Autosomal dominant hypophosphatemic rickets (ADHR) is a renal phosphate wasting disorder resulting from Fibroblast Growth Factor-23 (FGF23) missense mutations. These mutations prevent cleavage of FGF23 into inactive fragments. ADHR has a variable timing of penetrance and waxing and waning of FGF23 concentrations which we have demonstrated relates to iron concentrations in cross-sectional and longitudinal studies, such that only subjects with iron deficiency developed high FGF23 concentrations. In light of our novel findings, we propose testing the following hypothesis: Iron repletion with low dose oral iron will decrease C-terminal and intact FGF23 concentrations in ADHR patients having baseline iron concentrations in the deficient and insufficient range and rescue the hypophosphatemic phenotype. We propose the following specific aim: 1. Perform a pilot study in ADHR patients having low serum iron concentrations to determine if increasing serum iron concentrations above 100 mcg/dl results in decreasing intact FGF23 (primary endpoint) and C-terminal FGF23 concentrations and normalizes serum phosphorus and TMP/GFR. Successful completion of the proposed pilot study will enable the investigative team to choose an optimal dosing regimen; determine the kinetics of the iron/FGF23/phosphate relationship; determine which measure of iron status best reflects the relationship between iron and FGF23 (serum iron versus indices of iron stores or anemia); and determine the iron dosing and feasibility for performing a larger multicenter trial to treat ADHR with iron.
Autosomal dominant hypophosphatemic rickets (ADHR) results from mutations causing high Fibroblast Growth Factor-23 (FGF23) and low phosphate, and rickets/osteomalacia. Therapy with phosphate and calcitriol has significant risks of adverse events. Evaluating iron supplementation to achieve levels in the upper normal range has the potential to safely and inexpensively normalize FGF23 and phosphate in ADHR without the risks of current therapy.
| Econs, Michael J (2017) Genetic diseases resulting from disordered FGF23/klotho biology. Bone 100:56-61 |
