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Aida, N.;  Ohno, T.;  Azuma, T. Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2. Encyclopedia. Available online: https://encyclopedia.pub/entry/29872 (accessed on 16 December 2025).
Aida N,  Ohno T,  Azuma T. Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2. Encyclopedia. Available at: https://encyclopedia.pub/entry/29872. Accessed December 16, 2025.
Aida, Natsuko, Tatsukuni Ohno, Toshifumi Azuma. "Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2" Encyclopedia, https://encyclopedia.pub/entry/29872 (accessed December 16, 2025).
Aida, N.,  Ohno, T., & Azuma, T. (2022, October 18). Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2. In Encyclopedia. https://encyclopedia.pub/entry/29872
Aida, Natsuko, et al. "Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2." Encyclopedia. Web. 18 October, 2022.
Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2
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This entry is adapted from the peer-reviewed paper 10.3390/ijms231911374

Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated NOTCH2 causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient’s quality of life.

Hajdu-Cheney syndrome NOTCH2 osteoporosis bone disease

1. Background and Clinical Manifestations

Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder. It was first described by Hajdu and Kauntze in 1948 [1]. In 1965, Cheney reported a familial form of the disease [2][3]. HCS is registered in the OMIM (Online Mendelian Inheritance in Man) project database with reference #102500 and in ORPHANET under the reference ORPHA955. The prevalence of HCS is less than 1 in 1,000,000 making it an extremely rare genetic syndrome. The gender or racial differences in HCS prevalence remain unclear. HCS is characterized by resorption of the distal phalanges of the feet and in the fingers, often with inflammatory epiphyseal lysis, which causes pain and swelling. Progressive bone destruction, especially severe osteoporosis, is also found, including spinal abnormalities such as compression fractures and deformities, as well as craniofacial deformities. Moreover, cardiac diseases such as cardiovascular abnormalities and valvular insufficiency as well as dental issues, including abnormal redness of the gingiva, caries, severe periodontal disease, premature tooth loss, cleft palates, and abnormal tooth eruption, are also observed in HCS [1][4]. Neurological disorders and polycystic kidney disease may also occur [5]. In most patients with HCS, mental development is reported to progress at a normal rate [2]. Overall, Hajdu-Cheney Syndrome has complex clinical manifestations. The significant features in patients with HCS are listed below (Table 1).
Table 1. Clinical features of patients with Hajdu-Cheney Syndrome.
Craniofacial Abnormality Dental Abnormality Skeletal Abnormality Cardiac Diseases Others
Micrognathism Highly arched palates Acroosteolysis Cardiovascular abnormalities Polycystic kidneys
Facial dysmorphism Caries Fibular deformities, severe osteoporosis Valvular insufficiency Neurological disorders
Open sutures, wormian bones Severe periodontal disease Severe osteoporosis    
Platybasia and basilar invagination Premature tooth loss Fractures    
  Abnormal redness of gingiva Joint hyperlaxity    
  Abnormal of tooth eruption Compression fractures and deformities    
    Short stature, developmental delay    
Thus, HCS is a severe genetic disorder with wide-ranging clinical manifestations and a significant impact on the patient’s quality of life. Furthermore, patients diagnosed with HCS have a variable clinical presentation that varies from early infancy to late adulthood, worsening over time because of age-dependent progression [6][7]. 

