Introduction

In this chapter we will examine the molecular genetic basis of parathyroid gland tumorigenesis across a spectrum of heritable and sporadic disorders (Table 65.1). Two genetic predispositions to parathyroid (and other) tumors, multiple endocrine neoplasia types 1 and 2, are addressed in a separate chapter. We begin with a brief review of parathyroid gland physiology, because a major effect of parathyroid neoplasia involves its disruption, and because of its relevance to modern molecular-targeted therapeutics.

Role of the parathyroid glands in maintaining mineral ion homeostasis

The parathyroid glands, usually four in number, are located near the posterior surface of the thyroid gland and play a central role in maintaining homeostasis of mineral ions – especially extra-cellular calcium (Ca2+o), through the regulated release of parathyroid hormone (PTH; 3). This is achieved through the parathyroids’ ability to carefully orchestrate movements of Ca2+ into or out of the body via the intestines and kidneys, respectively. In addition, the skeleton provides a nearly inexhaustible supply of calcium that can be accessed by PTH action (3,4). A central element in this homeostatic system is the capacity of the parathyroid glands to sense minute (i.e. 1–2%) changes in Ca2+o via the Ca2+o-sensing receptor, a G-protein coupled, cell-surface receptor whose principal physiological ligand is Ca2+o (4). A drop in Ca2+o evokes a brisk increase in PTH secretion, and parathyroid glands have the capacity to increase their mass 10–100-fold or more in response to chronic hypocalcemia, so-called secondary hyperparathyroidism (SHPT). Parathyroid glands that have undergone secondary parathyroid hyperplasia, however, only regress in size and cell number very slowly, owing, at least in part, to the limited capacity of even normal parathyroid cells to undergo apoptosis (5).