X-linked hypophosphatemia and tumor-induced osteomalacia: a narrative review and expert opinion on the diagnostic and therapeutic challenges in the era of burosumab

: Hypophosphatemia presents with highly variable clinical manifestations. Among the identified hypophosphatemic disorders, X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) are caused by persistent excess fibroblast growth factor 23 (FGF23), which leads to phosphate renal wasting and reduced phosphate availability. Traditional treatments involving oral phosphate and active vitamin D supplements have limitations and potential side effects. By targeting FGF23, burosumab directly addresses the underlying pathophysiology of both XLH and TIO. This narrative review describes the diagnosis and management of XLH and TIO, highlighting key gaps and barriers within Italian clinical practice, which are often common in international healthcare settings; pragmatic solutions are also proposed to optimize patient care. Early diagnosis and appropriate treatment of XLH and TIO are crucial for preventing disease progression and improving patient outcomes. However, XLH diagnosis is often delayed or mistaken due to nonspecific symptoms, while TIO diagnosis is complicated by the challenge of localizing small FGF23-secreting tumors, which requires extensive imaging. A general lack of awareness among healthcare professionals about these rare diseases may further delay diagnosis. Management of XLH and TIO also faces hurdles. Although burosumab is now the recommended first-line treatment for XLH patients, both between 1 and 17 years old and adults, its continuous use is often limited by strict eligibility criteria, and adequate follow-up of XLH patients is difficult to maintain during the critical transition period from pediatric age to adulthood. For TIO, tumor resection remains the definitive treatment, but its success depends on tumor localization and surgical expertise. In cases where surgery is not feasible, burosumab or conventional therapy may be used, but long-term management strategies are lacking. Improving the care of XLH and TIO patients requires increased awareness, better access to advanced diagnostic tools, and enhanced multidisciplinary collaboration. Improving networking to discuss clinical cases and share best practices are crucial steps to ensure optimal patient outcomes. Implementing standardized protocols while setting personalized treatment goals and follow-up strategies can significantly improve the quality of life for patients with these rare diseases.