PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH), a renal phosphate (Pi) wasting disorder with 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 prevailing belief that hyperparathyroidism develops in response to Pi therapy. We report a 5-year-old girl with XLH (patient 1) who had significant hyperparathyroidism at presentation, prior to initiation of therapy. We examined her response to a single oral Pi dose, in combination with calcitriol, and 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 expression following parathyroidectomy. Patient 2 had autonomous hyperparathyroidism associated with chronic renal insufficiency, and patient 3, with XLH, developed autonomous hyperparathyroidism after 8 years of therapy with Pi and calcitriol. Following parathyroidectomy, patient 3 exhibited an increase in both serum Pi concentration and renal Pi reabsorption. The abundance of PHEX mRNA, relative to beta-actin mRNA, in parathyroid glands from patients 2 and 3 was several-fold greater than that in human fetal calvaria, as estimated by ribonuclease protection assay. In summary, we have shown that hyperparathyroidism can be a primary manifestation of XLH and that PHEX is abundantly expressed in the parathyroid gland. Given that PHEX has homology to endopeptidases, we propose that PHEX may have a role in the normal regulation of PTH.