DiagnosisClinical DiagnosisDiagnosis of cherubism is made on the presence of clinical findings and radiographic and histologic manifestations and is confirmed with molecular genetic testing of SH3BP2. No clinical diagnostic criteria have been established. However, the diagnosis is suspected in individuals with the following findings:Clinical findings Age of onset usually between two and five years Painless bilateral, symmetric enlargement of the mandible and/or maxilla including coronoids and condyles. Other cranial bones are usually unaffected. Slow progression of the jaw lesions up to adolescence and spontaneous regression typically starting after puberty and extending into the twenties Upturned tilting of eyeballs (in advanced stages); rim of sclera visible beneath iris Dental abnormalities: congenitally missing second and third molars; premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions Radiographic manifestations in the mandible and/or maxilla: well-defined bilateral multilocular areas of diminished density, very often extensive, with few irregular bony septa Histologic manifestations of lesions in the mandible and/or maxilla: non-neoplastic fibrotic lesions that contain numerous multinuclear giant cells and occasionally cysts. Increase in osteoid and newly formed bone matrix is observed in the periphery. Alkaline phosphatase, parathyroid hormone and calcium concentrations are normal, thus eliminating the diagnosis of hyperparathyroidism.Molecular Genetic TestingGene. SH3BP2 is the only gene in which mutations are known to cause cherubism. Evidence for locus heterogeneity. Failure to identify a SH3BP2 mutation in 20% of affected individuals suggests possible genetic heterogeneity [Ueki et al 2001]. Clinical testing Sequence analysis of exon 9 of SH3BP2 detects an estimated 80% of mutations in individuals tested [Ueki et al 2001]. The mutations are missense and are clustered within a six-amino acid sequence. Mutations in remaining exons are rare. Table 1. Summary of Molecular Genetic Testing Used in CherubismView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySH3BP2Sequence analysis of select exonsSequence variants 2 in exon 9 ~80% 3 Clinical Sequence analysisSequence variants 2 >80%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Ueki et al [2001]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic Allelic Variants).Testing StrategyTo confirm/establish the diagnosis in a proband Molecular genetic testing is used to confirm the diagnosis in a proband with the suggestive clinical findings and typical radiologic and/or histologic manifestations (see Clinical Diagnosis). Sequence analysis of exon 9 is typically performed first. Sequencing of the remaining exons of SH3BP2 is performed on individuals in whom a mutation in exon 9 is not identified.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SH3BP2.}

Natural HistoryIndividuals with cherubism are normal at birth. Usually, cherubism manifests in early childhood (age 2-5 years) and progresses until puberty when it begins to stabilize and starts to regress. By age 30 years, the facial abnormalities are not usually recognizable and residual deformity of the jaws is rare [Von Wowern 2000].Aside from the facial anomalies described, cherubism is an isolated benign condition; the affected person is mentally and otherwise physically normal.The symptoms and signs of cherubism are related to the severity of the condition, and range from clinically unrecognized features to severely deformed mandibular and maxillary overgrowth with respiratory, speech, and swallowing complications [Roginsky et al 2009]. Massive enlargement of the jaws is common and can also be associated with severe pain [Battaglia et al 2000, Timosca et al 2000, Silva et al 2002, Gomes et al 2005, Wang et al 2006].In some studies, males were found to be more commonly and severely affected than females [Von Wowern 2000]. Involvement of cranial bones. The disease starts with rapid bone degradation, usually restricted to the mandibular and maxillary regions, and leads to multiple symmetric cystic changes. These cysts are filled with fibrous tissue mass that consists of stromal cells and osteoclast-like cells, resulting in the typical facial phenotype [Ozkan et al 2003]. Dental. In most affected persons, teeth are displaced, unerupted, unformed, or absent, or may appear to be floating in cystlike spaces. Malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported [Kozakiewicz et al 2001]. Orbital and ophthalmologic. In rare instances, enlargement of the maxilla and penetration of the stromal mass into the orbital floor can cause lower lid retraction, proptosis, diploia, globe displacement, and/or visual loss as a result of optic atrophy [Carroll & Sullivan 2001, Font et al 2003]. Respiratory. Respiratory problems can include obstructive sleep apnea and upper airway obstruction caused by backward displacement of the tongue [Battaglia et al 2000, Ladhani et al 2003].

Genotype-Phenotype CorrelationsNo genotype/phenotype correlations have been described for cherubism.

