The calcium-sensing receptor (CASR), a critical regulator of extracellular calcium homeostasis, is a seven-transmembrane-spanning G-protein-coupled receptor, which is expressed in cells of the parathyroid gland and the kidney tubule. The discovery of the CASR was a surprise, since previously no small cation had been shown capable of acting as a ligand for a G-protein-coupled receptor.⁷ The human CASR, encoded by six exons of the gene located on chromosome 3q113.3-q21, is sensitive to changes in the ambient calcium concentration and when activated it inhibits parathyroid hormone (PTH) secretion and the renal reabsorption of calcium. With heterogenous inactivating mutations of the CASR gene the parathyroid cell fails to sense properly an increased serum calcium concentration, and the resulting increase in PTH secretion causes FHH, an autosomal dominant disease characterized by hypocalciuria, hypercalcemia, and parathyroid hyperplasia. It is important for clinicians to recognize this relatively mild form of familial hyperparathyroidism; although parathyroidectomy reduces the serum calcium level, it is only temporary. With inactivating mutations in both alleles of the CASR gene, neonatal severe hyperparathyroidism ([NSHPT] MIM 239200) develops with serum calcium levels in the range of 15 to 20 mg/dL. This disease represents a life-threatening emergency and urgent parathyroidectomy is indicated.⁸ Conversely, activating mutations of the CASR gene cause the parathyroid cells to sense that serum calcium is “elevated” when it is actually normal. There is a resulting decrease in the blood calcium level expressed as the syndrome of autosomal dominant hypoparathyroidism ([ADH] MIM 168468).⁹ To date approximately 115 mutations (60% inactivating and 40% activating) have been described in the CASR gene, and most are missense mutations clustered in exons 3, 4, and 7.

HPT-JT is characterized by the autosomal dominant occurrence of hyperparathyroidism, ossifying fibromas of the mandible or maxilla, renal cysts or solid tumors, and uterine fibromas.¹⁰ Approximately 50 families with HPT-JT have been reported and 80% of patients have hyperparathyroidism, and in 15% of cases the parathyroid tumors are malignant. It is noteworthy that the age-related penetrance of HPT-JT is approximately 40% by age 40 in contrast to MEN-1 where the age-related penetrance is 98% by age 40.¹¹ Members of kindreds with this disease need lifelong surveillance by physical examination and biochemical evaluation. It has even been suggested that serial ultrasound examination of the neck should be performed as parathyroid carcinoma has been reported in normocalcemic kindred members.¹²

The cause of HPT-JT appears to be a tumor suppressor gene, HRPT2, which is located on chromosome 1q25-q31. The HPRT2 gene consists of 17 exons and the mutations are scattered throughout the 1593 coding region, with the majority resulting in functional loss through premature truncation.¹³ Approximately 16 activating mutations of HRPT2, most of which are frameshift, have been identified. The HPRT2 gene encodes a 531 amino acid protein, parafibromin (named for parathyroid tumors and jaw fibromas).¹⁴ The function of parafibromin is unknown but it is thought to regulate posttranscriptional events and histone modification. There is recent evidence that parafibromin has pro-apoptotic activity, important as a tumor suppressor function.¹⁵ Germline mutations in HPRT2 have been identified in approximately half of HPT-JT families, and even in some families with MEN-2A.

Besides the evidence of germline mutations in patients with the HPT-JT somatic HRPT2 mutations have been detected in the majority of patients with sporadic parathyroid carcinoma.¹⁶,¹⁷ It is important to note that mutations in HRPT2 are rarely if ever seen in sporadic parathyroid adenomas, an important diagnostic finding distinguishing benign from malignant parathyroid tumors.¹⁵,¹⁸

The syndrome of FIHP is a heterogenous condition, and some kindreds thought to have this disease have been shown to have germline mutations of MEN1, CASR, or HRP-JT, suggesting that the disease represents incompletely expressed forms of MEN1, FHH, or HPT-JT.¹⁹ Over 100 families with FIHP have been reported and in most cases the causative genetic mutation is unknown, although there are convincing data that it resides on chromosome 2p13.3-14.²⁰

Pituitary adenomas can occur as a component of CNC, a familial disease characterized by hypersomatotropenemia, cardiac or cutaneous myxomas, spotty skin pigmentation, primary pigmented nodular adrenal disease, and testicular tumors.²¹ About
75% of patients exhibit subclinical increases in growth hormone (GH), insulinlike growth factor-1 (IGF-1), and prolactin. Acromegaly occurs in about 10% of patients. Genetic linkage analysis has shown two loci for CNC, one on chromosome 2p16 (CNC2), and the other on chromosome 17q22-24 (CNC1). Neither locus is associated with a specific phenotype. In more than 50% of cases the CNC has been linked to an inactivating mutation in the gene coding for the protein kinase A (PKA) type 1α subunit, PRKAR1A, at 17q24. The 2p16 locus is uncharacterized.

Pituitary adenomas can also occur as FIPA. Daly et al.²² evaluated 64 families with FIPA, residing in Belgium, France, Italy, and the Netherlands. Of the 138 affected family members, 55 had prolactinomas, 47 had somatotropinomas, 28 had nonsecreting adenomas, and 8 had adrenocorticotropic hormone-secreting tumors. The incidences of a homogenous (single tumor) phenotype and a heterogeneous tumors phenotype were approximately equal. Affected patients were found to have no mutations in either the MEN1 or PRKRA1A genes.

Recently, Vierimaa et al.,²³ in a study of cases of low penetrance familial pituitary adenoma in Northern Finland identified loss of mutation functions in the aryl hydrocarbon receptor interacting protein (AIP) gene. AIP forms a complex with the aryl hydrocarbon receptor (AHR) and two 90-kD heat-shock proteins (HSP90). AHR is a ligand-activated transcription factor and also participates in cellular signaling pathways.

Expression profiling in two families resulted in the identification of AIP as one of the candidate genes, and a nonsense mutation (Gln14X) was also identified and found to segregate with the GH-secreting adenomas.²³ Daly et al.²⁴ studied 73 FIPA families with 156 individuals and found that 11 of them harbored 10 AIP germline mutations. Kindred members with AIP mutations, compared to those without mutations, were younger and had larger tumors. Growth hormone producing tumors predominated among family members with AIP mutations.