Tumor-induced Osteomalacia Research Articles

Detection of recurrent phosphaturic mesenchymal tumors by using Ga-68 DOTATATE PET/CT

Phosphaturic mesenchymal tumor is a rare clinical condition and often causes osteomalacia due to tumor. Its diagnosis is often significantly delayed due to its rare occurrence in addition to the generalized and vague symptoms of their presentation. A 19-year-old female with a history of left facial nerve palsy, generalized weakness and hoarseness of voice revealed a dense mass in her brain. In this case, we reported successful application of a Ga-68 labeled DOTATATE PET/CT scan to identify the primary site and distant metastases of phosphaturic mesenchymal tumors and show the diagnostic value of Ga-68 labeled DOTATATE PET/CT imaging for the rare tumors.

Tumour-induced Osteomalacia: A Case Report

Tumour-induced Osteomalacia: A Case Report

Tumor-induced osteomalacia due to a phosphaturic mesenchymal maxillary tumor

ABSTRACT Tumor-induced osteomalacia is a rare paraneoplastic syndrome with hypophosphatemia due to renal phosphate wasting. The clinical presentation is bony pains and muscle wasting. A 23-year-old male presented to us in a wheelchair with joint pain and muscle weakness for 5 years. There was no history of a similar disease in the family. Treatment with non steroidal anti inflammatory drugs, steroids, and infliximab was unsuccessful. Positive examination findings revealed tenderness and swelling in both ankle and knee joints, tenderness in hip joints, proximal myopathy, and power grade 4/5 in the proximal leg muscles. On evaluation, he was found to have severe hypophosphatemia [serum phosphate 1.2 mg/dl], decreased renal phosphate absorption [tubular maximum for phosphate reabsorption adjusted for glomerular filtration rate (TMP/GFR) of 1.04], increased fibroblast growth factor 23 (FGF23), and decreased 1,25 dihydroxy vitamin D levels. Fluorodeoxyglucose-positron emission tomography (FDG PET-CT) revealed a left maxillary tumor. Histopathology revealed a mesenchymal tumor. Tumor excision resulted in cure of the patient’s symptoms and the normalization of serum phosphate levels and TMP/GFR.

Intracranial phosphaturic mesenchymal tumor: report of a case

Intracranial phosphaturic mesenchymal tumor: report of a case

Tumor-induced osteomalacia.

Tumor-induced osteomalacia is one of paraneoplastic syndromes characterized by hypophosphatemia caused by excessive actions of fibroblast growth factor 23 (FGF23). Since the cloning of FGF23 about 20 years ago, more widespread awareness of this disease has been achieved. However, there still remain several difficulties in the management of patients with this disease. In this review, these clinical problems are discussed together with the physiological and pathophysiological functions of FGF23. Personal proposals in the management of patients with suspected patients with tumor-induced osteomalacia are also presented.

Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO’s incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Spinal phosphaturic mesenchymal tumors: a rare etiology causing tumor-induced osteomalacia-a review of experience at a UK tertiary referral center and literature review.

This article aims to provide a comprehensive review of the management challenges associated with Spinal Phosphaturic Mesenchymal tumors (PMTs) and evaluates the surgical management outcomes for this rare entity linked to Tumor-induced osteolysis. The primary objective of this study is to enhance the familiarity of treating physicians with the clinical features, diagnosis, and treatment options for Spinal PMTs. A retrospective analysis was conducted, reviewing electronic medical records of patients diagnosed with spinal PMTs at our hospital between January 2019 and December 2022. The data collected included demographic information, clinical presentation, radiological findings, surgical details, and follow-up outcomes. A total of three cases of Spinal PMTs causing Tumor-induced osteomalacia were identified. The diagnosis of Spinal PMTs presented challenges, with incidental detection often occurring during routine imaging. Surgical management was undertaken, resulting in successful symptom resolution and normalization of phosphate levels. The application of 68Ga-DOTA-TATE PET/CT scans facilitated tumor localization, aiding in surgical planning. Spinal PMTs demonstrated a favorable response to surgical intervention. Spinal PMTs play a significant role in Tumor-induced osteolysis, warranting timely and accurate diagnosis. Although diagnosing Spinal PMTs presents challenges, surgical management has proven to yield favorable outcomes, effectively alleviating symptoms and restoring phosphate levels. A multidisciplinary approach and continued vigilance are essential in ensuring early diagnosis, effective treatment, and long-term monitoring for patients affected by spinal PMTs.

