CaSR gene (chr. 3q13.3-21) encodes for a protein of 1078 aminoacids present in the plasma membrane as a dimer. CaSR is a member of the G-protein coupled receptors and its structure has 3 different domains [
1,
2]. The extracellular domain (612 aminoacids) binds extracellular calcium through its multiple negative charges allowing the CaSR to function as a sensitive detector of extracellular calcium; the transmembrane part (250 aminoacids) has 7 membrane-spanning domains; the intracellular tail (216 aminoacids) interacts with the G-proteins and filamin A to translate within the cells the signal produced by the extracellular calcium binding [
3,
4]. Through these and other pathways, CaSR may influence cell function, especially PTH secretion from parathyroid cells, but also cell proliferation and gene expression [
5,
6]. This process takes place mainly in parathyroid and kidney tubular cells, regulating calcium concentrations in extracellular fluid. In the kidney, the CaSR performs different tasks depending on the various tubular segments in which it is located [
7]. It is expressed on the luminal membrane of the proximal tubular cells where it senses the increase in calcium luminal concentrations and inhibits cAMP production induced by PTH [
8,
9]. CaSR is expressed on the basolateral membrane of the thick ascending limb of Henle loop [
9], where modulates the electric gradient generated by sodium-potassium reabsorption and potassium recycling, inhibiting the sodium-potassium-chloride carrier activity. Therefore, after an increase in serum calcium, CaSR decreases the potential, eventually supporting calcium reabsorption and promoting calcium excretion [
5]. In the distal convoluted tubule, CaSR is located on the basolateral membrane of tubular cells where reduces the active calcium reabsorption by interfering with the calcium pump function through a phospholipase C dependent mechanism [
10]. In adults, inactivating mutations of CaSR gene are found in FHH, an autosomal dominant disease characterized by moderate but significant hypercalcemia, accompanied by few symptoms [
11,
12], with inappropriately normal serum PTH levels, and by a low or normal urinary calcium levels [
12‐
14] with histologically normal parathyroid glands. The condition does not require treatment, and responds poorly to parathyroidectomy. FHH should be distinguished from primary HPT, in which the elevated serum and urinary calcium levels are normalized by successful parathyroid surgery. Familial primary HPT is inherited as autosomal dominant mutation either as the single lesion (isolated HPT form) [
15] or in the context of multiple endocrine neoplasia (MEN) type 1 or 2A [
16] and the HPT-jaw tumor syndrome [
17].