Familial Hyperparathyroidism

Abstract

Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development.

Keywords: CASR; CDC73; GCM2; MEN1; jaw tumor syndrome; multiple endocrine neoplasia; oncogene; tumor suppressor.

Figure 1

The clinical manifestations and estimated tumor penetrance of multiple endocrine neoplasia type 1 (MEN1) syndrome. The main manifestations of MEN1 include anterior pituitary adenomas, pancreatic neuroendocrine tumors, and primary hyperparathyroidism. Except for multi-gland hyperparathyroidism which approximates 95% penetrance by age 50, the manifestations of other tumors in MEN1 have no genotype-phenotype correlation and cannot be predicted, even within kindreds. Neuroendocrine tumor (NET) hormone secretion in the anterior pituitary and pancreas can be considered functional or non-functional, while duodenal NET and parathyroid adenomas are always functional with the secretion of gastrin and parathyroid hormone, respectively. As pictured, Zollinger-Ellison Syndrome can present with multiple submucosal duodenal gastrinomas with simultaneous pancreatic gastrinomas, non-functional pancreatic tumors, as well as the development of gastric NET typically within thickened gastric folds (not pictured). Less frequent manifestations of MEN1 include foregut bronchopulmonary and thymic neuroendocrine tumors, as well as adrenal cortical adenomas and pheochromocytomas. Skin manifestations of MEN1 include lipomas that can occur anywhere on the body, collagenomas mostly on the trunk, and facial angiofibromas on the nasal bridge and cheeks. Manifestations that have been described but are not pictured include meningiomas, leiomyoma (uterus, esophagus, ureter, bladder), café-au-lait spots, and malignant breast tumors.

Figure 2

The relationship among familial forms of hyperparathyroidism that may present as familial isolated hyperparathyroidism (FIHP) as a Venn diagram. The large dashed circle represents the set of patients that can present with a provisional diagnosis of FIHP at the time of initial ascertainment. This includes patients with FIHP who have been evaluated for, but lack findings diagnostic of, MEN1, FHH, and HPT-JT (nonsyndromic FIHP; in a solid circle). Approximately 18% of nonsyndromic FIHP kindreds harbor germline gain-of-function mutations in GCM2 (inner dotted circle) (see text), whereas the remainder have currently unknown genetic etiologies. Subsets of patients with incomplete expression of MEN1, FHH and HPT-JT (the total set of patients in each syndrome represented by a solid circle) can also present with the FIHP phenotype (and thus overlap with the large dashed circle). The distinction between the nonsyndromic FIHP category and the syndromic categories arbitrarily depends on the depth and rigor of evaluation and the sensitivity of diagnostic tests used to detect the syndrome, testing that can include germline gene mutational analysis. MEN2A is a familial form of hyperparathyroidism that seldom if ever presents as FIHP, with patients usually coming to medical attention for signs and symptoms of medullary thyroid cancer and/or pheochromocytoma. Within each circle representing a defined syndrome are included the genetic locus (or loci in the case of FHH; see text) of the syndromic trait and the associated gene product. The causative gene for HPT-JT that encodes parafibromin is CDC73, formerly called HRPT2. The relationship among the patient sets illustrated as circles in this diagram is intended to be qualitative and neither the area of each circle nor the area of overlap between circles has any quantitative significance.