Multiple epiphyseal dysplasia

This is part of Rare diseases.

Diagnosis: Multiple epiphyseal dysplasia

Synonyms: MED


Date of publication: 2011-03-14
Version: 2.0

ICD 10 code


The disease

Multiple epiphyseal dysplasia (MED) is a hereditary, congenital skeletal disorder characterised by impaired growth at the ends of the long bones (the epiphyseal growth zones), short stature and progressive degeneration of joints and proximal skeletal areas (osteoarthritis). It belongs to the osteochondrodysplasia group of disorders (osteo = bone, chondro = cartilage, dysplasia = abnormal growth). A relatively mild form of the disease was first described in 1937 by Swedish radiologist Seved Ribbing and a more severe form in 1959 by another Swedish radiologist, Per Ödman.

In skeletal dysplasias, deformities of the skeleton become more pronounced when the individual grows and becomes heavier. Some affect the whole skeleton while others mainly affect particular areas, like the ends of the long bones or growth zones (the metaphysis). Abnormalities can affect bone, cartilege or connective tissue. Commonly, people with skeletal dysplasias are of short stature.

More than 200 inherited skeletal dysplasias are currently recognised. In the Swedish Board of Health and Welfare’s database of rare diseases there is information on other skeletal dysplasias including achondroplasia, diastrophic dysplasia, congenital spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, pseudoachondroplasia and late-onset spondyloepiphyseal dysplasia. Skeletal dysplasias are a complicated group of disorders in terms of both diagnosis and treatment. It is important that the diagnosis received by people with skeletal dysplasias is correct as it affects prognosis, treatment and information on inheritance patterns.


The prevalence of multiple epiphyseal dysplasia is approximately 5 cases per 100,000. In Sweden about 150 individuals have been diagnosed, but it is likely that many others affected by the disorder have not been diagnosed.


The disorder is caused by a mutation in one of the genes essential for the development and normal functioning of the intercellular constituent of cartilage. These mutations inhibit the development of articular cartilage and underlying bone, which in turn causes deterioration of the cartilage and a thickening of bone in its proximity, resulting in early onset osteoarthritis.

The dominant inherited forms (see under “Heredity”) are caused by mutations in five genes. The most common mutation (approximately 80 per cent of cases) is the COMP gene, which controls the production of (codes for) the cartilage oligomeric matrix protein and is located on chromosome 19 (19p13.1). Others are COL9A1, COL9A2, COL9A3, which control the production of the cartilage-specific protein, collagen 9. They are located on chromosome 6 (6q13), 1 (1p32.2-33) and 20 (20q13.3). The fifth chromosome is MATN3, which codes for the matrilin-3 protein, and is located on chromosome 2 (2p23-24). The less common, recessive form of the disease is caused by mutations on the SLC26A2 (DTDST) gene, located on chromosome 5 (5q32-33.1).


The inheritance pattern of multiple epiphyseal dysplasia is usually autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disorder and do not pass it down.

Figure: Autosomal dominant inheritance

There is also a less common form of the disease, where the inheritance pattern is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


Generally, children affected by the disease experience joint problems from infancy. This usually starts with pain in the knees followed by pain in the hips, especially after physical exertion. It may also make it difficult to rise from a sitting position, bend the knees, or walk long distances. Joint problems usually worsen with age. It is also common that people with the disease are of short stature and have small hands and feet.

Beside pains in the joints, children who have the recessive form of the disease may also have malformations of hands and feet (club foot), and knees with a double-layered patella.

The progression and severity of the disease vary greatly between families and individuals within the same family. Around the age of thirty, changes associated with arthrosis may cause stiffness, pain and reduced joint mobility. Knee joints are particularly affected and may lock, causing pain. With age other joints are affected, particularly hip, ankle, shoulder, hand and finger joints. The progression of the disease and wear and tear on the joints also affects muscles, with increasing muscle wastage (atrophy) resulting in muscle fatigue and eventually in brittle bones (osteoporosis). The spine usually remains unaffected until middle age, and then becomes curved (scoliosis).

In affected families, women often have a more severe form of the disorder than men. Most women over the age of 35 have had some symptoms requiring surgery on joints (arthroplasty) or an arthroscopy. Arthroscopy is a microsurgery technique used to examine and treat damage to the interior of joints.


Diagnosis is based on personal and family medical history and skeletal X-rays. X-ray examinations of children with the recessive form of the disease show that slightly more than 50 per cent have a double patella (kneecap), a characteristic of this form of the disease.

Using MRI (Magnetic Resonance Imaging) examinations it is possible to identify and assess degeneration of the joints caused by arthrosis before it can be seen in an ordinary X-ray. DNA-based diagnostics can confirm the diagnosis in over 80 per cent of affected families. If the mutation is known in the family pre-natal diagnosis, and frequently pre-implantation embryo diagnosis, are possible.

When the diagnosis is made, the family should be offered genetic counselling.


There is currently no cure for multiple epiphyseal dysplasia, but much can be done to relieve symptoms, correct bone malformations, alleviate other complications and help to compensate for functional limitations. Joint pain can be helped with medication.

Families with children with the disease require early contact with a paediatric orthopaedic surgeon and a habilitation team. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs.

It is important that the individual does not become overweight as this can overload the joints and cause further damage. Swimming and water gymnastics are a good way to exercise without damaging the joints.

