Identifying a Point Mutation in the SH3BP2 Gene in Cherubism

Cherubism is a rare developmental lesion of the jaw that is generally inherited as an autosomal dominant trait.  Few cases have been reported in Japan, and only comparatively more in Europe.  Cherubism presents as a painless jaw enlargement that is characterized by replacement of the osseous tissue by fibrous connective tissue.  Affected bones are expanded by bilateral, well-delineated multilocular radiolucencies with a “soap bubble" appearance.  The cortices may become thinned and focally perforated.  With advancing age, the initially fibrous tissue is replaced by bony structures, leading to sclerosis.  Therefore treatment is usually conservative, allowing natural regression to occur.  If surgical recontouring of expanded bone is necessary, it is best to defer it until after puberty.  During childhood and early adolescence, treatment should be directed toward facilitating the eruption of teeth.  The disease is classified as a non-neoplastic bone lesion in the World Health Organization histological typing of odontogenic tumors, but diagnostic criteria have not been established.  Genomic DNA sequence mutation of the SH3BP2 gene has been identified in subjects with cherubism.

We report a case of cherubism in a 6-year-old boy.  The patient visited our hospital with bilateral expansion of the mandible.  Radiographically, multilocular radiolucent lesions were found bilaterally from the mandibular first molar region to the coronoid process.  His mother has a history of cherubism.  Blood tests revealed a slightly elevated inorganic phosphorus level (6.2 mg/dL; normal 2.5 to 4.7); however, the serum calcium and alkaline phosphatase levels were within normal limits.  Biopsy specimens obtained from the mandibular lesions were diagnosed as giant cell granuloma.  In addition, genomic DNA was purified from a blood sample obtained from the patient, and used for DNA sequencing.  We found a mutation in the SH3BP2 gene of the patient.

Central jaw lesions that are characterized by multinucleated osteoclast-like giant cells include central giant cell granuloma, brown tumor of hyperparathyroidism, and cherubism.  The lesions of cherubism are microscopically indistinguishable from central giant cell granulomas.  Although the histology is not specific, the combination of clinical appearance, radiology and central giant cell lesion-like histology is diagnostic.  In addition, cherubism is related to an exon 9-SH3BP2 mutation that has not been identified in central giant cell granulomas.  The diagnosis is supported by characteristic clinical presentation such as bilateral enlargement of the jaws and the typical radiological findings on panoramic views, or CT scans.

This case suggests genetic analysis may be a useful method for differentiation of cherubism.  The patient is being examined periodically with no treatment due to his age and the grade of the lesion.

References

1. Ueki Y, Tiziani V, Santanna C, et al: Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet 28(2):125-6. 2001

2. Tsodoulos S, Ilia A, Antoniades K, et al: Cherubism: a case report of a three-generation inheritance and literature review. J Oral Maxillofac Surg 72(2):405.e1-9. 2014