Hyperparathyroid genes: sequences reveal answers and questions

Abstract

Objective: To review hyperparathyroid syndromes and genes.

Methods: Pertinent original studies from the literature are discussed.

Results: Six main hyperparathyroid syndromes are recognized; 5 are from germline mutations in 4 genes-CASR, MEN1, RET, and HRPT2. Each hyperparathyroid syndrome was first described around 1965; the main gene for each syndrome was identified about 30 years later. Gene identification addressed clinical issues. (1) Testing for mutation carriers among affected probands or among unaffected relatives is more robust than prior methods, which were based on syndromal traits such as serum calcium. (2) Interpreting a gene test (RET) could guide an important intervention; other gene tests could yield useful information for patients and physicians. (3) Proving the roles of each gene (in particular, MEN1 somatic mutations) provided insights about contributions to many common tumors. (4) Clarifying molecular pathways and drugs led, for example, to the CASR-aided development of calcimimetic and calcilytic drugs. (5) Explaining novel features, such as the CASR gene encoding a membrane calcium-sensing receptor and its mutations resulting in nonsuppressed parathyroid hormone secretion uncoupled from proliferation, characterized familial hypocalciuric hypercalcemia. (6) Disclosing probands without an identifiable mutation promoted searches for other syndromal genes. Subsequently, rare multiple endocrine neoplasia type 1-like families were shown to have inactivating germline mutations, first of p27 and subsequently of p15, p18, or p21.

Conclusion: The next frontier in mutation detection is arriving, with possible sequencing of the whole exome or even the whole genome for 1 case or 1 tumor at an affordable cost.

Fig. 1

Timeline for 5 of the 6 hyperparathyroid syndromes, showing their year of first discovery as a familial syndrome and their year of first association to a germline causative hyperparathyroid gene. Familial isolated hyperparathyroidism is omitted here because its gene (or genes) has not yet been identified. FHH = familial hypocalciuric hypercalcemia; HPT-JT = hyperparathyroidism-jaw tumor syndrome; MEN1 = multiple endocrine neoplasia type 1; MEN2A = multiple endocrine neoplasia type 2A; NS HPT = neonatal severe hyperparathyroidism.

Fig. 2

Two pathways for cellular cause of hyperparathyroidism. Either pathway can cause a downstream expression of inappropriate secretion of parathyroid hormone (PTH) in serum. The proliferation pathway involves a 2-hit process that demonstrates a years-long delay until monoclonal or oligoclonal overgrowth, with consequent expression as a tumor. The pathway with decreased suppression of hormone secretion is expressed from birth in all PTH secretory cells and may or may not detectably affect parathyroid pathologic features. FHH = familial hypocalciuric hypercalcemia; HPT = hyperparathyroidism; MEN = multiple endocrine neoplasia.