Molecular Genetics of Cherubism


Cherubism is a rare fibro‐osseous genetic disorder caused and maintained by autoinflammatory processes that are caused by mutations in the SH3BP2 gene. Cherubism is a form of fibrodysplasia of the jaws that affects children at 2–6 years of age. The typical symmetrical bone resorption lacunae are self‐limiting to the jaws. Bone is replaced with fibrous tissue that can expand significantly and lead to the characteristic facial swelling. Disease progression normally stops at puberty and regresses thereafter. Mutations in SH3BP2 affect a six‐amino acid recognition sequence for tankyrase, a poly(ADP‐ribose)polymerase that marks proteins for ubiquitination and degradation. SH3BP2 has multiple functions in cell types of hematopoietic origin. Elevated SH3BP2 protein levels in macrophage/osteoclast precursors cause increased osteoclastogenesis with reduced thresholds for stimulants. Increased TNF‐α levels generate an inflammatory environment in a cherubism mouse model and conceivably also in the oral cavity of cherubism patients. More research to explain the spatiotemporal progression of cherubism is needed.

Key Concepts

  • Cherubism is a temporospatially restricted bone lysis disorder with bone being substituted by expansile fibrous tissue.
  • Patients with cherubism develop symmetrical bone lesions only in the maxilla and mandible.
  • Signs of cherubism develop in children as early as 2 years of age and bone lysis typically resolves after puberty. First diagnosed often on dental radiographs.
  • Known mutations are in the adaptor protein SH3BP2, which is involved in regulating the adaptive and innate immune system.
  • Mutations in SH3BP2 are within a six‐amino acid interval and cause inhibition of tankyrase binding, which is needed for efficient degradation.
  • High levels of intracellular SH3BP2 protein cause increased osteoclastogenesis and bone resorption in jaws.
  • Bone lysis is regulated via TLR2/TLR4 and TNF‐α‐dependent autoinflammatory response.
  • Jaw‐specific bone resorption in cherubism patients likely involves response to oral bacteria (pathogen‐associated molecular patterns; PAMPS) and bone remodelling during tooth eruption (damage‐associated molecular patterns; DAMPS).
  • Diagnosis for some patients is consistent with cherubism but no mutations are found in exons of SH3BP2.

Keywords: cherubism; fibrous dysplasia of the jaws; SH3BP2 ; autoinflammation; osteoclast; fibrosis; bone; genetic

Figure 1. Patient with severe form of cherubism. CT scan shows expansion of fibrous tissue replacing the resorbed bone of the jaws and invading the orbital floor. Reproduced with permission from Ueki et al., 2001 © Nature Publishing Group.
Figure 2. Gene structure of human SH3BP2 (Bell et al., ) and mutations for cherubism in the 13‐exon SH3BP2 gene that are found in the coding region for a six‐amino acid interval (amino acids 415‐420). Mutations in unusual cherubism cases and in one case of central giant cell granuloma have been reported outside this region (asterisks). Modified from Ueki et al., 2001 © Nature Publishing Group.
Figure 3. Proposed mechanism for inflammation and bone loss in cherubism. Reproduced from Ueki et al. (2007) © Cell Press/Elsevier.


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Further Reading

Hero M , Suomalainen A , Hagstrom J , et al. (2013) Anti‐tumor necrosis factor treatment in cherubism – clinical, radiological and histological findings in two children. Bone 52: 347–353.

Kadlub N , Vazquez MP , Galmiche L , et al. (2015) The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism. Journal of Bone and Mineral Research 30: 878–885.

Levaot N , Simoncic PD , Dimitriou ID , et al. (2011) 3BP2‐deficient mice are osteoporotic with impaired osteoblast and osteoclast functions. Journal of Clinical Investigation 121: 3244–3257.

Pagnini I , Simonini G , Mortilla M , et al. (2011) Ineffectiveness of tumor necrosis factor‐alpha inhibition in association with bisphosphonates for the treatment of cherubism. Clinical and Experimental Rheumatology 29: 147.

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Prod'Homme V , Boyer L , Dubois N , et al. (2015) Cherubism allele heterozygosity amplifies microbe‐induced inflammatory responses in murine macrophages. Journal of Clinical Investigation 125: 1396–1400.

Yoshitaka T , Ishida S , Mukai T , et al. (2014) Etanercept administration to neonatal SH3BP2 knock‐in cherubism mice prevents TNF‐alpha‐induced inflammation and bone loss. Journal of Bone and Mineral Research 29: 1170–1182.

Yoshitaka T , Kittaka M , Ishida S , et al. (2015) Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock‐in cherubism mice. Bone 71: 201–209.

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Reichenberger, Ernst J, and Ueki, Yasuyoshi(Mar 2016) Molecular Genetics of Cherubism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024309]