Autosomal Dominant Multiple Epiphyseal Dysplasia

Disease Overview

Autosomal dominant multiple epiphyseal dysplasia (MED) is a group of rare genetic conditions that affect how bones grow, especially at the ends of long bones like those in the arms and legs. These rounded ends are called epiphyses, and they are important for healthy joint movement. In MED, these parts of the bones don’t develop properly, leading to joint problems and pain.

Symptoms usually begin in early childhood. Children may complain of pain in their hips or knees after physical activity and they might get tired more easily when walking long distances. Some children may develop a waddling walk. Over time, joint pain and stiffness usually get worse. This can lead to early-onset osteoarthritis, especially in large joints like the hips and knees that bear most of the body’s weight.

People with autosomal dominant MED often have limbs that are shorter in proportion to their torso. Adult height is usually slightly below average or in the lower part of the normal range.

Autosomal dominant MED is caused by changes (variants) in certain genes that are involved in building cartilage and bone. There are currently five known genes linked to this condition: COL9A1, COL9A2, COL9A3, COMP, and MATN3.

Based on the affected gene the subtypes include:

• Multiple Epiphyseal Dysplasia Type 1 (EDM1) caused by variants in the COMP gene
• Multiple Epiphyseal Dysplasia Type 2 (EDM2) caused by variants in the COL9A2 gene
• Multiple Epiphyseal Dysplasia Type 3 (EDM3) caused by variants in the COL9A3 gene
• Multiple Epiphyseal Dysplasia Type 5 (EDM5) caused by variants in the MATN3 gene
• Multiple Epiphyseal Dysplasia Type 6 (EDM6) caused by variants in the COL9A1 gene

Inheritance is autosomal dominant, which means only one copy of the changed gene is needed to have the condition.

Diagnosis can be made based on symptoms, a physical exam and X-rays that show how the bones are growing. A genetic test can confirm the diagnosis by identifying the known autosomal dominant MED-related genes.

There is no cure for autosomal dominant MED, but treatment can help manage symptoms and improve quality of life.

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Synonyms

• autosomal dominant MED
• AD-MED
• dMED
• AD EDM
• dominant multiple epiphyseal dysplasia

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Subdivisions

• multiple epiphyseal dysplasia type 1 (EDM1)
• multiple epiphyseal dysplasia type 2 (EDM2)
• multiple epiphyseal dysplasia type 3 (EDM3)
• multiple epiphyseal dysplasia type 5 (EDM5)
• multiple epiphyseal dysplasia type 6 (EDM6)

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Signs & Symptoms

Autosomal dominant multiple epiphyseal dysplasia (MED) varies from person to person and includes a spectrum of severity from early-onset joint pain, joint deformity and short stature to milder forms of MED that remain undiagnosed or are misdiagnosed.

The earliest symptom in children is usually pain in the hips and/or knees after exercise. Affected children get tired easily after walking long distances. A waddling gait may be present and can signal issues with hip or leg alignment.

Commonly reported signs and symptoms may include:

• Short stature starting in childhood with some children being shorter than their peers, however, many reach a normal adult height, just at the shorter end of the range
• Shorter arms and legs where the arms and legs may appear shorter than the torso and this typically becomes more noticeable as a child grows

• Joint and muscles issues that may include:
  • Inflammation and stiffness in the joints, especially the hips and knees, that can begin as early as age 5 or 6 and may get worse with age
  • Early-onset arthritis with many people developing joint wear and tear (osteoarthritis) in their 30s or even earlier
  • Persistent joint pain (arthralgia) particularly in the hips, knees and sometimes shoulders that can become a long-term issue
  • Muscle weakness and low muscular tone (muscular hypotonia), making movement harder
  • Joint flexibility and tightness with some children having loose joints in their fingers and knees (hypermobility) but limited motion in the elbows
  • Joint deformity that can occur over time due to joint damage leading to changes in joint shape or limited movement. In severe cases, surgery or joint replacement may be needed as early as a person’s 30s or 40s.

