Abstract
Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys. HCS is rare and is inherited as autosomal dominant although many sporadic cases have been reported. HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity. Although the number of cases with NOTCH2 mutations reported are limited, it would seem that the diagnosis of HCS can be established by sequence analysis of exon 34 of NOTCH2. Notch receptors are single-pass transmembrane proteins that determine cell fate, and play a critical role in skeletal development and homeostasis. Dysregulation of Notch signaling is associated with skeletal developmental disorders. There is limited information about the mechanisms of the bone loss and acroosteolysis in HCS making decisions regarding therapeutic intervention difficult. Bone antiresorptive and anabolic agents have been tried to treat the osteoporosis, but their benefit has not been established. In conclusion, Notch regulates skeletal development and bone remodeling, and gain-of-function mutations of NOTCH2 are associated with HCS.
Highlights
Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys
Definition Hajdu-Cheney syndrome (HCS) is a rare inherited connective tissue disease characterized by acroosteolysis of hands and feet, developmental defects of bones, teeth and joints causing distinctive craniofacial and skull changes, and manifested by severe osteoporosis and short stature
Clinical description Hajdu-Cheney syndrome (HCS) is a rare disease with autosomal genetic inheritance, the disease can have sporadic presentations. It is characterized by acroosteolysis of distal phalanges, severe osteoporosis with fractures, craniofacial and dental abnormalities and short stature [1,2,3,4,5,6,7]
Summary
Genetic mutations causing either gain- or loss-of-function of various components of the Notch signaling pathway are associated with diverse skeletal disorders, confirming that Notch is critical for skeletal development and homeostasis. HCS affects a limited number of individuals, discovering a cluster of mutations in a single domain of NOTCH2 in patients with HCS has advanced our knowledge regarding potential mechanisms leading to bone loss. Notch signaling is required for skeletal development and bone homeostasis and diseases associated with dysregulation of Notch signaling are uncommon, but present with severe clinical manifestations. Authors’ contributions EC and SZ participated in the conception and writing of the manuscript. Both authors have read and approve the manuscript
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