Autoimmune osteomalacia: a novel FGF23-related hypophosphatemic osteomalacia.

BACKGROUND: Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets/osteomalacia arises from excessive FGF23 activity, with X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) as the most common congenital and acquired forms, respectively. However, in a substantial subset of patients with acquired FGF23-related hypophosphatemic osteomalacia, phosphaturic mesenchymal tumors (PMTs) remain undetectable despite extensive imaging studies. A recent study identified autoantibodies against PHEX, the gene responsible for XLH, in 5 of 13 patients with acquired FGF23-related osteomalacia without detectable PMTs, thereby defining a novel disease entity termed autoimmune osteomalacia (AIO). Clinically, AIO presents with milder disease activity than TIO, comparable in severity to XLH.

FINDINGS: Some patients exhibited concomitant autoimmune disorders, and whole-genome sequencing revealed rare variants in autoimmune susceptibility genes, suggesting a genetic predisposition. Therapeutic options include burosumab and, potentially, immunosuppressive therapy such as glucocorticoids. Long-term follow-up indicates that AIO patients may develop ectopic ossifi cation, similar to XLH. Anti-PHEX autoantibodies were detected using both luciferase immunoprecipitation systems and fl ow cytometry, underscoring the importance of complementary methods for detecting antibodies against native conformational epitopes.

CONCLUSIONS: Recognition of AIO should be particularly considered in patients with acquired FGF23-related hypophosphatemia who have undetectable PMTs, relatively mild disease activity, and concurrent autoimmune diseases.