HDCT - Heritable Disorders of Connective Tissue
What Research Is Being Done on HDCTs?
Scientists are working to better understand these disorders at several levels: (1) to identify the genes in which the mutations reside, (2) to identify the mutations that result in the clinical condition, (3) to understand how these mutations result in the condition, and (4) to use all available information about the condition to plan new therapies and test their use and value, both in animal models and in affected individuals. Because most of these conditions are uncommon, and individuals with them are widely scattered, it is often difficult to gather information about the clinical course of the disorder and assemble enough people to plan effective clinical trials.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is the lead Federal agency for connective tissue research. Several other NIH institutes are also studying HDCTs. NIAMS supports research through grants to scientists around the country, in national and international clinical trials, and at the NIH campus. This is some of the research underway:
NIAMS is conducting an indepth natural history study of people who have Marfan syndrome (which leads to abnormally long bones), nail-patella syndrome (a congenital skeletal disorder), Stickler syndrome (which causes eye and joint problems), and Ehlers-Danlos syndrome (which causes skin and blood vessel problems). All of these disorders have multiple, interrelated symptoms. NIAMS scientists are closely observing the people in this study over a long period to get a more complete picture of the diseases. They hope to improve their understanding of the genetic origins of the symptoms, of disease progression, and of mutations in patients and their relatives. Scientists expect their findings to apply to other HDCTs as well.
Specific areas of research and findings arising from this long-term study include:
examining the efficacy of screening for dural ectasia (an enlargement of the membrane that surrounds the spinal cord) in the diagnosis of Marfan syndrome
analyzing the prevalence of spinal and hip abnormalities in Stickler syndrome and their relationship to chronic pain
documenting an increased risk of failure of the femoral head (the ball portion at the top of the thigh bone) in children with Stickler syndrome
developing proposed diagnostic criteria for Stickler syndrome based on clinical and molecular studies in this population
identifying a connective tissue disorder with features resembling Marfan syndrome, Stickler syndrome, and Ehlers-Danlos syndrome
studying the mechanism of chronic musculoskeletal pain in people with HDCTs and exploring ways, including mindfulness-based stress reduction, to ameliorate it
looking at some specific musculoskeletal complications of aging in patients with HDCTs, such as the prevalence and severity of osteoporosis and osteoarthritis
using molecular genetic studies to identify both new genes contributing to Stickler syndrome and Ehlers-Danlos syndrome, and mutations in previously recognized genes.
NIAMS-supported researchers have succeeded in healing wounds in a mouse model of a particularly severe form of epidermolysis bullosa called recessive dystrophic epidermolysis bullosa (RDEB) by injecting the mice with RDEB patient cells in which the gene defect has been corrected. This approach may be useful in developing therapies for the disease. Other NIAMS-supported research shows it may be possible to grow healthy new skin in the lab for people RDEB by using skin cells from patients that were modified to express a normal gene for type VII collagen. Having successfully transplanted the modified skin on mice, scientists can now try to grow larger sheets of skin and graft them back onto people affected by RDEB.
NIAMS is examining gene defects that lead to abnormal elastin, the connective tissue protein that allows arteries, muscles, and other organs to respond in certain ways to movement. So far, the investigators have shown how elastin gene mutations cause two specific diseases: a skin disease (cutis laxa) and a blood vessel disease (supravalvular aortic stenosis). Scientists hope to learn more about how mutations affect elastin fiber and tissue growth. They also hope to find out how gene defects lead to the development of elastin disease.
NIAMS is supporting research looking for ways to treat diseases such as osteogenesis imperfecta by using gene therapy. Stem cells, which have the potential to develop into more specialized cells, would replace bone cells that have gene defects. This research is being conducted on specially bred mice. Other research on osteogenesis imperfecta treatment focuses on the use of growth hormone (rGH) therapy to promote height increases and bone density. In some cases, rGH is being used in combination with medications known as bisphosphonates.
NIAMS is encouraging the establishment of new research registries for connective tissue disorders and other conditions. Through these registries, demographic and medical data from patients and families could be collected and used in research on disorders. Epidermolysis bullosa is one of the disorders for which the Institute has already established a research registry.
Other NIAMS-supported research is focused on:
the chemistry and biology of elastin genes
collagen gene defects (several types) that cause bone diseases
collagen IV gene defects in mice and humans (Alport syndrome)
proteoglycans, a group of proteins that maintain tissue stiffness
fibroblasts, cells that form the fibrous tissues in the body
cartilage, joints, and skin layers.
Ongoing studies of aneurysms (weak spots in blood vessel walls that threaten to burst) are taking place at several NIH institutes. Aneurysms can prove deadly to people with Marfan syndrome and other HDCTs. NIAMS has supported these studies by pioneering development of a breed of mice prone to aneurysms. Scientists hope the mutant mice will improve understanding of aneurysms and ways to prevent them.
The National Institutes of Health supports the annual Gordon Research Conference on Elastin and Elastic Fibers, which brings together basic scientists and clinicians to exchange data on the makeup of and problems associated with these critical components of connective tissue.
Studies have shown that the blood pressure medication losartan prevents aortic aneurysms in a mouse model of Marfan syndrome, and one small study of 18 patients with Marfan syndrome showed that losartan slowed the enlargement of the aorta. A large multicenter trial receiving funding from the National Heart, Lung, and Blood Institute is now under way to further evaluate the use of losartan in people with Marfan syndrome.
At the Eunice Kennedy Shriver National Institute of Child Health and Human Development, scientists are working with young patients who have osteogenesis imperfecta. They hope to learn more about the genetics of the disease and the natural history of the many secondary features involved, as well as rehabilitation techniques.
Clinical trials organized by the National Eye Institute are comparing different antiangiogenic compounds (drugs that inhibit blood vessel formation) for pseudoxanthoma elasticum (PXE). New antiangiogenic agents are also in development.
Scientists at the National Institute of Dental and Craniofacial Research are carrying out clinical studies on fibrous dysplasia of bone.
Where Can People Find More Information About HDCTs?
People with HDCTs can contact professional and support groups that can supply more detailed information than is found here. Most of them also have Internet websites. Some major groups are listed below.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information Clearinghouse
National Institutes of Health
1 AMS Circle
Bethesda, MD 20892-3675
Phone: 301-495-4484
Toll Free: 877-22-NIAMS (877-226-4267)
TTY: 301-565-2966
Fax: 301-718-6366
Email: [email protected]
Website: http://www.niams.nih.gov
American Academy of Orthopaedic Surgeons (AAOS)
Web site: http://www.aaos.org
American Academy of Dermatology (AAD)
Web site: http://www.aad.org
Coalition for Heritable Disorders of Connective Tissue
Web site: http://www.chdct.org
Web site: http://www.geneticalliance.org
National Organization For Rare Disorders (NORD)
Web site: http://www.rarediseases.org
National Society of Genetic Counselors, Inc.
Web site: http://www.nsgc.org
Dystrophic Epidermolysis Bullosa Research Association of America, Inc. (DebRA)
Web site: http://www.debra.org
Ehlers-Danlos National Foundation (EDNF)
Web site: http://www.ednf.org/
National Association for Pseudoxanthoma Elasticum (NAPE)
Web site: http://www.pxenape.org
National Marfan Foundation (NMF)
Web site: http://www.marfan.org
Osteogenesis Imperfecta Foundation
Web site: http://www.oif.org
Web site: http://www.pxe.org
