NORD gratefully acknowledges Robert P. Stanton, MD, FACS, Department of Orthopedics, Nemours Children's Clinic, and R. Curtis Rogers, MD, Senior Clinical Geneticist, Greenwood Genetic Center-Greenville Office, for assistance in the preparation of this report.
The specific signs and symptoms of these disorders can vary from one person to another, even among those with the same subtype. Onset is usually in early childhood. Pain in the hips and knees following exercise is usually the initial sign of these disorders. Affected children may fatigue easily. Some affected children develop a waddling manner of walking (abnormal gait). Growth deficiency occurs in childhood and some children may be short for their age (mild to moderate short stature). Adult height is usually normal, but in the shorter range. An individual’s arms and legs may be short in comparison to the torso, which can become apparent during childhood. These growth features may be mild and difficult to appreciate.
Some young children may exhibit low muscle tone and reduced muscle strength (muscular hypotonia), knee and finger joints that stretch farther than normal (hypermobility), and restricted movement of the elbows.
Affected individuals also experience early onset of inflammation, pain and stiffness in affected joints (early-onset arthritis) that can develop into chronic joint pain (arthralgia). Joint problems can begin as early as 5 or 6 years of age, but is more likely to occur in the 30s. Multiple joints may be affected, particularly in adolescents. The knees and hips are commonly affected and deformation of the hips may occur. Joint pain is usually worse after physical exercise. Pain and loss of motion in the shoulders may occur in adulthood. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures). In severe cases, progressive joint damage can potentially result in significant disability and the need for joint replacement in the 30s or 40s.
In rare cases, additional symptoms may occur including a hip deformity in which the thigh bone is angled toward the center of the body (cox vara), bowed legs (genu varum), and ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are apart. Another rare finding, known as a double-layered or double patella, may be associated with certain forms of dominant multiple epiphyseal dysplasia. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee.
Dominant multiple epiphyseal dysplasia is caused by a mutation in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, many organ systems of the body can be affected.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Dominant multiple epiphyseal dysplasia type 1 is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. The majority of cases (more than 70%) of multiple epiphyseal dysplasia are caused by mutations in the COMP gene. Investigators have determined that the gene is located on the short arm (p) of chromosome 19 (19p13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
Dominant multiple epiphyseal dysplasia type 2 is caused by mutations in the collagen type IX alpha-2 (COL9A2) gene. The gene is located on the short arm of chromosome 1 (1p34.2).
Dominant multiple epiphyseal dysplasia type 3 is caused by mutations in the collagen type IX alpha-3 (COL9A3) gene. The gene is located on the long arm 20q13.33.
Dominant multiple epiphyseal dysplasia type 5 gene is caused by mutations in the matrilin 3 (MATN3) gene. The gene is located on the short arm of chromosome 2 (2p24.1).
Dominant multiple epiphyseal dysplasia type 6 is caused by mutations in the collagen type IX alpha-1 (COL9A1) gene. The gene is located on the long arm of chromosome 6 (6q13).
The COMP and MATN3 genes create (encode) proteins that are found in the extracellular matrix, which is a network of tissue that provides support to cells. The proteins encoded by these genes are found in the part of the extracellular matrix surrounding cells that make up the ligaments or tendons, as well as nearby cartilage-forming cells known as chondrocytes. The exact functions of these proteins are not fully understood.
The COL9A2, COL9A3, and COL9A1 genes create (encode) various parts of type IX collagen, a protein that is essential to the development and strengthening of connective tissue. Connective tissue, which is the material between cells of the body, is made up of collagen of which there are several different varieties found in the body. Type IX collagen is an important part of cartilage.
Researchers have determined that the progression and severity of dominant multiple epiphyseal dysplasia may vary based upon the gene involved and the specific mutation present in a gene as well as the specific location of the mutation in the gene. This is known as genotype-phenotype correlation. For example, the three genes associated with type IX collagen are more likely to have severe joint involvement with the knees, while the hips are spared or only mildly affected. MATN3 mutations are associated with hip abnormalities that are more severe than those seen in individuals with a COL9A2 mutation, but less severe than those seen in individuals in a COMP mutation. Significant involvement of the head of the thigh bone (femoral epiphysis) is more likely with COMP mutations than other mutations. Researchers are studying these disorders to further understand the specific genotype-phenotype correlations.
Although five different genes known to cause dominant multiple epiphyseal dysplasia, many cases cannot be linked to any of these genes suggesting that additional, as-yet-unidentified genes may also cause the disorder. The known genes are estimated to account for less than half of the overall cases of this disorder.
Dominant multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence and prevalence is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult. Dominant multiple epiphyseal dysplasia type 1 accounts for approximately 70% of cases. Gene alterations of MATN3 are seen in roughly 20% of molecularly diagnosed cases and alterations of the three different COL9 genes account for another 10%.
A diagnosis of dominant multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.
Clinical Testing and Workup
Basic x-rays (radiographs) can help to establish a diagnosis by revealing abnormal epiphyses and other characteristic skeletal findings.
Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the specific genes known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories.
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating skeletal disorders (orthopedists and orthopedic surgeons), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Physical therapy in a pool (hydrotherapy) can be beneficial for individuals with arthritis. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.
In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgical procedures may be recommended to treat abnormalities of the knee.
A registry for skeletal dysplasias has been set up at the University of California Los Angeles. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, contact:
International Skeletal Dysplasia Registry
615 Charles E. Young Drive, South RM 410
Los Angeles CA 90095-7358
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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