Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution

Abstract

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.

Figure 1

Exon distribution of COMP missense mutations in PSACH and MED. The cumulative distribution of COMP missense mutations from this study and that published by Kennedy et al. [2005a] is represented graphically. The total number of patients reported in these two studies is 86 (n = 35 PSACH; n = 51 MED) and these data clearly show that exons 10 and 11 are enriched for MED missense mutations, while missense mutations in exon 13 mostly cause PSACH. In these two studies, we identified no COMP missense mutations in exons 15 (aa 557–572), 17 (aa 639–696), and 19 (aa 743–757) and only a single MED missense mutation in exon 12.

Figure 2

Radiographic findings in COMP negative patients referred as PSACH. ESDN-00074: Radiographs of the spine, pelvis, knees, and left hand. With the exception of the left hand taken at 4 years of age, all radiographs were taken at the age of 3 years. The vertebral bodies are flattened, the proximal femoral epiphyses are small, and the femoral necks are short. The trochanters minor are well ossified and prominent present. The knee epiphyses are small and irregularly ossified. The metaphyses in the knees are widened and the femoral distal metaphyses have spikes at both ends. The submetaphyseal regions have a striated pattern. The hands show shortening and broadening of the metacarpals and phalanges with small epiphyses. The epiphyses of the proximal phalanges are fragmented. There is advanced carpal ossification with rather rectangular (and not rounded) shape of the carpal bones. The distal ulna shows precocious ossification of the epiphysis and cupped metaphysis. ESDN-00618: Radiographs of spine, pelvis, knee, and hand taken at the age of 6 months. The pelvis is abnormal with flat and trident acetabular roof and small and broad iliac wings. The ischiadic bones are broad. The proximal femoral epiphyses are well ossified for age. The femoral necks appear broad. The hand shows shortening of phalanges and metacarpals, especially the proximal and middle phalanges are very short with poor diaphyseal modeling and precocious ossification of the epiphyses that are attached to the metaphysis. The vertebral bodies are mildly foreshortened with posterior scalloping. No gross abnormalities are seen at the knee. ESDN-00695: Radiographs of spine, pelvis, knee, and hand taken at the age of 7 years. The mini-epiphyses in the hips and the small epiphyses in the knees with translucent submetaphyseal areas in the proximal tibia are reminiscent of PSACH. However, the hand shows only mild shortening of the phalanges and metacarpals. In addition, there is marked delay in carpal ossification. The epiphyses in the wrist and hands are too small for age. The vertebral bodies are flattened and elongated.

Figure 3

Radiographic findings in PSACH and MED patients with mutations identified in the EGF-like repeats of COMP. ESDN-00521: Radiographs taken at the age of 6 years. The proximal femoral epiphyses are small and flattened. The distal femoral and proximal tibial epiphyses are also small for age. There is no ossification yet of the proximal fibular epiphysis. The hand radiograph shows normal phalanges and metacarpals but delayed ossification of the carpal bones and epiphyses in the wrist. The spine is normal. ESDN-1040: The radiographs of pelvis and knee taken at the age of 6 years shows very small epiphyses in the hips and knees, which is reminiscent of pseudoachondroplasia. Note, also the two round translucent areas in the distal femoral metaphysis, which are often seen in patients with pseudoachondroplasia.

Figure 4

Localization of COMP mutations identified in PSACH and MED patients in this study. An amino acid sequence alignment of the type III repeats region of COMP, with the linker region and each of the seven T3 repeats (T3_1-7) shown with their corresponding residue numbers. Residues comprising the N-type and C-type motif are boxed and the consensus sequence of each motif is indicated below. Also shown on the alignment are the missense mutations that cause either MED (*), PSACH (^), or both (+) phenotypes. In-frame deletions are underlined.