Abstract
BACKGROUND: 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). OBJECTIVES: To summarize the clinical characteristics of PSACH/EDM1 and variants of COMP gene, as well as to explore the correlations between them. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.