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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

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Cherubism

, MD, PhD, , MD, PhD, and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: March 20, 2025.

Estimated reading time: 30 minutes

Summary

Clinical characteristics.

Cherubism is a childhood-onset autoinflammatory bone disease characterized by proliferative fibroosseous lesions limited to the mandible and maxilla. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary bone lysis and cortical expansion with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications. In most affected persons, teeth are displaced, unerupted, hypoplastic, or absent, or they may appear to be floating in cyst-like spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. Respiratory manifestations can include obstructive sleep apnea and upper-airway obstruction. Orbital and ophthalmologic manifestations can occur with enlargement of the maxilla and orbital floor displacement. Intellect and development are typically normal. The course and duration of the active process of bone destruction varies between affected individuals; new lesions can occur until puberty, and rarely in adulthood. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are usually less obvious than during childhood.

Diagnosis/testing.

Diagnosis is established in a proband with typical clinical, radiographic, histologic, and family history findings and/or a heterozygous gain-of-function pathogenic variant in SH3BP2 or biallelic loss-of-function pathogenic variants in OGFRL1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Management through a craniofacial clinic with pediatric experience; surgical interventions include curettage with or without bone grafting; speech and language therapy as needed; treatment of obstructive sleep apnea and upper-airway obstruction per ENT and/or sleep specialist; orthodontic treatment for malocclusive bite, premature loss of deciduous teeth, and widely spaced, misplaced, uninterrupted, or absent permanent teeth; treatment per ophthalmologist in those with ocular manifestations.

Surveillance: Clinical and radiographic assessment of jaw lesions annually during cyst development and growth and then every two to three years or as needed after cyst growth stops; assess for feeding issues and jaw pain at each visit; assess for upper-airway obstruction and obstructive sleep apnea as needed; assess dental eruption and for displacement and dental anomalies every six months; ophthalmology evaluation annually or as needed.

Evaluation of relatives at risk: If the pathogenic variant(s) in the proband are known, molecular genetic testing can be used to clarify genetic status of at-risk family members; if the pathogenic variant(s) are not known, relatives at risk should be evaluated for clinical and radiographic manifestations of cherubism.

Genetic counseling.

Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner. Approximately 80% of affected individuals have the disorder as the result of a heterozygous gain-of-function pathogenic variant in SH3BP2. In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in OGFRL1 and inherited in an autosomal recessive manner.

Autosomal dominant inheritance: Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a de novo pathogenic variant. Each child of an individual with autosomal dominant cherubism has a 50% risk of inheriting the pathogenic variant.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an OGFRL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the OGFRL1 pathogenic variants in the family.

If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for cherubism have been published.

Suggestive Findings

Cherubism should be suspected in individuals with the following clinical, radiologic, and histologic findings and family history.

Clinical findings

  • Onset usually between age two and seven years
  • Bilateral, symmetric progressive enlargement of the mandible (See Figure 1.)
  • Symmetric or asymmetric enlargement of the maxilla
  • Swelling of submandibular and cervical lymph nodes (early in the disease course only)
  • Slow progression of the jaw lesions up to adolescence, with spontaneous regression typically starting after puberty and extending into the third decade
  • Exophthalmia in those with extensive maxillary lesions, through the orbital floor (See Figure 2.)
  • Dental abnormalities such as congenitally missing second and third molars, premature exfoliation of the deciduous teeth and displacement of permanent teeth secondary to the jaw lesions, and malocclusion
Figure 1. . Bilateral mandibular swelling with characteristic facial features of cherubism in a young girl.

Figure 1.

Bilateral mandibular swelling with characteristic facial features of cherubism in a young girl. Head CT showing lesions involving the mandible (arrow) and maxillary tuberosity without any sign of root resorption. Reprinted with permission from Kadlub (more...)

Figure 2.

Figure 2.

Coronal CT of child age six years with severe cherubism showing multilocular tissue expansion of the maxilla and mandible, bilaterally, with osteolysis and cortical bone expansion (arrows), tooth displacements (arrow heads), and elevation of the orbital (more...)

