**1. Introduction**

The inappropriate or excessive secretion of parathyroid hormone (PTH) from one or multiple abnormal parathyroid glands typically results in hypercalcemia and the disorder of mineral metabolism called primary hyperparathyroidism (HPT) [1]. Most cases of HPT are sporadic (~95%). Among the small remaining fraction of patients with an inherited basis for HPT, most harbor germline mutation of a known parathyroid tumor susceptibility gene (listed in **Table 1**). In spite of their infrequency, study of the genetics of these uncommon inherited syndromes has yielded substantial insight into the etiology of both sporadic and familial parathyroid tumor development. Since the release of PTH from parathyroid cells involves close regulation by the calcium-sensing receptor (CASR), a cell surface transmembrane receptor of the G protein-coupled receptor family C [2], the germline mutation of the CASR and other genes mediating its signaling can also result in inherited syndromes characterized by hypercalcemia and circulating levels of PTH that are elevated or inappropriately normal. This chapter will summarize current knowledge


#### **Table 1.**

*Genes implicated in syndromic parathyroid neoplasia and related hypercalcemic states.*

**115**

*Familial Syndromes of Primary Hyperparathyroidism DOI: http://dx.doi.org/10.5772/intechopen.93036*

enabling signaling through such binding [3].

non-hematopoietic bone marrow.

mammals results in tetany and death.

on calcium.

both benign and malignant parathyroid gland neoplasia**.**

**2. The evolution of calcium regulation in vertebrates**

of the clinical genetics and molecular pathophysiology of HPT that results from

a result, early eukaryotes living in a marine environment had easy access to calcium. Given this abundant supply of extracellular calcium, numerous intracellular processes evolved in simple eukaryotes that depended on this divalent cation. Such calcium-dependent processes were preserved in metazoans. Thus marine chordates and early vertebrate fish depended on calcium for cellular processes such as membrane permeability, neurotransmitter release, intracellular second messenger signaling, muscular contraction, neuromuscular excitability, and the actions of multiple calcium-dependent enzymes. Calcium's particular coordination chemistry facilitated many proteins' ability to reversibly bind divalent calcium ions, thus

In sea water the concentration of elemental calcium is approximately 10 mM. As

Calcium is much scarcer on land compared to the marine environment. As lobefinned fish, marine vertebrates believed to be the ancestors of the early amphibians, began to explore the periphery of the terrestrial environment, evolutionary pressure to develop a system of internal calcium balance mounted. A system of internal calcium homeostasis at the organismal level would ensure the continued preservation and function of numerous cellular and tissue operations that vitally depended

Metabolically-active trabecular or cancellous bone in lobe-finned fish and associated hematopoietic bone marrow likely co-evolved [4]. These developments probably both lightened overall skeletal mass and provided a reliable internal source of calcium as a basis for calcium homeostasis. The lightening of skeletal mass was critical since lobe-finned fish and early amphibians had to come to terms with full gravitational force in their terrestrial movements, no longer buoyed by surrounding seawater in accordance with Archimedes' principle [5]. The potential significance of the close physical apposition of hematopoietic bone marrow to spongiform bone, inferred from X-ray synchrotron microtomography of fossilized lobe-finned fish humerus [4], is suggested by the realization that osteoclasts, cells uniquely specialized to mobilize ionized calcium via resorption of bone, develop from hematopoietic stem cell precursors [6]. In contrast, osteoblasts, which lay down osteoid and mineralize bone, derive from mesenchymal stem cells which are abundant in

Although analogs of Gcm2, Gata3, CaSR, PTH, and other genes associated with the development and function of human parathyroid glands are expressed in the fish gills, actual parathyroid glands are first seen in amphibians [7–9]. Complete surgical excision of parathyroid gland tissue in amphibians, reptiles, birds, and

**3. The pathophysiology of primary hyperparathyroidism**

PTH secretion from cells of the parathyroid glands is finely regulated in response to changes in the ambient ionized calcium level in order to maintain the circulating calcium concentration within a defined physiologic range. The G protein-coupled CASR is a critical regulator of PTH secretion and is located on the plasma membrane of chief cells in the parathyroid glands [10, 11]. In a classic endocrine negative feedback loop, the active form of cholecalciferol,

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

*MEN1* Menin 11q13.1 Multiple endocrine

*CDKN1B* P27(Kip1) 12p13.1 Multiple endocrine

**Chromosomal location**

Parafibromin 1q31.2 Hyperparathyroidism-

**Associated hyperparathyroid syndrome: main syndromic manifestations**

neoplasia type 1 (MEN1): anterior pituitary, parathyroid, enteropancreatic, foregut carcinoid tumors

jaw tumor syndrome: fibro-osseous jaw, parathyroid, uterine tumors; renal cysts

neoplasia type 4 (MEN4): anterior pituitary, other involvement varies

hyperparathyroidism

hypercalcemia type 2

hypercalcemia type 1 (FHH1) with heterozygous inactivation; neonatal severe hyperparathyroidism (NSHPT) with homozygous inactivation

6p24.2 Familial isolated

primary

3q13.33-q21.1 Familial hypocalciuric

19p13.3 Familial hypocalciuric

19q13.32 Familial hypocalciuric

(FHH2)

hypercalcemia type 3 (FHH3): hypercalcemia more severe than in FHH1

neoplasia type 2A: medullary thyroid cancer, pheochromocytoma, parathyroid tumors

implicated in sporadic parathyroid tumors)

**Features of syndromic parathyroid tumors**

Multiple, asymmetric tumors typical (>99% benign)

Single tumor common (~20% malignant)

Single to multiple glands (benign in reports to date); can be recurrent

Single to multiple

FHH1: near-normal size and surgical pathology; altered serum calcium set-point for PTH

glands

release NSHPT: marked enlargement of multiple glands by polyclonal (non-neoplastic) mechanism

ND

ND

Single tumor common (>99% benign)

NA (to date, only implicated in sporadic parathyroid tumors)

**Gene Corresponding protein**

*GCM2* Glial cells missing

*CASR* Calcium-sensing receptor

*GNA11* G protein α11 subunit

> protein-2 sigma subunit

*RET* c-Ret 10q11.21 Multiple endocrine

*Genes implicated in syndromic parathyroid neoplasia and related hypercalcemic states.*

Cyclin D1 11q13.3 NA (to date, only

*AP2S1* Adaptor

transcription factor 2

*CDC73/ HRPT2*

**114**

**Table 1.**

*CCND1/ PRAD1*

of the clinical genetics and molecular pathophysiology of HPT that results from both benign and malignant parathyroid gland neoplasia**.**
