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Tumor-induced osteomalacia (TIO) is the most common acquired form of fibroblast growth factor 23-related hypophosphatemic rickets-osteomalacia (FGF23rHR) and is characterized by excessive secretion of FGF23 from tumors.1 First-line treatment for TIO is surgical removal of the relevant tumor; however, in 27–45% of patients with suspected TIO, such tumors are undetectable, despite thorough examinations.2–4 We hypothesized that the absence of a tumor in some patients with suspected TIO might be related to autoantibodies against proteins regulating plasma phosphate levels.

rgical removal of the relevant tumor; however, in 27–45% of patients with suspected TIO, such tumors are undetectable, despite thorough examinations.2–4 We hypothesized that the absence of a tumor in some patients with suspected TIO might be related to autoantibodies against proteins regulating plasma phosphate levels. Through a combination of genetic and tumor screening approaches, 13 patients with unexplained acquired FGF23rHR were identified (Tables S1 and S2). Although acquired FGF23rHR affects all races, all participants in this study were Japanese (Table S3). Sera from patients and controls were screened for autoantibodies against causative proteins for congenital FGF23rHR, including DMP1, ENPP1, FGFR1, and PHEX, with the use of luciferase immunoprecipitation system (LIPS) immunoassays.5 Immunoassay screening detected autoantibodies to PHEX (phosphate regulating endopeptidase X-linked) in four of the 13 patients with unexplained acquired FGF23rHR (Patients No. 9 and No. 11–13); none had detectable autoantibodies against DMP1, ENPP1, or FGFR1 (Fig. 1A). These results, obtained with a PHEX-NanoLuc assay, were confirmed with a construct carrying NanoLuc conjugated to the N-terminus of PHEX (NanoLuc-PHEX; Fig. S1). Serum samples from 18 TIO patients, 9 X-linked hypophosphatemia (XLH) patients, and 10 persons with other endocrine disorders were all seronegative for autoantibodies (Fig. 1A).

ined with a PHEX-NanoLuc assay, were confirmed with a construct carrying NanoLuc conjugated to the N-terminus of PHEX (NanoLuc-PHEX; Fig. S1). Serum samples from 18 TIO patients, 9 X-linked hypophosphatemia (XLH) patients, and 10 persons with other endocrine disorders were all seronegative for autoantibodies (Fig. 1A). Flow cytometry was also used to screen for autoantibodies. Flow cytometry confirmed the autoantibodies in these 4 patients, and identified another patient (No. 10) with PHEX autoantibodies. Thus, five of 13 patients (38%) had PHEX autoantibodies (Fig. 1B). This finding suggested that the conformation of the epitope detected in the cell lysate changed from that of the original membranous form in the LIPS assay. The clinical characteristics of the PHEX-seropositive patients, as well as those of patients with TIO and patients with XLH in this study, are summarized in Tables S2 and S4–S6. Among the five PHEX-seropositive patients, one (No. 9) had multiple autoimmune findings, including Graves’ disease, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, and antiphospholipid syndrome.

as those of patients with TIO and patients with XLH in this study, are summarized in Tables S2 and S4–S6. Among the five PHEX-seropositive patients, one (No. 9) had multiple autoimmune findings, including Graves’ disease, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, and antiphospholipid syndrome. Our report describes unique cases of autoimmune osteomalacia with pathogenic autoantibodies targeting PHEX. While further studies are needed to mechanistically determine how PHEX autoantibodies cause osteomalacia, we infer that not only burosumab, an anti-FGF23 monoclonal antibody, but also immunomodulatory therapy might be effective for this subset of PHEX-seropositive patients. Our findings also suggest the potential utility of early antibody confirmation to reduce unnecessary tumor detection procedures and facilitate the prompt initiation of targeted therapies, such as burosumab. In conclusion, our findings report an acquired osteomalacia associated with autoantibodies against PHEX, which might be termed autoimmune osteomalacia (AIO).