2. NOTCH Signaling

In 2011, a mutation in the NOTCH2 gene on chromosome 1 (locus 1p13-p11) was identified as a causative gene in patients with HCS based on whole exome analysis [8][9].
NOTCH signaling is an evolutionarily conserved pathway in multicellular organisms, which maintains homeostasis in living tissues by determining and regulating the proliferation and differentiation of various cells during development. Loss of function in NOTCH is known to cause Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis, and congenital cardiac disease. In contrast, gain of function in NOTCH causes HCS, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis, and lateral meningocele syndrome [8][9][10][11][12][13].
The NOTCH pathway is described as a cell-contact signaling pathway that requires physical contact between adjacent cells in a short-range. NOTCH proteins are heterodimeric, single transmembrane proteins functioning as receptors for DSL (Delta, Serrate, Lag2) family ligands. They are divided into three major parts: the extracellular domain (NECD), the transmembrane domain, and the intracellular domain (NICD). The extracellular domain, which is the receptor part, is transported to the cell surface and exits the cell by exocytosis, allowing it to bind ligands. There are four variants of NOTCH (NOTCH1-4) and their ligands include five known proteins (JAG1, JAG2, DLL1, DLL3, DLL4) on the adjacent cell surface [14][15]. NOTCH protein is activated by binding to one of these ligands. The intracellular domain of NOTCH (NICD) is then detached and transported into the nucleus, where it forms a complex with a DNA-binding protein called CSL to induce the expression of downstream target genes (Figure 1).
Ijms 23 11374 g001 550
Figure 1. An overview of NOTCH signaling, and its involvement in Hajdu-Cheney Syndrome.
The NOTCH receptor consists of the NOTCH extracellular domain (NECD) and NOTCH intracellular domain (NICD). Mutations of NOTCH2 cause the deletion of the PEST domain in the NICD, which results in NOTCH2 overexpression, leading to the Hajdu-Cheney syndrome.