Radiographic findings

  • Enlargement of the mandible typically with bilateral, symmetric lesions usually located at the angles and rami. The coronoid processes may be involved, whereas the condyles are rarely affected. Lesions can be symmetric or asymmetric in the maxilla and mandible (see Figure 1).
  • Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucent areas with a coarse trabecular pattern [Khandelwal et al 2024].
  • Other cranial bones are usually unaffected.

Histologic findings of mandibular and/or maxillary lesions include dense non-neoplastic fibrotic lesions that contain numerous multinuclear giant cells, fibroblasts, and occasionally cysts. An increase in osteoid and newly formed bone matrix is observed in the periphery. These histologic features are not specific to cherubism; they are also seen in central giant cell reparative granuloma or brown tumor of hyperparathyroidism. However, unlike in these latter conditions, lesions are typically bilateral in cherubism [Jaffe 1953, Hobbs et al 1999, Regezi 2002]. Since cherubic phenotypes can be mimicked by other jaw tumors requiring different therapeutic strategies, a thoughtful consideration of histologic analysis is required [Friedrich et al 2016].

Family history is consistent with autosomal dominant (e.g., affected males and females in multiple generations) or autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of cherubism is established in a proband with typical clinical, radiographic, and histologic findings and family history and/or one of the following identified by molecular genetic testing (see Table 1):

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of cherubism, molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel.

  • Serial single-gene testing. Sequence analysis of SH3BP2 can be performed first to detect missense gain-of-function pathogenic variants. Note: (1) The majority of disease-associated variants have been reported in exon 9. (2) Cherubism occurs through a gain-of-function mechanism; therefore, large intragenic deletions or duplications are unlikely to cause disease. If no SH3BP2 pathogenic variant is found, sequence analysis of OGFRL1 can be done to detect biallelic loss-of-function pathogenic variants.
  • A multigene panel that includes SH3BP2, OGFRL1, and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by jaw lesions or the diagnosis of cherubism is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, most SH3BP2 and OGFRL1 pathogenic variants reported are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Cherubism

Gene 1, 2Proportion of Cherubism Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Identified by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
OGFRL1 2 families 6100% 6None reported 7
SH3BP2 ~80% 8100% 9None reported 9
Unknown 1010%-20%NA
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on variants detected in these genes.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

8.
9.

Cherubism caused by a heterozygous SH3BP2 pathogenic variant occurs through a gain-of-function mechanism; therefore, large intragenic deletions or duplications are unlikely to cause disease.

10.

Failure to identify a SH3BP2 pathogenic variant in 10%-20% of affected individuals suggests possible additional genetic heterogeneity [Reichenberger et al 2012, Prescott et al 2013]. The small number of individuals reported with pathogenic variants in OGFRL1 suggest that this gene would not account for all genetic heterogeneity.

Clinical Characteristics

Clinical Description

Cherubism is a childhood-onset bone disease characterized by bilateral proliferative lesions typically limited to the mandible and maxilla. Regression of the lesions occurs during the second and third decade of life. Findings associated with cherubism range from clinically unrecognized features to severe mandibular and maxillary overgrowth with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications [Roginsky et al 2009, Kueper et al 2022]. There is wide phenotypic variability even among individuals from the same family [Stoor et al 2017].

Onset and course. Individuals with cherubism have a normal appearance at birth. Usually, cherubism manifests in early childhood (age 2-7 years) and progresses until puberty, when it begins to stabilize and starts to regress. Submandibular and cervical lymph nodes are enlarged during the early stages of cherubism and may present before the recognition of bony lesions. By age 30 years, the facial abnormalities associated with cherubism are not usually recognizable and significant residual deformity of the jaws is rare; however, persisting bone abnormalities are often seen in adults with cherubism [Von Wowern 2000, Redfors et al 2013].

Bone lesions. The disease starts with progressive bone degradation, with rapid evolution in individuals with severe disease. Disease is usually restricted to the mandibular and maxillary regions and leads to multiple bilateral, symmetric cystic changes. Bone lesions develop preferentially at the mandibular level before affecting the maxilla [Roginsky et al 2009].

