Abstract
Dominantly inherited mutations in COMP gene encoding cartilage oligomeric matrix protein may cause two dwarfing skeletal dysplasias, milder multiple epiphyseal dysplasia (MED) and more severe pseudoachondroplasia (PSACH). We studied the phenotype and X-rays of 11 patients from 5 unrelated families with different COMP mutations. Whole exome and/or Sangers sequencing were used for molecular analyses. Four to ten X-ray images of hands hips, knees or spine were available for each patient for retrospective analyses. Eight patients with MED have mutation c.1220G>A and 3 children with PSACH mutations c.1359C>A, c.1336G>A, or the novel mutation c.1126G>T in COMP. Progressive failure in growth developed in all patients from early childhood and resulted in short stature < 3rd percentile in 7 patients and very short stature < 1st percentile in four. Most patients had joint pain since childhood, severe stiffness in shoulders and elbows but increased mobility in wrists. Six children had bowlegs and two had knock knees. In all patients, X-rays of hands, hips and knees showed progressive, age-dependent skeletal involvement more pronounced in the epiphyses of long rather than short tubular bones. Anterior elongation and biconvex configuration of vertebral bodies were more conspicuous for kids. Six children had correction of knees and two adults had hip replacement. Skeletal and joint impairment in patients with MED and PSACH due to COMP mutation start in early childhood. Although the clinical severity is mutation and age dependent, many symptoms represent a continuous phenotypic spectrum between both diseases. Most patients may benefit from orthopaedic surgeries.
Highlights
Cartilage oligomeric matrix protein (COMP) encoded by COMP gene and synthesized by chondrocytes, is the multifunctional extracellular matrix calcium-binding glycoprotein involved in the enhancement of chondrocyte attachment, proliferation and cartilage production, maintenance, and homeostasis (Hecht et al, 2005; Merritt et al, 2006; Briggs et al, 2014; Posey et al, 2019)
Mutations in COMP may cause two different types of severe short-limb dwarfism with autosomal dominant inheritance pattern affecting especially the epiphyses of long bones including multiple epiphyseal dysplasia (MED/EDM1, MIM132400) and pseudoachondroplasia (PSACH, MIM177170), but an overlap between both disorders was described as a part of a continuous phenotypic spectrum ( Jackson et al, 2012; Spranger et al, 2012)
Molecular analyses in 8 patients with MED/EDM1 from families A and B revealed a dominantly inherited mutation c.1220G>A (p.Cys407Tyr) in COMP gene
Summary
Cartilage oligomeric matrix protein (COMP) encoded by COMP gene and synthesized by chondrocytes, is the multifunctional extracellular matrix calcium-binding glycoprotein involved in the enhancement of chondrocyte attachment, proliferation and cartilage production, maintenance, and homeostasis (Hecht et al, 2005; Merritt et al, 2006; Briggs et al, 2014; Posey et al, 2019). Mutations in COMP may cause two different types of severe short-limb dwarfism with autosomal dominant inheritance pattern affecting especially the epiphyses of long bones including multiple epiphyseal dysplasia (MED/EDM1, MIM132400) and pseudoachondroplasia (PSACH, MIM177170), but an overlap between both disorders was described as a part of a continuous phenotypic spectrum ( Jackson et al, 2012; Spranger et al, 2012). In our study we analysed the clinical course of the disease and available X-rays in 11 patients from 5 unrelated families with MED/EDM1 or PSACH due to different heterozygous mutations in COMP gene including c.1220G>A, c.1359C>A, c.1336G>A, and a novel mutation c.1126G>T
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