title: PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia.
abstract: 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.
authors.affiliation: Department of Pediatrics, McGill University, Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3H 1P3.
authors.forename: T D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.forename: H S
authors.initials: HS
authors.lastname: Tenenhouse
authors.forename: P
authors.initials: P
authors.lastname: Goodyer
mesh_terms: D000293:Adolescent; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D006961:Hyperparathyroidism / Q000209:etiology; D017674:Hypophosphatemia / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D007223:Infant; D007676:Kidney Failure, Chronic / Q000150:complications; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010280:Parathyroid Glands / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D010375:Pedigree; D010710:Phosphates / Q000493:pharmacokinetics / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics*
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human