Less common features may include:

• Hip deformity (coxa vara) where, in rare cases, the top of the thigh bone angles inward more than normal
• Bowed legs (genu varum) or knock knees (genu valgum) where the legs may curve outward or inward, affecting walking and alignment
• Double patella (double kneecap), a very rare finding where the kneecap has two bony layers with cartilage in between. This may not cause symptoms but in some people, it leads to knee pain, frequent dislocations and trouble moving the knee.

Autosomal dominant MED symptoms can vary depending on the specific gene involved (genotype-phenotype correlation):

• COMP gene: Variants in this gene tend to cause more severe hip involvement and irregular hip sockets. Some forms may be milder depending on the exact variant.
• COL9A1, COL9A2, COL9A3 genes (type IX collagen): Variants in these genes usually cause more severe problems in the knees but hips are less affected.
• MATN3 gene: Variants in this gene often causes similar knee issues to type IX collagen-related forms but with slightly more hip involvement. Symptoms can vary widely even within the same family due to genetic or environmental factors.

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Causes

Dominant multiple epiphyseal dysplasia is caused by a variant in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, many organ systems of the body can be affected.

• Dominant multiple epiphyseal dysplasia type 1 is caused by variants in the cartilage oligomeric matrix protein (COMP) gene.
  • Most cases (more than 70%) of multiple epiphyseal dysplasia are caused by variants in the COMP
• Dominant multiple epiphyseal dysplasia type 2 is caused by variants in the collagen type IX alpha-2 (COL9A2) gene.
• Dominant multiple epiphyseal dysplasia type 3 is caused by variants in the collagen type IX alpha-3 (COL9A3) gene.
• Dominant multiple epiphyseal dysplasia type 5 is caused by variants in the matrilin 3 (MATN3) gene.
• Dominant multiple epiphyseal dysplasia type 6 is caused by variants in the collagen type IX alpha-1 (COL9A1) gene.

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 autosomal dominant multiple epiphyseal dysplasia may vary based upon the gene involved and the specific variant present in a gene as well as the specific location of the variant in the gene. This is known as genotype-phenotype correlation, as commented in the signs and symptoms section.

For example, variants in the three genes associated with type IX collagen are more likely to be associated with severe joint involvement with the knees, while the hips are spared or only mildly affected. MATN3 variants are associated with hip abnormalities that are more severe than those seen in individuals with a COL9A2 variant, but less severe than those seen in individuals in a COMP variant. Significant involvement of the head of the thigh bone (femoral epiphysis) is more likely with COMP variants than other variants. 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.

Inheritance

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

Autosomal dominant multiple epiphyseal dysplasia affects males and females in equal numbers. The prevalence of autosomal dominant MED is estimated to be at least one in 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of dominant multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis.

Skeletal dysplasias: This is a large group of conditions that affect the growth and development of bones and cartilage. There are more than 700 different types. Some are severe and cause life-threatening problems shortly after birth, while others may be milder and only affect growth or joint function. Some skeletal dysplasias cause short limbs or affect both the limbs and trunk, and each type can come with its own set of bone and joint changes.

Pseudoachondroplasia is another condition that can resemble MED. It causes delayed growth, a waddling walk, joint pain and progressive joint damage, particularly in the large joints like hips and knees. People with pseudoachondroplasia are typically shorter than average and have shortened arms and legs. They may also have loose joints and spine curvature (scoliosis). This condition is caused by variants in the same gene that causes a common type of MED, known as the COMP gene, but pseudoachondroplasia represents the more severe end of the spectrum.

Recessive multiple epiphyseal dysplasia (rMED), which is similar to dominant MED but inherited in an autosomal recessive pattern. People with rMED also have joint pain and bone malformations, especially in the hips, knees, hands and feet. Some may be born with conditions like clubfoot or mild spine curvature (scoliosis). A distinctive finding in about 60% of children with rMED is a “double-layered” kneecap (patella), which can be seen on X-rays before the skeleton finishes growing. There are two types of AR MED, one caused by variants in the SLC26A2 gene and also known as multiple epiphyseal dysplasia type 4. The second form is multiple epiphyseal dysplasia-7 (EDM7) which is caused by variants in the CANT1 gene.