Differential DiagnosisNoonan-like/multiple giant-cell lesion syndrome is a rare condition, with phenotypic overlap with Noonan syndrome and cherubism [Lee et al 2005]. It is characterized by dysmorphic features, developmental delay, short stature, pulmonary stenosis, and giant-cell lesions of bones and soft tissues. The giant-cell lesions are frequently found in the jaws and therefore persons with mild Noonan-like/multiple giant-cell lesion syndrome can be misdiagnosed with cherubism [Jafarov et al 2005]. Mutations in PTPN11 and SOS1 [Hanna et al 2009] have been described in both familial and simplex cases (i.e., a single occurrence in a family) of Noonan-like/multiple giant-cell lesion syndrome. Central giant-cell granuloma is a rare benign lesion that usually occurs in the mandible and maxilla. The lesions can lead to facial deformity and displacement of the teeth. The condition occurs in children and young adults, with a higher frequency in females. Histologically, central giant-cell granuloma cannot be separated from cherubism. The two conditions can be distinguished by radiologic findings because the majority of lesions in cases of central giant-cell granuloma are unilocular, whereas in cherubism the lesions are usually multilocular [De Lange & Van den Akker 2005]. A somatic mutation in SH3BP2 has been identified in one individual with central giant-cell granuloma [Carvalho et al 2009]. In the majority of individuals, the etiology of central giant-cell granuloma is unknown, although in most instances in which molecular genetic testing of SH3BP2 was performed, testing was limited to exon 9. Fibrous dysplasia. Fibrous dysplasia of the jaw is characterized by benign giant-cell lesions localized asymmetrically in the maxilla rather than the mandible. The condition usually presents in childhood and is progressive until after adolescence [Zenn & Zuniga 2001]. Cherubism can be distinguished from fibrous dysplasia on a clinical basis. Hyperparathyroidism. Brown tumors are rare benign giant-cell lesions that arise as a result of parathyroid hormone effects on bone tissue in persons with hyperparathyroidism. Brown tumors can occur in both the maxilla and mandible [Lessa et al 2005]. The age of onset is usually in adulthood. Hyperparathyroidism can be distinguished from cherubism with biochemical investigations, since serum concentrations of calcium, parathyroid hormone, and alkaline phosphatase are elevated in hyperparathyroidism [Silva et al 2002]. Other. Cherubism is also part of Ramon syndrome, which is characterized by short stature, intellectual disability, and gingival fibromatosis. Cherubism has also been reported in association with neurofibromatosis 1 [Martinez-Tello et al 2005, van Capelle et al 2007], fragile X syndrome, a single case of coronal and sagittal craniosynostosis, which is likely to be a coincidental association [Stiller et al 2000]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with cherubism, the following evaluations are recommended:Radiologic assessment to determine facial bone involvement Orthodontic assessment Ophthalmologic examination Assessment of family history Treatment of ManifestationsTreatment protocols for cherubism are not well established since both ends of the spectrum (mild clinically unrecognized cases and severe cases with extensive bone loss) are seen. Given that cherubism is considered to be a self-limited condition that improves over time, treatment should be tailored to the individual's needs. Depending on the severity, surgery may be needed for functional and esthetic concerns. Children with cherubism should be referred to a craniofacial clinic with pediatric experience for evaluation. A craniofacial clinic associated with a major pediatric medical center usually includes a surgical team, medical geneticist, dentist, orthodontic specialist, ophthalmologist, and social worker. Surgical interventions include curettage with or without bone grafting [Kozakiewicz et al 2001, Roginsky et al 2009]. Liposuction has also been used successfully to re-contour the jaws. Surgical interventions are likely to occur between ages five to 15 years in individuals with disfiguring enlargement of jaws or locally aggressive lesions associated with complications. Orthodontic treatment is commonly required as the jaw distortion leads to permanent dental abnormalities including a malocclusive bite, premature loss of deciduous teeth, and widely spaced, misplaced, unerupted, or absent permanent teeth. Ophthalmologic treatment is necessary in rare individuals in whom orbital manifestations such as lower lid retraction, proptosis, diplopia, globe displacement, and visual loss caused by optic atrophy are present. Prevention of Secondary ComplicationsEarly treatment (i.e., orthodontic and surgical reconstruction of the jaw) may reduce the risk for secondary complications such as upper airway obstruction, obstructive sleep apnea, and tooth displacement.SurveillanceGenerally, long-term follow up including clinical, radiographic, dental, orthodontic, and ophthalmologic evaluations is indicated [Silva et al 2007]. Evaluation of Relatives at RiskAt-risk relatives could be offered clinical and radiographic evaluations given that manifestations may not be evident in all affected individuals. When the disease-causing mutation is known in the proband, molecular genetic testing can be used to evaluate relatives at risk for the disorder. This may allow mildly affected relatives to benefit from early surveillance and intervention. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA mouse model for cherubism demonstrated that increased cytokine tumor necrosis factor α (TNF-α) production by myeloid cells is causative [Ueki et al 2007]. If TNF-α were found to be pathogenic in humans, anti-TNF therapies could provide new treatment options for cherubism. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherResults in the two reports to date on the use of calcitonin in the treatment of cherubism have not been promising [Hart et al 2000, Lannon & Earley 2001].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cherubism: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSH3BP24p16​.3SH3 domain-binding protein 2SH3BP2 homepage - Mendelian genesSH3BP2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cherubism (View All in OMIM) View in own window 118400CHERUBISM 602104SH3 DOMAIN-BINDING PROTEIN 2; SH3BP2Normal allelic variants. The SH3BP2 transcript spans approximately 2.4 kb and comprises 13 exons. The gene was identified in a search for candidate tumor suppressor genes [Bell et al 1997]. Pathologic allelic variants. Ueki et al [2001] first described missense mutations in SH3BP2 in cherubism. Eleven missense mutations identified are located in exon 9 and affect four amino acids within a six-amino acid sequence [Ueki et al 2001, Lo et al 2003, Lietman et al 2006]. A missense mutation in exon 4 in the pleckstrin homology domain has been described by Carvalho et al [2009] in an individual with cherubism. Normal gene product. SH3BP2 encodes the adaptor protein SH3-domain binding protein 2. It is required in several intracellular protein tyrosine kinase-dependent signaling pathways during hematopoietic cell differentiation and function [Foucault et al 2005]. SH3BP2 positively regulates the activity of the transcription factor NFAT, which is involved in osteoclastogenesis [Lietman et al 2008]. Abnormal gene product. Cherubism results from presumed gain-of-function mutations in SH3BP2 [Lietman et al 2006]. A knock-in mouse model with the most common human SH3BP2 mutation (p.Pro416Arg) alters the bone quality and reduces osteoblast function [Wang et al 2010].