title: Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations.
abstract: Notch plays an important function in skeletal homeostasis, osteoblastogenesis, and osteoclastogenesis. Hajdu-Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested. HCS is inherited as an autosomal dominant disease although sporadic cases exist. HCS is characterized by craniofacial developmental defects, including platybasia and wormian bones, osteoporosis with fractures, and acro-osteolysis. Subjects may suffer severe neurological complications, and HCS presents with cardiovascular defects and polycystic kidneys. An experimental mouse model harboring a HCSNotch2 mutation exhibits osteopenia secondary to enhanced bone resorption suggesting this as a possible mechanism for the skeletal disease. If the same mechanisms were operational in humans, anti-resorptive therapy could correct the bone loss, but not necessarily the acro-osteolysis. In conclusion, HCS is a devastating disease associated with a gain-of-NOTCH2 function resulting in diverse clinical manifestations.
authors.affiliation: Departments of Orthopaedic Surgery and Medicine, and the UConn Musculoskeletal Institute, UConn Health, Farmington, CT, 06030-5456, USA. canalis@uchc.edu.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.affiliation: Departments of Orthopaedic Surgery and Medicine, and the UConn Musculoskeletal Institute, UConn Health, Farmington, CT, 06030-5456, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanotti
mesh_terms: D030981:Acro-Osteolysis / Q000209:etiology; D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D004195:Disease Models, Animal; D000073659:Gain of Function Mutation; D031845:Hajdu-Cheney Syndrome / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009422:Nervous System Diseases / Q000209:etiology; D010024:Osteoporosis / Q000209:etiology; D058866:Osteoporotic Fractures / Q000209:etiology; D010985:Platybasia / Q000209:etiology; D007690:Polycystic Kidney Diseases / Q000209:etiology; D051883:Receptor, Notch2 / Q000235:genetics
chemical_list: C497764:NOTCH2 protein, human; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2
keywords: Acro-osteolysis; Bone remodeling; Fractures; Hes; Notch