Alternative titles; symbols
SNOMEDCT: 715674008; ORPHA: 93311; DO: 0070299;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p24.1 | Epiphyseal dysplasia, multiple, 5 | 607078 | Autosomal dominant | 3 | MATN3 | 602109 |
A number sign (#) is used with this entry because of evidence that multiple epiphyseal dysplasia-5 (EDM5) is caused by heterozygous mutation in the matrilin-3 gene (MATN3; 602109) on chromosome 2p24.
Multiple epiphyseal dysplasia-5 (EDM5) is an autosomal dominant skeletal dysplasia characterized by mildly impaired or normal growth and signs of early-onset osteoarthritis. Onset is in early childhood with pain in hips, knees, and ankles. Epiphyses are small with irregular contours in multiple joints, with the distal femoral epiphyses being most severely affected. Most patients have severe involvement of both hips and knees. Severity varies considerably both within and between families (summary by Makitie et al., 2004).
Mortier et al. (2001) reported a 3-generation Belgian family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) characterized by easy fatigue and joint pain, mainly in the knees and hips, starting in early childhood; normal stature; and osteoarthrosis in early adulthood. Linkage analysis with microsatellite markers, which were either intragenic or closely linked, excluded linkage of the MED phenotype to previously identified autosomal dominant MED loci.
In the family studied by Chapman et al. (2001), originally described by Mortier et al. (2001), all affected individuals had normal birth length and adult height around the third percentile (150 to 165 cm). Most had complained of knee and hip pain after exercise from early childhood, and some of the affected individuals had had hip replacements or undergone knee surgery for deformities and early-onset osteoarthritis. Radiographs at or after the age of puberty showed a normal spine but persisting epiphyseal dysplasia, mainly of hips and knees. An affected individual carrying the arg121-to-trp mutation (602109.0002) presented at the age of 10 years with knee pain after exercise, genu valgum, and normal stature. Radiographs of the skeleton revealed normal spine and hands but predominant involvement of the epiphyses of the hips, knees, and ankles. On follow-up, the genu valgum had resolved spontaneously. Complaints of joint pain became less frequent and, surprisingly, knee and hip radiographs normalized by the age of 24 years. His affected father also experienced joint pain as a teenager with spontaneous improvement after puberty.
Elsbach (1959) described a 4-generation Delft family with what they called bilateral microepiphyseal dysplasia. Mostert et al. (2003) provided follow-up on this family. The index case had died before reevaluation but his affected younger brother was available for study. He had onset of hip and knee pain at age 4 years. He had hip replacement on the left side at age 28 and on the right side at age 37. He had a right knee replacement at age 43. Although he was the smallest in height among his peers in primary school, he eventually reached a height of 1.71 m (less than 15th centile for Dutch reference population). Clinical features of affected members included bilateral simultaneous onset of pain in hip and knee joints, short stature, waddling gait, and decreased range of motion of the hip. Radiographic findings included coxa valga, flattened femoral head, an unusual teardrop configuration of the medial acetabular wall, small epiphyses of the proximal and distal femur, and small epiphyses of the proximal tibia with or without flattened condyles of the knees.
Makitie et al. (2004) reviewed the clinical and radiographic features in 12 affected members from 7 families with autosomal dominant multiple epiphyseal dysplasia due to mutation in the MATN3 gene. They found a uniform pattern of skeletal anomalies in all patients with considerable degree of variability in severity, both between and within families. The characteristic clinical findings were onset of symptoms in early childhood with predominance of knee- and hip-related complaints, normal stature, and early-onset osteoarthritis. Radiographs showed small and irregular epiphyses and mild metaphyseal irregularities and striations, especially at the knees and hips, and mild spinal changes.
The transmission pattern of EDM5 in the families reported by Chapman et al. (2001) was consistent with autosomal dominant inheritance.
In the family originally described by Mortier et al. (2001) and in an unrelated family with MED, Chapman et al. (2001) identified heterozygous mutations in the MATN3 gene (602109.0001 and 602109.0002, respectively). Both mutations occurred within the single von Willebrand factor A (vWFA) domain.
