{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:52:50Z","timestamp":1791363170538,"version":"4.3.1"},"reference-count":88,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Legg\u2013Calv\u00e9\u2013Perthes 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.<\/jats:p>","DOI":"10.3390\/ijms27198890","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:28:57Z","timestamp":1791361737000},"page":"8890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Proposed Convergent Genetic and Molecular Framework for Legg\u2013Calv\u00e9\u2013Perthes Disease: A Scoping Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7511-4155","authenticated-orcid":false,"given":"Edgar","family":"Hern\u00e1ndez-Zamora","sequence":"first","affiliation":[{"name":"Genomic Medicine, Instituto Nacional de Rehabilitaci\u00f3n \u201cLuis Guillermo Ibarra Ibarra\u201d, Calzada M\u00e9xico-Xochimilco 289, Arenal de Guadalupe, Tlalpan, Mexico City 14389, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4447-8343","authenticated-orcid":false,"given":"Armando Odiseo","family":"Rodr\u00edguez-Olivas","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Universidad Aut\u00f3noma de Ciudad Ju\u00e1rez, Campus Cuauht\u00e9moc, Km. 3.5 Carretera An\u00e1huac s\/n, An\u00e1huac, Municipio de Cuauht\u00e9moc, Chihuahua 31600, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3411-6231","authenticated-orcid":false,"given":"Marlene Alejandra","family":"Galicia-Alvarado","sequence":"additional","affiliation":[{"name":"Neurociencias Cl\u00ednicas, Instituto Nacional de Rehabilitaci\u00f3n \u201cLuis Guillermo Ibarra Ibarra\u201d, Calzada M\u00e9xico-Xochimilco 289, Arenal de Guadalupe, Tlalpan, Mexico City 14389, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonora","family":"Casas-\u00c1vila","sequence":"additional","affiliation":[{"name":"Genomic Medicine, Instituto Nacional de Rehabilitaci\u00f3n \u201cLuis Guillermo Ibarra Ibarra\u201d, Calzada M\u00e9xico-Xochimilco 289, Arenal de Guadalupe, Tlalpan, Mexico City 14389, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-6484","authenticated-orcid":false,"given":"Elba","family":"Reyes-Maldonado","sequence":"additional","affiliation":[{"name":"Morphology Department, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala s\/n, Santo Tom\u00e1s, Gustavo A. Madero, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref_1","unstructured":"(2026, March 05). Worldometers. Current World Population. Available online: https:\/\/www.worldometers.info\/es\/poblacion-mundial\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13073-022-01026-w","article-title":"A guide for the diagnosis of rare and undiagnosed disease: Beyond the exome","volume":"14","author":"Marwaha","year":"2022","journal-title":"Genome Med."},{"key":"ref_3","unstructured":"(2026, March 05). RARE Facts\u2014Global Genes. Global Genes. Available online: https:\/\/globalgenes.org\/rare-disease-facts\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.drudis.2017.11.002","article-title":"Rare genetic diseases: Update on diagnosis, treatment and online resources","volume":"23","author":"Pogue","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrg.2017.101","article-title":"Genetic architecture: The shape of the genetic contribution to human traits and disease","volume":"19","author":"Timpson","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00223-020-00702-6","article-title":"The Genetic Epidemiology of Joint Shape and the Development of Osteoarthritis","volume":"109","author":"Wilkinson","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"946","DOI":"10.4045\/tidsskr.10.0456","article-title":"[Legg-Calv\u00e9-Perthes disease]","volume":"131","author":"Wiig","year":"2011","journal-title":"Tidsskr. Nor. Laegeforen."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1097\/BPO.0b013e318173ed54","article-title":"A histological and ultrastructural study of the iliac crest apophysis in Legg-Calve-Perthes disease","volume":"28","author":"Kitoh","year":"2008","journal-title":"J. Pediatr. Orthop."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.3928\/00904481-20160310-03","article-title":"Legg-Calv\u00e9-Perthes Disease","volume":"45","author":"Divi","year":"2016","journal-title":"Pediatr. Ann."