Molecular pathogenesis of primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, mostly caused by a monoclonal parathyroid adenoma. The hereditary syndromes include multiple endocrine neoplasia types 1 (MEN 1) and 2A (MEN 2A), hereditary hyperparathyroidism-jaw tumor (HPTJT), familial isolated hyperparathyroidism (FIHP), familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Mutations of MEN1 and CDKN1B genes are responsible for MEN 1 in 70-80% and about 2% of cases, respectively. MEN1 and CDKN1B genes have also a role in the pathogenesis of sporadic parathyroid adenomas. HRPT2/CDC73 gene mutations are responsible for HPT-JT and sporadic parathyroid carcinoma. MEN1 and HRPT2/CDC73 genes mutations have also been found in a subset of FIHP families. FHH and NSHPT represent the mildest and severest variants of PHPT, caused by heterozygous and homozygous mutations in the calcium sensing receptor (CASR) gene, respectively.