Cherubism

Cherubism is a benign, self-limiting autoinflammatory bone disease characterized by bilateral, symmetric proliferative fibro-osseous lesions limited to the mandible and maxilla.[1][2] The condition results from germline gain-of-function mutations in the SH3BP2 gene on chromosome 4p16.3, identified in approximately 80% of cases.[3][4] Mutant SH3BP2 protein escapes tankyrase-mediated proteasomal degradation, leading to aberrant accumulation that hyperactivates osteoclast and macrophage signaling pathways (SRC, SYK, VAV, NFATc1), promoting excessive osteoclastogenesis and inflammatory bone resorption.[5][6] The WHO classification lists cherubism among the giant cell lesions of the jaws, distinct from fibro-osseous disorders.[7][8] Radiographically, lesions present as bilateral multilocular radiolucencies with expansile remodeling and coarse trabeculation, centered on the mandibular angles and rami.[2][9] The disease is typically self-limiting, with spontaneous regression after puberty; management ranges from observation to surgical intervention for functionally or aesthetically significant cases.[1][2]

• Cherubism is the accepted designation, first applied by Jones in 1933 to describe the cherub-like facial fullness caused by bilateral jaw enlargement.[3][10]
• The WHO 5th edition classifies cherubism under giant cell lesions of the jaws within the odontogenic and maxillofacial bone tumours section.[7][8]
• Historical synonyms include familial fibrous dysplasia of the jaw, familial benign giant-cell tumor of the jaw, and familial multilocular cystic disease of the jaws. These terms are obsolete; cherubism is genetically and pathologically distinct from fibrous dysplasia (GNAS mutations) and from sporadic central giant cell granuloma.[3][4][8]
• The term "Noonan-like/multiple giant cell lesion syndrome" was previously used when cherubism-like jaw lesions occurred in RASopathies; current consensus recommends reserving "cherubism" for SH3BP2-related disease and describing RASopathy-associated jaw lesions as "Noonan syndrome with multiple giant cell lesions".[11]

• Prevalence is unknown; approximately 600 individuals have been reported in the literature.[2]
• Age of onset: typically between 2 and 7 years; affected children appear normal at birth.[1][2]
• Sex distribution: a systematic review of 92 SH3BP2-confirmed individuals found equal distribution between males and females. Older literature suggested a male predilection, likely reflecting reduced penetrance in females (reported at 50–75% vs. near 100% in males), though more recent data suggest penetrance may be equivalent between sexes.[2][10][12]
• Inheritance: autosomal dominant with variable expressivity and incomplete penetrance. Sporadic (nonfamilial) cases account for approximately 15% of genetically confirmed cases.[3][12]
• Anatomic distribution: the mandible is involved in virtually all cases; combined mandibular and maxillary involvement occurs in approximately 54% of genetically confirmed cases, while isolated mandibular disease accounts for approximately 36%.[12]

Presentation and Symptoms

• Bilateral, symmetric, painless enlargement of the jaws is the hallmark, producing the characteristic round-faced "cherubic" appearance.[1][2]
• Swelling typically begins in the mandibular body and angles, with maxillary involvement developing subsequently in more extensive disease.[2]
• Submandibular and cervical lymphadenopathy may be the earliest clinical finding, sometimes preceding recognizable bony enlargement.[2]

Dental Abnormalities

• Congenitally missing teeth (particularly second and third molars) are reported in approximately 38% of genetically confirmed cases.[2][12]
• Premature exfoliation of deciduous teeth, displacement and impaction of permanent teeth, malocclusion, and root resorption are common.[2][13]
• Teeth may appear to "float" within radiolucent cyst-like spaces.[2]

Tempo and Complications

• Lesions proliferate until puberty, then stabilize and gradually regress; by age 30, facial abnormalities are usually no longer clinically apparent, though residual radiographic changes may persist.[1][2]
• Wide phenotypic variability exists even within the same family.[2][3]
• Aggressive disease may cause impaired chewing and swallowing, speech difficulties, obstructive sleep apnea, and upper-airway obstruction.[2][14]
• Extensive maxillary lesions can extend into the orbital floor, producing proptosis, globe displacement, lower lid retraction, and the classic "eyes-to-heaven" appearance; optic neuropathy and diplopia occur rarely.[2][15]

