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Connective Tissue

May 2013

Questions and Answers about Heritable Disorders of Connective Tissue

This publication contains general information about heritable (genetic) disorders of connective tissue (HDCTs). It describes what they are, what causes them, and diagnosis and treatment options. Highlights of current research are also included. At the end is a list of key words to help you understand the medical terms used in this publication. If you have further questions after reading this publication, you may wish to discuss them with your health care provider.

What Are Heritable Disorders of Connective Tissue?

Heritable (genetic) disorders of connective tissue are a family of more than 200 disorders that affect connective tissues. These disorders result from alterations (mutations) in genes, and thus are called “heritable.” All of these diseases are directly related to mutations in genes that are responsible for building tissues. Alterations in these genes may change the structure and development of skin, bones, joints, the heart, blood vessels, lungs, eyes, and ears. Some mutations also change how these tissues work.

Some other connective tissue problems are not directly linked to mutations in tissue-building genes, although some people may be genetically predisposed to becoming affected. Many, but not all, of the disorders discussed in this publication are rare. See the box "Some Common Heritable Disorders of Connective Tissue".

Some Common Heritable Disorders of Connective Tissue

Physicians and scientists have identified more than 200 heritable connective tissue disorders. Some of the more common ones are listed below. Some of these are really groups of disorders and may be known by other names.

Ehlers-Danlos syndrome. The problems present in the group of disorders known as Ehlers-Danlos syndrome (EDS) include changes in the physical properties of skin, joints, blood vessels, and other tissues such as ligaments and tendons. People with Ehlers-Danlos syndrome have some degree of joint looseness; fragile, small blood vessels; abnormal scar formation and wound healing; and soft, velvety skin that stretches excessively but returns to normal after being pulled. Some forms can cause problems with the eyes and spine. Ehlers-Danlos syndrome can also lead to weak internal organs, including the uterus, intestines, and large blood vessels. Mutations in several different genes are responsible for varying symptoms in the several types of Ehlers-Danlos syndrome. In most cases, the genetic defect involves collagen, the major protein-building material of bone.

Epidermolysis bullosa. The characteristic feature of epidermolysis bullosa (EB) is blistering of the skin, which results when skin layers separate after minor trauma. People with a mild form of the disease may have just a few blisters on skin, whereas others may have many blisters. In some forms, blisters may form in the mouth, stomach, esophagus, bladder, and other parts of the body. Epidermolysis bullosa can be both disabling and disfiguring, and some forms may lead to early death. Defects in several proteins within the skin are at fault.

Marfan syndrome. People with Marfan syndrome tend to have a tall, thin build with long arms and legs and “spider-like” fingers. Other problems include a sideways curve of the spine (scoliosis); crowded teeth; flat feet; abnormal position of the lens of the eye; and enlargement of the beginning part of the aorta, the major vessel carrying blood away from the heart. If left untreated, an enlarged aorta can lead to hemorrhage and even death. Marfan syndrome results from mutations in the gene that determines the structure of fibrillin-1, a protein important to connective tissue.

Osteogenesis imperfecta. Osteogenesis imperfecta (OI) is characterized by fragile bones, low muscle mass, and loose joints and ligaments. There are several identified types of osteogenesis imperfecta, ranging in severity from mild to lethal. The appearance of people with osteogenesis imperfecta varies considerably, depending on the particular form they have and its severity. Some may have a blue or gray tint to the sclera (whites of the eyes), thin skin, growth deficiencies, and fragile teeth. They may develop scoliosis, respiratory problems, and hearing loss. Also known as “brittle bone disease,” this disorder is caused by a mutation in one of several genes that play a role in how the body makes collagen, the main component of connective tissue.

What Is Connective Tissue and What Does Heritable Disorders Mean?

Connective tissue is the material between the cells of the body that gives tissues form and strength. This “cellular glue” is also involved in delivering nutrients to the tissue, and in the special functioning of certain tissues. Connective tissue is made up of dozens of proteins, including collagens, proteoglycans, and glycoproteins. The combination of these proteins can vary between tissues.

