Poster Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

A 58 year-old man with a childhood history of a right-sided mandibular lesion noted growth of a left mandibular lesion and corresponding mandibular nerve paresthaesia without dental pain. Past history was notable for ocular shingles and dyslipidaemia. He has had no fractures.

At age 5y, he was diagnosed with a right-sided mandibular lesion for which he had multiple childhood surgeries. There was no history of developmental delay. In his 20s, a biopsy confirmed a giant cell granuloma of the right mandible and he underwent enucleation and debulking to his right maxilla and orbit. This was followed by a right hemi-mandible resection and iliac crest bone graft in his 30s. He had multiple adult teeth that never developed and required implants.

There was a family history for dental problems on his paternal side in an autosomal dominant inheritance pattern. His father had significant dental issues without clear bone lesions, his sister also had mild dental issues. Two paternal cousins had giant cell lesions, a nephew had deformed nasal passages as a child and a grand-nephew was diagnosed with dental issues secondary to cherubism.

More recently, he was referred to the oral maxillofacial surgical unit for workup of the left mandibular lesion. OPG and CT revealed an expansile lucent lesion of the left hemi-mandible with internal osseous septation, cortical thickening and a lack of periosteal reaction. Subsequent biopsy revealed numerous osteoclast-like giant cells in the stroma and no evidence of malignancy. He was referred to the endocrinology unit for consideration of a trial of medical therapy with the intention to avoid major facial reconstructive surgery.

Further investigations revealed elevated bone-turnover markers, with otherwise normal biochemistry. Myeloma screening was unremarkable (Table 1). DXA showed osteopaenia of the lumbar spine (Table 2). Genetic testing revealed a heterozygous pathogenic missense mutation in Exon 9 of the SH3BP2 gene (SH3BP2 NM_001122681.2: c.1253C>G; p.(Pro418Arg), Exon 9 missense) which causes autosomal dominant cherubism.

Given the high risk of recurrence post-surgical resection due to his genetic predisposition, a multi-disciplinary team consensus decision was made to treat with denosumab 60mg 6monthly - the involvement of the mandible likely predisposes him to antiresorptive associated osteonecrosis of the jaw (ONJ), however the alternative was major surgical intervention. He also commenced colecalciferol 1000IU daily.

6 months after starting denosumab, there was notable improvement in his mandibular nerve paresthaesia. Whilst on anti-resorptive therapy, he lost a tooth and the socket healed well without issue. Bone-turnover markers are now suppressed (Table 1). Repeat OPG and CT shows a clear improvement in the left hemi-mandible lesion which is less expansile and has increased internal bone matrix. 

 Cherubism

Cherubism is a rare autosomal dominant condition resulting in giant cell lesions of the jaw. This presents with progressive swelling of the face and fullness of the cheeks due to expansion of the underlying bony structures that are eventually replaced by fibrous tissue. Dental structures are commonly affected and tooth eruption is impacted. Maxillary bone changes also lead to stretching of the skin of the cheeks creating the appearance of an upturned eye. Onset of clinical or radiographical findings are during childhood and generally regress by adulthood but persist occasionally. This condition has a male predominance (56%); females typically have reduced penetrance and a less severe phenotype.

The majority of cherubism cases (93.5%) are due to a mutation of Exon 9 of the SH3BP2 (SH3-domain binding protein 2) gene. Mutations are generally familial in nature, however sporadic cases do occur. A gain of function mutation is typical and modulates osteoclastogenesis. When RANKL binds RANK expressed on osteoclast progenitor cells, this induces osteoclast formation via activation of transcription factor NFATc1. Over-expression of SH3BP2 has been shown to increase NFATc1 and also TRAP activation, leading to the osteoclastic bone lesions of cherubism.

Primary treatment for severe cases is surgical resection of granulomas and fibrous tissue. Orthodontic treatment is also required to avoid permanent dental issues. There is limited evidence for medical treatment of cherubism and current literature is exclusively confined to the paediatric population. A recent systematic review identified 5 cases treated with denosumab. All reported positive outcomes including increased bone density and reduced expansion of bony lesions. There were no reports of ONJ. In adults, there are no case reports of cherubism managed with medical therapy. Other medical treatments of cherubism had variable outcomes, including includes bisphosphonates, calcitonin, tacrolimus, TNF-alpha inhibitors and imatinib.

Key Points

1. Cherubism is predominantly inherited in an autosomal dominant pattern and caused by a mutation in exon 9 of the SH3BP2 This has downstream effects on osteoclastogenesis resulting in giant-cell lesions of the jaw.
2. In severe phenotypes, primary treatment is surgical resection and jaw reconstruction, with orthodontic intervention to preserve dental health.
3. There have been promising case reports of treatment with denosumab. Other medical therapies that have been trialled include bisphosphonates, calcitonin, tacrolimus, TNF-alpha inhibitors and imatinib. Most target osteoclast proliferation and function as the mechanism of action.