Familial Hyperparathyroidism

Abstract

Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development.

Parathyroid Tumors: Molecular Signatures

“…As for other human malignancies, the deregulation of epigenetic mechanisms can cooperate with genetic alterations in parathyroid tumor development and growth, driving the tumor phenotype, and it is strongly suspected to be a main factor responsible for the wide heterogeneity in biological and clinical presentation of different neoplasms. However, as opposed to other human cancers that have shown a genome-wide DNA hypomethylation of the intragenic regions, parathyroid tumors do not appear to be affected by changes in global DNA methylation pattern compared to normal tissue [49,50]. On the contrary, the site-specific methylation of CpG dinucleotides, and the subsequent silencing of the regulated gene, in the promoters of tumor suppressor genes and genes known to be related to regulation of parathyroid pathophysiology, cell cycle progression and Wnt signaling appear to be a pro-oncogenic factor in parathyroid tumors.…”

Germline Mutations Related to Primary Hyperparathyroidism Identified by Next-Generation Sequencing

“…We classified MEN, FHH, and FIHP as familial PHPT. ( 8 ) Persistent PHPT was defined as elevated serum calcium levels within 6 months after primary surgery for PHPT, whereas recurrent PHPT was defined as elevated serum calcium levels that presented after 6 months of initial normocalcemia following primary surgery for PHPT. ( 9 ) Multiglandular PHPT was defined as the presence of two or more enlarged parathyroid glands.…”

Metabolic Bone Diseases and New Drug Developments

“…In benign parathyroid tumors, multiple associated mutations and potential epigenetic processes have been distinguished. MEN1 abnormalities seem to be prevalent in benign parathyroid tumors, whereas CDC73 mutations are found in 70% of hypothyroidism carcinoma cells, but in only just around 2% of hypothyroidism adenomas ( Blau and Simonds, 2021 ). Thyroid cancer is uncommon, accounting for less than 1% of all PHPT case scenarios and 0.005% of all forms of cancer.…”