The genes that encode these proteins can harbor defects or mutations, which can affect the functioning of certain properties of connective tissue in selected tissues. When this occurs, the result can be a heritable disorder—one that can be inherited, or passed from parent to child—of connective tissue.

How Do People Get Gene Alterations?

People with heritable disorders of connective tissue inherit an altered gene either from one or from both parents. We have two copies of most genes: one inherited from each parent. Males have one copy of each gene on the X chromosome, because they have only one X chromosome, and one copy of each gene on the Y chromosome. In contrast, females have two copies of X chromosome genes because they have two X chromosomes.

Some genetic disorders require that only a single copy of a gene be altered. These disorders can be seen in many generations of a family because the altered copy of the gene is passed from parent to child (dominant inheritance). The same disorder can occur in a person without a family history of the condition if there is a new mutation in the right gene at conception. Some disorders are seen only when the person has received an altered copy of the gene from each parent (recessive inheritance); in these families, the person with only a single copy is called a “carrier” and is not actually affected.

If a mutation occurs on an X chromosome, it generally produces a condition in which the pattern of affected individuals in a family is unusual. Often, women are carriers (that is, they have only a single altered copy of the gene), but males show the condition because they do not have a second protective copy of the gene. Such a condition is referred to as “X-linked.”

Who Gets Heritable Disorders of Connective Tissue?

Heritable disorders of connective tissue can affect people of all ethnic groups. All ages, and both sexes are affected. Many of these disorders are rare. Some may not be evident at birth, but only appear after a certain age or after exposure to a particular environmental stress.

Does Anything Increase the Chances of Having a Genetic Disease?

Several factors increase the likelihood that a person will inherit an alteration in a gene. If you are concerned about your risk—or the risk to your children or future children—you should talk to your health care provider or a genetic counselor.

The following factors may increase the chance of getting or passing on a genetic disease:

  • parents who have a genetic disease
  • a family history of a genetic disease
  • parents who are closely related or part of a distinct ethnic or geographic community
  • parents who do not show disease symptoms, but “carry” a disease gene in their genetic makeup (this can be discovered through genetic testing).

How Does Genetic Counseling Help?

People seek genetic counseling to make better decisions about their lives and families. Because genetic counselors understand how genetic disorders are passed on through families, they can help couples estimate the risks of having children with genetic diseases. They can also tell parents about tests to determine if they are carrying certain altered genes, tests for newborns who may have inherited certain altered genes, and tests that can be done in early pregnancy to determine if a fetus either carries an altered copy of a gene or is affected with a disorder. The information derived from all these studies can facilitate family planning.

Your health care team can help you find genetic counseling if you wish to better understand your or your child’s disease or risk of disease.

What Are the Symptoms of a Heritable Disorder of Connective Tissue?

The symptoms are different for different disorders. Some of them cause bone growth problems. People with bone growth disorders may have brittle bones or bones that are too long or too short. Some cause people to be unusually tall (Marfan syndrome) or short (chondrodysplasias, osteogenesis imperfecta), or to have head and facial structure malformations (Apert syndrome, Pfeiffer syndrome). In others, joints may be stiff or immobile (fibrodysplasia ossificans progressiva or FOP).

Some disorders affect the skin. For example, Ehlers-Danlos syndrome results in stretchy or loose skin, while in another connective tissue disorder, cutis laxa, deficient elastic fibers cause the skin to hang in folds. Epidermolysis bullosa results in blistered skin.

Other tissues can be affected as well. Pseudoxanthoma elasticum (PXE) causes skin, eye, and heart problems, and closed-off or blocked blood vessels. Marfan syndrome and some forms of Ehlers-Danlos syndrome lead to weak blood vessels.

It is critical for people with these disorders and their family members to work closely with their health care teams to get a proper diagnosis and the best treatment. Symptoms of heritable disorders of connective tissue are extremely variable, and some disorders can pose severe health risks even when affected individuals have no symptoms.

How Do Doctors Diagnose Heritable Disorders of Connective Tissue?

