What is the pathophysiology of XLH?

• A. PHEX mutation leads to increased FGF23 activity causing renal phosphate wasting and decreased 1,25(OH)2D.
• B. PHEX mutation leads to decreased FGF23 activity causing renal phosphate retention and increased 1,25(OH)2D.
• C. FGF23 mutation causes increased phosphate reabsorption and increased 1,25(OH)2D.
• D. Vitamin D receptor mutation leading to phosphate wasting.

Answer: (B)

XLH is driven by loss-of-function mutations in PHEX that lead to increased FGF23 activity. FGF23 acts on the kidney to promote phosphate wasting by downregulating the sodium-phosphate cotransporters in the proximal tubule, which lowers phosphate reabsorption and causes hypophosphatemia. It also suppresses 1α-hydroxylase, reducing production of 1,25-dihydroxyvitamin D (calcitriol), further decreasing intestinal phosphate (and calcium) absorption. The combination of low phosphate and low calcitriol impairs bone mineralization, producing rickets in children and osteomalacia in adults. The description that matches XLH is a PHEX mutation leading to increased FGF23 activity with renal phosphate wasting and decreased calcitriol. A statement claiming decreased FGF23 activity would predict phosphate retention and increased calcitriol, which does not fit XLH.