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, D., Li, Y.N., Li, C.L., and Guo, W.L. (2025). Radiomics and deep learning model based on X-ray imaging for the assisted diagnosis of early Legg-Calv\u00e9-Perthes disease. BMC Musculoskelet. Disord., 26.","DOI":"10.1186\/s12891-025-09189-4"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.2106\/JBJS.M.01221","article-title":"Perfusion MRI in Early Stage of Legg-Calv\u00e9-Perthes Disease to Predict Lateral Pillar Involvement: A Preliminary Study","volume":"96","author":"Kim","year":"2014","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.2106\/JBJS.RVW.15.00063","article-title":"The Pathogenesis and Treatment of Legg-Calv\u00e9-Perthes Disease","volume":"4","author":"Ibrahim","year":"2016","journal-title":"JBJS Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00132-019-03737-2","article-title":"Perthes disease-news in diagnostics and treatment","volume":"48","author":"Westhoff","year":"2019","journal-title":"Orthopade"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13023-022-02275-z","article-title":"Legg-Calv\u00e9-Perthes disease overview","volume":"17","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/aje\/kwr293","article-title":"Racial and geographic factors in the incidence of Legg-Calv\u00e9-Perthes\u2019 disease: A systematic review","volume":"175","author":"Perry","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref_16","first-page":"504393","article-title":"The epidemiology and demographics of legg-calv\u00e9-perthes\u2019 disease","volume":"2011","author":"Loder","year":"2011","journal-title":"ISRN Orthop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1302\/0301-620X.98B5.36453","article-title":"The lognormal age of onset distribution in Perthes\u2019 disease: An analysis from a large well-defined cohort","volume":"98","author":"Perry","year":"2016","journal-title":"Bone Jt. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e178","DOI":"10.1097\/BPO.0000000000000819","article-title":"The Declining Incidence of Legg-Calve-Perthes\u2019 Disease in Northern Ireland: An Epidemiological Study","volume":"37","author":"Mullan","year":"2017","journal-title":"J. Pediatr. Orthop."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1177\/230949901302100230","article-title":"Legg-Calve-Perthes disease in two generations of male family members: A case report","volume":"21","year":"2013","journal-title":"J. Orthop. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00439-007-0354-y","article-title":"A recurrent mutation in type II collagen gene causes Legg-Calv\u00e9-Perthes disease in a Japanese family","volume":"121","author":"Miyamoto","year":"2007","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1002\/ccr3.3357","article-title":"Legg-Calv\u00e9-Perthes disease in a patient with Bardet-Biedl syndrome: A case report of a novel MKKS\/BBS6 mutation","volume":"8","author":"Mishima","year":"2020","journal-title":"Clin. Case Rep."},{"key":"ref_22","first-page":"68","article-title":"Buschke-Ollendorff syndrome in two generations imitated Calv\u00e9-Legg-Perthes disease","volume":"177","author":"Ali","year":"2015","journal-title":"Ugeskr. Laeg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1016\/j.jtha.2024.05.014","article-title":"The convergent model of coagulation","volume":"22","author":"Yong","year":"2024","journal-title":"J. Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zheng, X., Dong, Z., Ding, X., Huang, Q., Tang, S., Zhang, Y., Li, B., and Liao, S. (2025). Progress in understanding Legg-Calv\u00e9-Perthes disease etiology from a molecular and cellular biology perspective. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1514302"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Olivas, A.O., Reyes-Maldonado, E., Casas-\u00c1vila, L., Galicia-Alvarado, M.A., Rosales-Cruz, E., Zavala-Hern\u00e1ndez, C., and Hern\u00e1ndez-Zamora, E. (2025). Association of IL-23R rs1569922 and Other Probable Frequent Etiological Factors with Legg-Calv\u00e9-Perthes Disease in Mexican Patients. Genes, 16.","DOI":"10.3390\/genes16101126"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Alfaro, M.D., P\u00e9rez-Nu\u00f1ez, M.I., Amigo, M.T., Arbona, C., Ballesteros, M.\u00c1., and Gonz\u00e1lez-Lamu\u00f1o, D. (2021). PlA2 Polymorphism of Platelet Glycoprotein IIb\/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg-Calv\u00e9-Perthes Disease. Children, 8.","DOI":"10.3390\/children8070614"},{"key":"ref_27","first-page":"1","article-title":"Prothrombin Time and Coagulation Factor IX as Hemostatic Risk Markers for Legg-Calv\u00e9-Perthes Disease","volume":"29","year":"2023","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jor.22473","article-title":"Meta-analysis of hypercoagulability genetic polymorphisms in Perthes disease","volume":"32","author":"Woratanarat","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1097\/BPO.0b013e31815584bf","article-title":"Legg-Calve-Perthes disease, venous and arterial thrombi, and the factor V Leiden mutation in a four-generation kindred","volume":"27","author":"Glueck","year":"2007","journal-title":"J. Pediatr. Orthop."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"NP16","DOI":"10.1177\/1558944715627274","article-title":"Bilateral Legg-Calve-Perthes Disease and Kienbock\u2019s Disease in a Child with Factor V Leiden Thrombophilia: A Case Report","volume":"11","author":"Baltzer","year":"2016","journal-title":"Hand"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2106\/JBJS.I.00157","article-title":"Coagulation abnormalities in Legg-Calv\u00e9-Perthes disease","volume":"92","author":"Vosmaer","year":"2010","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1007\/s00431-015-2510-z","article-title":"Predictive genetic markers of coagulation, inflammation and apoptosis in Perthes disease\u2014Serbian experience","volume":"174","author":"Spasovski","year":"2015","journal-title":"Eur. J. Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-Zamora, E., Rodr\u00edguez-Olivas, A.O., Galicia-Alvarado, M.A., Casas-\u00c1vila, L., Rosales-Cruz, E., Zavala-Hern\u00e1ndez, C., and Reyes-Maldonado, E. (2026). Familial Cases of Legg-Calv\u00e9-Perthes Disease-Hemostatic and Molecular Markers. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27052195"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/17474086.2019.1583555","article-title":"Thrombophilia, risk factors and prevention","volume":"12","author":"Campello","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/clc.23282","article-title":"Genetic association between plasminogen activator inhibitor-1 rs1799889 polymorphism and venous thromboembolism: Evidence from a comprehensive meta-analysis","volume":"42","author":"Huang","year":"2019","journal-title":"Clin. Cardiol."},{"key":"ref_36","first-page":"468","article-title":"Plasminogen Activator Inhibitor-1 4G\/5G Polymorphism Contributes to Osteonecrosis of the Femoral Head Susceptibility: Evidence from a Systematic Review and Meta-analysis","volume":"6","author":"Sobhan","year":"2018","journal-title":"Arch. Bone Jt. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13023-022-02264-2","article-title":"Association of MTHFR rs1801133 and homocysteine with Legg-Calv\u00e9-Perthes disease in Mexican patients","volume":"17","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e8627","DOI":"10.7717\/peerj.8627","article-title":"Single nucleotide polymorphism of MTHFR rs1801133 associated with elevated Hcy levels affects susceptibility to cerebral small vessel disease","volume":"8","author":"Yuan","year":"2020","journal-title":"PeerJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1097\/BPB.0000000000000725","article-title":"Influence of passive smoking on the onset of Legg-Calv\u00e8-Perthes disease: A systematic review and meta-analysis","volume":"29","author":"Gao","year":"2020","journal-title":"J. Pediatr. Orthop. B"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1089\/dna.2023.0411","article-title":"Bone Remodeling and Bone Structural Genes in Legg-Calv\u00e9-Perthes Disease: The OPG rs2073618 and IL-6 rs1800795 Are Associated with High Risk in Mexican Patients","volume":"43","year":"2024","journal-title":"DNA Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1080\/1744666X.2025.2517164","article-title":"Genetic polymorphisms and cytokine levels in ischemic stroke: Associations with subtypes and prognosis","volume":"21","author":"Pacinella","year":"2025","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.3892\/etm.2016.3111","article-title":"Endothelial nitric oxide synthase gene polymorphism is associated with Legg-Calv\u00e9-Perthes disease","volume":"11","author":"Zhao","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jor.2019.02.024","article-title":"Association of eNOS 27-bp VNTR, 894G>T and 786T>C polymorphisms with susceptibility to Legg-Calv\u00e9-Perthes Disease in Iranian children","volume":"16","author":"Azarpira","year":"2019","journal-title":"J. Orthop."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13550","DOI":"10.1038\/s41598-017-13623-6","article-title":"Prothrombin G20210A (rs1799963) polymorphism increases myocardial infarction risk in an age-related manner: A systematic review and meta-analysis","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"608","DOI":"10.3390\/pathophysiology31040044","article-title":"Factor V Leiden (R506Q), Prothrombin G20210A, and MTHFR C677T Variants and Thrombophilia in Qatar Biobank Participants: A Case Control Study","volume":"31","author":"Shibeeb","year":"2024","journal-title":"Pathophysiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1080\/15513815.2019.1693671","article-title":"Association of IL-6 -174G>C and -572G>C Polymorphisms with Risk of Legg-Calve-Perthes Disease in Iranian Children","volume":"40","author":"Dastgheib","year":"2021","journal-title":"Fetal Pediatr. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.intimp.2015.12.011","article-title":"Role of interleukin-23 as a biomarker in rheumatoid arthritis patients and its correlation with disease activity","volume":"31","author":"Zaky","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/s41584-018-0091-8","article-title":"Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis","volume":"14","author":"Gravallese","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"450","DOI":"10.2298\/SARH1408450S","article-title":"Association of gene variants in TLR4 and IL-6 genes with Perthes disease","volume":"142","author":"Spasovski","year":"2014","journal-title":"Srp. Arh. Celok. Lek."