In affected members of 7 families with MED, Jackson et al. (2004) identified 4 novel heterozygous mutations (see, e.g., 602109.0004; 602109.0008-602109.0009) and 1 recurrent mutation (R121W; 602109.0002) in the MATN3 gene. All of the disease-causing mutations were located within the beta sheet of the vWFA domain.
In all available affected members of the family with MED described by Elsbach (1959), Mostert et al. (2003) identified heterozygosity for a missense mutation (602109.0007) within the vWFA domain of the MATN3 gene.
Maeda et al. (2005) noted that previous reports regarding more than 18 families with MED indicated that MATN3 mutations in EDM5 are confined to exon 2, which encodes the vWFA domain. Maeda et al. (2005) reported a novel MATN3 mutation outside the vWFA domain (602109.0006) in a 38-year-old patient with MED. The man presented with bilateral hip pain at age 32 years. His height was 155 cm. Radiographic changes were found in the hips and hands. His mother and an elder sister had acetabular dysplasia.
Using targeted copy number variant screening, Pettersson et al. (2018) identified a de novo heterozygous tandem duplication of exons 2 to 5 in the MATN3 gene (602109.0010) in a girl with EDM5. Sequencing and breakpoint junction PCR indicated a tandem orientation, and the 10.4-kb duplication was shown to be Alu-mediated. The intragenic duplication was predicted to cause premature termination of the MATN3 protein, resulting in complete loss of the last 2 domains of the protein.
Chapman, K. L., Mortier, G. R., Chapman, K., Loughlin, J., Grant, M. E., Briggs, M. D. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nature Genet. 28: 393-396, 2001. [PubMed: 11479597] [Full Text: https://doi.org/10.1038/ng573]
Elsbach, L. Bilateral hereditary micro-epiphyseal dysplasia of the hips. J. Bone Joint Surg. Br. 41: 514-523, 1959. [PubMed: 13849708] [Full Text: https://doi.org/10.1302/0301-620X.41B3.514]
Jackson, G. C., Barker, F. S., Jakkula, E., Czarny-Ratajczak, M., Makitie, O., Cole, W. G., Wright, M. J., Smithson, S. F., Suri, M., Rogala, P., Mortier, G. R., Baldock, C., Wallace, A., Elles, R., Ala-Kokko, L., Briggs, M. D. Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J. Med. Genet. 41: 52-59, 2004. [PubMed: 14729835] [Full Text: https://doi.org/10.1136/jmg.2003.011429]
Maeda, K., Nakashima, E., Horikoshi, T., Mabuchi, A., Ikegawa, S. Mutation in the von Willebrand factor-A domain is not a prerequisite for the MATN3 mutation in multiple epiphyseal dysplasia. (Letter) Am. J. Med. Genet. 136A: 285-286, 2005. [PubMed: 15948199] [Full Text: https://doi.org/10.1002/ajmg.a.30832]
Makitie, O., Mortier, G. R., Czarny-Ratajczak, M., Wright, M. J., Suri, M., Rogala, P., Freund, M., Jackson, G. C., Jakkula, E., Ala-Kokko, L., Briggs, M. D., Cole, W. G. Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients. Am. J. Med. Genet. 125A: 278-284, 2004. [PubMed: 14994237] [Full Text: https://doi.org/10.1002/ajmg.a.20486]
Mortier, G. R., Chapman, K., Leroy, J. L., Briggs, M. D. Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. Europ. J. Hum. Genet. 9: 606-612, 2001. [PubMed: 11528506] [Full Text: https://doi.org/10.1038/sj.ejhg.5200690]
Mostert, A. K., Dijkstra, P. F., Jansen, B. R. H., van Horn, J. R., de Graaf, B., Heutink, P., Lindhout, D. Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up. Am. J. Med. Genet. 120A: 490-497, 2003. [PubMed: 12884427] [Full Text: https://doi.org/10.1002/ajmg.a.20034]
Pettersson, M., Vaz, R., Hammarsjo, A., Eisfeldt, J., Carvalho, C. M. B., Hofmeister, W., Tham, E., Horemuzova, E., Voss, U., Nishimura, G., Klintberg, B., Nordgren, A., Nilsson, D., Grigelioniene, G., Lindstrand, A. Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias. Hum. Mutat. 39: 1456-1467, 2018. [PubMed: 30080953] [Full Text: https://doi.org/10.1002/humu.23605]