Severe malformation of the jaw may impede chewing and swallowing. An ache in the mouth and discomfort when eating food are frequently reported [Prescott et al 2013]. Massive enlargement of the jaw is common and can also be associated with severe pain in severe forms; however, bony lesions are usually painless in cherubism. Recurrence of jaw lesions is possible after surgery.

The facial disfigurement in cherubism can affect an individual's feelings of self-worth and be the source of bullying. However, one study reported that persons with cherubism were psychosocially well adapted and enjoyed a good quality of life [Prescott et al 2013].

Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. Although the facial disfigurement is expected to improve due to involution of the jaw lesions in early adulthood, this may not be the case for all individuals [Laroche et al 2022].

Dental abnormalities. In most affected persons, teeth are displaced, unerupted, hypoplastic, or absent, or they may appear to be floating in cyst-like spaces. Malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported [Kozakiewicz et al 2001, Stoor et al 2017]. Orthodontic treatment is commonly required, as the jaw distortion leads to permanent dental abnormalities.

Respiratory manifestations can include obstructive sleep apnea and upper-airway obstruction caused by backward displacement of the tongue [Battaglia et al 2000, Ladhani et al 2003, Khirani et al 2013].

Orbital and ophthalmologic manifestations. Ophthalmic manifestations of cherubism vary greatly depending on the level of involvement of the maxilla [Mirmohammadsadeghi et al 2015, Yoo et al 2015]. In rare instances, enlargement of the maxilla and penetration of the stromal mass into the orbital floor can cause lower lid retraction, proptosis, strabismus, diplopia, globe displacement, and/or visual loss as a result of optic atrophy, retinal vein occlusion, and macular folds with scarring [Carroll & Sullivan 2001, Font et al 2003]. Prior reports of individuals with maxillary involvement leading to orbital mass effect have varied in their ophthalmic sequelae and age of occurrence, with occurrence ranging from age seven to 27 years [Colombo et al 2001, Ahmadi et al 2003].

Intellect and development are normal. Difficulty with pronunciation has not been reported as a significant problem [Prescott et al 2013].

Other

Pathophysiology. The cysts are filled with fibrous tissue that consists of stromal cells and osteoclast-like cells. The bone inflammatory findings are similar to other autoinflammatory syndromes with bone involvement, such as chronic recurrent multifocal osteomyelitis (CRMO) and deficiency of interleukin-1 receptor antagonist [Wipff et al 2011, Morbach et al 2013, Kadlub et al 2015, Bader-Meunier et al 2018]. One main difference in the pathology of cherubism when compared to CRMO is the degree of osteolysis, which is significantly more profound in cherubism [Wipff et al 2011]. NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) immunohistochemistry on bone lesions may be helpful in defining a more aggressive form of the disease [Kadlub et al 2016].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Penetrance

Penetrance has not been systematically studied in cherubism. However, penetrance seems to be equivalent between males and females without ethnic predilection [Preda et al 2010, Papadaki et al 2012, Prescott et al 2013].

Nomenclature

Cherubism was first described as "familial multilocular cystic disease of the jaws" by Jones [1933]; however, shortly thereafter he renamed the condition "cherubism" because of the resemblance of affected individuals to the cherubs in Renaissance art.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], cherubism is referred to as SH3BP2-related cherubism and included in the disorganized development of skeletal components group.

Prevalence

Prevalence is unknown. Approximately 600 individuals have been reported in the medical literature. Clinical variability may result in underdiagnosis in children, especially in individuals with mild or asymptomatic cherubism. Furthermore, as bone remodeling occurs into adulthood, the radiologic findings during adulthood may not reflect the activity of the disease during childhood, despite the presence of a SH3BP2 pathogenic variant.

Differential Diagnosis

Disorders of interest in the differential diagnosis of cherubism are listed in Tables 2a and 2b.

Table 2a.

