Refractory Hypophosphatemia Secondary to Tumor-Induced Osteomalacia: Diagnostic Challenges and Successful Management With Burosumab.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by fibroblast growth factor-23 (FGF-23) overproduction from mesenchymal tumors, leading to renal phosphate wasting, hypophosphatemia, and impaired 1,25-dihydroxyvitamin D (1,25 Vit D) synthesis. This report details a 69-year-old woman with obesity post-gastric bypass, iron deficiency anemia treated with ferric carboxymaltose (FCM) six months prior, osteoporosis post-zoledronic acid, hiatal hernia, and gastroesophageal reflux disease. She presented with generalized weakness, fatigue, and severe refractory hypophosphatemia (0.9 mg/dL) unresponsive to high-dose sodium phosphate supplementation. Laboratory evaluation showed renal phosphate loss (fractional excretion of phosphate (FEPO4) 10.4%, 24-hour urine phosphate > 100 mg/day), normal 25-hydroxyvitamin D (42 ng/mL), low-normal 1,25 Vit D (18 pg/mL), elevated parathyroid hormone (PTH) (110 pg/mL), and initially normal C-terminal FGF-23 (53 RU/mL). Genetic testing via the Renasight panel was negative for pathogenic mutations, including those associated with X-linked hypophosphatemia (XLH), and whole-exome sequencing revealed no CYP27B1 mutations. Repeat testing with an intact FGF-23 assay demonstrated elevation (92 pg/mL), supporting a diagnosis of TIO despite the remote FCM exposure and negative NetSpot scan (Etwok Inc., Dover, DE, United States) for tumor localization. Burosumab (0.5 mg/kg monthly) was initiated, normalizing serum phosphate without additional supplementation, though side effects included headaches and dental caries. This case highlights the critical role of intact FGF-23 assays over C-terminal assays for improved diagnostic accuracy in TIO, the indicative value of hypophosphatemia with low or inappropriately normal 1,25 Vit D, the necessity of understanding phosphate homeostasis feedback loops, and the efficacy of burosumab therapy in cases of strong clinical suspicion despite elusive tumors. Ongoing annual imaging aims for potential curative resection.