ORPHA: 166002; DO: 0070298;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Epiphyseal dysplasia, multiple, 2 | 600204 | Autosomal dominant | 3 | COL9A2 | 120260 |
A number sign (#) is used with this entry because multiple epiphyseal dysplasia-2 (EDM2) is caused by heterozygous mutation in the COL9A2 gene (120260) on chromosome 1p34.
Multiple epiphyseal dysplasia is a clinically and genetically heterogeneous skeletal disorder characterized by joint pain and stiffness, mild short stature, and degenerative joint disease. Onset of the disorder is usually in childhood (summary by Jackson et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of EDM, see EDM1 (132400).
Briggs et al. (1994) summarized the clinical findings in the family with multiple epiphyseal dysplasia (MED) originally reported by Barrie et al. (1958). Affected individuals typically presented at 2.5 to 6 years of age with pain in the knees. Knee and ankle pain was present throughout childhood. Bilateral osteotomies were required for gross varus deformities of the knees in some individuals. Hands were mildly short and joints prominent. There were no abnormalities of the spine or chest. Examination of x-rays revealed flattened, irregular epiphyses in most joints, particularly the knees. Childhood x-rays showed small epiphyses with a large physeal space. The vertebrae appeared normal in adulthood, but there were some anterior defects at earlier ages.
Fiedler et al. (2002) reported a 4-generation family in which 12 members had a relatively hip-sparing MED phenotype most consistent with EDM2. The disorder was characterized by childhood onset of pain and stiffness in the knees. Finger joints, ankles, and elbows became symptomatic during early adult life. Some adult patients had free articular bodies which resulted in locking of the joints. Electron microscopic studies showed that collagen fibrils from arthroscopically removed free articular bodies of 2 patients were not obviously different from normal articular cartilage.
Jackson et al. (2010) reported a large 4-generation family with autosomal dominant transmission of EDM2 confirmed by genetic analysis (120260.0001). The family had previously been reported by Versteylen et al. (1988). The proband was a 33-year-old woman with short stature who complained of stiff and painful hands and knees since age 4 years. Radiographs of the knees showed Blount disease (progressive varus deformity of the proximal tibia associated with internal torsion of the tibia), and of the spine showed mild spondyloarthrotic abnormalities in the thoracic region. Her sister had painful and swollen knees since age 4 years and developed severe osteochondritis dissecans as an adult. Two sons of the proband were also affected, showing pain in the knees during walking and clumsy walking. These boys also had frontal bossing, depressed nasal bridge, and were easily fatigued with mild muscle weakness. Radiographs of 1 son at age 3 years showed delayed ossification of the epiphyses, small proximal femoral epiphyses, and small femoral and tibial epiphyses around the knees. Skeletal muscle biopsy and mitochondrial studies showed no significant abnormalities, only mild variations in fiber size and slightly diminished ATP production. Jackson et al. (2010) also reported an individual from a second unrelated family with EDM2 characterized by onset at age 3 years of an abnormal gait associated with proximal muscle weakness. He had left-sided developmental dysplasia of the hip. The family history was positive for hypodontia and for osteochondritis dissecans. However, 2 affected adult family members showed improvement of the disorder after puberty. Jackson et al. (2010) commented on the mild myopathy present in some affected members of both families, and noted that EDM is characterized by clinical variability even within the same family. The mild myopathic and mitochondrial changes observed may be secondary to a tendinopathy and/or cell stress response resulting from expression of mutant collagen.
The transmission pattern of EDM2 in the family reported by Versteylen et al. (1988) was consistent with autosomal dominant inheritance.
