UConn Health Center Cherubism Study

Cherubism Study
Please visit: http://reichenbergerlab.uchc.edu/index.html
What is the purpose of this genetic research study? The goal of this research study is to identify genes and regulatory elements on chromosomes that cause cherubism. Together with our collaborators we 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. Cherubism is a very rare bone disorder where bone gets 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, which gives patients with progressed cherubism the characteristic facial appearance. Bone resorption (cherubism lesions) in this disorder is always symmetrical in the mandible, the maxilla or 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. What do we know about the genetics of cherubism? In 2001 we have found mutations for cherubism in a gene called SH3BP2 on chromosome 4. Cherubism can be inherited and run in families. Most of the familial cherubism is inherited in an autosomal dominant mode. This means that one copy of chromosome 4 carries the normal copy of SH3BP2 and the other copy of chromosome 4 the mutated SH3BP2. There are patients with cherubism who do not have any family history of cherubism. Their parents have a normal set of SH3BP2 genes and the patient developed the mutation spontaneously during early embryonic development, as a so called de novo mutation. One explanation for different patients developing the same mutation is that the SH3BP2 gene may be located in a genetic hot spot where the likelihood for a mutation is higher than in other chromosomal regions. There is also the autosomal recessive form of cherubism for which no mutation has been published yet. Both parents have one copy of a mutated gene (yet unknown) and their children have a then a 25% chance to inherit both mutated copies of this gene. Only individuals with 2 mutant copies of the gene will develop cherubism. In most cases the parents have common ancestors. There are yet other patients who have been diagnosed with cherubism who do not have the recessive form of cherubism nor a mutation in SH3BP2. We believe there are other genes that can cause CMD or a CMD-like condition (= genetic heterogeneity) and we do our best to find those genes. Cherubism-like phenotypes can be associated with the Noonan Syndrome (NS) spectrum. Several genes have been associated with NS. SH3BP2 codes for a protein that helps other proteins come together (adapter protein) as a complex to carry signals from one cell to another or within the cell. In cherubism this SH3BP2 protein that carries the mutation is highly active for longer than normal because it cannot be degraded. The current evidence is that all known cherubism mutations are germline mutations, which means that they can be passed on to offspring. Do we treat cherubism? No, we do not treat cherubism. We and our collaborators at the University of Missouri-Kansas City perform basic research to understand what happens in bone cells that they lead to this characteristic bone phenotype. Based on this knowledge we hope that better treatment can be developed in the future. Why should I participate in such a genetic study? Although we know some mutations in the SH3BP2 gene, we are looking for more cherubism patients to participate. The goal is to identify additional mutations and additional genes that can lead to cherubism. This knowledge will help to better understand the molecular pathways of cherubism and what regulates the initiation and maintenance of cherubic lesions. Click here to read more about our research. YOUR participation will help to reach our goal. Will I directly benefit from this study? You will not directly benefit from the results of this study. Who can participate in the study? Any individual who was diagnosed with cherubism is eligible to participate. Sometimes it may not be clear whether it is cherubism or a very similar disorder. In such instances we will ask for doctors’ letters or X-Rays. If we do not find a known mutation in SH3BP2 it may be helpful to have certain family members participate as well. What if I do not live close to UCHC? We can communicate with you by email and telephone. You do not have to come to UCHC. However, if you live close by you are welcome to see us in person. What do I need to do if I wish to participate? You will be asked to donate a onetime saliva sample. If you have surgery we would also like to obtain bone tissue that would otherwise be discarded by the surgeon. What are the procedures for participation? To donate saliva:
1. You contact us by email or by phone.
2. We will establish whether you have cherubism and answer your questions about the study.
3. We will send you a saliva collection kit and consent forms as well as a prepaid return envelope.
4. We will make an appointment to talk you through the consent form and the questionnaire. We will answer any question you may have.
5. You return the signed papers and the saliva sample by prepaid FedEx envelope.
6. We will also need clinical information like doctors’ letters or X-Rays (by email or hard copies). To donate tissue:
1. You will have gone through the recruitment procedures for the saliva collection.
2. Please let us know about any upcoming surgery and tell your doctor that you participate in this cherubism study.
3. We will arrange with your doctor to receive tissue that he would otherwise discard. No extra tissue will be removed! We will send special tubes to the doctor who will send it back via a prepaid FedEx envelope.
4. We may ask you to give us a tube of blood at the same time you have the surgery. Why do we need these samples? The saliva samples will be used to isolate DNA from the cells in the saliva. DNA is the material that makes up genes and chromosomes. We will look for mutations in the SH3BP2 gene or other candidate genes. Tissue samples from will be used to isolate cells and to study the histology in detail. Confidentiality and privacy? We do our best to protect your personal data. All samples will be given a number and kept separate from the paperwork which links the number to your personal data. We will not pass any information on to your insurance. We will not enter our research data into any of your medical records. Can I withdraw from the study? If you choose to withdraw from the study after your sample has been obtained, we will destroy all records in our research files connecting your identity with your samples. This way samples can only be used anonymously from this point forward. Can I obtain results from this study? You can choose to receive general information about results once we have made significant progress. No research results pertaining to your person will be shared with you or any member of your family. We can send information about your own sample to your physician or genetic counselor who can explain the significance of the finding. This is to avoid any confusion about genetic information. What if I have questions? You can contact the study team at any time and we will give you contact information for regulatory entities that oversea our research. To participate or ask questions and to obtain more information please email, call or fax to the following address:

Ernst Reichenberger. (Associate Professor)
University of Connecticut Health Center (UCHC)
Department of Reconstructive Medicine
263 Farmington Avenue
Farmington, CT 06030-3705

Toll free: 1-866-512-9897
Tel: 860-679-2062
Fax: 860-679-2910
Email: reichenberger@uchc.edu
http://reichenbergerlab.uchc.edu/index.html


Literature on Cherubism:
PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez?holding=uchclib (type in cherubism)
GeneReviews: http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=genetests (type in craniometaphyseal)