A Proposed Convergent Genetic and Molecular Framework for Legg–Calvé–Perthes Disease: A Scoping Review

Legg–Calvé–Perthes disease (LCPD) is a rare pediatric disorder characterized by avascular osteonecrosis of the femoral head. Its pathogenesis is multifactorial, and genetic, epigenetic, vascular, and inflammatory mechanisms may contribute to disease susceptibility and progression. To map and characterize the available evidence on genetic and epigenetic factors and molecular pathways associated with LCPD, with particular emphasis on potential interactions and convergence across biological pathways. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR, PRISMA 2020 for Abstracts checklist). PubMed/MEDLINE was searched for studies published between March 2006 and March 2026. Relevant genetic, epigenetic, and molecular findings were extracted and synthesized according to biological pathways. See the PRISMA 2020 for Abstracts checklist. Seventeen genes and 25 single-nucleotide variants (SNVs), as reported in the included literature, were identified and grouped into three major biological axes: hypercoagulability, inflammation, and bone metabolism and remodeling. Associations with LCPD were reported in at least one study for F5 rs6025, MTHFR rs1801133, IL6 rs1800795, IL23R rs1569922, NOS3 rs1799983 and rs2070744, and OPG rs2073618. Epigenetic mechanisms, including DNA methylation and microRNA dysregulation, were also reported. Interpretation was limited by methodological heterogeneity, small study populations, limited functional validation, and a predominance of observational studies. Accumulating evidence suggests that thrombotic, inflammatory, bone remodeling, and epigenetic mechanisms contribute to LCPD susceptibility and pathogenesis. Our findings point to a potential biological convergence among these pathways; however, whether this convergence stems from a shared genetic architecture remains to be fully elucidated. LCPD pathogenesis involves a complex interplay of coagulation, inflammation, bone remodeling, and epigenetic pathways. While these mechanisms suggest biological convergence, their precise shared genetic architecture remains uncertain. Consequently, future studies utilizing independent replication and functional validation are critically needed.