Diagnosis always rests first on a combination of family history, medical history, and physical examination. Because many of these conditions are uncommon, the family physician may suspect a diagnosis but be uncertain about how to confirm it. At this point, referral to experienced clinicians, often medical geneticists, can be extremely valuable to either confirm or exclude the suspected diagnosis. Laboratory tests are available to confirm the diagnosis for many heritable disorders of connective tissue, but not for all. Once a diagnosis is made, laboratory studies may be available to provide some or all of the following:

  • Prenatal testing to identify an affected fetus and assist in family planning.
  • Newborn screening to spot a condition that may become evident later in life.
  • Carrier testing to identify adults who, without symptoms, carry a genetic mutation for a disease.
  • Predictive testing to spot people at risk for developing a genetic connective tissue disease later in life. These tests are helpful for diseases that run in the family.

What Treatments Are Available?

The term heritable disorders of connective tissue refers to a wide range of disorders, each requiring a specific program for management and treatment. In most instances, regular monitoring is important to assess, for example, the diameter of the aorta in people with Marfan syndrome, the extent of scoliosis (spine curvature) in people with osteogenesis imperfecta and those with some forms of Ehlers-Danlos syndrome, and whether there is protrusion of the spine into the base of the skull in people with osteogenesis imperfecta. For some conditions, specific metabolic treatment is useful, for example, vitamin B6 in people with homocystinuria, a metabolic disorder resulting from a liver enzyme deficiency. In others, drugs like beta-blockers are useful for slowing the dilation of the aorta, and bone-building drugs called bisphosphonates may be help strengthen fragile bones. Maintaining general health though a nutritious diet, exercise, and healthy lifestyle habits is also important for people with all heritable disorders of connective tissue.

What Research Is Being Conducted on Heritable Disorders of Connective Tissue?

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 U.S. 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 heritable disorders of connective tissue. The 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:

  • The NIAMS is conducting an indepth natural history study of people who have Marfan syndrome (which leads to abnormally long bones), nail-patella syndrome or NPS (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 heritable disorders of connective tissue 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 heritable disorders of connective tissue and exploring ways, including mindfulness-based stress reduction, to ameliorate it.
    • Looking at some specific musculoskeletal complications of aging in patients with heritable disorders of connective tissue, 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 recessive dystrophic epidermolysis bullosa 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 with recessive dystrophic epidermolysis bullosa 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 recessive dystrophic epidermolysis bullosa.
  • The 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.
  • The 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 recombinant growth hormone (rGH) therapy to promote height increases and bone density. In some cases, recombinant growth hormone is being used in combination with medications known as bisphosphonates.
  • The 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 (Apert 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 heritable disorders of connective tissue. The 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 NIH 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 NIH National Heart, Lung, and Blood Institute is now under way to further evaluate the use of losartan in people with Marfan syndrome.
  • At the NIH 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 NIH National Eye Institute are comparing different antiangiogenic compounds (drugs that inhibit blood vessel formation) for pseudoxanthoma elasticum. New antiangiogenic agents are also in development.
  • Scientists at the NIH National Institute of Dental and Craniofacial Research are carrying out clinical studies on fibrous dysplasia of bone.

More information on research is available from the following websites:

  • NIH Clinical Research Trials and You was designed to help people learn more about clinical trials, why they matter, and how to participate. Visitors to the website will find information about the basics of participating in a clinical trial, first-hand stories from actual clinical trial volunteers, explanations from researchers, and links to how to search for a trial or enroll in a research-matching program.
  • ClinicalTrials.gov offers up-to-date information for locating federally and privately supported clinical trials for a wide range of diseases and conditions.
  • NIH RePORTER is an electronic tool that allows users to search a repository of both intramural and extramural NIH-funded research projects from the past 25 years and access publications (since 1985) and patents resulting from NIH funding.
  • PubMed is a free service of the U.S. National Library of Medicine that lets you search millions of journal citations and abstracts in the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and preclinical sciences.

Where Can People Find More Information About Heritable Disorders of Connective Tissue ?

