Multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia is a disorder of cartilage and bone development primarily affecting the ends of the long bones in the arms and legs (epiphyses). There are two types of multiple epiphyseal dysplasia, which can be distinguished by their pattern of inheritance. Both the dominant and recessive types have relatively mild signs and symptoms, including joint pain that most commonly affects the hips and knees, early-onset arthritis, and a waddling walk. Although some people with multiple epiphyseal dysplasia have mild short stature as adults, most are of normal height. The majority of individuals are diagnosed during childhood; however, some mild cases may not be diagnosed until adulthood.

Recessive multiple epiphyseal dysplasia is distinguished from the dominant type by malformations of the hands, feet, and knees and abnormal curvature of the spine (scoliosis). About 50 percent of individuals with recessive multiple epiphyseal dysplasia are born with at least one abnormal feature, including an inward- and upward-turning foot (clubfoot), an opening in the roof of the mouth (cleft palate), an unusual curving of the fingers or toes (clinodactyly), or ear swelling. An abnormality of the kneecap called a double-layered patella is also relatively common.

The incidence of dominant multiple epiphyseal dysplasia is estimated to be at least 1 in 10,000 newborns. The incidence of recessive multiple epiphyseal dysplasia is unknown. Both forms of this disorder may actually be more common because some people with mild symptoms are never diagnosed.

Mutations in the COMP, COL9A1, COL9A2, COL9A3, or MATN3 gene can cause dominant multiple epiphyseal dysplasia. These genes provide instructions for making proteins that are found in the spaces between cartilage-forming cells (chondrocytes). These proteins interact with each other and play an important role in cartilage and bone formation. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears.

The majority of individuals with dominant multiple epiphyseal dysplasia have mutations in the COMP gene. About 10 percent of affected individuals have mutations in the MATN3 gene. Mutations in the COMP or MATN3 gene prevent the release of the proteins produced from these genes into the spaces between the chondrocytes. The absence of these proteins leads to the formation of abnormal cartilage, which can cause the skeletal problems characteristic of dominant multiple epiphyseal dysplasia.

The COL9A1, COL9A2, and COL9A3 genes provide instructions for making a protein called type IX collagen. Collagens are a family of proteins that strengthen and support connective tissues, such as skin, bone, cartilage, tendons, and ligaments. Mutations in the COL9A1, COL9A2, or COL9A3 gene are found in less than five percent of individuals with dominant multiple epiphyseal dysplasia. It is not known how mutations in these genes cause the signs and symptoms of this disorder. Research suggests that mutations in these genes may cause type IX collagen to accumulate inside the cell or interact abnormally with other cartilage components.

Some people with dominant multiple epiphyseal dysplasia do not have a mutation in the COMP, COL9A1, COL9A2, COL9A3, or MATN3 gene. In these cases, the cause of the condition is unknown.

Mutations in the SLC26A2 gene cause recessive multiple epiphyseal dysplasia. This gene provides instructions for making a protein that is essential for the normal development of cartilage and for its conversion to bone. Mutations in the SLC26A2 gene alter the structure of developing cartilage, preventing bones from forming properly and resulting in the skeletal problems characteristic of recessive multiple epiphyseal dysplasia.

Genetic Testing Information

• Genetic Testing Registry: Epiphyseal dysplasia, multiple, 2
• Genetic Testing Registry: Epiphyseal dysplasia, multiple, 3
• Genetic Testing Registry: Epiphyseal dysplasia, multiple, 6
• Genetic Testing Registry: Multiple epiphyseal dysplasia type 1
• Genetic Testing Registry: Multiple epiphyseal dysplasia type 4
• Genetic Testing Registry: Multiple epiphyseal dysplasia type 5

Genetic and Rare Diseases Information Center

• Multiple epiphyseal dysplasia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• COLLAGEN, TYPE IX, ALPHA-1; COL9A1
• EPIPHYSEAL DYSPLASIA, MULTIPLE, 1; EDM1
• EPIPHYSEAL DYSPLASIA, MULTIPLE, 4; EDM4
• EPIPHYSEAL DYSPLASIA, MULTIPLE, 3; EDM3
• EPIPHYSEAL DYSPLASIA, MULTIPLE, 2; EDM2
• EPIPHYSEAL DYSPLASIA, MULTIPLE, 5; EDM5

Scientific Articles on PubMed

• PubMed

• Ballhausen D, Bonafe L, Terhal P, Unger SL, Bellus G, Classen M, Hamel BC, Spranger J, Zabel B, Cohn DH, Cole WG, Hecht JT, Superti-Furga A. Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W. J Med Genet. 2003 Jan;40(1):65-71. doi: 10.1136/jmg.40.1.65. No abstract available. Citation on PubMed or Free article on PubMed Central
• Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002 May;19(5):465-78. doi: 10.1002/humu.10066. Citation on PubMed
• Briggs MD, Wright MJ, Mortier GR. Multiple Epiphyseal Dysplasia, Autosomal Dominant. 2003 Jan 8 [updated 2019 Apr 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1123/ Citation on PubMed
• Jackson GC, Marcus-Soekarman D, Stolte-Dijkstra I, Verrips A, Taylor JA, Briggs MD. Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy. Am J Med Genet A. 2010 Apr;152A(4):863-9. doi: 10.1002/ajmg.a.33240. Citation on PubMed or Free article on PubMed Central
• Lachman RS, Krakow D, Cohn DH, Rimoin DL. MED, COMP, multilayered and NEIN: an overview of multiple epiphyseal dysplasia. Pediatr Radiol. 2005 Feb;35(2):116-23. doi: 10.1007/s00247-004-1323-4. Epub 2004 Oct 21. Citation on PubMed
• Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001 Mar;17(3):159-71. doi: 10.1002/humu.1. Erratum In: Hum Mutat 2001;18(1):82. Citation on PubMed
• Seo SG, Song HR, Kim HW, Yoo WJ, Shim JS, Chung CY, Park MS, Oh CW, Jeong C, Song KS, Kim OH, Park SS, Choi IH, Cho TJ. Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study. BMC Musculoskelet Disord. 2014 Mar 15;15:84. doi: 10.1186/1471-2474-15-84. Citation on PubMed or Free article on PubMed Central
• Superti-Furga A, Neumann L, Riebel T, Eich G, Steinmann B, Spranger J, Kunze J. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. J Med Genet. 1999 Aug;36(8):621-4. Citation on PubMed or Free article on PubMed Central
• Unger S, Hecht JT. Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments. Am J Med Genet. 2001 Winter;106(4):244-50. Citation on PubMed
• Unger S, Superti-Furga A. SLC26A2-Related Multiple Epiphyseal Dysplasia. 2002 Aug 29 [updated 2023 Jan 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1306/ Citation on PubMed