Legg-Calvé-Perthes disease (LCPD) is very similar to AD MED, especially during childhood. LCPD affects the top of the thigh bone (called the femoral head) when the blood supply to the bone is interrupted. This leads to temporary bone death (avascular necrosis) followed by healing and new bone formation. Children with LCPD may have limp and hip or groin pain and may show delayed bone growth and reduced hip movement. LCPD usually affects boys between ages 3 and 15 and often involves just one hip, although both sides can be affected. X-ray findings in LCPD often show not just changes in the epiphysis but also the metaphysis and neck of the femur, which can help distinguish it from MED.

Meyer dysplasia also affects the femoral epiphyses and often begins around the age of two. It can cause hip pain and a limp, along with reduced motion and a waddling gait. Unlike MED, Meyer dysplasia is usually temporary, often resolving by age six as the bones mature. Because of this, it’s important to recognize Meyer dysplasia early so that children aren’t misdiagnosed with a more serious condition.

Spondyloepimetaphyseal dysplasia, Di Rocco type is caused by variants in the UFSP2 gene. This disorder is marked by short stature and abnormal growth at the spine, ends of bones (epiphyses) and middle sections of bones (metaphyses), which can mimic the skeletal findings seen in MED.

Spondyloepiphyseal dysplasia congenita is caused by variants in the COL2A1 gene and may also appear similar. People with this form of SED may have joint pain, short stature and X-ray findings that overlap with MED, making diagnosis more challenging.

Because these conditions can be very similar to MED, especially in childhood, genetic testing and detailed imaging studies are often needed to make the correct diagnosis.

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Diagnosis

Doctors may suspect autosomal dominant multiple epiphyseal dysplasia (MED) when a person shows a combination of the following:

• Compatible medical history including information about symptoms (like joint pain (especially in the hips or knees) and fatigue after physical activity in children, limited movements in major joints like the elbows and signs of early arthritis), family history and when symptoms began
• Physical examination showing short stature, joint stiffness or hypermobility and skeletal differences
• X-rays that show the characteristic bone changes associated with MED such as:

• • Delayed ossification in the epiphyses
  • Abnormally shaped epiphyses especially in the knees and hips
  • Shorter than average long bones
  • Increased density of the epiphyses in the hands (ivory epiphyses)
  • Abnormalities in the spine where some people may have small indentations of spinal discs into the bones (Schmorl bodies) and uneven bone edges in the spine (irregular vertebral end plates)
  • Arthritis changes in the joints in adults (but adult X-rays alone are often not enough to confirm MED, as the signs become harder to distinguish from other joint problems.)

Genetic testing identifying variants in any of the known genes that cause autosomal dominant MED can confirm the diagnosis.

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Standard Therapies

Treatment

Treatment for autosomal dominant MED focuses on managing symptoms, improving comfort and mobility and preventing complications. Since symptoms can vary from person to person, care is personalized.

People affected with autosomal dominant MED need to be cared for by several medical specialists that may include pediatricians, orthopedic doctors, surgeons, rheumatologists, physical therapists, pain management specialists, genetic counselors, mental health professionals and others. The different specialists should work together as a team in a coordinated way.

Pain can be one of the most challenging symptoms and the treatment may include pain medication, physical therapy, including pool-based therapy (hydrotherapy) which helps improve movement and reduce stiffness. Rheumatologists and pain specialists may be needed for more complex cases.

Surgery might be recommended if joint problems are causing pain or limiting movement:

• Osteotomy (repositioning bones) may help reduce strain and slow joint damage.
• Hip surgeries, including reshaping or even total hip replacement, may be needed if the hip joint becomes severely damaged.
• Knee surgery may also be considered if there are significant issues.

Living with chronic joint pain or short stature can affect mental health and day-to-day life. Support may include counseling for the affected person and family, help with school or work accommodation and support for managing disability or chronic pain.

