Genetic and Functional Analysis of Cherubism

Cherubism Clinical Trial

— CBM  

Official title:

Identification of Mutations That Lead to Cherubism in Families and Isolated Cases and Studies of Cellular and Molecular Mechanisms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01630447
• Other study ID #: UCHC03-008CBM
• Status: Recruiting
• Start date: April 2009
• Est. completion date: December 2025

Study information

• Verified date: September 2023
• Source: UConn Health
• Contact: Ernst J Reichenberger, PhD
• Phone: 860-679-2062
• Email: reichenberger[@]uchc.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this research study is to identify genes and regulatory elements on chromosomes that cause cherubism. Together with the investigators collaborators the investigators also study blood samples and tissue samples from patients to learn about the processes that lead to this disorder. The long-term goal of researchers involved in this study is to find mechanisms to slow down bone resorption in cherubism patients.

Description:

Cherubism is a very rare bone disorder where bone gets excessively resorbed only in the jaw bones (mandible and maxilla). The resulting cavities in bone fill up with soft fibrous (fibro-osseous) tissues that can expand and push the bony shells apart. Thus the characteristic facial appearance in patients with progressed cherubism. Bone resorption (cherubism lesions) in this disorder occurs always symmetrically in the mandible, the maxilla or in both. This distinguishes cherubism from similar disorders. As cherubism progresses, the lesions can invade the eye sockets (inferior and/or lateral orbital walls) and displace the eye balls and push down the eyelids. As a result the sclera (white of the eye) below the iris becomes visible and patients have an upward gazing appearance (cherubic look) which gave the name to this fibro-proliferative bone disorder.

Cherubism typically appears between ages of 2-7 years. It is often diagnosed during dental evaluations. At early stages cherubism is accompanied by lymph node swelling. Proliferation of the fibro-osseous tissue typically stops after puberty and in many the soft tissue in the cherubic bone cavities are replaced by new bone.

For this study we will:

• Send out study participation kits and consent by phone

• Collect a saliva sample from eligible individuals

• Obtain information regarding cherubism

• Document disorder with photos and doctor's letters

• If patients undergo surgery for cherubism we ask to obtain some bone tissue that would otherwise be discarded

• Isolate DNA from the saliva sample

• Perform genetic analyses of the DNA with the most up-to-date methods available to identify genetic variations

• Study in the laboratory why the genetic variations cause the disorder

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• cherubism; unaffected individuals only if part of a participating cherubism family

Exclusion Criteria:

• no cherubism unaffected individuals only as part of a participating cherubism family

Related Conditions & MeSH terms

• Cherubism

Locations

Country	Name	City	State
United States	University of Connecticut Health Center	Farmington	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
UConn Health

Country where clinical trial is conducted

United States, 

References & Publications (13)

Fujii Y, Monteiro N, Sah SK, Javaheri H, Ueki Y, Fan Z, Reichenberger EJ, Chen IP. Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice. JBMR Plus. 2021 Oct 30;6(1):e10562. doi: 10.1002/jbm4.10562. eCo — View Citation

Gilbert G, Defillo M, Delcan JL, David P. [Results of anastomoses in the tetralogy of Fallot]. Union Med Can. 1966 Dec;95(12):1377-84. No abstract available. French. — View Citation

Kittaka M, Yoshimoto T, Schlosser C, Kajiya M, Kurihara H, Reichenberger EJ, Ueki Y. Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice. JBMR Plus. 2020 Apr 14;4(6):e10352. doi: 10.1002/jbm4.10352. eCollection 2020 Jun. — View Citation

Levaot N, Simoncic PD, Dimitriou ID, Scotter A, La Rose J, Ng AH, Willett TL, Wang CJ, Janmohamed S, Grynpas M, Reichenberger E, Rottapel R. 3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions. J Clin Invest. 2011 Aug;12 — View Citation

Levaot N, Voytyuk O, Dimitriou I, Sircoulomb F, Chandrakumar A, Deckert M, Krzyzanowski PM, Scotter A, Gu S, Janmohamed S, Cong F, Simoncic PD, Ueki Y, La Rose J, Rottapel R. Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell. 2011 Dec 9;147(6):1324-39. doi: 10.1016/j.cell.2011.10.045. — View Citation

Mione MC, Dhital KK, Amenta F, Burnstock G. An increase in the expression of neuropeptidergic vasodilator, but not vasoconstrictor, cerebrovascular nerves in aging rats. Brain Res. 1988 Sep 13;460(1):103-13. doi: 10.1016/0006-8993(88)91210-3. — View Citation

Papadaki ME, Lietman SA, Levine MA, Olsen BR, Kaban LB, Reichenberger EJ. Cherubism: best clinical practice. Orphanet J Rare Dis. 2012 May 24;7 Suppl 1(Suppl 1):S6. doi: 10.1186/1750-1172-7-S1-S6. Epub 2012 May 24. — View Citation

Reichenberger EJ, Levine MA, Olsen BR, Papadaki ME, Lietman SA. The role of SH3BP2 in the pathophysiology of cherubism. Orphanet J Rare Dis. 2012 May 24;7 Suppl 1(Suppl 1):S5. doi: 10.1186/1750-1172-7-S1-S5. Epub 2012 May 24. — View Citation

Ueki Y, Lin CY, Senoo M, Ebihara T, Agata N, Onji M, Saheki Y, Kawai T, Mukherjee PM, Reichenberger E, Olsen BR. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 "cherubism" mice. Cell. 2007 Jan 12;128(1):71-8 — View Citation

Ueki Y, Tiziani V, Santanna C, Fukai N, Maulik C, Garfinkle J, Ninomiya C, doAmaral C, Peters H, Habal M, Rhee-Morris L, Doss JB, Kreiborg S, Olsen BR, Reichenberger E. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet — View Citation

Wang CJ, Chen IP, Koczon-Jaremko B, Boskey AL, Ueki Y, Kuhn L, Reichenberger EJ. Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. Bone. 2010 May;46(5):1306-15. doi: 10.1016/j.bone.2010 — View Citation

Yoshimoto T, Hayashi T, Kondo T, Kittaka M, Reichenberger EJ, Ueki Y. Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model. J Bone Miner Res. 2018 Aug;33(8):1513-1519. d — View Citation

Yoshitaka T, Mukai T, Kittaka M, Alford LM, Masrani S, Ishida S, Yamaguchi K, Yamada M, Mizuno N, Olsen BR, Reichenberger EJ, Ueki Y. Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification of genetic elements	The goal is to identify relevant genes or genetic elements that cause the disease or contribute to the disease progression and severity.	at time of identification

External Links

•   Description of lab research and patient recruitment procedures