Interaction Between Local Growth Plate Mechanisms and Systemic Endocrine Signals in X-Linked Hypophosphatemia (XLH) Impaired Linear Growth

Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on pathophysiology of XLH. Particular attention was given to the interaction between systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of alteration of calcium-phosphate metabolism, systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.