Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia

Abstract

Skeletal dysplasias are difficult to diagnose for the nonexpert. In a previous study of patients with multiple epiphyseal dysplasia (MED), we identified cartilage oligomeric matrix protein (COMP) mutations in only 36% of cases and suspected that the low-mutation detection rate was partially due to misdiagnosis. We therefore instituted a clinical-radiographic review system, whereby all cases were evaluated by a panel of skeletal dysplasia experts (European Skeletal Dysplasia Network). Only those patients in whom the diagnosis of MED was confirmed by the panel were screened for mutations. Under this regimen the mutation detection rate increased to 81%. When clinical-radiological diagnostic criteria were relaxed the mutation rate dropped to 67%. We conclude that expert clinical-radiological review can significantly enhance mutation detection rates and should be part of any diagnostic mutation screening protocol for skeletal dysplasias.

Figure 1

Radiographs of a case diagnosed as ‘classical’ MED by the expert panel (ESDN-00080, 11 years old). The patient complained of joint pain and had mild-short stature. An Arg718Trp mutation in COMP was identified in this patient. Note small and irregular epiphyses in the knees, and flattening and irregular shape of the femoral heads.

Figure 2

Radiographs of a case diagnosed as a possible ‘MED variant’ by the expert panel (ESDN-00049, 16 years). The small size and irregular shape of the femoral head, and the flattened appearance of the femoral and tibial condyles are consistent with the post-pubertal changes seen in MED. The slender appearance of the long bones was not considered typical of MED. An Asp385Asn mutation in COMP was identified in this patient.

Figure 3

ESDN-00050: affected mother and son. Mother, 33 years, 1.68 m, two hip replacements. Radiographs show small and irregular femoral head (a), flattened appearance of the femoral and tibial condyles (b), slightly irregular vertebral bodies (c). Son 2.5 years, growing along the third centile. Radiograph shows slightly small femoral heads (d).

Figure 4

ESDN-00160: 50-year-old female who has suffered from painful knees and elbows since childhood. She has short stature (150 cm) and genu vara. Her father and six of her 12 siblings reportedly have short stature and varying degrees of hip and knee abnormalities. An affected sister had bilateral knee replacement at age 40. Radiographs show small but well-preserved femoral heads and flattened and irregularly shaped femoral condyles.

Figure 5

ESDN-00196: 4-year-old boy, normal height (98.5 cm). Radiographs show very small and irregular femoral heads and broad femoral necks, irregularly shaped epiphyses in the knee and a normal spine.