Molecular Pathophysiology of Parathyroid Tumorigenesis—The Lesson from a Rare Disease: The “MEN1 Model”

Primary hyperparathyroidism represents the third more prevalent endocrine disease in general population consisting of an excessive secretion of parathyroid hormone from one, more frequently, or more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells, and promoting their aberrant proliferation, and mutations determining the shift of PTH "set-point”, thus interfering with the normal pathways of PTH secretion, and leading to a “resetting” of Ca2+-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5%, of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with Multiple Endocrine Neoplasia type 1 Syndrome (MEN1) represents a fascinating topic and model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to the syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular-genetics studies, and reviews, have been considered. Only studies submitted to PubMed in English language were included, without time constraints.