Autosomal dominant multiple epiphyseal dysplasia (MED) presents early in childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.
The diagnosis of autosomal dominant MED is based on the clinical and radiographic findings in the proband and other family members. In the initial stage of the disorder, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is found on radiographs. With the appearance of the epiphyses, the ossification centers are small with irregular contours, usually most pronounced in the hips and/or knees. The tubular bones may be mildly shortened. By definition, the spine is normal, although Schmorl bodies and irregular vertebral end plates may be observed. Mutations in five genes are causative: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 10%-20% of all samples analyzed, a mutation cannot be identified in any of the five genes above, suggesting that mutations in other as-yet unidentified genes are also involved in the pathogenesis of dominant MED.
Dominant MED is inherited in an autosomal dominant manner. Many individuals with dominant MED have inherited the mutant allele from one parent. The prevalence of new gene mutations is not known. Each child of an individual with dominant MED has a 50% chance of inheriting the mutation. Prenatal diagnosis of pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member.