FGF-23 (fibroblast growth factor-23), secreted by osteocytes, is central to phosphate homeostasis. In X-linked hypophosphataemia (XLH), PHEX mutations cause elevated FGF-23. What is the resulting biochemical phenotype?
- A Hyperphosphataemia, hypercalcaemia, elevated 1,25(OH)2D3, and elevated PTH
- B Hypophosphataemia, low 1,25(OH)2D3 (due to FGF-23 inhibiting CYP27B1 and activating CYP24A1), normal calcium, and rickets ✓
- C Hypophosphataemia, elevated 1,25(OH)2D3, hypercalciuria, and nephrolithiasis
- D Hyperphosphataemia, low PTH, elevated 1,25(OH)2D3, and soft-tissue calcification
Explanation
FGF-23 acts on the kidney to: (1) downregulate NaPi-2a/2c sodium-phosphate cotransporters in the proximal tubule, causing phosphaturia and hypophosphataemia; and (2) suppress CYP27B1 (25-OH-D 1α-hydroxylase) and activate CYP24A1 (24-hydroxylase), reducing 1,25(OH)2D3 production. Low 1,25(OH)2D3 impairs intestinal calcium and phosphate absorption. The combined hypophosphataemia and low active vitamin D causes rickets (in children) or osteomalacia (in adults) that is resistant to standard vitamin D supplementation — treatment requires phosphate supplements plus calcitriol. Burosumab (anti-FGF-23 monoclonal antibody) is now approved for XLH.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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