People with ongoing pain or visible bone alignment issues like bowlegs (genu varum) or knock-knees (genu valgum), should see an orthopedic surgeon to regularly monitor changes and decide if treatment is needed.

To protect the joints and reduce stress on the body, people should be educated to maintain a healthy weight (as extra weight puts more pressure on the hips and knees) and avoid repetitive or high-impact activities that could strain the joints (like running or jumping sports).

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Clinical Trials and Studies

The International Skeletal Dysplasia Registry at the University of California Los Angeles contains information about individuals with skeletal dysplasias. This data may help researchers to increase the understanding of these conditions, expand the search for treatments and accelerate clinical trials into specific treatment options. For more information contact:

International Skeletal Dysplasia Registry, UCLA
https://www.uclahealth.org/departments/ortho/isdr/about-isdr

Information on current clinical trials is posted on the Internet at https://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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Mankin HJ, Mankin KP, eds. Multiple Epiphyseal Dysplasias. In: Rare Genetic Disorders that Affect the Skeleton. AuthorHouse, LLC, Bloomington, IN; 2013:88-95.

Jones KL, Jones MC, del Campo Casanelles, eds. Multiple Epiphyseal Dysplasia. In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:494-495.

JOURNAL ARTICLES
Unger S, Ferreira CR, Mortier GR & cols. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023 May;191(5):1164-1209. doi: 10.1002/ajmg.a.63132. Epub 2023 Feb 13. PMID: 36779427; PMCID: PMC10081954.

Seo SG, Song HR, Kim HW, et al. Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study. BMC Musculoskelet Disord. 2014;15:84. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984757/

Jackson GC, Mittaz-Cettrol L, Taylor JA, et al. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the know disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. 2012;33:144-157. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272220/

Kim OH, Park H, Seong MW, et al. Revisit of multiple epiphyseal: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes. Am J Med Genet A. 2011;155A:2669-2680. https://www.ncbi.nlm.nih.gov/pubmed/21965141

Dahlqvist J, Orlen H, Matsson H, et al. Multiple epiphyseal dysplasia. Acta Orthop. 2009;80:711-715. www.ncbi.nlm.nih.gov/pmc/articles/PMC2823319/

Nakashima E, Ikegawa S, Ohashi H, Kimizuka M, Nishimura G. Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation. Am J Med Genet A. 2005;133A-106-107. https://www.ncbi.nlm.nih.gov/pubmed/15633184/

Jakkula E, Makitie O, Czarny-Ratajczak M, et al. Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. Eur J Hum Genet. 2005;13:292-301. https://www.ncbi.nlm.nih.gov/pubmed/15523498

Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002;19:465-478. https://www.ncbi.nlm.nih.gov/pubmed/11968079/

Czarny-Ratajczak M, Lohiniva J, Rogala P, et al. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. 2001;69:969-980. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1274373/

INTERNET

Briggs MD, Wright MJ, Mortier GR. Multiple Epiphyseal Dysplasia, Autosomal Dominant. 2003 Jan 8 [Updated 2024 Jul 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1123/ Accessed May 20, 2025.

Multiple Epiphyseal Dysplasia. Orphanet. Available at: https://www.orpha.net/en/disease/detail/251 Accessed May 20, 2025.

Zanelli SA. Skeletal Dysplasias.Medscape Reference. December 13, 2023. Available at: https://emedicine.medscape.com/article/943343-overview Accessed May 20, 2025.

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Patient Organizations

Human Growth Foundation

Phone: 516-671-4041 Email: [email protected] Fax: 516-671-4055

Related Rare Diseases: Recessive Multiple Epiphyseal Dysplasia, Schimke Immuno-Osseous Dysplasia, Pseudoachondroplasia, ...

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Little People of America, Inc.

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Restricted Growth Association

Phone: 300-111-1970 Email: [email protected] Fax: 300-111-2454

Related Rare Diseases: Spondylothoracic Dysplasia, Recessive Multiple Epiphyseal Dysplasia, Pseudoachondroplasia, ...

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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