Hajdu Cheney Syndrome due to NOTCH2 defect - First case report from Pakistan and review of literature.

Introduction And Importance: Hajdu Cheney Syndrome (HCS) is a rare skeletal disease characterized by severe, progressive focal bone loss with osteoporosis, variable craniofacial, vertebral anomalies and distinctive facial features. It is inherited as an autosomal dominant disease although sporadic cases have been described in literature. Identifying these cases in clinical practice is important for proper diagnosis and management.

Case Presentation: We report a case of a 36-year-old male patient presented at metabolic bone disease clinic at the Aga Khan University Hospital with history of multiple fragility fractures and juvenile osteoporosis since childhood. DNA sequence analysis of the NOTCH2 coding sequence revealed a pathogenic variant in NOTCH 2, Exon 34, c.6426_6427insTT (p.Glu2143Leufs*5), consistent with a NOTCH2 related conditions including HCS.

Clinical Discussion: The multitude of presentations associated with HCS are linked to the NOTCH2 gene, as Notch signaling is one of the core signaling pathways that control embryonic development. Hence, mutations in the Notch signaling pathway cause developmental phenotypes that affect various organs including the liver, skeleton, heart, eye, face, kidney, and vasculature.

Conclusion: To the best of our knowledge, nucleotide mutations of c.6933delT, c.6854delA, c.6787C.T, and c.64246427delTCTG were all determined to be novel, with c.6428T > C being the most common mutation found in literature. The c.6426_6427insTT mutation our patient was found to have via gene sequencing too appears to be a novel mutation, which has not previously been reported in literature.