Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia-1 (EDM1) are two rare skeletal diseases that represent distinct endpoints of a continuous phenotypic spectrum with substantial clinical overlap, caused by variants in the gene coding cartilage oligomeric matrix protein (COMP). To summarize the clinical characteristics of PSACH/EDM1 and variants of COMP gene, as well as to explore the correlations between them. PubMed, China National Knowledge Infrastructure, and Wanfang were searched for case reports and case series of patients with genetic diagnosis of PSACH/EDM1 from the inception to 24 March 2025. The clinical characteristics and gene variants of enrolled patients were analyzed and compared to explore genotype-phenotype correlation. A total of 830 PSACH/EDM1 patients (471probands) harboring 224 different variants of COMP gene were enrolled from 106 articles, with missense variants accounting for the majority (80.8%). Exon 13 (183 probands, 38.9%) and type III (T3) repeat domain (413 probands, 87.7%) were the most commonly affected regions, with c.1417_1419del (p.Asp473del) being the most common hotspot variant. Compared with EDM1, PSACH manifested earlier age of onset (p < 0.001), shorter stature (p < 0.001), higher rates of lower limb deformity (p < 0.001), joint laxity (p = 0.041), anterior beaking of the vertebra and irregular/flared metaphysis (p < 0.001), while lower rate of joint pain/osteoarthritis (p < 0.001) and abnormal femoral head (p = 0.008). Missense variants in T3-4 and T3-5 were more likely to cause EDM1 (all p < 0.001), while those in T3-1 and T3-6 to T3-8 were associated with a greater frequency of PSACH (p = 0.002 to 0.023). Majority of in-frame variants were found in PSACH, as c.1417_1419del (p.Asp473del) being PSACH specific. PSACH exhibits more severe phenotypes than EDM1, even with phenotypic overlap. In-frame variants are more strongly associated with PSACH, as the hotspot variant p.Asp473del exclusively identified in PSACH. In contrast, missense variants in T3-4 and T3-5 show a stronger association with EDM1.

The intracellular retention of misfolded extracellular matrix proteins is a common disease mechanism in various rare skeletal diseases. This discovery has driven the study of ER stress and the unfolded protein response (UPR) as a promising therapeutic target in several skeletal dysplasias. In the case of COL10A1 mutations, targeting the UPR resulted in a clinical trial of the repurposed drug carbamazepine; however, for other closely related skeletal disorders, treatment with carbamazepine was ineffective, indicating the need for suitable markers for in vitro screenings of potential drug treatments. Mutations in cartilage oligomeric matrix protein (COMP), a cartilage structural protein, cause both multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH); together referred to as the COMPopathies, which result from the intracellular retention of mutant COMP to varying degrees. In contrast to other closely related skeletal disorders, caused by mutations in cartilage structural proteins, the involvement of the UPR is less clear, and so far, no common COMPopathy marker has been identified. Here, using cell models of COMPopathies, we identified MMP9 upregulation as a common feature of six pathogenic COMP variants that do not induce a prominent UPR. We further show that the archetypal p.V194D matrilin-3 MED variant (which causes MED) does not induce MMP9 expression, suggesting that MMP9 upregulation could serve as a specific marker of COMPopathies in vitro.

