Phenotype variability in Hajdu-Cheney syndrome

Area of Science:

• Genetics and rare diseases
• Skeletal dysplasias
• Molecular diagnostics

Background:

• Hajdu Cheney syndrome (HCS) is a rare autosomal dominant skeletal dysplasia characterized by multi-organ involvement.
• Pathogenic variants in the NOTCH2 gene are the known cause of HCS.
• HCS presents with progressive bone destruction, craniofacial anomalies, hearing loss, cardiovascular, and renal involvement.

Observation:

• Diagnosis of HCS is often delayed due to its rarity and wide phenotypic variability.
• Distinct radiographic findings like a serpentine fibula can aid in diagnosis.
• Two unrelated patients from Turkish/Lebanese Jewish and Ashkenazi Jewish descent presented with unique clinical challenges.

Findings:

• Molecular diagnosis was achieved in both patients after distinct diagnostic journeys.
• The cases illustrate the broad spectrum of clinical manifestations in HCS.
• NOTCH2 pathogenic variants confirmed the diagnosis in both individuals.

Implications:

• These case reports contribute valuable knowledge to the understanding of HCS.
• Recognizing the phenotypic variability is crucial for timely HCS diagnosis.
• Further research into NOTCH2 variants can improve diagnostic strategies for HCS.