PHEX expression in parathyroid gland and parathyroid hormone dysregulationin X-linked hypophosphatemia

X-linked hypophosphatemia (XLH), a renal phosphate (Pi) wasting disorder wi th defective bone mineralization, is caused by mutations in the PHEX gene ( a Pi-regulating gene with homology to endopeptidases on the X chromosome). Parathyroid hormone (PTH) status in XLH has been controversial, with the pr evailing belief that hyperparathyroidism develops in response to Pi therapy . We report a 5-year-old girl with XLH (patient 1) who had significant hype rparathyroidism at presentation, prior to initiation of therapy. We examine d her response to a single oral Pi dose, in combination with calcitriol, an d demonstrated a rise in serum concentration of intact PTH, which peaked at 4 h and paralleled the rise in serum Pi concentration. We also present two other patients whose parathyroid glands were analyzed for PHEX mRNA expres sion following parathyroidectomy. Patient 2 had autonomous hyperparathyroid ism associated with chronic renal insufficiency, and patient 3, with XLH, d eveloped autonomous hyperparathyroidism after 8 years of therapy with Pi an d calcitriol. Following parathyroidectomy, patient 3 exhibited an increase in both serum Pi concentration and renal Pi reabsorption. The abundance of PHEX mRNA, relative to p-actin mRNA, in parathyroid glands from patients 2 and 13 was severalfold greater than that in human fetal calvaria, as estima ted by ribonuclease protection assay. In summary, we have shown that hyperp arathyroidism can be a primary manifestation of XLH and that PHEX is abunda ntly expressed in the parathyroid gland. Given that PHEX has homology to en dopeptidases, we propose that PHEX may have a role in the normal regulation of PTH.