Clinical features, diagnostics and treatment of FGF23 secreting tumors: series of 40 clinical cases

Tumor-induced osteomalacia is an acquired rare disease manifested by hypophosphatemic osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23). FGF 23 is a non-classical hormone secreted by bone tissue (osteocytes) and regulates phosphorus metabolism.The aim of this work is to present clinical experience in the diagnosis, treatment and rehabilitation of patients with tumor-induced osteomalacia. 40 patients with clinically-confirmed tumor-induced osteomalacia were included in the study, 34 of whom had the tumor localized, 27 underwent surgical treatment and 21 achieved stable remission. The median age was 48 [41; 63] years, 43% were men, the time left from the the onset of the disease was 8 [4; 10] years. Biochemical findings were hypophosphatemia 0.47 [0.4; 0.53] mmol/l, a decrease in the tubular reabsorption phosphate 62 [52; 67]%, and an increase in alkaline phosphatase of 183 [112; 294] units/l. At the time of diagnosis, 100% had multiple pathological fractures, only 10% could move independently, and 77.5% classified the pain as unbearable (8-10 points according to the 10-point pain syndrome scale ). Among the methods used to detect tumors, the most sensitive were scintigraphy with tectrotide with SPECT/CT 71.4% (20/28) and MRI 90% (18/20). In 35% of cases, the tumor was localized in soft tissues and in 65% in bone tissue; The tumor was most often detected in the lower extremities, followed by the head in frequency of localization. 18 patients currently have no remission and they receive conservative treatment (phosphorus and alfacalcidol n=15 and burosumab n=3). In case of achieving remission (n=21), regression of clinical symptoms and restoration of bone and muscle mass was observed. Extensive excision of the tumor without prior biopsy resulted in the best percentage of remission - 87%. Tumor-induced osteomalacia is characterized by severe damage to bone and muscle tissue with the development of multiple fractures, muscle weakness and severe pain syndrome. In laboratory diagnostics, attention should be paid to hypophosphatemia, a decrease in the tubular reabsorption phosphate index and increased alkaline phosphatase. The use of functional diagnostic methods with a labeled somatostatin analogue to the subtype 2 receptor and MRI with contrast enhancement are the most accurate methods of topical diagnostics. In case of localization of the tumor, a wide excision without a preliminary biopsy is recommended.

Phosphaturic mesenchymal tumor: Clinicopathological features with outcomes in 10 patients with review of literature.

Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal tumors, associated with long-standing, non-specific but often debilitating symptoms in the affected patients. These tumors display characteristic histopathological features and in case, identified timely, can be a boon for patients, given an excision is completely curative. To evaluate the clinical and histopathological features of 10 PMTs, diagnosed at our institution, along with clinical outcomes in those patients. This was a retrospective study, wherein 10 PMTs, diagnosed from January 2013 to July 2022, were included. The average age at the time of diagnosis was 40 years with an M:F ratio of 4:1. Clinical features included lumps, weakness, bone pain, difficulty in moving and walking, and pathologic fractures. The biochemical analysis showed normal serum calcium levels (average = 9.5 mg/dL), with low serum phosphorus (average = 2.2 mg/dL) and raised serum fibroblast growth factor 23 (FGF23) levels, in all the cases, wherever available. On histopathology, all tumors showed cells arranged in a hemangiopericytomatous pattern, including oval to short spindle forms. Multinucleate giant cells were present in nine tumors, and characteristic "grungy calcifications" was observed in eight tumors. Prominent pseudo cystic spaces were seen in eight tumors. A significant number of mitotic figures and tumor necrosis were not seen in any tumor. In five cases where follow-up was available, there was complete resolution of symptoms post-resection with no recurrence or metastasis. All those patients were free of disease until the last follow-up. This constitutes the first largest comprehensive study on these rare tumors from our country. PMTs can be diagnosed based on certain histopathological features and correlation with clinicoradiological and biochemical findings. These are invariably benign neoplasms. Patients are relieved of their debilitating symptoms after adequate surgical tumor resection. Therefore, their correct and timely diagnosis is crucial.

Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

THU463 Etiology Of Hypophosphatemia In A Patient With Co-existing Mesenchymal Tumor And Fibrous Dysplasia

Abstract Disclosure: M. Patil: None. S. Wangsiricharoen: None. A. Lazar: None. T.A. Guise: None. Tumor induced osteomalacia (TIO) is a rare paraneoplastic phenomenon. Fibroblast growth factor-23 (FGF23) secretion from phosphaturic mesenchymal tumor (PMT) is implicated as the cause for hypophosphatemia and osteomalacia. Other rare conditions associated with dysregulated FGF23 production include fibrous dysplasia (FD). Coexistence of two unusual conditions which could increase FGF23 concentrations is rare. We report a case of PMT causing TIO in a patient with evidence of FD. A 79-year-old male was evaluated for worsening rib and right flank pain of more than one year duration. He also complained of generalized muscle weakness. His total alkaline phosphatase (ALP) levels were noted to be increased for many years. Computed tomography (CT) showed scattered sclerosis within ribs, and lytic lesions with cortical bone destruction in right iliac bone (4.3 x1.5 cm) and L4 vertebra. Biopsy of the right iliac lesion revealed findings compatible with PMT. Positron Emission Tomography (PET) showed fluorodeoxyglucose (FDG) avid lesion of the right anterior iliac wing, diffuse osteomalacia, insufficiency fractures of the ribs, as well as FDG avid lesions in left supra-acetabular area and in L4 vertebral body concerning for metastatic disease. Laboratory evaluation revealed ALP 306 (40-129 U/L), bone specific ALP 99 (0-20 mcg/L), phosphorus 1.5 (2.5-4.5 mg/dL), 25-(OH)-vitamin D 27 (30- 100 ng/mL), 24 hour urinary phosphorus 0.6 (0.4-1.3 g/24 hr), PTH 51.3 (15-65 pg/mL), FGF23 303 (<180 RU/mL), Calcium 10.3 (8.4-10.2 mg/dL), albumin 4.4 (3.5- 5.2 gm/dL), C-terminal telopeptide of type 1 collagen (CTX) 1611 (10-854 pg/mL). CT-guided cryoablation of the right iliac lesion was performed. Also, biopsy and cryoablation of the left supra-acetabular lesion was performed; pathology showed fibrous dysplasia (FD). Mutation analysis confirmed a mutation in exon 8 of GNAS gene. Post ablation, FGF23 dropped to 102 RU/mL and phosphorus increased to 3.0 mg/dL. The patient had significant improvement in bone pain and weakness. The patient with classic features of TIO improved with simultaneous cryoablation of both the PMT as well as the FD lesions. The unusual feature of the case is co-existence of PMT and FD. Malignant transformation of FD lesions is a rare complication. We confirmed that the PMT did not have GNAS mutation and is unlikely to arise from FD. And FGF23 in situ hybridization was strongly positive in the PMT and negative in the FD, ruling out FD as a contributor to patient’s hypophosphatemia. We plan to perform DOTATATE scan to differentiate PMT from FD in the L4 lesion. This is a unique case of coexistence of two separate conditions, both of which could secrete intact FGF23. Our studies suggest that PMT is the only etiology of hypophosphatemia and TIO. Presentation: Thursday, June 15, 2023

THU465 Significant Improvement In Bone Mineral Density Following Treatment For Tumor Induced Osteomalacia

