{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:33:48Z","timestamp":1787315628160,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy of Craiova"},{"id":[{"id":"https:\/\/ror.org\/031d5vw30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background\/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed\/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand\u2013receptor blockade, drug repurposing, Wnt\/\u03b2-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK\/ERK, STAT, PI3K\/AKT, IHH\/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt\/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence.<\/jats:p>","DOI":"10.3390\/children13081121","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:37:34Z","timestamp":1787312254000},"page":"1121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From FGFR3 Hyperactivation to Disease-Modifying Therapy in Pediatric Achondroplasia: Molecular Mechanisms, Clinical Evidence, and Emerging Treatments"],"prefix":"10.3390","volume":"13","author":[{"given":"Rebecca Cristiana","family":"\u0218erban","sequence":"first","affiliation":[{"name":"Regional Centre of Medical Genetics Dolj, Emergency County Hospital Craiova, 200642 Craiova, Romania"},{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Mitut-Veliscu","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Dumitra","sequence":"additional","affiliation":[{"name":"Regional Centre of Medical Genetics Dolj, Emergency County Hospital Craiova, 200642 Craiova, Romania"},{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana","family":"Marica","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Popescu","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy, Department of Anatomy, ENT County Hospital Craiova, University of Medicine and Pharmacy, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Costache","sequence":"additional","affiliation":[{"name":"Department of Biophysics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0218erban","family":"Teona","sequence":"additional","affiliation":[{"name":"Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca-Lelia","family":"Riza","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodica","family":"Dirnu","sequence":"additional","affiliation":[{"name":"Department of Health and Motricity, Faculty of Medical and Behavioral Sciences, Constantin Br\u00e2ncu\u0219i University of T\u00e2rgu Jiu, 210185 T\u00e2rgu Jiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata-Maria","family":"Varut","sequence":"additional","affiliation":[{"name":"Research Methodology Department, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Strea\u021b\u0103","sequence":"additional","affiliation":[{"name":"Regional Centre of Medical Genetics Dolj, Emergency County Hospital Craiova, 200642 Craiova, Romania"},{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","unstructured":"Chamarthi, V.S., Chamarthi, S., and Karsonovich, T. 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