Discussion

This case highlights three important aspects of the diagnosis and management of TIO. TIO remains a major diagnostic challenge because of its nonspecific presentation with bone pain, proximal muscle weakness, fatigue, and fragility fractures. Misdiagnosis rates approach 95%, with a median diagnostic delay of approximately three years, often resulting in progressive disability [9]. Our patient's clinical course closely reflected this pattern, having initially been diagnosed with osteoporosis and osteoarthritis before hypophosphatemia prompted further investigation. In adults presenting with unexplained musculoskeletal symptoms, systematic evaluation of hypophosphatemia is therefore essential [10]. Demonstration of renal phosphate wasting should prompt measurement of circulating FGF-23. Once FGF-23-mediated hypophosphatemia is established and hereditary disorders are excluded, localization of the responsible tumor becomes the priority. Combined functional and anatomical imaging, particularly 68Ga-DOTATATE PET/CT, has become the imaging modality of choice for tumor localization [11,12]. Although histopathological confirmation remains the diagnostic gold standard, the diagnosis in our patient was supported by characteristic biochemical abnormalities, concordant imaging findings, and normalization of phosphate metabolism following tumor resection.

This case illustrates that TIO may recur despite apparently curative surgery. Although complete tumor excision is curative in most patients, recurrence occurs in approximately 7-15% of cases, usually within the first three years after surgery [13,14]. Female sex, spinal location, bone involvement, malignancy, and low preoperative serum phosphate have been associated with an increased risk of recurrence [15]. Tumors involving the spine are exceptionally rare. To the best of our knowledge, 22 cases have been reported in the literature [8], and present considerable surgical challenges because of their infiltrative nature and proximity to critical neurovascular structures. In our patient, biochemical remission after cervical tumor resection was followed by recurrence within one year, emphasizing the need for continued biochemical and imaging surveillance even after apparently successful surgery.

In this context, burosumab provided an alternative to further treatment. Conventional treatment with oral phosphate and active vitamin D analogues is frequently limited by poor tolerability and long-term complications, including secondary hyperparathyroidism, hypercalciuria, nephrolithiasis, and nephrocalcinosis [16]. By neutralizing excess FGF-23, burosumab restores phosphate homeostasis without the need for chronic oral supplementation. Although it is not a tumor-directed therapy and does not replace complete surgical resection when feasible, previous reports have demonstrated its efficacy in patients with unidentifiable or unresectable TIO [17].

Day et al. described a patient with two somatostatin receptor-avid intracranial meningiomas in whom surgery was considered unsuitable; burosumab resulted in normalization of serum phosphate and improvement in pain and mobility [18]. Similarly, burosumab has been reported to normalize phosphate levels and improve pseudofractures, pain, and functional capacity in patients in whom extensive imaging and venous sampling failed to localize the responsible tumor [8]. Our case differs from these reports in that burosumab was used for recurrent disease after initially successful surgical resection, rather than as the initial definitive treatment. Furthermore, the patient achieved sustained biochemical and clinical control for 25 months despite persistent uptake of the recurrent calvarial lesion on serial 68Ga-DOTATATE PET/CT. Of note, there were no new fragility fractures or treatment-related adverse events.

To our understanding, this is the first reported case of TIO in Portugal successfully treated with burosumab. These findings are consistent with prospective clinical studies and published case reports demonstrating durable biochemical correction and improvements in physical function and health-related quality of life [19]. Nevertheless, continued biochemical and imaging surveillance remains essential to monitor disease progression.