3. Gene Mutation in NOTCH2

Isidor B. et al. reported that a genetic mutation in NOTCH2 causes HCS [9]. Further reports indicated that a frameshift in exon 34, which is located upstream of the PEST (proline–glutamic acid–serine–threonine-rich) domain in the final exon on the C-terminal side of NOTCH2, results in deletion of the sequence the PEST domain. The PEST domain regulates NICD stability by its ubiquitination. The ubiquitination of PEST promotes proteolysis of the NICD domain. Thus, deletion of the PEST domain prolongs the survival of NICD and results in excessive NOTCH signaling. The NOTCH2 signaling pathway plays an important role in osteoclast differentiation and in the promotion of osteoclastogenesis [16]. Deviating from proteasome-dependent proteolysis via ubiquitination by the SCFFBW7 ubiquitin ligase complex, non-degraded stable NOTCH2 mutants accumulate in excess. The over-accumulated NOTCH2 involved in osteoclast differentiation continues to signal excessively, which enhances osteoclast differentiation and causes abnormal bone resorption.
Another mechanism for excessive bone resorption caused by the overactivation of NOTCH signaling is through increased tumor necrosis factor-alpha (TNFα), which may promote osteoclast differentiation [17].
In HCS, the proto-oncogene c-Fos (c-FOS) and nuclear factor of activated T cells 1 (NFATc1) show increased expression, which promotes osteoclast differentiation. HCS is a unique disorder that causes inflammation and bone destruction simultaneously, along with systemic osteolysis and osteoporosis. Therefore, it is necessary to elucidate why osteolysis is accompanied by inflammation and the pathogenesis of HCS.
Table 2. Classification of Hajdu-Cheney Syndrome variants according to the standards and Guidelines for sequence interpretation of variants of the American College of Medical Genetics and Genomics (ACMC). This classification shows 26 cases of “Pathogenic” variants including nucleotide changes, amino acid definitions, and molecular consequences.
Human Genome Variation Society (HGVS) Variant Type Nucleotide Change Protein (Amino Acid Definition) Molecular Consequence (Functional Effect) dbSNP
M_024408.4(NOTCH2):c.1668C>A(p.Cys556Ter) SNV c.1668C>A p.Cys556Ter nonsense -
NM_024408.4(NOTCH2):c.2235_2236del (p.Cys745_Asp746delinsTer) Microsatelite c.2235_2236del p.Cys745_Asp746delinsTer nonsense -
NM_024408.4(NOTCH2):c.3415del(p.Leu1139fs) Deletion c.3415del p.Leu1139fs frameshift -
NM_024408.4(NOTCH2):c.4174C>T(p.Gln1392Ter) SNV c.4174C>T p.Gln1392Ter nonsense rs1649449471
NM_024408.4(NOTCH2):c.5123_5132delinsAGA(p.Gln1392Ter) Indel c.5123_5132delinsAGA p.Gln1392Ter nonsense rs1649314295
NM_024408.4(NOTCH2):c.5345del(p.Asp1782fs) Deletion c.5345del p.Asp1782fs frameshift rs1553193977
NM_024408.4(NOTCH2):c.6272del(p.Phe2091fs) Deletion c.6272del p.Phe2091fs frameshift rs1557802353
NM_024408.4(NOTCH2):c.6386del(p.Ser2129fs) Deletion c.6386del p.Ser2129fs frameshift -
NM_024408.4(NOTCH2):c.6403_6404del(p.Leu2135fs) Microsatelite c.6403_6404del p.Leu2135fs frameshift rs1649067817
NM_024408.4(NOTCH2):c.6424_6427del(p.Ser2142fs) Deletion c.6424_6427del p.Ser2142fs frameshift rs1064793515
NM_024408.4(NOTCH2):c.6426_6427insTT(p.Leu2135fs) Insertion c.6426_6427insTT p.Leu2135fs frameshift rs1649066485
NM_024408.4(NOTCH2):c.6449_6450del(p.Pro2150fs) Deletion c.6449_6450del p.Pro2150fs frameshift rs1553193574
NM_024408.4(NOTCH2):c.6503del(p.Pro2168fs) Deletion c.6503del p.Pro2168fs frameshift rs1557802165
NM_024408.4(NOTCH2):c.6622C>T(p.Gln2208Ter) SNV c.6622C>T p.Gln2208Ter nonsense rs387906746
NM_024408.4(NOTCH2):c.6832dup(p.Thr2278fs) Duplication c.6832dup p.Thr2278fs frameshift -
NM_024408.4(NOTCH2):c.6853C>T(p.Gln2285Ter) SNV c.6853C>T p.Gln2285Ter nonsense rs1553193507
NM_024408.4(NOTCH2):c.6877del(p.His2293fs) Deletion c.6877del p.His2293fs frameshift rs1649047546
NM_024408.4(NOTCH2):c.6895G>T(p.Glu2299Ter) SNV c.6895G>T p.Glu2299Ter nonsense rs387906748
NM_024408.4(NOTCH2):c.6909del(p.Ile2304fs) Deletion c.6909del p.Ile2304fs frameshift rs771237928
NM_024408.4(NOTCH2):c.6909dup(p.Ile2304fs) Duplication c.6909dup p.Ile2304fs frameshift rs771237928
NM_024408.4(NOTCH2):c.6949C>T(p.Gln2317Ter) SNV c.6949C>T p.Gln2317Ter nonsense rs387906747
NM_024408.4(NOTCH2):c.7078C>T(p.Gln2360Ter) SNV c.7078C>T p.Gln2360Ter nonsense rs1553193485
NM_024408.4(NOTCH2):c.7090del(p.Gln2364fs) Deletion c.7090del p.Gln2364fs frameshift rs1649037695
NM_024408.4(NOTCH2):c.7119T>G(p.Tyr2373Ter) SNV c.7119T>G p.Tyr2373Ter nonsense rs1557801639
NM_024408.4(NOTCH2):c.7165C>T(p.Gln2389Ter) SNV c.7165C>T p.Gln2389Ter nonsense rs387906749
NOTCH2, 1-BP DEL, 6460T Deletion 6460T - - -

