Multiple endocrine neoplasia type 1: Genetics

INTRODUCTION — The multiple endocrine neoplasia (MEN) syndromes are rare, but recognition is important both for treatment and for evaluation of family members.

This topic will review the genetics of the MEN type 1 (MEN1) syndrome (OMIM #131100). The clinical manifestations, diagnosis, and therapy of MEN1 and the MEN type 2 (MEN2) syndromes are discussed separately:

●(See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

●(See "Multiple endocrine neoplasia type 1: Management".)

●(See "Classification and genetics of multiple endocrine neoplasia type 2".)

●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

●(See "Approach to therapy in multiple endocrine neoplasia type 2".)

DEFINITION — Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder classically characterized by predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells [1,2]. MEN1 also includes a predisposition to gastrinomas in the duodenum, bronchopulmonary and thymic neuroendocrine tumors (NETs), gastric carcinoids, adrenal adenomas (occasionally carcinomas), angiofibromas, lipomas, and other tumors (figure 1). Other associated tumors include angiofibromas, angiomyolipomas, spinal cord ependymomas, and a two- to threefold increased risk of breast cancer has been reported [3]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

The presence of MEN1 is defined clinically as the occurrence of two or more primary MEN1 tumor types (parathyroid, enteropancreatic endocrine, and pituitary tumors), or in family members of a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors. Multiple parathyroid tumors causing primary hyperparathyroidism are the most common component of MEN1, occurring in the large majority of patients by age 50 years, and is the initial manifestation of the disorder in most patients (figure 2) [2,4,5]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

The current major morbidity and premature mortality associated with MEN1 is most frequently related to pancreatic NETs (in particular, nonfunctioning pancreatic NETs and, to a lesser extent, gastrinoma), as well as thymic NETs [6]. Subclinical involvement is more common; anatomic or intensive biochemical studies reveal evidence of microscopic pancreatic islet abnormalities in almost all patients. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Nonfunctioning pancreatic tumors' and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary neuroendocrine tumors'.)

The prevalence of MEN1 is approximately 2 per 100,000 [2]. The incidence ranges from 1 to 18, 16 to 38, and less than 3 percent in patients with parathyroid adenomas, gastrinomas, and pituitary adenomas, respectively [1].

GENETICS

MEN1 gene — The inheritance of classical MEN1 follows an autosomal dominant pattern, indicating that Mendelian inheritance of a single mutant gene is responsible for transmitting the tumor predisposition within a given family. In 1988, genetic linkage analysis implicated a region on the long arm of chromosome 11 (11q13) as the site of the "MEN1 gene" [7]. A decade later, the critical gene in this region was identified, given the gene symbol designation MEN1, and its protein product termed "menin" [8].

Across multiple studies, pathogenic deoxyribonucleic acid (DNA) sequence variants (ie, "mutations") in the MEN1 gene have been detected in 70 to 90 percent of unrelated MEN1 kindreds [9-12], although this figure is variable across studies and is sensitive to the mode of case selection. More than 600 different germline MEN1 mutations have been identified, with the majority (approximately 70 percent) predicting premature truncation or loss of the Menin protein (eg, as a result of frameshift, nonsense, or splice site DNA variants), although missense variants (eg, single amino acid substitutions) are also reported and are presumed to disrupt key functional domains of the protein or alter protein stability. In addition, larger structural variants (eg, partial or whole gene deletions) may occur, accounting for <5 percent of cases. Furthermore, it has been reasonably hypothesized that most typical MEN1 kindreds without detectable pathogenic variants in the MEN1 gene nonetheless have inactivating germline variants in (or near and in "cis" with) the same gene but outside the coding region that is typically sequenced in diagnostic and research laboratories. Disease-associated pathogenic MEN1 variants have been reported in noncoding untranslated regions (eg, 5' UTR) of the MEN1 gene [13].

