Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation

Abstract

Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype–phenotype correlation has been established.In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype–phenotype correlation.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study

“…In families carrying mutations within the JunD interacting domain, patient survival was significantly lower, with a twofold increased risk of dying from MEN1-related cancers (19). The existence of intrafamilial correlations in MEN1 disease was also identified for most of the tumor types, and this hypothesis was in accordance with literature data (13). Nevertheless, the statistical approach was dedicated to genotype-phenotype association analysis and did not allow accurate estimations of intrafamilial correlations -that is to say, correlations according to the degree of the family relationship (i.e., parent-offspring, siblings, etc.).…”

“…In addition, we reported the first arguments for the implication of genetic factors able to modify MEN1 disease expression. Indeed, a global trend for heterogeneity across families was observed, suggesting the existence of other genetic factors able to modify MEN1 disease expressivity, as expected since the discovery of the MEN1 gene (13,14,19). These preliminary results were a first step toward unraveling the genetic determinants of MEN1 disease expressivity.…”

“…Prolactinomas are specifically overrepresented in the Burin families, suggesting the existence of a founder effect (10). Gender is recurrently shown to modify tumor development in patients, notably for pituitary or thNETs (8,11,12,13). Additionally, several families from various ethnic origins are reported to present recurrent thNETs (11,14,15).…”

Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database

“…Mutation analysis of the MEN1 gene allows the early identification of asymptomatic carriers, years before any MEN1-associated biochemical and/or instrumental abnormalities are detected [6,8]. Unfortunately, as reported by the great majority of worldwide epidemiology studies, a genotype-phenotype correlation, like in MEN2 syndromes, has not clearly been identified in MEN1 syndrome, strongly reducing the possibility to foresee exact future clinical manifestations of the disease by the specific gene mutation [6,[9][10][11][12]. Recently, two studies by the "Groupe d'étude des tumors endocrines (GTE)" reported a trend for intrafamilial correlation in disease expression and severity and in heritability of MEN1 tumors [13,14].…”

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

“…Although the implementation of such testing helps the clinical management of this syndrome, further studies still need to be conducted to reduce the potential of post-genetic analyses uncertainties (8,9,10,11). For example, while in the absence of a detectable mutation, mutation-negative asymptomatic relatives are excluded from the periodic clinical surveillance, the presence of a mutation remains baffling, as patients harboring exactly the same MEN1 mutation (including first-degree relatives) usually present very different clinical and tumoral outcomes (4,5,6,7,8,9,10,11,12).…”