Chapter 60 - Molecular Basis of PTH Overexpression

Abstract

Parathyroid hyperfunction is found in several disease states including sporadic primary and secondary hyperparathyroidism and familial disorders such as the multiple endocrine neoplasia (MEN) syndromes. Primary hyperparathyroidism is a common disorder characterized by hypercalcemia caused by an excessive secretion of parathyroid hormone (PTH). This is due to both an increased parathyroid gland mass and a resetting of the control of PTH secretion from the parathyroid cell by the ambient calcium concentration. Hyperparathyroidism may also occur as part of familial syndromes, such as multiple endocrine neoplasia types 1 and 2 (MEN1 and 2), the hereditary hyperparathyroidism and jaw tumor (HPT-JT) syndrome, and familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). This chapter explains the molecular basis of sporadic parathyroid tumorigenesis. The cyclin D1/PRAD1 oncogene has been identified as a parathyroid oncogene, is overexpressed in 20% to 40% of parathyroid adenomas, and is also involved in the development of many additional tumor types. The gene responsible for MEN1 has been identified, and mutations in menin contribute in up to 20% of sporadic parathyroid adenomas. The identification of the tumor suppressor parafibromin encoded by the HRPT2 gene has provided important insight into parathyroid disease, especially parathyroid carcinoma. Ultimately, a description of parathyroid tumorigenesis will need to account for such features as the rarity of parathyroid carcinoma, the increased incidence of tumors after neck irradiation, and the increased frequency of hyperparathyroidism in postmenopausal women.