Hajdu-Cheney syndrome: a review

Orphanet J Rare Dis. 2014 Dec 10:9:200. doi: 10.1186/s13023-014-0200-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Bone Density Conservation Agents / therapeutic use
  • Diagnosis, Differential
  • Hajdu-Cheney Syndrome / diagnosis*
  • Hajdu-Cheney Syndrome / genetics*
  • Hajdu-Cheney Syndrome / therapy
  • Humans
  • Mutation / genetics*
  • Osteoporosis / diagnosis
  • Osteoporosis / genetics
  • Osteoporosis / therapy
  • Receptor, Notch2 / genetics*


  • Bone Density Conservation Agents
  • NOTCH2 protein, human
  • Receptor, Notch2