People with heritable disorders of connective tissue 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: NIAMSinfo@mail.nih.gov
Website: http://www.niams.nih.gov

Other Resources

American Academy of Orthopaedic Surgeons

Website: http://www.aaos.org

American Academy of Dermatology

Website: http://www.aad.org

Coalition for Heritable Disorders of Connective Tissue

Website: http://www.chdct2.org

Genetic Alliance

Website: http://www.geneticalliance.org

National Organization for Rare Disorders

Website: http://www.rarediseases.org

National Society of Genetic Counselors

Website: http://www.nsgc.org

The Dystrophic Epidermolysis Bullosa Research Association of America, Inc.

Website: http://www.debra.org

Ehlers-Danlos National Foundation

Website: http://www.ednf.org/

National Association for Pseudoxanthoma Elasticum (NAPE)

Website: http://www.pxenape.org

National Marfan Foundation

Website: http://www.marfan.org

Osteogenesis Imperfecta Foundation

Website: http://www.oif.org

PXE International

Website: http://www.pxe.org

Key Words

Apert syndrome. One of a group of genetic disorders, called acrocephalosyndactyly, characterized by malformations of the skull, face, hands, and feet. Apert syndrome is an autosomal dominant trait due to a mutation in a gene called FGFR2 (fibroblast growth factor receptor 2).

Beta-blockers. A class of medications also known as beta-adrenergic blockers that affect the body’s response to certain nerve impulses. This, in turn, decreases the rate and force of the heart’s contractions, which lowers blood pressure and reduces the heart’s demand for oxygen. In addition to treating high blood pressure, beta-blockers may be used for angina, and to prevent heart attacks, migraine headaches, and glaucoma.

Carrier. A person who carries a gene for a recessive genetic disorder. The person has the potential to pass the disorder on to his or her child, but is not personally affected by the disorder.

Chondrodysplasias. Once referred to as dwarfism. A group of genetic disorders, often caused by a single gene variation that affects the structure or metabolism of the bone, cartilage, or connective tissue.

Collagen. The principal protein of the skin, bones, cartilage, tendons, and other connective tissues.

Cutis laxa. Latin for loose or lax skin, cutis laxa refers to an extremely rare connective tissue disorder in which the skin lacks elasticity and hangs in loose folds. Caused by underlying genetic defects in connective tissue structure, the disorder can also result in serious problems with vocal cords, bones, cartilage, blood vessels, and vital internal organs.

Dominant. A genetic trait (or genetically transmitted disorder) that is evident when only one copy of the gene for that trait is present. Most dominant traits are due to genes on the autosomes (nonsex chromosomes). They affect males and females equally.

Dural ectasia. An enlargement of the dura, a primary membrane of connective tissue that covers the spine and contains the spinal fluid. Common in people with Marfan syndrome, dural ectasia occurs mainly in the lower spine and can cause low back pain, abdominal pain, headaches, leg pain, and perineal pain and numbness.

Ehlers-Danlos syndrome (EDS). A heritable connective tissue disease characterized by easy bruising, joint laxity (the ability to bend beyond normal range of motion), lax skin, and tissue weakness.

Epidermolysis bullosa (EB). A potentially disabling, disfiguring, and sometimes lethal connective tissue disorder caused by defects of several proteins in the skin, resulting in skin blistering. Some forms of the disease may involve the gastrointestinal tract, the pulmonary system, muscles, or the bladder.

Fibrodysplasia ossificans progressiva (FOP). An extremely rare disorder in which a genetic mutation causes fibrous tissue such as muscles, tendons, and ligaments to ossify, or turn to bone, when damaged. The disease is also characterized by a deformity of the big toe.

Glycoprotein. An organic compound composed of a protein and a carbohydrate joined together. In the body, these compounds have many uses and comprise many of the proteins released by cells into the blood and other fluids.

Heritable. Capable of being transmitted from parent to child through genes.

Homocystinuria. A genetically transmitted disease in which an enzyme deficiency permits the buildup of the amino acid homocyteine. The result, if not treated, can be mental retardation, blood vessel disease, and atherosclerosis (hardening of the arteries).

