Diagnostic Dilemma of Elevated FGF23 in a Patient With Osteomalacia: A Case Report

Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to FGF23 hypersecretion. It is mostly seen with benign mesenchymal tumors. Establishing the diagnosis could be challenging due to occult nature of the disease. Case: A 54-year-old female presented with right thigh and upper back pain. On presentation, she had hypophosphatemia (1.8 mq/dl), low 25-hydroxyvitamin D (23 ng/ml), normal ionized calcium and normal iPTH (53 pg/mL). CT scan showed healing right 10(th) rib fracture and right proximal femoral fracture. DEXA scan was remarkable for osteoporosis. 99m-Technetium nuclear bone scan displayed hyperactivity on bilateral femurs and multiple ribs concerning for stress fractures. Patient was thought to have osteomalacia from vitamin D insufficiency and started on ergocalciferol. Two months later, patient was diagnosed with invasive ductal carcinoma. She had unilateral mastectomy and adjuvant chemotherapy. Surveillance studies were negative for recurrence. Patient lost to follow up for 2 years until she returned with right hip and upper back pain. Her labs showed hypophosphatemia (1.2 mg/dL), normocalcemia, elevated iPTH (131 pg/mL), low 25-hydroxyvitamin D (26 ng/ml), low normal 1,25-dihydroxyvitamin D (25 pg/ml, normal: 18 -72) and elevated FGF23 (285 RU/ml, normal level <180). 24-hour urine studies showed phosphate of 330 mg and fractional phosphate excretion (FEPO4) of 12%. Nuclear bone scan reported subacute fractures in left 11(th) and right 6(th) ribs and right proximal femur. TIO was entertained as the unifying diagnosis. She was started on calcium, phosphate, ergocalciferol and calcitriol. Localizing studies with a PET scan showed FDG hyperactivity in the right vocal cord. Subsequent MRI showed asymmetric fat tissue between esophagus and left common carotid artery concerning for lipoma. She lost to follow up again during COVID-19 pandemic. Discussion: We present a case of elevated FGF23 with renal phosphate wasting concerning for TIO. This case represents the diagnostic dilemma of elevated FGF23 as well as difficulty in discerning the source in TIO. Although exact tumor source remained unclear in our patient, adipose tissue in the thoracic inlet was a potential culprit. Elevated FGF23 leads to urinary phosphate wasting and inhibition of 1α- hydroxylase. Daily urine phosphate excretion > 100 mg or FEPO4 > 5 % strongly suggest renal phosphate wasting. TIO and iron-induced hypophosphatemia are two most common acquired causes of high FGF23. TIO is mostly caused by benign soft tissue and bone tumors. It can take years to establish the diagnosis due to small size and obscure location of the tumors. Advanced investigation with FDG-PET, (68)Ga-DOTATATE scan, octreotide scan and venous sampling of FGF23 can aid in diagnosis. Tumor resection is usually curative. Burosumab (anti-FGF23 monoclonal antibody) can be considered when the tumor is not amenable to resect.