Hyaline cartilage is essential for bone formation and joint function. It contains a dense extracellular matrix that is produced in the ER of chondrocytes. Therefore, the ER contains a complex machinery of enzymes including chaperones, glycosyltransferases and hydroxylases that control folding, modification and secretion of newly synthesized matrix proteins. Loss or malfunction of ER-resident chaperones and proteins leads to misfolding and accumulation of matrix proteins in the ER. This causes ER stress and disrupts crucial cellular processes including chondrocyte differentiation, signaling and matrix production. During skeletal development, deficiency of ER chaperones disrupts cartilage and bone formation by impairing the folding and maturation of collagens and other matrix proteins, causing chondrodysplasia, pseudoachondroplasia and other skeletal diseases. Loss of ER-resident chaperones also impairs the integrity and stability of the cartilage matrix, promoting its degeneration during osteoarthritis. Due to the complexity of the ER protein processing machinery, the specific roles of ER-resident proteins in cartilage and bone homeostasis largely remain elusive. This review provides an overview of the most common ER-resident proteins and our current understanding of their function in cartilage homeostasis and disease.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are rare, autosomal dominant skeletal dysplasias characterised by disproportionate short stature, joint deformities, and early-onset osteoarthritis. These conditions result from mutations in key cartilage extracellular matrix (ECM) components, including cartilage oligomeric matrix protein (COMP), matrilin-3, and type IX collagen. Although genetically and clinically heterogeneous, PSACH and MED share convergent pathogenic mechanisms. Misfolded mutant ECM proteins are retained within the endoplasmic reticulum (ER) of growth plate chondrocytes, triggering chronic ER stress and impairing chondrocyte proliferation, differentiation, and survival. Moreover, some of the mutant protein is secreted and incorporated into the matrix, leading to altered collagen fibrillogenesis, disrupted proteoglycan distribution, and compromised biomechanical integrity. These alterations extend beyond cartilage, impacting tendons, ligaments, and muscle-tendon junctions, contributing to joint laxity, impaired force transmission, and mild myopathy. This review discusses the structural and functional consequences of ECM disorganisation in PSACH and MED, highlighting its central role in disease progression and emphasising the importance of considering ECM abnormalities when developing therapeutic strategies for rare short stature-associated skeletal disorders.

Objective: To summarize the clinical and genetic characteristics of pseudoachondroplasia and multiple epiphyseal dysplasia caused by COMP gene variants in pediatric patients. Methods: This retrospective study concluded 15 pediatric patients with COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from July 2013 to August 2024. This paper analyzed clinical manifestations, laboratory findings and genetic testing. Results: This cohort comprised 15 pediatric patients (8 males and 7 females) with a diagnostic age of 5.3 (1.8,9.3) years. The major clinical presentations included abnormal gait (15/15), brachydactyly (11/15), genu varum (12/15), irregular metaphyseal changes (14/14) and epiphyseal dysplasia (14/14). Genetic analysis revealed 13 cases of pseudoachondroplasia and 2 multiple epiphyseal dysplasias cases associated with COMP gene variants. Fifteen variants were identified (8 pathogenic and 7 likely pathogenic), including 2 novel variants (c.1223A>G, c.1378G>C). Thirteen of these patients had variations clustered in exons 8-14 encoding the calmodulin-like domains, with c.1414_1419dupGACGAC emerging as a hotspot variant. Conclusions: COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia predominantly manifest with gait abnormalities and skeletal deformities. COMP gene pathogenic variations were mainly located in calmodulin-like domains. 目的： 总结COMP基因变异导致假性软骨发育不良和多发性骨骺发育不良患儿的临床与遗传学特点。 方法： 回顾性病例分析。收集2013年7月至2024年8月在上海交通大学医学院附属上海儿童医学中心就诊的15例COMP基因变异导致假性软骨发育不良和多发性骨骺发育不良患儿的临床资料，分析其临床表现、实验室检查及基因检测结果等。 结果： 15例患儿中男8例、女7例，诊断年龄为5.3（1.8，9.3）岁，主要表现包括步态异常（15/15）、短指（11/15）、膝内翻（12/15）、不规则的干骺端（14/14）及骨骺发育异常（14/14）等。15个COMP基因变异分别导致假性软骨发育不良13例和多发性骨骺发育不良2例，其中8个为“致病性变异”，7个为“可能致病性变异”，有2个新发现变异（c.1223A>G，c.1378G>C）。13例患儿变异位点处在8~14号外显子即钙调蛋白样结构域，热点变异位点为c.1414_1419dupGACGAC。 结论： COMP基因变异导致假性软骨发育不良和多发性骨骺发育不良的主要临床特征为步态异常和骨骼畸形，致病基因变异位点主要集中在钙调蛋白结构域。.