Genes of Interest in the Differential Diagnosis of Cherubism

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/cherubismDistinguishing from cherubism
BRAF
KRAS
LZTR1
MAP2K1
MAP2K2
MRAS
NRAS
PTPN11
RAF1
RASA2
RIT1
RRAS2
SOS1
SOS2
RASopathies 1 incl: AD
(AR) 2
Giant cell lesions of bones & soft tissues frequently found in jaws
  • Characteristic facial & neurocutaneous findings
  • Congenital anomalies in multiple systems
CDC73 Hyperparathyroidism-jaw tumor syndrome (See CDC73-Related Disorders.)AD
  • Benign ossifying fibromas of mandible or maxilla
  • Occasionally bilateral/multifocal & recurrent
Hyperparathyroidism
CDC73
MEN1 3
CASR
GCM2
Familial isolated hyperparathyroidism (OMIM PS145000)AD
AR
  • Brown tumors (rare benign giant cell lesions) resulting from parathyroid hormone effects on bone tissue in persons w/hyperparathyroidism
  • Can occur in both maxilla & mandible 4
Hyperparathyroidism: ↑ serum concentrations of calcium, parathyroid hormone, & alkaline phosphatase 3
GNAS Fibrous dysplasia / McCune-Albright syndrome (FD/MAS)See footnote 5.Craniofacial form of FD/MAS may show clinical & radiologic overlap w/cherubism & thus be difficult to differentiate. 6FD:
  • Lesions affecting other body parts incl femur, tibia, or ribs (exceptional in cherubism)
  • Absence of typical symmetric swelling of lower face (typical of cherubism)
  • On radiographs, characteristic ground-glass pattern
MAS:
  • Café au lait macules
  • Endocrine abnormalities
  • Chronic bony involvement that does not resolve at puberty
1.

"RASopathies" refers to disorders of the RAS-MAPK pathway.

2.

Noonan syndrome is most often inherited in an autosomal dominant manner; Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. Cardiofaciocutaneous syndrome is inherited in an autosomal dominant manner. Neurofibromatosis 1 is inherited in an autosomal dominant manner. Noonan syndrome with multiple lentigines is inherited in an autosomal dominant manner.

3.

Familial isolated hyperparathyroidism (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies. Heterozygous MEN1 germline pathogenic variants have been reported in 20% [Miedlich et al 2001, Villablanca et al 2002] to 57% [Pannett et al 2003] of families with FIHP.

4.
5.

Fibrous dysplasia / McCune-Albright syndrome, a sporadically occurring disorder, is caused by an early embryonic postzygotic somatic activating (gain-of-function) pathogenic variant in GNAS.

6.

Table 2b.

Disorders of Unknown Genetic Cause of Interest in the Differential Diagnosis of Cherubism

DisorderFeatures of Disorder
Overlapping w/cherubismDistinguishing from cherubism
Central giant cell granuloma 1, 2
  • Benign lesion usually occurring in mandible & maxilla
  • Histologically, central giant cell granuloma cannot be distinguished from cherubism.
Lesions are most often unilocular (in cherubism, lesions are usually multilocular).
Ramon syndrome (OMIM 266270)Gingival fibromatosis
  • Short stature
  • Epilepsy
  • Intellectual disability
1.
2.

A somatic pathogenic variant in SH3BP2 has been identified in one individual with central giant cell granuloma [Carvalho et al 2009].

Management

No clinical practice guidelines for cherubism have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with cherubism, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment protocols for the complications of cherubism are not well established and are evolving due to recent advances in the understanding of the autoinflammatory nature of this bone disease. Given that cherubism is considered to be a self-limited condition that improves over time, treatment should be tailored to the individual's presentation and the evolution of the disease. Depending on the severity, surgery may be needed for functional and esthetic concerns.

Note: Several pharmacologic treatments have been proposed and administrated to individuals with cherubism, mostly to treat severe forms, among them calcitonin, anti-TNF-α drugs, anti-calcineurin (tacrolimus), tyrosine kinase inhibitor (imatinib), and denosumab (human monoclonal antibody against RANKL). These treatments act within different mechanisms on the modulation of bone formation and resorption [Cailleaux et al 2023]. Despite the effectiveness of some drugs, the pharmacologic mechanisms are not completely elucidated, some treatments are not authorized for children, and no consensus or standard treatment have yet been recommended [Cailleaux et al 2023].

Table 4.

