Cherubism

Definition & Genetics

Cherubism is a rare, autosomal dominant fibro-osseous disorder of the jaws caused by gain-of-function mutations in the SH3BP2 gene (chromosome 4p16.3). SH3BP2 is a cytoplasmic adaptor protein that interacts with TNFAIP3/A20 and protein tyrosine kinases (ABL1, SYK) that regulate transcriptional activity in immune cells. Approximately 50% of cases are de novo mutations (no family history). Penetrance is gender-dependent: ~100% in males, 50-70% in females. Around 10-20% of cases have no identified SH3BP2 mutation, suggesting additional genetic heterogeneity.

Rheumatology, 2-Volume Set (2022, Elsevier); GeneReviews - Cherubism

Epidemiology & Age of Onset

Rare disorder; precise incidence unknown
Onset typically 2-5 years of age
Affects children; lesions often spontaneously regress after puberty

Clinical Features

Feature	Details
Facial appearance	Bilateral, symmetric fullness/swelling of the lower face (jaw) - "chubby cheeks" resembling cherubs in Renaissance paintings
Mandible	Most prominently affected - posterior rami/angles
Maxilla	Also affected in more severe cases
Eyes	Upward deviation of the eyes (exposure of inferior sclera) due to floor of orbit involvement; can cause visual problems in severe disease
Teeth	Delayed eruption, displacement, mobility, root resorption, failure of permanent teeth to develop
Lymph nodes	Submandibular and cervical lymphadenopathy
Speech/Swallowing	Impaired in severe cases
Respiratory	Can cause airway compromise in aggressive disease

Severity ranges widely - from subclinical lesions to severe maxillomandibular overgrowth. - K.J. Lee's Essential Otolaryngology; Scott-Brown's Otorhinolaryngology, Vol. 1

Pathology

Lesions consist of giant cell reparative granulomas replacing normal bone with fibrous tissue
Histology: cellular fibroblastic stroma containing aggregates of multinucleated giant cells (smaller and fewer nuclei than true giant cell tumour)
Histologically indistinguishable from giant cell granuloma and the solid variant of aneurysmal bone cysts
Mitoses may be present (benign despite this)
Pathological mechanism: SH3BP2 mutation leads to abnormal osteoclast activity and exaggerated inflammatory signaling via NF-kB and RANKL pathways

Radiology

Plain X-ray/CT: Bilateral, symmetric multilocular radiolucent/lytic ("soap bubble") lesions in the mandible +/- maxilla
Expanded bone with coarse trabecular pattern and cortical thinning
CT shows expansile lytic lesions with well-demarcated edges
Submandibular lymphadenopathy may be visible
Grainger & Allison's Diagnostic Radiology; Radiopaedia - Cherubism

Diagnosis

Diagnosis is based on:

Characteristic clinical presentation (bilateral jaw swelling in a child)
Imaging (bilateral multilocular radiolucency)
Histopathology (giant cell lesion)
Molecular genetic testing (SH3BP2 pathogenic variant)

Differential diagnosis includes:

Brown tumour of hyperparathyroidism (check serum calcium, phosphate, alkaline phosphatase)
Fibrous dysplasia
Central giant cell granuloma
Aneurysmal bone cyst

Classification (by severity)

Inactive lesions - typically found in adolescence; non-progressive
Non-aggressive lesions - seen in younger children; very slow growth
Aggressive lesions - childhood onset; rapid expansion; tooth mobility, root resorption, cortical bone weakening

Treatment

Approach	Details
Watchful waiting	First-line for most; majority regress spontaneously after puberty (increased sex steroids normalize osteoclast activity)
Surgery	Reserved for significant cosmetic deformity, functional compromise (airway, vision, swallowing), or aggressive lesions. Includes curettage, osteoplasty, bone recontouring
Curettage	Associated with ~15% recurrence; excision preferred where possible
Dental management	Extraction of teeth from areas of fibrous change
Denosumab	Emerging therapy - a 2024 report documented successful treatment with denosumab 60 mg every 6 months in adult cherubism, targeting osteoclast activity via RANKL inhibition
Timing	Early surgical intervention before puberty may be needed in severe cases; conservative post-pubertal recontouring is preferred if possible

Scott-Brown's Otorhinolaryngology, Vol. 1; 2024 surgical case review

Prognosis

Most cases self-limit and regress during the second and third decades of life. Severe cases can cause permanent jaw deformity, dental loss, or orbital/visual complications. Early recognition and appropriate monitoring are key to preventing long-term morbidity.

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