The majority of pathogenic MEN1 variants are inherited from an affected parent. However, it is estimated that approximately 10 percent of pathogenic MEN1 variants occur de novo (ie, occurring for the first time in the affected individual). In addition, both germline and somatic MEN1 mosaicism have been observed in patients presenting with MEN1 phenotypes [14]. Genetic variants in the MEN1 gene are not responsible for all individuals, or even kindreds, with an MEN1 phenotype (see 'Other genes' below). Furthermore, rare phenocopies have been reported, ie, individuals within MEN1 kindreds who were initially classified as having the syndrome when they developed a typical tumor (eg, prolactinoma) but were then proven by DNA testing to have not inherited the pathologic mutation [15].

Much has been learned about the biochemical and cellular functions of menin, but the precise way(s) in which these functions relate to tumorigenesis is still not well established. However, it is clear that most of the pathogenic MEN1 gene variants found in MEN1 patients would be expected to inactivate or disrupt menin function. Typical of a classical tumor suppressor gene, the spectrum of reported germline MEN1 pathogenic variants occur throughout the gene and yield no strong genotype/phenotype relationships [12]. The genotype-phenotype correlations are often unclear, even within a family [16]. In addition, biallelic somatic mutations within this gene have been found in 12 to 17 percent of typical nonfamilial parathyroid adenomas [17-19] and some sporadic gastrinomas and insulinomas [20], sporadic neuroendocrine tumors (NETs) of the foregut [21], sporadic carcinoid tumors of the lung [22], and sporadic pituitary tumors [23], further supporting the relationship between inactivation of the MEN1 gene (and Menin function) and tumorigenesis (see "Primary hyperparathyroidism: Pathogenesis and etiology"). However, the large majority of non-MEN1-associated pituitary tumors, whether sporadic or familial, do not have an MEN1 mutation [24,25].

Other genes — Syndromes clinically related to but genetically distinct from MEN1 do exist. At least one family with an unusual expression of MEN1 (eg, a lower than expected incidence of hyperparathyroidism and higher than expected incidence of pituitary tumors) was reported to have a predisposing gene at a location distinct from the chromosome 11q13 site [26,27]. Germline AIP mutation, in the absence of MEN1 gene mutation, has been reported in the setting of pituitary plus parathyroid neoplasia [28]. Furthermore, pathogenic variants in the MEN1 gene are infrequent in kindreds with familial isolated hyperparathyroidism [29,30] and were not found in three kindreds with familial pituitary adenoma [31] and one with isolated familial acromegaly [32]. A small minority of patients presenting with a clinical diagnosis of MEN1 (eg, presence of two or more MEN1-assocated tumors) may harbor pathogenic variants in other monogenic disease genes more typically associated with alternate phenotypes (eg, CDC73 variants associated with the hyperparathyroidism jaw tumour syndrome) [33].

●Cyclin-dependent kinase inhibitor genes – An inherited mutation of the p27 cyclin-dependent kinase (CDK) inhibitor gene, CDKN1B, was reported in one kindred whose proband had hyperparathyroidism and acromegaly due to a growth hormone-producing pituitary tumor; the proband's father had acromegaly, and the sister had a renal angiomyolipoma [34]. Germline pathogenic variants in CDKN1B were also reported in a few other cases of MEN1 that collectively exhibited features including hyperparathyroidism, Cushing disease, cervical carcinoid tumor, bilateral nonfunctioning adrenal masses, and Zollinger-Ellison syndrome with duodenal and pancreatic masses [35,36]. MEN1-like disease caused by germline CDKN1B mutation has been termed MEN4 (OMIM #610755). However, MEN4 is rare (<30 kindreds reported in the literature) and is estimated to account for only 1 to 3 percent of unrelated MEN1-like cases without identifiable MEN1 mutations [36-38].

Rare germline variants in three other CDK inhibitor genes, CDKN2B, CDKN2C, and CDKN1A, encoding the p15, p18, and p21 proteins, respectively, have also been identified in this setting and may collectively account for another 1 to 2 percent of MEN1-like cases without detectable MEN1 mutations [36].

