Epiphyseal Dysplasia, Multiple, 5

A number sign (#) is used with this entry because multiple epiphyseal dysplasia-5 (EDM5) is caused by heterozygous mutation in the matrilin-3 gene (MATN3; 602109) on chromosome 2p24.

Clinical Features

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.

Molecular Genetics

In the family originally described by Mortier et al. (2001) with MED, Chapman et al. (2001) identified mutations in the MATN3 gene (602109.0001-602109.0002). The 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 mutations (see 602109.0004) 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.