Location and Distribution

• Lesions are characteristically bilateral and symmetric, centered on the mandibular angles and rami. The mandibular body is frequently involved; the coronoid processes may be affected, whereas the condyles are typically spared.[2][7][9]
• Maxillary lesions, when present, commonly involve the tuberosities and posterior alveolar regions and may extend into the maxillary sinuses and orbital floor.[9][10]
• Other cranial bones are usually unaffected; disease is essentially limited to the gnathic bones. Rare cases with condylar involvement have been documented in aggressive disease.[2][7]

Periphery and Shape

• Lesions appear as well-defined, multilocular radiolucencies with distinct borders divided by bony septations.[13][16]
• Margins are typically corticated; with increasing age and quiescence, thick sclerotic borders become more prominent.[13]
• In aggressive, rapidly growing lesions, margins may become less well defined with cortical thinning and perforation.[1]

Internal Architecture

• The internal pattern is characteristically multilocular with a coarse trabecular (soap-bubble) pattern created by bony septations traversing the radiolucent lesion.[2][9]
• Heterogeneous ground-glass sclerosis may be seen on cross-sectional imaging, particularly in maturing or regressing lesions.[17]
• CBCT demonstrates the coarse internal trabeculation and septations with greater clarity than panoramic radiography, and can reveal foci of calcification within the lesion.[10]

Effects on Teeth and Adjacent Structures

• Tooth displacement, impaction, and ectopic positioning are common; teeth may appear suspended within radiolucent spaces.[2][13]
• Root resorption occurs, particularly in aggressive lesions.[1][18]
• Premature loss of deciduous teeth and failure of eruption of permanent teeth are frequently observed.[2]
• The inferior alveolar canal may be displaced but is typically identifiable.[19]

Cortical Involvement and Extent

• Expansile remodeling of involved bones with thinning of buccal and lingual cortices is characteristic.[2][9]
• Cortical perforation occurs in aggressive disease and is a feature distinguishing aggressive from non-aggressive lesions.[1]
• CBCT is superior to panoramic radiography for evaluating cortical integrity, the true three-dimensional extent of lesions, and the relationship to the orbital floor in maxillary disease.[10][20]

Growth Pattern and Maturation

• Active lesions in young children are predominantly radiolucent with thin septations.[1]
• As lesions mature and regress (typically after puberty), progressive bone fill occurs; lesions become increasingly radiopaque with thicker sclerotic borders and eventually may become radiographically undetectable.[1][13]
• Lesions have been classified by clinical-radiographic behavior as quiescent (older patients, no progressive growth), non-aggressive (teenagers, stable), and aggressive (young children, large, rapidly growing with cortical perforation and tooth displacement).[1]

CT

• Medical CT demonstrates the expansile, multilocular lytic process with thinning and scalloping of the residual cortex. Foci of internal calcification may be identified. CT is particularly useful for evaluating orbital floor integrity and airway compromise in severe maxillary disease.[10][20][21]

MRI

• On MRI, cherubic lesions show heterogeneous signal intensity: intermediate to low signal on T1-weighted images and heterogeneous high signal on T2-weighted images, with enhancement after gadolinium administration.[10][22]
• Hypointense foci on both T1 and T2 sequences correspond to calcific deposits and hemosiderin deposition.[10]
• MRI may reveal signal abnormalities in areas that appear normal on radiographs and CT, potentially identifying early or subclinical disease extent.[22]

The bilateral, symmetric, multilocular radiolucent pattern centered on the mandibular angles in a child is highly suggestive of cherubism, but several entities produce overlapping giant cell–rich or multilocular jaw lesions and must be excluded.

The highest-risk diagnostic pitfall is failing to exclude hyperparathyroidism, which produces histologically identical giant cell lesions; serum calcium, PTH, and alkaline phosphatase should be obtained in any patient presenting with bilateral giant cell lesions of the jaws before attributing the findings to cherubism.[2]

Microscopic Features

• Lesions consist of a cellular fibrous stroma containing variably distributed osteoclast-like multinucleated giant cells (MNGCs), fibroblasts, and vascular spaces.[2][23]
• MNGCs tend to cluster around areas of hemorrhage but may also be dispersed throughout the stroma.[23]
• Eosinophilic perivascular collagen cuffing around small blood vessels is a characteristic (though not pathognomonic) histologic feature.[13][24][25]
• Focal hemosiderin deposits are common.[25]
• Peripheral new bone formation (osteoid and woven bone) is typically present at the lesion margins.[2]
• The histologic appearance is indistinguishable from central giant cell granuloma and brown tumor of hyperparathyroidism; the diagnosis of cherubism requires clinico-radiographic and genetic correlation.[2][23][26]