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"395","DOI":"10.17816\/PTORS34927","article-title":"Role of combinations of polymorphisms of cytokine genes in the diagnosis of Legg\u2013Calve\u2013Perthes disease in children","volume":"8","author":"Shabaldin","year":"2020","journal-title":"Pediatr. Traumatol. Orthop. Reconstr. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jocn.2019.02.019","article-title":"Oxidative stress-induced angiogenesis","volume":"63","author":"Huang","year":"2019","journal-title":"J. Clin. Neurosci."},{"key":"ref_52","first-page":"421746","article-title":"Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells","volume":"2015","author":"Sasso","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_53","first-page":"149","article-title":"Avascular Necrosis of the Femoral Head: Are Any Genes Involved?","volume":"3","author":"Pouya","year":"2015","journal-title":"Arch. Bone Jt. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Melchiorre, D., Manetti, M., and Matucci-Cerinic, M. (2017). Pathophysiology of Hemophilic Arthropathy. J. Clin. Med., 6.","DOI":"10.3390\/jcm6070063"},{"key":"ref_55","first-page":"592297","article-title":"Research Advances on the Mechanism and Diagnosis of Bone Bridging in Ankylosing Spondylitis","volume":"18","author":"Wang","year":"2026","journal-title":"Orthop. Res. Rev."},{"key":"ref_56","first-page":"213","article-title":"TNF-\u03b1 and IL-6: The Link between Immune and Bone System","volume":"21","author":"Wang","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.jor.2018.08.042","article-title":"Association of MTHFR and TNF-\u03b1 genes polymorphisms with susceptibility to Legg-Calv\u00e9-Perthes disease in Iranian children: A case-control study","volume":"15","author":"Azarpira","year":"2018","journal-title":"J. Orthop."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ocl.2011.04.007","article-title":"Pathophysiology, classifications, and natural history of Perthes disease","volume":"42","author":"Kim","year":"2011","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1302\/0301-620X.99B8.BJJ-2016-1282.R1","article-title":"A case control study to determine the association between Perthes\u2019 disease and the recalled use of tobacco during pregnancy, and biological markers of current tobacco smoke exposure","volume":"99","author":"Perry","year":"2017","journal-title":"Bone Jt. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1007\/s11999-011-2180-8","article-title":"Environmental tobacco and wood smoke increase the risk of Legg-Calv\u00e9-Perthes disease","volume":"470","author":"Daniel","year":"2012","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s11999.0000000000000214","article-title":"Is Legg-Calv\u00e9-Perthes Disease a Local Manifestation of a Systemic Condition?","volume":"476","author":"Hailer","year":"2018","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"660","DOI":"10.5435\/JAAOS-D-16-00120","article-title":"Prevalence of Obesity in Patients With Legg-Calv\u00e9-Perthes Disease","volume":"24","author":"Neal","year":"2016","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1097\/BPO.0000000000000096","article-title":"Female patients with late-onset legg-calv\u00e9-perthes disease are frequently gymnasts: Is there a mechanical etiology for this subset of patients?","volume":"33","author":"Larson","year":"2013","journal-title":"J. Pediatr. Orthop."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1243\/09544119JEIM597","article-title":"A two-degree-of-freedom hip exoskeleton device for an immature animal model of exercise-induced Legg-Calv\u00e9-Perthes disease","volume":"223","author":"Zhang","year":"2009","journal-title":"Proc. Inst. Mech. Eng. H."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1097\/BPO.0000000000000157","article-title":"Legg-Calv\u00e9-perthes disease: Quality of life, physical activity, and behavior pattern","volume":"34","author":"Hailer","year":"2014","journal-title":"J. Pediatr. Orthop."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1177\/0300060515591062","article-title":"Epigenetics in Legg-Calv\u00e9-Perthes disease: A study of global DNA methylation","volume":"43","author":"Zheng","year":"2015","journal-title":"J. Int. Med. Res."},{"key":"ref_67","first-page":"685","article-title":"The role and underlying mechanisms of microRNA-214 in Legg-Calve-Perthes disease","volume":"20","author":"Zhu","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"110184","DOI":"10.1016\/j.cellsig.2021.110184","article-title":"MicroRNA sequence analysis of plasma exosomes in early Legg-Calv\u00e9-Perthes disease","volume":"91","author":"Huang","year":"2022","journal-title":"Cell. Signal."