Marfan syndrome. A heritable disorder of connective tissue resulting from mutations in the gene that specifies the genetic code for fibrillin-1, a protein important to connective tissue. The disorder is characterized by excessively long leg bones and long “spider-like” fingers. Other problems include skeletal malformations, abnormal position of the lens of the eye, and enlargement at the beginning part of the aorta, the major vessel carrying blood away from the heart. If left untreated, an enlarged aorta can lead to hemorrhage and even death.

Mutations. Changes in genes that can occur randomly or as a result of some factor in the environment.

Nail-patella syndrome (NPS). A rare genetic disorder that causes abnormalities of bones, joints, fingernails, and kidneys. Nail-patella syndrome is commonly characterized by absent or underdeveloped kneecaps and thumbnails. It is estimated to occur in one in 50,000 newborns.

Osteogenesis imperfecta. A condition that results from mutation in two genes that make type I collagen, a protein important to bones and teeth. These mutations cause the body to either make too little collagen or poor-quality collagen. The result includes bones that fracture easily, low muscle mass, and joints and ligaments that move beyond their intended range of motion.

Pfeiffer syndrome. Also called type V acrocephalosyndactyly, Pfeiffer syndrome is one of a group of genetic disorders characterized by malformations of the skull, face, hands, and feet. Like the more common Apert syndrome, Pfeiffer syndrome is caused by a mutation in the FGFR2 (fibroblast growth factor receptor 2) gene.

Proteoglycans. A class of glycoproteins that perform various functions and serve as the “filler” substance between the cells. An inability to break down proteoglycans is characteristic of a series of genetic disorders called mucopolysaccharidoses.

Pseudoxanthoma elasticum (PXE). A rare disorder of degeneration of the elastic fibers with tiny areas of calcification in the skin, the back of the eyes (retinae), and the blood vessels. Pseudoxanthoma elasticum typically causes skin abnormalities, eye abnormalities that can lead to blindness, atherosclerosis (hardening of the arteries), mitral valve prolapse, and fragile blood vessels that can lead to problems with circulation and abnormal bleeding into internal organs, including the bowel. Pseudoxanthoma elasticum is inherited either as an autosomal recessive or as an autosomal dominant trait.

Recessive. A genetic trait or disorder that is usually expressed when only two copies of a gene for that trait, one from each parent, are present.

Scoliosis. A lateral side-to-side curvature of the spine. In most cases the cause is not known, but it may be more common in people who have a family history of the condition. Treatment can include braces, physical therapy, and, in some cases, surgery.

Acknowledgments

The NIAMS gratefully acknowledges the assistance of the following individuals in the preparation and review of the original version of this booklet: Bernadette Tyree, Ph.D., NIAMS/ NIH; Priscilla Ciccarielo, Director Emeritus, National Marfan Foundation, Port Washington, NY; Harry C. Dietz, M.D., Johns Hopkins University School of Medicine, Baltimore, MD; Carolyn Levering and Eileen Masciale, National Marfan Foundation ; Francisco Ramirez, M.D., Mount Sinai School of Medicine of the City University of New York, New York, NY; and Joel Rosenbloom, M.D., Ph.D., University of Pennsylvania, Philadelphia, PA.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. The NIAMS Information Clearinghouse is a public service sponsored by the NIAMS that provides health information and information sources. Additional information can be found on the NIAMS website at www.niams.nih.gov.

For Your Information

This publication contains information about medications used to treat the health condition discussed here. When this publication was developed, we included the most up-to-date (accurate) information available. Occasionally, new information on medication is released.

For updates and for any questions about any medications you are taking, please contact

U.S. Food and Drug Administration

Toll Free: 888–INFO–FDA (888–463–6332)
Website: http://www.fda.gov

For additional information on specific medications, visit Drugs@FDA at www.accessdata.fda.gov/scripts/cder/drugsatfda. Drugs@FDA is a searchable catalog of FDA-approved drug products.

This publication is not copyrighted. Readers are encouraged to duplicate and distribute as many copies as needed.

Additional copies of this publication are available from:

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: NIAMSinfo@mail.nih.gov
Website: http://www.niams.nih.gov

NIH Publication No.: 13-7843

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