Poster Presentation ANZBMS-MEPSA-ANZORS 2022

Clinical case details

A 15 year-old female of Tongan heritage was referred to the endocrinology department with bilateral, multifocal, radiolucent lesions on mandibular X-rays. She had presented to an orthodontist for dental alignment with no prior history of facial pain, swelling or dental caries.

 Developmental milestones were completed and puberty commenced with no delays. She was previously affected by sinusitis and perennial rhinitis, but is currently asymptomatic on no regular medications. She is one of six siblings, all of whom have similar facial features. Her father, multiple paternal aunts and uncles, also have a similar jaw structure.

 On examination she appeared overweight, with a BMI calculated at 40.8 kg/m². Her face had a full and rounded appearance, with no evidence of exophthalmos. She had misaligned dentition, with no tenderness on palpation of her teeth. She had a normal cardiovascular examination. There were no clinical features of neurofibromatosis type 1 (NF-1), apart from a single café au lait spot on her thigh. There were no features consistent with Noonan’s syndrome.

Lab and medical imaging findings:

She was normocalcemic and normophosphataemic on routine biochemistry, with a PTH of 2.2 pmol/L. ALP was 129 U/L and PINP 222 ug/L, both within the normal limits. She had mild vitamin D deficiency with a 25-hydroxy Vitamin D of 33 nmol/L, and was commenced on replacement. Creatinine was preserved at 63 umol/L.

 X-ray of her mandible revealed large, multilocular lesions at the angle of the mandible bilaterally. A further small unilocular lesion is seen in the left anterior mandible.

Figure 2: Computed tomography (CT) reconstruction showed bilateral multilocular lesions within the angle of the mandible and vertical rami, sparing the teeth.

 DXA showed preserved bone density with a Z-score of +1.3 at the total lumbar spine and +2.4 at the hip. Biopsies of the mandibular lesions were consistent with multifocal, central giant cell granulomas.

 Based on the clinical and family history, examination findings, imaging and biopsy results, the most likely diagnosis is cherubism of Grade I severity. The patient is awaiting a review by the genetic service. Given the absence of disfiguring facial appearance or dental pain, she has elected for a ‘watch and wait’ approach.

Brief outline of literature:

Cherubism is a variant of fibrous dysplasia, with the presentation ranging from painless, bilateral, jaw enlargement to the rarer, severe phenotype, associated with nasal obstruction and respiratory compromise(1, 2). The nomenclature ‘cherubism’ reflects the cherubs or angels of the Renaissance period, with the characteristic appearance of a rounded face and upturned eyes(3). 

A family history is supportive, as seen in this case, with cherubism typically inherited in an autosomal dominant manner(1). In 2001, mutations in exon 9 of the SH3BP2 gene were identified as the cause(4). Gain-of-function mutations in SH3BP2 can result in inflammation and activation of osteoclasts, resulting in isolated bone resorption, cyst formation, and deposition of fibrous tissue in the jaws(5)

Radiological appearances include hyperlucent, well-defined, multilocular lesions. The mandible is almost always involved with varying involvement of the maxilla and zygoma. Severe cases can be associated with infiltration of the maxillary sinus and the orbital cavity, resulting in exophthalmos and limited eye movements(6).

Histological findings include clusters of giant cell granulomas within vascular fibrous connective tissue, which are non-specific and also seen in Brown’s tumour, Central Giant Cell Granuloma (CGCG), Noonan syndrome and NF-1(5). Perivascular eosinophilic ‘cuffing’ is less common, but is pathognomonic of cherubism.

This rare, usually benign condition, begins with proliferative lesions in the jaw in childhood. The bony lesions typically regress following puberty, undergoing remodelling and filling in by woven bone(7). The majority of case reports have relied on expectant observation, with involution of the lesions seen on transition to adulthood. Medical management has been trialled with mixed success, including use of bisphosphonates, calcitonin, denosumab, imatinib, and tumour necrosis factor (TNF) inhibitors(1). In some cases surgery is performed, but has been associated with recurrence if undertaken too early(8).

Take home messages::

• Cherubism is a rare variant of fibrous dysplasia inherited in an autosomal dominant manner. The disease process usually involves the mandible, and occasionally the maxilla and/or zygoma.
• The infiltration of the jaws with fibro-osseous lesions begin in childhood but often spontaneously regresses following transition to adulthood.
• Histologically, clusters of giant cell granulomas are observed, although this is not pathognomonic for the condition, and the differential diagnosis must include Brown’s tumour, CGCG, Noonan syndrome and NF-1.
• A watch-and-wait approach is commonly utilised in cherubism. For more severe cases, management with medical therapy such as bisphosphonates, calcitonin, denosumab, imatinib and more recently TNF inhibitors have been trialled with varying success. Surgery is reserved for the most severe of cases.