A Rare Case of Severe Hypophosphatemia

Introduction: Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia is a rare paraneoplastic syndrome characterized by excess production of fibroblast growth factor 23 (FGF23), which leads to hyperphosphaturic hypophosphatemia. Clinical manifestations are often nonspecific and the syndrome is underdiagnosed and recognized late. It is important to have a high index of suspicion when evaluating hypophosphatemia, as early intervention of TIO can prevent or reverse osteomalacia and lead to an expedited investigation of a culprit neoplasm. Case Description: A 67-year-old male with actively-treated mesothelioma was referred to nephrology for hypophosphatemia despite aggressive oral repletion. History and physical revealed nonspecific symptoms of fatigue, myalgias, decreased appetite, and lower extremity swelling, but was negative for malnutrition, causative medications, or other specific etiology. Further labwork revealed a normal parathyroid level, low vitamin-D level, and elevated fractional excretion of urine phosphorous. An FGF23 level was markedly elevated, confirming the presence of a FGF23-mediated hypophosphatemia, consistent with TIO. Vitamin D supplementation and continued oral phosphorous repletion only mildly improved his serum phosphorous. Unfortunately, our patient's cancer was resistant to treatment and he ultimately passed away under hospice care. Discussion: TIO is rare and underdiagnosed, with a prevalence of less than 1 per 100,000 adults in the general population. Correct diagnosis is often delayed by over 3 years on average after symptom onset, with treatment delayed further. As nephrologists, we routinely measure serum phosphate levels. Once hypophosphatemia is identified, it is paramount to rule out poor diet, medication effects, and other associated conditions (such as refeeding syndrome, hyperparathyroidism or vitamin D deficiency). Renal phosphorus wasting should be confirmed with an inappropriately elevated urinary phosphorous (fractional excretion > 5% or a ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate < 85%). In this setting, an elevated FGF23 level will be diagnostic of FGF23-mediated hypophosphatemia, after which localization of the culprit tumor should be performed with functional imaging studies. Early identification of TIO can lead to early intervention of a causative tumor, and limit the debilitating complications of osteomalacia and malignancy.