips. The variant was also found in a healthy sib of the proband .

Source: GeneReviews — "PPP2R5D-Related Neurodevelopmental Disorder"

Diagnostic Criteria

No consensus clinical diagnostic criteria for PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) have been published.

Suggestive Findings

PPP2R5D-NDD should be considered in individuals presenting with the following clinical and brain MRI findings.

Clinical findings

• Generalized hypotonia of infancy

• Mild-to-profound developmental delays and/or intellectual disability

• Autism spectrum disorder

• Macrocephaly

• Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms)

• Early-onset parkinsonism

Brain MRI findings

Source: GeneReviews — "PPP2R5D-Related Neurodevelopmental Disorder"

Differential Diagnosis

Genes of interest in the differential diagnosis of PPP2R5D-related neurodevelopmental disorder are listed in .

Table 3.

Disorders to Consider in the Differential Diagnosis of PPP2R5D-Related Neurodevelopmental Disorder

Gene/ Genetic Mechanism | Disorder | MOI | Features of Disorder

Overlapping w/PPP2R5D-NDD | Distinguishing from PPP2R5D-NDD

~593-kb 16p11.2 deletion | 16p11.2 recurrent deletion | AD | • ID; speech language disorders

• Autism spectrum disorder

• Seizures

| • Obesity in adolescence later in life

• Congenital anomalies such as low-set ears syndactyly of toes

AKT3

CCND2

PIK3R2

| MPPH (megalencephaly-polymicrogyria-polydactyly-hydrocephalus) syndrome | AD | • DD/ID; expressive language or speech delay

• Epilepsy

• Hypotonia

• Megalencephaly

Management Guidelines

Clinical practice guidelines for PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PPP2R5D-NDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

PPP2R5D-Related Neurodevelopmental Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Assessment of growth (head circumference, stature, weight) |

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | Screen persons age 12 mos for behavior concerns, sleep issues, /or findings suggestive of ASD.

Neurologic

| Neurologic eval | Incl EEG if seizures are suspected.

Eyes | Ophthalmologic eval vision assessment | Assess for astigmatism strabismus.

Gastrointestinal/

Feeding

| Gastroenterology/ nutrition/ feeding team eval | Incl feeding assessment related to hypotonia eval for GERD, constipation, diarrhea.

Skeletal

| Orthopedic eval | Assess for scoliosis.

Movement disorders

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

Cardiac

| Full cardiac eval if audible m...

Source: GeneReviews — "PPP2R5D-Related Neurodevelopmental Disorder"

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. PPP2R5D-Related Neurodevelopmental Disorder: Recommended Surveillance

Source: GeneReviews — "PPP2R5D-Related Neurodevelopmental Disorder"