Clinical trial NCT01630447: Genetic and Functional Analysis of Cherubism
Official title: Identification of Mutations That Lead to Cherubism in Families and Isolated Cases and Studies of Cellular and Molecular Mechanisms
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cherubism
Keywords: cherubism
bone
autoinflammatory disorder
osteoblast
osteoclast
mandible
maxilla
Lead sponsor: UConn Health
Sponsor class: OTHER
First posted: 2012-06-28
Enrollment: 600
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals with clinically diagnosed cherubism

Brief 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.

Detailed 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

Eligibility criteria: 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

Primary outcomes:
measure: Identification of genetic elements
timeFrame: at time of identification
Secondary outcomes:
Other outcomes:
Locations:
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
Study officials:
affiliation: UConn Health
name: Ernst J Reichenberger, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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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. 2001 Jun;28(2):125-6. doi: 10.1038/88832.
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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.2010.01.380. Epub 2010 Feb 1.
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;121(8):3244-57. doi: 10.1172/JCI45843. Epub 2011 Jul 18.
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.
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.
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. doi: 10.1002/jbmr.3449. Epub 2018 May 22.
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. Cell Rep. 2014 Sep 25;8(6):1752-1766. doi: 10.1016/j.celrep.2014.08.023. Epub 2014 Sep 15.
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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.
citation: 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. eCollection 2022 Jan.