Diagnostic Yield of Genetic Disorders in Children with Hip Dysplasia Mimicking Bilateral Legg-Calvé-Perthes Disease

Background: Pathogenic variants in genes that cause skeletal dysplasias may, instead of producing classic findings, present in children with a phenotype whose hip radiographs resemble bilateral Legg-Calvé-Perthes disease (LCPD). Objectives: This study aims to investigate the efficacy of genetic diagnosis in children with waddling gait or joint pain and radiological evidence of hip dysplasia mimicking bilateral LCPD. Methods: Forty children with bilateral femoral head dysplasia from 36 families were included in the study. Exome sequencing was performed, and all identified variants were confirmed within the families by Sanger sequencing. Results: Twelve pathogenic or likely pathogenic variants were identified: six in COL2A1, two in COL9A1, and one each in RPL13, EIF2AK3, DNAJC21, and ARSK; six are novel. The diagnostic yield was 33.3% (12/36) in 12 families. Additionally, variants of uncertain significance (VUS), proposed as causative, were detected in five families (5/36:13.9%): two in COL11A1 and one each in COL9A3, COL11A2, and ARSK. Based on bilateral epiphyseal dysplasia of the femoral head, it was observed that seven families may be compatible with mild spondyloepiphyseal dysplasia and six families may have Stickler syndrome. Notably, among these, three children carrying closely localized pathogenic/likely pathogenic variants in COL2A1 shared a novel phenotype characterized by short stature and bilateral irregular femoral heads. In four families, EIF2AK3, DNAJC21, and ARSK were also responsible for the ultra-rare disorders Wolcott-Rallison syndrome, bone marrow failure syndrome 3, and mucopolysaccharidosis 10, respectively. Conclusions: This study, for the first time, investigated the frequency of associated genes in a pediatric cohort with bilateral hip dysplasia resembling LCPD, providing important information for pathogenesis and differential diagnosis.