Prognostic Histologic Markers

• In aggressive cherubism, MNGCs display osteoclast-like features with positive TRAP activity and nuclear NFATc1 localization; in non-aggressive disease, MNGCs differentiate toward macrophages and are TRAP-negative with cytoplasmic NFATc1.[27][28]
• TRAP activity and NFATc1 nuclear localization have been proposed as prognostic indicators that may guide management decisions.[28]

Molecular Correlation

• Approximately 80% of cases harbor heterozygous missense mutations in the RSPPDG hexapeptide sequence of exon 9 of SH3BP2. Rare mutations outside exon 9 have been reported.[3][4][18]
• Genotype does not reliably predict phenotypic severity; identical mutations can produce markedly different clinical behaviors.[3]
• A somatic SH3BP2 mutation has been identified in a single case of sporadic central giant cell granuloma, suggesting molecular overlap between these entities.[8][18]

Initial Workup

• Clinical and radiographic assessment (panoramic radiograph; CBCT or CT for extent characterization).[1][9]
• Serum calcium, PTH, and alkaline phosphatase to exclude hyperparathyroidism.[2]
• Family history assessment and genetic testing for SH3BP2 mutations to confirm diagnosis.[2][12]
• Biopsy when the clinical-radiographic presentation is atypical or unilateral.[14]
• Referral to a multidisciplinary craniofacial team (oral and maxillofacial surgery, orthodontics, ophthalmology, pediatrics) is recommended.[2]

Treatment

• Observation is the initial management for most patients, given the self-limiting nature of the disease.[1][2]
• Surgical intervention (curettage with or without bone grafting, surgical contouring, or debulking) is indicated for functionally significant disease (airway obstruction, impaired swallowing, severe dental displacement) or marked aesthetic concerns. Surgery is ideally deferred until the disease becomes quiescent, as operating during the active phase carries a higher risk of recurrence.[1][2][14]
• Pharmacologic therapy remains investigational with no consensus or standard regimen:[2]
  • Denosumab (anti-RANKL monoclonal antibody) has shown clinical and radiologic improvement in severe cases, but carries risk of calcium homeostasis disturbances requiring close biochemical monitoring.[29][30][31]
  • Imatinib (tyrosine kinase inhibitor) has demonstrated tumor size reduction in a small series.[32]
  • Calcitonin, bisphosphonates, and anti-TNF-α agents have been used in individual cases.[2]

Recurrence and Prognosis

• Recurrence after surgery is the most significant risk, particularly when intervention occurs during the active growth phase.[28][33]
• Spontaneous regression after puberty is the expected natural history; lesions progressively fill with bone and remodel, with facial abnormalities typically becoming unrecognizable by age 30.[1][2]
• Persistent radiographic abnormalities may be seen in adults despite clinical resolution.[2]
• Aggressive disease with orbital or airway involvement requires closer surveillance and may necessitate multiple interventions.[7][14]

Syndromic Associations

• Cherubism-like bilateral giant cell jaw lesions occur in several RASopathies, including Noonan syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Noonan syndrome with multiple lentigines. These are caused by germline RAS-MAPK pathway mutations (PTPN11, SOS1, BRAF, and others), not SH3BP2 mutations, and should be classified separately.[2][11][34]
• Ramon syndrome (gingival fibromatosis, short stature, intellectual disability) includes cherubism-like jaw lesions.[2][4]
• Cherubism-like features have rarely been reported in fragile X syndrome.[4]

Pediatric Considerations

• All treatment decisions must account for the child's growth status, dental development, and the expected natural regression after puberty.[1][2]
• Pharmacologic agents such as denosumab are not specifically authorized for cherubism in children; use is off-label and requires individualized dosing with structured biochemical surveillance for hypocalcemia.[2][29]
• Orthodontic management of malocclusion and displaced teeth is typically coordinated with the craniofacial team and may be staged according to disease activity.[2]

Extragnathic Bone Phenotype

• Recent evidence suggests that patients with severe cherubism may exhibit increased bone metabolism markers (CTx, P1NP) and potentially reduced bone density outside the craniofacial region, indicating a systemic skeletal effect of SH3BP2 mutations that warrants further investigation.[35]