Broadening the PHIP-Associated Neurodevelopmental Phenotype.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Syndromology

Background:

• Chung-Jansen syndrome (CHUJANS) is a novel neurodevelopmental disorder linked to monoallelic damaging variants in the Pleckstrin Homology Domain Interacting Protein (PHIP).
• CHUJANS typically presents with developmental delay/intellectual disability (DD/ID), obesity, and congenital anomalies, often described as an ID-overweight syndrome.

Observation:

• A child with DD/ID and a Pitt-Hopkins syndrome (PTHS)-like craniofacial phenotype was evaluated.
• Clinical exome analysis revealed a novel pathogenic variant in PHIP.
• DeepGestalt technology (Face2Gene) suggested a PTHS-like condition, but clinical review noted a lack of typical CHUJANS features.

Findings:

• A novel PHIP variant was identified in the evaluated child, confirmed via protein modeling.
• This variant expands the known phenotypic spectrum of CHUJANS.
• The patient's presentation mimicked PTHS, a distinct ID syndrome caused by TCF4 variants, which is not usually considered in CHUJANS differential diagnosis.

Implications:

• This case highlights the importance of considering PHIP variants in individuals with atypical neurodevelopmental presentations.
• The findings suggest that CHUJANS may have a broader clinical spectrum than previously recognized.
• Further patient descriptions are encouraged to better delineate the phenotypes associated with PHIP variants and inform differential diagnoses for ID syndromes.