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Cherubism

, PhD, FCCMG, FACMG, , BM, MSc, MRCPCH (UK), and , PhD, FCCMG, FACMG.

Author Information
, PhD, FCCMG, FACMG
Clinical Genetics
Uppsala University Hospital
Uppsala, Sweden
, BM, MSc, MRCPCH (UK)
Staff Physician, Division of Clinical and Metabolic Genetics
The Hospital for Sick Children
Assistant Professor, University of Toronto
Toronto, Ontario
, PhD, FCCMG, FACMG
Head, Division of Molecular Genetics
The Hospital for Sick Children
Professor, Department of Molecular and Medical Genetics
University of Toronto
Toronto, Ontario

Initial Posting: ; Last Update: September 1, 2011.

Summary

Disease characteristics. Cherubism is characterized by progressive, painless, bilateral enlargement of the mandible and/or maxilla resulting from replacement of bone with multilocular cysts composed of fibrotic stromal cells and osteoclast-like cells. The enlargement is usually symmetric in nature. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary overgrowth with respiratory, vision, speech, and swallowing problems. Onset is typically between ages two and five years. Other bones are usually not affected and the affected person is otherwise normal. The jaw lesions progress slowly until puberty when they stabilize and then regress. Dental abnormalities include congenitally missing teeth, premature exfoliation of the deciduous teeth, and displacement of permanent teeth by the jaw lesions. By age 30 years, facial abnormalities are no longer apparent; residual jaw deformity is rare.

Diagnosis/testing. Diagnosis depends on typical clinical findings and radiographic findings of well-defined, often extensive bilateral multilocular areas of diminished density in the mandible and/or maxilla. SH3BP2 is the only gene in which mutation is currently known to cause cherubism. Sequence analysis of exon 9 is typically performed first as most missense mutations identified to date are in exon 9.

Management. Treatment of manifestations: Care by a craniofacial team in a major pediatric medical center; surgery (curettage with or without bone grafting) as needed between ages five to 15 years for disfiguring enlargement of jaws or locally aggressive lesions; orthodontic treatment; ophthalmologic treatment for displacement of the globe or vision loss.

Prevention of secondary complications: Early orthodontia and/or jaw reconstruction may reduce risk for upper airway obstruction, obstructive sleep apnea, and tooth displacement.

Surveillance: Long-term follow up with clinical, radiographic, dental, orthodontic, and ophthalmologic evaluations.

Evaluation of relatives at risk: When the disease-causing mutation in the family is known, molecular testing can be used to identify mildly affected relatives who may benefit from early intervention; otherwise, clinical and radiographic evaluations can identify relatives at risk.

Genetic counseling. Cherubism is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is unknown because of variable expressivity and reduced penetrance. Each child of an individual with cherubism has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

Diagnosis 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 Testing

Gene. 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 Cherubism

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SH3BP2Sequence analysis of select exonsSequence variants 2 in exon 9 ~80% 3
Sequence analysisSequence variants 2 >80%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 Strategy

To 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.

Clinical Description

Natural History

Individuals 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 Correlations

No genotype/phenotype correlations have been described for cherubism.

Penetrance

Penetrance is close to 100% in males and 50%-75% in females [Anderson & McClendon 1962, Roginsky et al 2009].

Anticipation

Anticipation has not been described in cherubism.

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.

Prevalence

Prevalence is unknown. Variability of the cherubism phenotype may result in underdiagnosis of the condition.

Differential Diagnosis

Noonan-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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 Manifestations

Treatment 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 Complications

Early 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.

Surveillance

Generally, long-term follow up including clinical, radiographic, dental, orthodontic, and ophthalmologic evaluations is indicated [Silva et al 2007].

Evaluation of Relatives at Risk

At-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 Investigation

A 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.

Other

Results 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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cherubism is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with cherubism have an affected parent.
  • A proband with cherubism may have the disorder as the result of a new gene mutation and no previous family history of cherubism will exist. The proportion of cases caused by de novo mutations is unknown since variable expressivity and reduced penetrance are observed in cherubism.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and molecular genetic testing for the identified SH3BP2 mutation in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

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, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and/or the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with cherubism has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

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.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like cherubism) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • National Library of Medicine Genetics Home Reference
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SH3BP24p16​.3SH3 domain-binding protein 2SH3BP2 homepage - Mendelian genesSH3BP2

Data 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)

118400CHERUBISM
602104SH3 DOMAIN-BINDING PROTEIN 2; SH3BP2

Normal 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].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  31. van Capelle CI, Hogeman PH, van der Sijs-Bos CJ, Heggelman BG, Idowu B, Slootweg PJ, Wittkampf AR, Flanagan AM. Neurofibromatosis presenting with a cherubism phenotype. Eur J Pediatr. 2007;166:905–9. [PubMed: 17120035]
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  33. Wang CJ, Chen IP, Koczon-Jaremko B, Boskey AL, Ueki Y, Khun L, Reichenberger EJ. Pro416Arg cherubism mutation in sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. Bone. 2010;46:1306–15. [PMC free article: PMC2854251] [PubMed: 20117257]
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  35. Zenn MR, Zuniga J. Treatment of fibrous dysplasia of the mandible with radical excision and immediate reconstruction: case report. J Craniofac Surg. 2001;12:259–63. [PubMed: 11358100]

Suggested Reading

  1. de Lange J, van Maarle MC, van den Akker HP, Redeker EJ. DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma. Br J Oral Maxillofac Surg. 2007;45:499–500. [PubMed: 16713042]
  2. Peters WJ. Cherubism: a study of twenty cases from one family. Oral Surg Oral Med Oral Pathol. 1979;47:307–11. [PubMed: 285398]
  3. Rice DP. Craniofacial anomalies: from development to molecular pathogenesis. Curr Mol Med. 2005;5:699–722. [PubMed: 16305494]

Chapter Notes

Author History

Berivan Baskin, PhD, FCCMG, FACMG (2007-present)
Sarah Bowdin, BM, MSc, MRCPCH (UK) (2011-present)
Peter N Ray, PhD, FCCMG, FACMG (2007-present)
Ahmad Teebi, MD, FRCPC, FACMG; Weill Cornell Medical College - Qatar (2007-2011)

Revision History

  • 1 September 2011 (me) Comprehensive update posted live
  • 26 February 2007 (me) Review posted to live Web site
  • 8 December 2006 (pr) Original submission
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Bookshelf ID: NBK1137PMID: 20301316
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Tests in GTR by Gene

Tests in GTR by Condition

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