Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies
Mary Scott Roberts, … , Michael T. Collins, Rachel I. Gafni
Mary Scott Roberts, … , Michael T. Collins, Rachel I. Gafni
Published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5368-5373. https://doi.org/10.1172/JCI122004.
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Concise Communication Bone biology Endocrinology

Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies

Abstract

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient’s plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment.

Authors

Mary Scott Roberts, Peter D. Burbelo, Daniela Egli-Spichtig, Farzana Perwad, Christopher J. Romero, Shoji Ichikawa, Emily Farrow, Michael J. Econs, Lori C. Guthrie, Michael T. Collins, Rachel I. Gafni

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Figure 3

The effect of patient plasma on FGF23 signaling in HEK293-Klotho cells.

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The effect of patient plasma on FGF23 signaling in HEK293-Klotho cells. ...
Relative EGR1 mRNA expression compared with 18S rRNA in HEK293-Klotho cells treated for 2 hours with either recombinant human FGF23 (vehicle, 25, 50, or 100 ng/ml) (A and B) or recombinant human bFGF (vehicle or 10 ng/ml) (C) and ±2% patient plasma (A and C) or ±2% control plasma (B). n = 3. Single independent experiments were normalized to their untreated controls. Fold change of phosphorylated ERK1/2 (p-ERK1/2) protein abundance compared with ERK1/2 in HEK293-Klotho cells treated for 15 minutes with either vehicle, recombinant human FGF23 (25 ng/ml) (D, E, G, H), or recombinant human bFGF (10 ng/ml) (F and I) and ±2% patient plasma (D, F, G, I) or ±2% control plasma (E and H). n = 3–6. Single independent experiments were normalized to vehicle control. Representative blots of single experiments show decreased p-ERK1/2 protein abundance with recombinant FGF23 (25 ng/ml) compared with vehicle-treated cells in the presence of patient’s plasma (G). Addition of control plasma in the presence of FGF23 resulted in no change in p-ERK1/2 protein abundance (H). There was no change in p-ERK1/2 protein abundance with bFGF (10 ng/ml) in the presence of patient’s plasma (I). Data are presented as mean + SD, and 2-way ANOVA followed by Tukey’s test for multiple comparisons was used for statistical analysis. *P < 0.05.