Abstract Disclosure: L.C. McHan: None. M. Augustine: None. Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting and impaired activation of vitamin D due to excess secretion of FGF23, often from phosphaturic mesenchymal tumors (PMTs). TIO typically presents with months to years of bone pain, muscle weakness, and fractures often leading to functional decline. Given these nonspecific symptoms, diagnosis of TIO can be delayed for years. Removal of the tumor is curative, though it can sometimes be a challenge to localize. For those whose tumors are unable to be localized or removed, medical management with phosphorus and vitamin D is recommended. Patients with TIO have low bone mineral density (BMD) at time of diagnosis. Case Reports: We are presenting two cases of TIO, one managed surgically and one managed medically. Patient 1 is a 45-year-old man with Fabry disease who presented with years of progressive pain, difficulty ambulating, and multiple fractures. Lab workup revealed low serum phosphorus, elevated urinary phosphorus, elevated FGF23, and negative genetic testing for heritable causes of hypophosphatemic osteomalacia. DOTATATE imaging identified a subcutaneous left flank mass, which was excised resulting in improvement in symptoms and resolution of biochemical abnormalities. Additionally, lumbar spine (LS) bone mineral density (BMD) nearly doubled; prior to diagnosis of TIO, LS BMD was 0.601 g/cm2 and 8 months after surgical excision of the tumor, LS BMD was 1.178 g/cm2. Patient 2 is a 55-year-old nonverbal man with autism and intellectual disability who presented with months of progressive difficulty ambulating, presumed pain, functional decline, and multiple fractures. Workup revealed low serum phosphorus, elevated urinary phosphorus, and elevated FGF23 concerning for TIO. He was initiated on phosphorus and vitamin D supplementation, but no culprit tumor has been identified despite multiple scans over the course of years. However, the patient has had a significant improvement in functioning with medical management in addition to a remarkable 48% improvement in LS BMD, from 0.855 g/cm2 prior to diagnosis of TIO and 1.264 g/cm2 following 3 years of medical management. Clinical Lessons: In our review of the literature, there are few case reports and case series documenting the significant improvements in BMD with treatment of TIO. In our experience, two patients who had months to years of debilitating symptoms exhibited remarkable improvements in symptoms and marked improvement in LS BMD following treatment. This emphasizes the importance of recognizing the diagnosis of TIO, as even when the causative tumor is not identified, treatment typically has a significant impact on patient functioning and quality of life. Presentation: Thursday, June 15, 2023

THU462 Clinical Features & Management Of FGF23 Secreting Tumors: Series Of 40 Clinical Cases

Abstract Disclosure: S. Gronskaia: None. Z. Belaya: None. L. Rozhinskaya: None. T. Dubovitskaya: None. E. Mamedova: None. E.A. Pigarova: None. M. Degtyarev: None. S. Rodionova: None. Y. Buklemishev: None. D. Babaeva: None. V. Vladimirova: None. N. Tarbaeva: None. S. Serzhenko: None. A. Grigoriev: None. L. Dzeranova: None. V. Karpenko: None. A. Karasev: None. R. Fedotov: None. I. Ulyanova: None. D. Trukhina: None. N. Toroptsova: None. O. Lesnyak: None. N.G. Mokrysheva: None. G.A. Melnichenko: None. I. Dedov: None. Introduction: Tumor-induced osteomalacia is an acquired rare disease manifested by hypophosphatemic osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23). FGF 23 is a non-classical hormone secreted by bone tissue (osteocytes) and regulates phosphorus metabolism.The aim of this work is to present clinical experience in the diagnosis, treatment and rehabilitation of patients with tumor-induced osteomalacia. Materials and methods: 40 patients with clinically-confirmed tumor-induced osteomalacia were included in the study, 34 of whom had the tumor localized, 27 underwent surgical treatment and 21 achieved stable remission. Results: The average age was 48 +/- 14 years, 43% were men, the time left from the the onset of the disease was 8 +/- 6 years. Biochemical fundings were hypophosphatemia 0.47 [0.4 ; 0.53] mmol/l, a decrease in the tubular reabsorption phosphate 62 [52 ; 67]%, and an increase in alkaline phosphatase of 183 [112 ; 294] units/l. At the time of diagnosis, 100% had multiple pathological fractures, only 10% could move independently, and 76.3% classified the pain as unbearable (8-10 points according to the 10-point pain syndrome scale ). Among the methods used to detect tumors, the most sensitive were scintigraphy with tectrotide with SPECT/CT 71.4% (20/28) and MRI 90% (18/20). In 55% of cases, the tumor was localized in soft tissues and in 45% in bone tissue; The tumor was most often detected in the lower extremities, followed by the head in frequency of localization. 18 patients currently have no remission and they receive conservative treatment (phosphorus and alfacalcidol n=15 and burozumab n=3). In case of achieving remission (n=21), regression of clinical symptoms and restoration of bone and muscle mass was observed. Extensive excision of the tumor without prior biopsy resulted in the best percentage of remission - 87%. Conclusion: Tumor-induced osteomalacia is most common in the middle age people. It is characterized by severe damage to bone and muscle tissue with the development of multiple fractures, muscle weakness and severe pain syndrome. In laboratory diagnostics, attention should be paid to hypophosphatemia, a decrease in the tubutar reabsorption phosphate index and increased alkaline phosphatase. The use of functional diagnostic methods with a labeled somatostatin analogue to the subtype 2 receptor and MRI with contrast enhancement are the most accurate methods of topical diagnostics. In case of localization of the tumor, a wide excision without a preliminary biopsy is recommended. Presentation: Thursday, June 15, 2023

