Bone Abstracts

Background: Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder due to deficiency of or resistance to intact fibroblast growth factor 23 (FGF23). This leads to hyperphosphatemia, increased renal reabsorption of phosphorus (TRP), and elevated or inappropriately normal 1,25-dihydroxyvitamin D (1,25D). Affected individuals may develop ectopic calcifications and/or diaphyseal hyperostosis. Mutations in FGF23, GALNT3, or KLOTHO have been identified as causative for HFTC/HHS. Here we present the first case of autoimmune hyperphosphatemic tumoral calcinosis.

Case: A 6-year old boy presented with right hip pain and a firm lesion on the lateral aspect of the hip, biopsy-confirmed as tumoral calcinosis. Biochemical evaluation showed hyperphosphatemia (7.2 mg/dl; nl 3–5.7), increased TRP (98%), and inappropriately normal 1,25D (68 pg/ml; nl 24–86). Intact and C-terminal FGF23 were elevated at 9600 pg/ml (nl 22–63) and 28,500 RU/ml (nl < 230), respectively, findings suggestive of FGF23 resistance due to a KLOTHO or possibly an FGFR1 mutation. However, no causative mutation was identified in GALNT3, FGF23, KLOTHO, or FGFR1. Exome sequencing did not reveal any variants that could explain the phenotype. The subject was prescribed a low phosphate diet, sevelamer and acetazolamide, with subsequent decrease in blood phosphorus and tumor size. Eight months later, he presented with a 2-week history of polyuria and polydipsia. Blood glucose was 433 mg/dl, insulin 4 mcU/ml, and hemoglobin A1c 10.7%, with positive islet antigen two antibodies. Given this new diagnosis of type 1 diabetes, investigation was undertaken to evaluate for possible autoimmune causes of his tumoral calcinosis. Luciferase immunoprecipitation systems (LIPS) were used to evaluate autoantibodies against FGF23, FGFR1, KLOTHO and several other autoantigen targets. LIPS revealed significantly elevated autoantibodies against FGF23 in the patient that were over 50-fold higher than healthy controls and other subjects with HFTC/HHS. In contrast, there were no detectable autoantibodies against FGFR1 or KLOTHO. FGF23 functional assays showed anti-FGF23 autoantibodies in the patient’s plasma blocked FGF23 downstream signaling in a dose-dependent manner.

Conclusion: This is the first reported case of autoimmune hyperphosphatemic tumoral calcinosis with autoantibodies against FGF23. Identification of this novel pathophysiology suggests that immunomodulatory therapy may be an effective treatment.

Disclosure: The authors declared no competing interests.