Briggs et al. (1994) performed linkage studies with chromosome 19 markers in the family originally reported by Barrie et al. (1958) with autosomal dominant multiple epiphyseal dysplasia and demonstrated that the phenotype locus could not be in the region of chromosome 19 where the mutations in other families with multiple epiphyseal dysplasia (132400) and the mutation for pseudoachondroplastic dysplasia (177170), possibly allelic disorders, had been mapped. Further studies demonstrated that the form of MED in this family mapped to the short arm of chromosome 1 in a region containing the COL9A2 gene (120260) which encodes the alpha-2 chain of type IX collagen, a structural component of the cartilage extracellular matrix. Warman et al. (1994) mapped the COL9A2 gene to 1p33-p32 and to chromosome 4 of the mouse.
In a Dutch kindred with MED linked to DNA markers in the 1p32 region, Muragaki et al. (1996) demonstrated a mutation in the COL9A2 gene (120260.0001). The family had been reported previously by Versteylen et al. (1988).
In 12 affected members of a 4-generation family with a relatively hip-sparing MED phenotype most consistent with EDM2, Fiedler et al. (2002) identified a splice site mutation in the COL9A2 gene (120260.0005).
Nakashima et al. (2005) reported a Japanese family with EDM2 confirmed by genetic analysis (120260.0002). The proband had bilateral double-layered patellae, indicating that this unusual feature is not unique to autosomal recessive multiple epiphyseal dysplasia with homozygous mutations in the DTDST gene (606718; see EDM4 226900).
Barrie, H., Carter, C., Sutcliffe, J. Multiple epiphysial dysplasia. Brit. Med. J. 2: 133-137, 1958. [PubMed: 13560805] [Full Text: https://doi.org/10.1136/bmj.2.5089.133]
Briggs, M. D., Choi, H., Warman, M. L., Loughlin, J. A., Wordsworth, P., Sykes, B. C., Irven, C. M. M., Smith, M., Wynne-Davies, R., Lipson, M. H., Biesecker, L. G., Garber, A. P., Lachman, R., Olsen, B. R., Rimoin, D. L., Cohn, D. H. Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene. Am. J. Hum. Genet. 55: 678-684, 1994. [PubMed: 7942845]
Fiedler, J., Stove, J., Heber, F., Brenner, R. E. Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2). Am. J. Med. Genet. 112: 144-153, 2002. [PubMed: 12244547] [Full Text: https://doi.org/10.1002/ajmg.10554]
Jackson, G. C., Marcus-Soekarman, D., Stolte-Dijkstra, I., Verrips, A., Taylor, J. A., Briggs, M. D. 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. 152A: 863-869, 2010. [PubMed: 20358595] [Full Text: https://doi.org/10.1002/ajmg.a.33240]
Muragaki, Y., Mariman, E. C. M., van Beersum, S. E. C., Perala, M., van Mourik, J. B. A., Warman, M. L., Olsen, B. R., Hamel, B. C. J. A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nature Genet. 12: 103-105, 1996. [PubMed: 8528240] [Full Text: https://doi.org/10.1038/ng0196-103]
Nakashima, E., Ikegawa, S., Ohashi, H., Kimizuka, M., Nishimura, G. Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation. (Letter) Am. J. Med. Genet. 133A: 106-107, 2005. [PubMed: 15633184] [Full Text: https://doi.org/10.1002/ajmg.a.30481]
Versteylen, R. J., Zwemmer, A., Lorie, C. A. M., Schuur, K. H. Multiple epiphyseal dysplasia complicated by severe osteochondritis dissecans of the knee: incidence in two families. Skeletal Radiol. 17: 407-412, 1988. [PubMed: 3238439] [Full Text: https://doi.org/10.1007/BF00361659]
Warman, M. L., McCarthy, M. T., Perala, M., Vuorio, E., Knoll, J. H. M., McDaniels, C. N., Mayne, R., Beier, D. R., Olsen, B. R. The genes encoding alpha2 (IX) collagen (COL9A2) map to human chromosome 1p32.2-p33 and mouse chromosome 4. Genomics 23: 158-162, 1994. [PubMed: 7829066] [Full Text: https://doi.org/10.1006/geno.1994.1472]