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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 09 July 2025).
Aida N, Ohno T, Azuma T. Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2. Encyclopedia. Available at: https://encyclopedia.pub/entry/29872. Accessed July 09, 2025.
Aida, Natsuko, Tatsukuni Ohno, Toshifumi Azuma. "Hajdu-Cheney Syndrome and Gene Mutation in NOTCH2" Encyclopedia, https://encyclopedia.pub/entry/29872 (accessed July 09, 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.
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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).
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
- Hajdu, N.; Kauntze, R. Cranio-skeletal dysplasia. Br. J. Radiol. 1948, 21, 42–48.
- Canalis, E.; Zanotti, S. Hajdu-Cheney syndrome: A review. Orphanet J. Rare Dis. 2014, 9, 200.
- 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.
- 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.
- 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.
- Brennan, A.M.; Pauli, R.M. Hajdu-Cheney syndrome: Evolution of phenotype and clinical problems. Am. J. Med. Genet. 2001, 100, 292–310.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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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