Journal of Clinical Endocrinology & Metabolism, Vol 81, 3584-3588, Copyright © 1996 by Endocrine Society

ARTICLES

Hypercalcemia due to constitutive activity of the parathyroid hormone (PTH)/PTH-related peptide receptor: comparison with primary hyperparathyroidism

AM Parfitt, E Schipani, DS Rao, W Kupin, ZH Han and H Juppner
Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, Michigan 48202, USA.

In Jansen's disease (JD), the hypercalcemia found in about half the cases is the result of a mutant, constitutively overactive, form of the PTH/PTHrP receptor, which in these cases also causes the skeletal dysplasia. The subject of the present report was first seen in 1956 and is still under treatment at the same medical center. We report the clinical course and a detailed study of calcium and bone metabolism carried out in 1976 and compare the results with those of six typical patients with mild primary hyperparathyroidism in whom exactly the same studies were carried out. In the patient with JD, the hypercalcemia was of early onset; chronic and nonprogressive; refractory to the administration of phosphate, glucocorticoid, and calcitonin; and accompanied by suppressed PTH levels as determined by two different immunoassays, an undetectable PTHrP level, increased excretion of nephrogenous cAMP (an in vivo bioassay of endogenous PTH production), decreased tubular reabsorption of phosphate, increased tubular reabsorption of calcium, increased biochemical indexes of bone turnover, and increased histological indexes of bone turnover on iliac bone histomorphometry after double tetracycline labeling. There was exaggerated loss of cortical bone and preservation of cancellous bone. All the results in JD relating to renal or skeletal effects of PTH excess were within or close to the ranges found in the hyperparathyroid patients, except that tubular reabsorption of phosphate was more depressed. Because PTH secretion was suppressed, any effects mediated by putative alternative receptors would have been diminished. We conclude that 1) the hypercalcemia due to constitutive overactivity of the PTH/PTHrP receptor is indistinguishable from that of mild primary hyperparathyroidism in clinical characteristics and renal tubular and skeletal features; and 2) the classic laboratory manifestations of primary hyperparathyroidism, with the possible exception of osteitis fibrosa cystica, can all be accounted for by overactivity of a single receptor.

This article has been cited by other articles:

				Z. Ding, S. Kim, and S. P. Kunapuli Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor Mol. Pharmacol., January 1, 2006; 69(1): 338 - 345. [Abstract] [Full Text] [PDF]

				T. P. Jacobs and J. P. Bilezikian Rare Causes of Hypercalcemia J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6316 - 6322. [Abstract] [Full Text] [PDF]

				M. Ai, S. L. Holmen, W. Van Hul, B. O. Williams, and M. L. Warman Reduced Affinity to and Inhibition by DKK1 Form a Common Mechanism by Which High Bone Mass-Associated Missense Mutations in LRP5 Affect Canonical Wnt Signaling Mol. Cell. Biol., June 15, 2005; 25(12): 4946 - 4955. [Abstract] [Full Text] [PDF]

				T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands Endocr. Rev., February 1, 2005; 26(1): 78 - 113. [Abstract] [Full Text] [PDF]

				E. Schipani, C. Langman, J. Hunzelman, M. Le Merrer, K. Y. Loke, M. J. Dillon, C. Silve, and H. Jüppner A Novel Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation in Jansen's Metaphyseal Chondrodysplasia J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3052 - 3057. [Abstract] [Full Text]

				E. Schipani, G. S. Jensen, J. Pincus, R. A. Nissenson, T. J. Gardella, and H. Jüppner Constitutive Activation of the Cyclic Adenosine 3',5'-Monophosphate Signaling Pathway by Parathyroid Hormone (PTH)/PTH-Related Peptide Receptors Mutated at the Two Loci for Jansen's Metaphyseal Chondrodysplasia Mol. Endocrinol., June 1, 1997; 11(7): 851 - 858. [Abstract] [Full Text]