Overall, because patients presenting with the combination of sporadic parathyroid plus pituitary tumor have a much lower yield of detectable MEN1 mutation than in typical MEN1 kindreds or in sporadic cases of parathyroid plus pancreatic tumor [39], it seems likely that this phenotype may often be due to mutation in a gene other than MEN1, or possibly the coincidental presence of sporadic tumors absent of any major genetic predisposition. However, as noted above, the extent to which mutation in CDKN1B or other CDK inhibitor genes is responsible for MEN1-like phenotypes, sporadic or familial, in the absence of MEN1 mutation appears to be small [36,38,40].

●MAX gene – Two kindreds have been reported with a spectrum of endocrine tumors partially overlapping with MEN1 including pheochromocytoma, NETs (eg, paravertebral ganglioneuroma, abdominal neuroblastoma, pulmonary adenocarcinoma), pituitary adenomas, and primary hyperparathyroidism. These kindreds were observed to harbor pathogenic germline variants in the MAX gene, and the possibility was raised that this could be considered an additional MEN syndrome (ie, MEN5) [41].

DNA testing — Direct DNA testing for MEN1 mutation is available for clinical use, has a useful role in certain settings, and should be considered on an individual basis [1]. However, in contrast with testing for RET gene mutations in MEN2, presymptomatic DNA diagnosis has not been shown to yield equally clear benefits in preventing morbidity and mortality in individuals at risk for MEN1. DNA testing is reviewed in detail separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Genetic testing'.)

PATHOGENESIS — Patients with classical MEN1 have often inherited one inactivated copy of the MEN1 gene from an affected parent [8,10]. The actual outgrowth of a tumor is thought to require the subsequent somatic inactivation, often by gross deletion, of the remaining normal copy of the gene in one cell (so-called "two-hit" effect described by Knudson). Such a parathyroid cell, as an example, would then be devoid of the MEN1 gene's normal tumor suppressor function and could gain a selective advantage over its neighbors, resulting in a clonal proliferation (figure 3). The high incidence of endocrine tumors in MEN1 (which has over 90 percent penetrance) and the common multiplicity of these tumors implies that somatic inactivation of the remaining normal copy of the gene occurs at an appreciable frequency and contributes importantly to tumorigenesis in the clinically affected tissues. This model also appears to apply to some of the nonendocrine tumors that occur in patients with MEN1.

Although, a range of in vitro and in vivo studies have provided extensive insights into the function of the Menin protein, the mechanisms leading to tumorigenesis in MEN1-associated tumors remain poorly defined. Notably, Menin is a ubiquitously expressed predominantly nuclear protein implicated in a broad range of cellular activities including transcription and epigenetic regulation through direct or indirect interactions with a large number of protein partners and complexes. However, understanding how tissue-specific functions are established remains to be defined. The identification and analysis of other genes whose somatic alteration is also important in the emergence of clonal tumors in this syndrome should further clarify the relationship between genotype and phenotype in MEN1.

SUMMARY

●Definition – Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder with a prevalence of approximately 2 per 100,000. MEN1 is defined clinically as the presence of two of the three main MEN1 tumor types (parathyroid, enteropancreatic endocrine, and pituitary tumors), or in family members of a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors. Patients with MEN1 may have tumors other than those in the parathyroid, pituitary glands, and in the pancreatic islet cells, including duodenal gastrinomas, thymic or bronchial carcinoid tumors, enterochromaffin cell-like gastric tumors, adrenocortical adenomas, lipomas, angiofibromas, angiomyolipomas, and spinal cord ependymomas (figure 2 and figure 1). (See 'Definition' above.)

●MEN1 gene – The MEN1 tumor suppressor gene is located on the long arm of chromosome 11 (11q13). Its protein product is termed "menin." Over 1000 MEN1 gene mutations have been detected that inactivate or disrupt menin function. Inactivation of menin results in loss of tumor suppression. Families with the same types of mutations do not necessarily have the same clinical phenotype. (See 'MEN1 gene' above.)

●Other genes – Syndromes clinically related to but genetically distinct from MEN1 do exist, and mutations in the MEN1 gene are not responsible for all individuals, or even kindreds, with an MEN1 phenotype. (See 'Other genes' above.)