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. Hum Mutat 33:144–157, 2012. © 2011 Wiley Periodicals, Inc.

Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients

“…Clinical Study I Flechtner and others Impact of skeletal dysplasia on growth ossification; and the pelvis for iliac wings, shortness of the femoral necks, and metaphyseal and epiphyseal anomalies (21,32,33,34). All radiographs were read by a panel of specialists including geneticists from the French reference center for skeletal dysplasia, radiologists, and pediatric endocrinologists.…”

Generalized Disorders and Syndromes of Orthopedic Importance

“…A double-layered patella is associated with, but not diagnostic of, a DTDST mutation (Fig. 23.62 ) [ 76 ]. The spine may be mildly abnormal in both COMP and MATN3 mutations.…”

“…The reported birth prevalence of MED is 9 per 100,000 [ 1 ]. MED is a clinically variable disease that manifests in early to mid-childhood with joint pain and stiffness, particularly involving the hips and knees; mild to moderate short stature; and earlyonset osteoarthritis [ 76 ]. Body proportions are normal, but fi ngers may be short.…”

Genetics for orthopaedics

“…AR MED is caused by mutations in the SLC26A2 gene (mutations in this gene also cause other skeletal dysplasias with severe phenotypes including diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB). 12 The diagnosis of AD MED is based on clinical (see above) and radiographic features. Radiological features include delayed ossification of epiphyses in long bones, which later become fragmented and irregular.…”