Different forms of treatment and intervention need to be co-ordinated to achieve the best results. Orthopaedic surgery is often needed to minimise joint deformation and maintain mobility. It is sometimes necessary to replace a damaged joint, such as the hip joint, with a prosthesis.

Adults with the disease need ongoing contact with an orthopaedic surgeon, an occupational therapist, a physiotherapist, and sometimes also with adult habilitation services. Mobility is often a problem, and a wheelchair is sometimes required. To prevent hand injuries resulting from excess strain, it is often beneficial to use an electric wheelchair. Special orthopaedic shoes can also be of great help.

Training in how to relieve pressure on joints and prevent injuries can be provided by occupational therapists and physiotherapists. When pregnant, women with the disorder should be in touch with specialist maternity care services.

Occupational guidance can sometimes be needed, as well as adjustments to the work environment. The Public Employment Service and the Swedish Social Insurance Agency can provide information and support.

Practical advice


National and regional resources in Sweden

The diagnosis is made at the paediatric clinics of Swedish regional hospitals. If the diagnosis is inconclusive, investigations can be carried out at the National Centre for Skeletal Dysplasias, located at Uppsala University Children’s Hospital where the Swedish Centre for Deformities and Syndromes is also located. The Centre offers diagnostic services and assistance for both adults and children.

The skeletal dysplasia team at the Astrid Lindgren Children’s Hospital has wide experience of monitoring children and young people with skeletal dysplasia. The team consists of representatives from the following specialisms: respiratory physiology, neurosurgery, neuroradiology, skeletal radiology, paediatric orthopaedics, paediatric endocrinology, physiotherapy, urinary incontinence therapy and clinical genetics. Contacts are research nurse, Lo Neumeyer, tel: +46 8 517 775 81, and chief physician Lars Hagenäs, Astrid Lindgren’s Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Resource personnel

Professor Nils Dalén, Orthopaedic Clinic, Danderyds Hospital AB, SE-182 88 Stockholm, Sweden. Tel: +46 8 655 50 00.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se.

Courses, exchanges of experience for personnel


Research and development (R&D)

DNA-based research into multiple epiphyseal dysplasia is proceeding at the Department of Clinical Genetics at Uppsala University Children’s Hospital.


Ballhausen D, Bonafe L, Terhal P, Unger SL, Bellus G, Classen M et al. Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W. J Med Genet 2003; 40: 65-71.

Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia. Mutation review, molecular interactions and genotype to phenotype correlations. Hum Mutat 2002; 19: 465-478.

Dahlqvist J, Örlén H, Matsson H, Dahl N, Lönnerholm T, Gustavson K-H. Multiple epiphyseal dysplasia. A clinical and genetic study of 12 cases in a Swedish 6-generation family. Acta Orthop 2009; 80: 711-715.

Fairbank T. Dysplasia epiphysialis multiplex. Br J of Surg 1947; 34: 225-232.

Itoh T, Shirahama S, Nakashima E, Maeda K, Haga N, Kitoh H et al. Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population. Am J Med Genet A 2006; 140: 1280-1284.

Jakkula E, Makitie O, Czarny-Ratacjzak M, Jackson GC, Damignani R, Susic M et al. Mutations in the known genes are not the major cause of MED. J Med Genet 2003; 40: 65-71.

Jakkula E, Makitie O, Czarny-Ratacjak M, Jackson GC, Damignani R, Susic M et al. Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. Europ J Hum Genet 2005; 13: 292-301.

Lachman RS, Krakow D, Cohn D, Rimoin DL. MED, COMP, multilayered and NEIN: an overview of multiple epiphyseal dysplasia. Pediatr Radiol 2005; 35: 116-123.

Lohmander S. Många vägar leder till artros. Kunskapen om riskfaktorer och sjukdomsmekanismer ökar snabbt. Läkartidningen 2002; 99: 4480-4483.

Lohmander S. Forskning, framsteg och kontroverser kring artros. Läkartidningen 2002; 99: 4720-4722.

Loughlin J. Genetic epidemiology of primary osteoarthritis. Curr Opin Rheumatol 2001; 13: 111-116.

Petersson I. Läkemedel komplement till annan smärtlindring vid artros. Läkartidningen 2002; 99: 4647-4650.

Ribbing S. Stüdien über hereditäre, multiple Epiphysenstörungen. Acta Radiol 1937; Suppl. 34: 7-107.

Ryd L. Utmärkta resultat efter artroskirurgi. Artroplastik och osteotomi ger både smärtfrihet och god ledfunktion. Läkartidningen 2002; 99: 4651-4653.

Unger S, Hecht JT. Pseudoachondroplasia and multiple epiphyseal dysplasia: new etiologic development. Am J Med Genet 2001; 106: 244-250.

Zankl A, Jackson GC, Crettol LM, Taylor J, Elles R, Mortier GR et al. Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. Eur J Hum Genet 2007; 15: 150-154.

Ödman P. Hereditary enchondral dysostosis: twelve cases in three generations mainly with peripheral location. Acta Radiol 1959; 52: 97-113.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: epiphyseal dysplasia

GeneReviews (University of Washington)
www.genetests.org (klicka på GeneReviews, sedan Titles)
Sökord: multiple epiphyseal dysplasia, dominant och multiple epiphyseal dysplasia, recessive

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert Professor Karl-Henrik Gustavson, Uppsala University Hospital, wrote the draft of this information material.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2011-03-14
Version: 2.0
Publication date of the Swedish version: 2010-11-23

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.