**6. Multiple endocrine neoplasia type 1 (MEN1)**

MEN1 is the most common hereditary cause of primary hyperparathyroidism [26]. The syndrome of MEN1 is characterized by the predisposition to develop tumors derived from cells in the anterior pituitary, parathyroid glands, and endocrine cells present in the gut and pancreatic islets (such as gastrinomas, and pancreatic neuroendocrine tumors such as insulinomas) [27]. Tumors in several other endocrine organs and non-endocrine tumors such as lipomas, angiofibromas, and leiomyomas affecting the esophagus, uterus, and/or ureters for example, can also be associated with the syndrome [27]. HPT is the most penetrant hormonal feature of MEN1.

Familial MEN1 is characterized by autosomal dominant transmission. The predisposition to tumor development in one of the tissues characteristically involved in the MEN1 syndrome is caused by germline inactivating mutation in one copy of the *MEN1* gene on chromosome 11q13 [28]. As of 2015, 576 unique germline mutations in *MEN1* were reported from patients and families with MEN1 [29]. The study of DNA derived from pituitary, parathyroid, and entero-pancreatic tumors from MEN1 patients has shown that most syndromic tumors possess an acquired deletion or other inactivating mutation of the second, wild-type *MEN1* allele [18, 30]. Approximately 10% of patients with MEN1 on a clinical basis are germline *MEN1* mutation-negative.

Conventional DNA sequencing of tumor DNA has identified somatic *MEN1* mutation in up to 35% of sporadic parathyroid adenomas [31–35]. In studies testing for loss-of-heterozygosity (LOH) in sporadic parathyroid adenomas, the frequency of LOH at the *MEN1* locus on chromosome 11q13 ranged from 26 to 37%. Using whole exome sequencing (WES) methodology, somatic *MEN1* mutation was found in some 35% of parathyroid benign tumors, comparable to results using conventional Sanger DNA sequencing [36, 37]. As mentioned above, HPT is the most penetrant feature of MEN1 and is usually the initial manifestation. As a result, true MEN1 families may sometimes be initially mis-assigned a clinical diagnosis of familial isolated hyperparathyroidism (FIHP) if only younger affected members are considered at the time that the family is ascertained (see **Figure 1**).

Mutation of the *MEN1* gene is only rarely associated with parathyroid carcinoma. The occurrence of parathyroid carcinoma in the context of familial MEN1 is extremely uncommon. Fewer than 20 patients with HPT due to parathyroid cancer in the context of the MEN1 syndrome have been reported [38]. LOH analysis of parathyroid tumor-extracted DNA has shown that DNA loss at the location of the *MEN1* gene on chromosome 11q, though frequently seen in benign parathyroid tumors, is quite uncommon in parathyroid carcinomas [39]. Recent studies that use next-generation WES of tumor-derived DNA to profile parathyroid cancers did not report any somatic mutations in *MEN1* [40, 41].

#### **Figure 1.**

*The relationship among familial forms of hyperparathyroidism that may present as familial isolated hyperparathyroidism (FIHP) as a Venn diagram. The dashed circle represents the set of patients that can present with a provisional diagnosis of FIHP at the time of initial ascertainment. This includes patients with FIHP who have been evaluated for, but lack findings diagnostic of, MEN1, FHH and HPT-JT (nonsyndromic FIHP; in a solid circle). Approximately 18% of nonsyndromic FIHP kindreds harbor germline gain-of-function mutations in GCM2 (see text), whereas the remainder have currently unknown genetic etiologies. Subsets of patients with incomplete expression of MEN1, FHH and HPT-JT (the total set of patients in each syndrome represented by a solid circle) can also present with the FIHP phenotype (and thus overlap with the dashed circle). The distinction between the nonsyndromic FIHP category and the syndromic categories arbitrarily depends on the thoroughness of evaluation and the sensitivity of diagnostic tests used to detect the syndrome that can include germline gene mutational testing. MEN2A is a familial form of hyperparathyroidism that seldom if ever presents as FIHP. Within each circle representing a defined syndrome are included the genetic locus (or loci in the case of FHH; see text) of the syndromic trait and the associated gene product. The causative gene for HPT-JT encoding parafibromin is CDC73, formerly called HRPT2. The relationship among the patient sets illustrated as circles in this diagram is intended to be qualitative and neither the area of each circle nor the area of overlap between circles has any quantitative significance.*
