Other entities represented in this entry:
ORPHA: 166002; DO: 0070304;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.33 | Epiphyseal dysplasia, multiple, 3, with or without myopathy | 600969 | Autosomal dominant | 3 | COL9A3 | 120270 |
A number sign (#) is used with this entry because of evidence that multiple epiphyseal dysplasia-3 (EDM3) is caused by heterozygous mutation in the COL9A3 gene (120270) on chromosome 20q13.
Multiple epiphyseal dysplasia is characterized by early-onset short stature, waddling gait, and stiffness and/or pain in the knees and sometimes other joints (Muragaki et al., 1996).
For a general phenotypic description and a discussion of genetic heterogeneity of multiple epiphyseal dysplasia, see EDM1 (132400).
Individuals with multiple epiphyseal dysplasia (MED) typically present during childhood and adolescence with waddling gait and stiffness and/or pain in the knees. Few patients experience involvement of other joints such as the elbow, wrist, or ankle. Some patients are mildly short statured and/or have stubby hands. Often patients do not seek medical advice because of the mildness of their complaints. X-rays show flattened, irregular epiphyses, varus or valgus deformity of the knees, and gradually appearing osteoarthritis with or without loose bodies. Precocious osteoarthritis of the hips often requires early hip replacement. Typically there are no spine abnormalities (Muragaki et al., 1996).
Clinical Variability
Bonnemann et al. (2000) reported a family with autosomal dominant EDM affecting predominantly the knee joints and a mild proximal myopathy. The proband was a 10-year-old boy referred for evaluation of proximal muscle weakness and mildly elevated serum creatine kinase. He walked at 1 year of age but at age 3 was noted to have difficulty walking and climbing stairs. He always had difficulty rising from the floor and sometimes used a one-handed Gowers maneuver. He tired easily, never ran well, and complained of knee pain. He had significant weakness of neck flexion, mild weakness of shoulder abduction and elbow extension, and proximal lower limb weakness (hamstrings weaker than quadriceps). By x-ray, the epiphyseal changes characteristic of MED were most marked in the knee joints, followed by the ankle joints. Affected family members likewise showed MED predominantly affecting the knee joints and sparing the hips. The proband's mother had weak neck flexors and minimal weakness of the proximal extremities. Bonnemann et al. (2000) suggested that patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
The transmission pattern of EDM3 in the family reported by Paassilta et al. (1999) was consistent with autosomal dominant inheritance.
In a large family with EDM, Paassilta et al. (1999) found an inheritance pattern consistent with linkage to the COL9A3 gene on chromosome 20q13.
In affected members of a large family with EDM3, Paassilta et al. (1999) identified a heterozygous mutation in the acceptor splice site of intron 2 of the COL9A3 gene (120270.0001).
In a 3-generation Japanese family with MED, Nakashima et al. (2005) identified a heterozygous donor splice site mutation in intron 2 of the COL9A3 gene (120270.0004). Affected members had knee pain ('occasional' in females) but were of normal height and had no signs or symptoms of muscle weakness. Nakashima et al. (2005) commented that these cases were milder than those reported by Paassilta et al. (1999).
In affected members of a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy, Bonnemann et al. (2000) detected a heterozygous splice acceptor mutation in intron 2 of the COL9A3 gene (120270.0002) that resulted in the skipping of exon 3. The authors suggested that the MED and mild myopathy was likely caused by a dominant-negative effect of this mutation.
Bonnemann, C. G., Cox, G. F., Shapiro, F., Wu, J.-J., Feener, C. A., Thompson, T. G., Anthony, D. C., Eyre, D. R., Darras, B. T., Kunkel, L. M. A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc. Nat. Acad. Sci. 97: 1212-1217, 2000. [PubMed: 10655510] [Full Text: https://doi.org/10.1073/pnas.97.3.1212]
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., Kitoh, H., Maeda, K., Haga, N., Kosaki, R., Mabuchi, A., Nishimura, G., Ohashi, H., Ikegawa, S. Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am. J. Med. Genet. 132A: 181-184, 2005. [PubMed: 15551337] [Full Text: https://doi.org/10.1002/ajmg.a.30411]
Paassilta, P., Lohiniva, J., Annunen, S., Bonaventure, J., Le Merrer, M., Pai, L., Ala-Kokko, L. COL9A3: a third locus for multiple epiphyseal dysplasia. Am. J. Hum. Genet. 64: 1036-1044, 1999. Note: Erratum: Am. J. Hum. Genet. 65: 1214 only, 1999. [PubMed: 10090888] [Full Text: https://doi.org/10.1086/302328]