Surgical and biochemical outcomes of phosphaturic mesenchymal tumors causing tumor-induced osteomalacia in the head and neck region

ObjectivesWe aimed to report the surgical outcomes of phosphaturic mesenchymal tumors causing tumor-induced osteomalacia in the head and neck. MethodsThis study analyzed nine patients who underwent surgical excision of phosphaturic mesenchymal tumors in the head and neck region. The primary sites were two in the maxilla and ethmoid sinus, and one in the intracranial, skull, parotid gland, maxillary sinus, and nasal cavity in each patient. Outcomes were compared with those in the extremities and trunk (n = 32). ResultsFive of nine patients (56%) developed residual disease/local recurrence associated with low serum phosphate level after initial surgical excision. At the last follow-up, the biochemical parameters were normalized in four of the five patients after re-excision without any medication. The local recurrence/residual disease risk was significantly higher for the head and neck compared with the extremities and trunk (56% vs. 25%, p = 0.048). The rate of remission (normalized serum phosphate without medication) at final follow-up was similar in both groups after re-excision (head and neck vs. extremities and trunk, 86% vs. 73%, p = 0.827). ConclusionsPhosphaturic mesenchymal tumor resection in the head and neck region was challenging because of its complex anatomy and proximity to the brain or other crucial organs, which was associated with high local recurrence/residual disease rate. However, biological remission was achieved in the majority of the patients after re-excision.

Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered “fusion-negative” (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

Elevated morbidity and mortality in patients with chronic idiopathic hypophosphatemia: a nationwide cohort study.

Chronic idiopathic hypophosphatemia (CIH) induced by X-linked hypophosphatemic rickets or tumor-induced osteomalacia is a rare inherited or acquired disorder. However, due to its rarity, little is known about the epidemiology and natural course of CIH. Therefore, we aimed to identify the prevalence and long-term health outcomes of CIH patients. Using the Korean Health Insurance Review and Assessment claims database, we evaluated the incidence of hypophosphatemia initially diagnosed from 2003 to 2018. After excluding secondary conditions that could change serum phosphorus levels, we identified 154 patients (76 men and 78 women) with non-secondary and non-renal hypophosphatemia. These hypophosphatemic patients were compared at a ratio of 1:10 with age-, sex-, and index-year-matched controls (n = 1,540). In the distribution of age at diagnosis, a large peak was observed in patients aged 1-4 years and small peaks were observed in ages from 40-70 years. The age-standardized incidence rate showed non-statistically significant trend from 0.24 per 1,000,000 persons in 2003 to 0.30 in 2018. Hypophosphatemic patients had a higher risk of any complication (adjusted hazard ratio [aHR], 2.17; 95% confidence interval [CI], 1.67-2.69) including cardiovascular outcomes, chronic kidney disease, hyperparathyroidism, osteoporotic fractures, periodontitis, and depression. Hypophosphatemic patients also had higher risks of mortality and hospitalization than the controls (aHR, 3.26; 95% CI, 1.83-5.81; and aHR, 2.49; 95% CI, 1.97-3.16, respectively). This first nationwide study of CIH in South Korea found a bimodal age distribution and no sex differences among patients. Hypophosphatemic patients had higher risks of complications, mortality, and hospitalization compared to age- and sex-matched controls.