Cherubism: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Jaw lesions Mgmt by craniofacial clinic w/pediatric experienceCraniofacial clinic assoc w/major pediatric medical center usually includes surgical team, dentist, orthodontic specialist, ophthalmologist, & child psychologist or social worker
  • Surgical interventions include curettage w/ or w/o bone grafting. 1
  • Liposuction has been used to recontour jaws.
  • Surgical interventions are likely to occur between ages 5 & 15 yrs in persons w/disfiguring enlargement of jaws or locally aggressive lesions assoc w/complications such as impaired swallowing, respiratory issues, nasal airway obstruction, or tongue displacement.
  • Surgical therapy needs to be individually tailored & avoid unrealistic expectations since recurrence of lesions is possible & surgery may not halt disease progression. 2
Speech-language therapy may be necessary in rare instances where physical obstruction to production of speech or swallowing is present.
Respiratory Treatment of obstructive sleep apnea & upper-airway obstruction per ENT &/or sleep specialist
Dental Orthodontic treatment for malocclusive bite, premature loss of deciduous teeth, & widely spaced, misplaced, unerupted, or absent permanent teeth
Eyes Treatment per ophthalmologist in those w/lower lid retraction, proptosis, diplopia, globe displacement, & visual loss caused by optic atrophy

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from surveillance and early intervention. Evaluations can include:

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with cherubism have an affected parent.
  • Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a de novo pathogenic variant.
  • If a molecular diagnosis of SH3BP2-related cherubism has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, or a milder phenotypic presentation. Therefore, de novo occurrence of a SH3BP2 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the SH3BP2 pathogenic variant.
  • If the SH3BP2 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the SH3BP2 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Intrafamilial variable expressivity and reduced penetrance have been observed in cherubism.
  • If a molecular diagnosis of SH3BP2-related cherubism has been established in the proband and the SH3BP2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Prescott et al 2013].
  • If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for cherubism because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant cherubism has a 50% risk of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an SH3BP2 pathogenic variant and/or is clinically affected, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of a child with OGFRL1-related cherubism are presumed to be heterozygous for an OGFRL1 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an OGFRL1 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an OGFRL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with OGFRL1-related cherubism are obligate heterozygotes (carriers) for a pathogenic variant in OGFRL1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an OGFRL1 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the OGFRL1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a cherubism-related pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cherubism (View All in OMIM)

118400CHERUBISM
602104SH3 DOMAIN-BINDING PROTEIN 2; SH3BP2

Molecular Pathogenesis

SH3BP2 encodes the adaptor protein SH3 domain-binding protein 2 (3BP-2), which is required in several intracellular protein tyrosine kinase-dependent signaling pathways during hematopoietic cell differentiation and function [Foucault et al 2005]. 3BP-2 positively regulates the activity of the transcription factor NFAT, which is involved in osteoclastogenesis [Lietman et al 2008]. 3BP-2 contains an N-terminal pleckstrin homology (PH) domain, a proline-rich stretch that binds to Src holomolgy (SH) 3 domain-containing proteins, and a C-terminal SH2 domain that binds to phosphotyrosine residues [Deckert 2006].

SH3BP2-related cherubism results from pathogenic variants that are primarily clustered within the peptide sequence RSPPDG lying between the PH and SH2 domains. It is unclear how abnormal 3BP-2 causes excessive bone resorption and soft tissue proliferation primarily restricted to the jaws, and why cherubism lesions regress after puberty.