References

  1. Hajdu, N.; Kauntze, R. Cranio-skeletal dysplasia. Br. J. Radiol. 1948, 21, 42–48.
  2. Canalis, E.; Zanotti, S. Hajdu-Cheney syndrome: A review. Orphanet J. Rare Dis. 2014, 9, 200.
  3. Vingerhoedt, E.; Bailleul-Forestier, I.; Fellus, P.; Schoenaers, J.; Frijns, J.P.; Carels, C. Syndrome of Hajdu-Cheney: Three cases. Cleft Palate-Craniofacial J. 2010, 47, 645–653.
  4. Antoniades, K.; Kaklamanos, E.; Kavadia, S.; Hatzistilianou, M.; Antoniades, V. Hajdu-Cheney syndrome (acro-osteolysis): A case report of dental interest. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2003, 95, 725–731.
  5. Kaczoruk-Wieremczuk, M.; Adamska, P.; Adamski, L.J.; Wychowanski, P.; Jereczek-Fossa, B.A.; Starzynska, A. Oral surgery procedures in a patient with Hajdu-Cheney syndrome treated with denosumab—A rare case report. Int. J. Environ. Res. Public Health 2021, 18, 9099.
  6. Brennan, A.M.; Pauli, R.M. Hajdu-Cheney syndrome: Evolution of phenotype and clinical problems. Am. J. Med. Genet. 2001, 100, 292–310.
  7. Cortés-Martín, J.; Díaz-Rodríguez, L.; Piqueras-Sola, B.; Rodríguez-Blanque, R.; Bermejo-Fernández, A.; Sánchez-García, J.C. Hajdu–Cheney syndrome: A systematic review of the literature. Int. J. Environ. Res. Public Health 2020, 17, 6174.
  8. Simpson, M.A.; Irving, M.D.; Asilmaz, E.; Gray, M.J.; Dafou, D.; Elmslie, F.V.; Mansour, S.; Holder, S.E.; Brain, C.E.; Burton, B.K.; et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 2011, 43, 303–305.
  9. Isidor, B.; Lindenbaum, P.; Pichon, O.; Bézieau, S.; Dina, C.; Jacquemont, S.; Martin-Coignard, D.; Thauvin-Robinet, C.; Le Merrer, M.; Mandel, J.L.; et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat. Genet. 2011, 43, 306–308.
  10. Gray, M.J.; Kim, C.A.; Bertola, D.R.; Arantes, P.R.; Stewart, H.; Simpson, M.A.; Irving, M.D.; Robertson, S.P. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur. J. Hum. Genet. 2012, 20, 122–124.
  11. Han, M.S.; Ko, J.M.; Cho, T.J.; Park, W.Y.; Cheong, H.I. A novel NOTCH2 mutation identified in a Korean family with Hajdu-Cheney syndrome showing phenotypic diversity. Ann. Clin. Lab. Sci. 2015, 45, 110–114.
  12. Isidor, B.; Le Merrer, M.; Exner, G.U.; Pichon, O.; Thierry, G.; Guiochon-Mantel, A.; David, A.; Cormier-Daire, V.; Le Caignec, C. Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2. Hum. Mutat. 2011, 32, 1239–1242.
  13. Majewski, J.; Schwartzentruber, J.A.; Caqueret, A.; Patry, L.; Marcadier, J.; Fryns, J.P.; Boycott, K.M.; Ste-Marie, L.G.; McKiernan, F.E.; Marik, I.; et al. Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. Hum. Mutat. 2011, 32, 1114–1117.
  14. Gazave, E.; Lapébie, P.; Richards, G.S.; Brunet, F.; Ereskovsky, A.V.; Degnan, B.M.; Borchiellini, C.; Vervoort, M.; Renard, E. Origin and evolution of the Notch signalling pathway: An overview from eukaryotic genomes. BMC Evol. Biol. 2009, 9, 249.
  15. Helmi, S.A.; Rohani, L.; Zaher, A.R.; El Hawary, Y.M.; Rancourt, D.E. Enhanced osteogenic differentiation of pluripotent stem cells via γ-secretase inhibition. Int. J. Mol. Sci. 2021, 22, 5215.
  16. Fukushima, H.; Nakao, A.; Okamoto, F.; Shin, M.; Kajiya, H.; Sakano, S.; Bigas, A.; Jimi, E.; Okabe, K. The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol. Cell Biol. 2008, 28, 6402–6412.
  17. Yu, J.; Canalis, E. The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α. J. Biol. Chem. 2019, 294, 14203–14214.
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