Phosphaturic Mesenchymal Tumors with or without Phosphate Metabolism Derangements.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms, which can give rise to a multifaceted syndrome, otherwise called tumor-induced osteomalacia (TIO). Localizing these tumors is crucial to obtain a cure for the phosphate metabolism derangement, which is often the main cause leading the patient to seek medical help, because of invalidating physical and neuromuscular symptoms. A proportion of these tumors is completely silent and may grow unnoticed, unless they become large enough to produce pain or discomfort. FGF-23 can be produced by several benign or malignant PMTs. The phosphate metabolism, radiology and histology of these rare tumors must be collectively assessed by a multidisciplinary team aimed at curing the disease locally and improving patients' quality of life. This narrative review, authored by multiple specialists of a tertiary care hospital center, will describe endocrine, radiological and histological features of these tumors, as well as present surgical and interventional strategies to manage PMTs.

Burosumab - new potent treatment for X-linked hypophosphatemia and tumor-induced osteomalacia

Introduction and purpose: Elevated FGF23 in X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) leads to systemic hypophosphatemia, several musculoskeletal manifestations and rickets in children. In this review we describe advances in the management of XLH and TIO using burosumab, which is a new therapeutic option approved both for adults and children. A search was conducted using PubMed and Google Scholarship databases. Brief description of the state of knowledge: Patients with XLH and TIO exhibit a similar clinical picture and way of treatment. Although in TIO surgery is the only definitive treatment, some tumors cannot be removed due to their location. In this case oral conventional therapy is used in treating both in TIO and XLH. Another approved treatment option is the use of burosumab, which is a fully humanised FGF23-antibody. This therapy led to normalisation of phosphate homoeostasis and resulted in improvement of bone turnover, fracture healing, subjective pain, and physical function. Compared to conventional, oral therapy burosumab has been shown to be superior for treatment of XLH and TIO.Conclusions: While burosumab appears to improve treatment outcomes, the effects of chronic or lifelong use have yet to be established. Long term follow-up studies would be necessary to assess especially the potential risk of nephrocalcinosis and cardiac calcification.

Diagnostic accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting osteomalacia-associated tumors.

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) SPECT/CT in detecting TIO. 99mTc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The 99mTc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results. Using 99mTc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the 99mTc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of 99mTc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25). The 99mTc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.

Diagnosis and management of tumor-induced osteomalacia: a single center experience.

The aim of this study is to review the clinical and laboratory characteristics, diagnostic and treatment modalities of tumor-induced osteomalacia (TIO) cases managed in a single center. Demographic and clinical features, biochemical findings, diagnostic procedures, treatment modalities, and outcomes of nine patients who had the diagnosis of TIO were reviewed retrospectively. Mean age of the study group (F/M: 4/5) was 45.8 ± 10.8 years, and mean time from the onset of symptoms to diagnosis was 4.7 ± 2.8 years. The clinical manifestations were muscle weakness and difficulty in walking (8/9), hip pain (3/9), multiple fractures (2/9), stress fracture (2/9). Mean plasma phosphorus concentration was 1.28 ± 0.4 mg/dl at presentation. We performed radionuclide imaging modalities (18F-FDG PET/CT, Ga68-DOTATATE PET/CT, octreotide scintigraphy) in seven of nine patients, and tumor was detected in all. Lower extremity (n = 6; %67), head region (n = 2; %22) and thorax (n = 1; %11) were the tumor locations of our cases. Eight patients underwent surgery and remission was achieved postoperatively in all of the operated patients and plasma phosphorus level normalized in 4 ± 2 days. Pathological examination revealed mesenchymal tumors with different subtypes. Recurrence occurred in three patients at 13 ± 10.5 months after the first surgery. Two patients were reoperated and radiotherapy was also performed in one of them. Hypophosphatemia necessitates careful evaluation for the etiology. TIO is one of the important causes of adult-onset hypophosphatemic osteomalacia. Diagnosis of TIO is essential because the laboratory and clinical findings resolve after appropriate treatment.