The generation of mice models of cherubism helped to decipher the underlying molecular mechanisms leading to the development of giant cell granulomas and excessive bone resorption. A knock-in mouse model with the most common pathogenic variant in human 3BP-2 (p.Pro418Arg) developed severe osteoporosis associated with highly activated osteoclasts, demonstrating that pathogenic variants within this peptide sequence result in a gain-of-function activity [Ueki et al 2007, Wang et al 2010]. It has been shown that Sh3bp2 activating mutation led to increased NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) nuclear translocation downstream to RANKL (receptor activator of nuclear factor-κB ligand) induced PLCγ (phospholipase C-gamma) phosphorylation and increased osteoclast-specific gene induction and multinuclear giant cell differentiation [Lietman et al 2010]. Ueki et al [2007], using their mouse model, showed that TNF-α (tumor necrosis factor-alpha) plays a central role in the pathogenesis of cherubism, as it stimulates M-CSF (macrophage colony-stimulating factor) and RANKL stromal cell production, in turn stimulating macrophage and osteoclast differentiation, in a vicious circle. Cherubism is thus considered an autoinflammatory bone disease [Ueki et al 2007]. It has been proposed that the bone autoinflammation is the result of TLR (toll-like receptors) reacting to oral microbiota and damage-associated molecular patterns during jaw remodeling. Cherubism lesions usually begin to regress after puberty by mechanisms that may involve the TLR-MYD88 (myeloid differentiation primary response 88) pathway [Yoshitaka et al 2014, Prod'Homme et al 2015]. However, mice models of cherubism do not fully mimic human pathology; the study of molecular and pathologic aspects in human cohorts will help to gain insights into the onset and evolution of the disease.

Sequence analysis of exon 9 of SH3BP2 detects an estimated 80% of pathogenic variants in individuals tested [Ueki et al 2001, Reichenberger et al 2012]. Reported pathogenic variants are missense and mainly cluster within a six-amino-acid sequence from p.Arg415 to p.Gly420. Pathogenic variants in remaining exons are rare [Ueki et al 2001, Lo et al 2003, Lietman et al 2006]. A pathogenic missense variant in exon 4 in the pleckstrin homology domain has been described by Carvalho et al [2009] in an individual with cherubism.

Mechanism of disease causation. Gain of function

Table 6.

SH3BP2 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment
NM_003023​.4
NP_003014​.3
c.1253C>Gp.Pro418ArgSee Molecular Genetics.

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Our research team has investigated cherubism for several years. Our work helped to decipher new molecular and physiopathologic aspects in human cherubism (see PMIDs 23129383, 25491283, 27498064, 30236129, and 32825821), demonstrating that cherubism may not be restricted to the maxillofacial region and may be associated with systemic bone loss and inflammation, especially in those with severe disease (see PMID 32825821).

Natacha Kadlub
rf.phpa@buldak.ahcatan
Maxillofacial Surgery Unit
Hôpital Necker-Enfants malades
APHP
Paris, France

Amélie Coudert
rf.mresni@treduoc.eilema
BIOSCAR
INSERM U1132
Hôpital Lariboisière
Paris, France

Anne Morice
rf.sruot-uhc@ecirom.a
Maxillofacial Surgery Unit
CHRU
Tours, France

Natacha Kadlub, Amélie Coudert, and Anne Morice a are actively involved in clinical research regarding individuals with cherubism. They would be happy to communicate with persons who have any questions regarding diagnosis of cherubism or other considerations. They are also interested in hearing from clinicians treating families affected by cherubism in whom no causative variant has been identified in SH3BP2.

Acknowledgments

We thank our colleagues from the radiology department (Dr Kahina Belhous) and the pathology department (Dr Philippe Drabent), Hôpital Necker-Enfants malades, APHP, Paris, France.

Author History

Berivan Baskin, PhD, FCCMG, FACMG; University Hospital Uppsala (2007-2025)
Sarah Bowdin, BM, MSc, MRCPCH; Addenbrooke's Hospital Cambridge (2011-2025)
Amelie Coudert, PhD (2025-present)
Natacha Kadlub, MD, PhD (2025-present)
Peter Kannu, MB ChB, PhD, DCH, FRACP, FRCPC; The Hospital for Sick Children (2018-2025)
Anne Morice, MD, PhD (2025-present)
Peter N Ray, PhD, FCCMG, FACMG; University of Toronto (2007-2018)
Ahmad Teebi, MD, FRCPC, FACMG; Weill Cornell Medical College - Qatar (2007-2011)

Revision History

  • 20 March 2025 (sw) Comprehensive update posted live
  • 21 November 2018 (ha) Comprehensive update posted live
  • 1 September 2011 (me) Comprehensive update posted live
  • 26 February 2007 (me) Review posted live
  • 8 December 2006 (pr) Original submission

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