Clinical Guidance

In general, no differences in phenotype have been observed between individuals with a molecularly confirmed diagnosis and those with only a clinical diagnosis. The exceptions are several individuals with a molecularly confirmed diagnosis of MPPH syndrome who had BPP but lacked the core clinical feature of megalencephaly .

Source: GeneReviews — "MPPH Syndrome"

Penetrance

Penetrance is predicted to be 100% in individuals with a germline variant in AKT3, CCND2, or PIK3R2.

Source: GeneReviews — "MPPH Syndrome"

Diagnostic Criteria

Suggestive Findings

MPPH syndrome should be suspected in individuals with the following clinical and imaging findings . Note: Findings shown in bold are core features.

Clinical findings

• Macrocephaly or megalencephaly (occipital frontal circumference ≥2 SD above the mean); onset either prenatally or postnatally

• Postaxial polydactyly of one or more extremities

• Hypotonia

• Early-onset epilepsy

• Intellectual disability

• Oromotor dysfunction (including speech/swallowing difficulties, excessive drooling, expressive speech delays)

Imaging findings

Source: GeneReviews — "MPPH Syndrome"

Differential Diagnosis

Table 4. Genes of Interest in the Differential Diagnosis of MPPH Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with MPPH syndrome

System/Concern | Evaluation | Comment

Constitutional

| Physical exam w/particular attn to head size (OFC) |

Neurologic

| Assessment by pediatric neurologist w/eval of suspected seizures as indicated | • To incl baseline brain MRI careful eval for medulloblastoma, incl diffusion-weighted imaging to differentiate early neoplastic transformation w/in dysplastic cerebellar tissue early consideration of contrast-enhanced studies in suspicious cases

• In the presence of hydrocephalus /or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation

Gastrointestinal/

Feeding

| Feeding assessment by feeding specialist, nutritionist, gastroenterologist for evidence of chewing swallowing difficulties dysphagia | Consider eval for gastric tube placement as needed.

Development

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

• Eval for early intervention / special education

Musculoskeletal

| Referral to orthopedist as needed for polydactyly |

Eyes | Ophthalmologic eval | To assess for vision abnormalities

Cardiovascular

| Echocardiogram | To...

Source: GeneReviews — "MPPH Syndrome"

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 — "MPPH Syndrome"

Surveillance Guidelines

Given the limited number of individuals reported with MPPH syndrome, formal surveillance guidelines do not exist. Table 7. Recommended Surveillance for Individuals with MPPH Syndrome

Source: GeneReviews — "MPPH Syndrome"