},{"key":"ref_69","first-page":"1319","article-title":"Downregulated SOX9 mediated by miR-206 promoted cell apoptosis in Legg-Calv\u00e9-Perthes disease","volume":"15","author":"Luo","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1651-2227.2008.00653.x","article-title":"Gaucher disease: Unmet treatment needs","volume":"97","author":"Mehta","year":"1992","journal-title":"Acta Paediatr."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1302\/0301-620X.90B11.20318","article-title":"Perthes\u2019 disease and the search for genetic associations: Collagen mutations, Gaucher\u2019s disease and thrombophilia","volume":"90","author":"Kenet","year":"2008","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4103\/ajps.AJPS_90_17","article-title":"A constellation of orthopaedic deformities in connection with cartilage oligomeric matrix protein mutation","volume":"16","author":"Ghachem","year":"2019","journal-title":"Afr. J. Paediatr. Surg."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1615\/CritRevOncog.2013006060","article-title":"Gaucher disease: A comprehensive review","volume":"18","author":"Rosenbloom","year":"2013","journal-title":"Crit. Rev. Oncog."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/ajmg.c.31970","article-title":"Bardet-Biedl syndrome: The pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins","volume":"190","author":"Gupta","year":"2022","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1590\/S0004-27492009000500019","article-title":"Pigmentary retinopathy due to Bardet-Biedl syndrome: Case report and literature review","volume":"72","author":"Andrade","year":"2009","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1097\/MS9.0000000000003077","article-title":"Bardet-Biedl syndrome in a Syrian adolescent: A rare case report","volume":"87","author":"Alabed","year":"2025","journal-title":"Ann. Med. Surg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000445491","article-title":"Bardet-Biedl Syndrome","volume":"7","author":"Suspitsin","year":"2016","journal-title":"Mol. Syndromol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2478\/bjmg-2018-0005","article-title":"Floating-Harbor Syndrome: Presentation of the First Romanian Patient with a SRCAP Mutation and Review of the Literature","volume":"21","author":"Budisteanu","year":"2018","journal-title":"Balk. J. Med. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/ajmg.a.38605","article-title":"Perthes disease: A new finding in Floating-Harbor syndrome","volume":"176","author":"Milani","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1080\/03008207.2020.1816994","article-title":"Diversity in heritable disorders of connective tissue at a single center","volume":"62","author":"Hsu","year":"2021","journal-title":"Connect. Tissue Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1002\/pd.5974","article-title":"Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield","volume":"41","author":"Zhang","year":"2021","journal-title":"Prenat. Diagn."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3944\/AOTT.2013.3128","article-title":"Legg-Calv\u00e9-Perthes disease in children with Down syndrome","volume":"47","author":"Talmac","year":"2013","journal-title":"Acta Orthop. Traumatol. Turc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/bjd.14366","article-title":"Buschke-Ollendorff syndrome: A novel case series and systematic review","volume":"174","author":"Pope","year":"2016","journal-title":"Br. J. Dermatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1080\/1744666X.2017.1232165","article-title":"Kawasaki disease: Etiopathogenesis and novel treatment strategies","volume":"13","author":"Agarwal","year":"2017","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1111\/ped.14595","article-title":"A case of Kawasaki disease complicated by acute onset Legg-Calv\u00e9-Perthes disease","volume":"63","author":"Takahashi","year":"2021","journal-title":"Pediatr. Int."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s13023-014-0192-7","article-title":"Overcoming the barriers to diagnosis of Morquio A syndrome","volume":"9","author":"Bhattacharya","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s002470050481","article-title":"Trichorhinophalangeal syndrome type I in monozygotic twins discordant for hip pathology. Report on the morphological evolution of cone-shaped epiphyses and the unusual pattern of skeletal maturation","volume":"28","author":"Naselli","year":"1998","journal-title":"Pediatr. Radiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00431-015-2514-8","article-title":"Stickler syndrome associated with epilepsy: Report of three cases","volume":"174","author":"Savasta","year":"2015","journal-title":"Eur. J. Pediatr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8890\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:31:01Z","timestamp":1791361861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":88,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198890"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198890","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}