Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/ computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited.

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77-and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wildtype ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis.

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Context Fibroblast growth factor (FGF) 23 is a hormone that regulates serum phosphate levels, the excess action of which causes chronic hypophosphatemic rickets/osteomalacia. To date, there are only two identified causes of acquired FGF23-related hypophosphatemic osteomalacia: tumor-induced osteomalacia (TIO) and osteomalacia induced by the intravenous infusion of some forms of iron preparations. In the current study, two cases of FGF23-related hypophosphatemia probably induced by chronic alcohol consumption were first introduced. Case description Case 1 and case 2 had been drinking high amounts of alcohol for more than twenty years until they were admitted to the hospital. Case 1 was a 43-year-old man with progressive worsening multiple pains and muscle weakness who exhibited chronic hypophosphatemia with increased intact FGF23 levels. A week after admission, the serum phosphate level recovered to the reference range, and the intact FGF23 level declined. Case 1 resumed drinking after discharge, and hypophosphatemia concomitant with high intact FGF23 levels recurred. The alleviation of FGF23-related hypophosphatemia was observed each time he temporarily abstained from drinking for a short period. Case 2 was a 60-year-old man with recurrent fractures and exacerbation of pain in multiple joints who also exhibited hypophosphatemia with increased intact FGF23 levels. After admission, the serum phosphate level gradually increased to the lower limit of the normal range. The intact FGF23 level decreased, but it was still higher than 30 pg/ml, and causative FGF23-producing tumors were not identified even with thorough examinations, including somatostatin receptor scintigraphy, fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) and systemic venous FGF23 sampling. He completely abstained from alcohol after discharge. Along with the serum phosphate level, intact FGF23 was subsequently decreased and had been normalized for 5 months. Both patients had no genetic mutation related to hereditary FGF23-related hypophosphatemic rickets/osteomalacia, including autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR). Conclusion Two cases of FGF23-related hypophosphatemia probably induced by alcohol were first introduced in this study. Identifying this reversible condition among acquired FGF23-related hypophosphatemic osteomalacia is critical to obtain better patient outcomes and save medical resources. This condition is similar to iron infusion-induced FGF23-related hypophosphatemia in terms of the dysregulation of FGF23 due to exogenous factors. Future research to elucidate the precise mechanism of these conditions is warranted.

Context Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to 18F-FDG PET/CT (FDG-PET) and 111In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective To evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Design Observational retrospective study. Patients Patients with adult-onset FGF23-related osteomalacia who underwent all of the following imaging studies: FDG-PET, SRS, and FGF23VS. Main outcome measures The rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of two or three tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.