Multiple Endocrine Neoplasia, Type I

A number sign (#) is used with this entry because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (613733) on chromosome 11q13.

Description

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by Chandrasekharappa et al., 1997).

Familial isolated hyperparathyroidism (see 145000) occasionally results from the incomplete expression of MEN1 (summary by Simonds et al., 2004).

Genetic Heterogeneity of Multiple Endocrine Neoplasia

Other forms of multiple endocrine neoplasia include MEN2A (171400) and MEN2B (162300), both of which are caused by mutation in the RET gene (164761), and MEN4 (610755), which is caused by mutation in the CDKN1B gene (600778).

Clinical Features

Underwood and Jacobs (1963) identified an affected father, son, and daughter. Hypoglycemia was the presenting manifestation in all 3. In addition to islet cell adenomas, the father had bronchial carcinoma and hyperparathyroidism (145000) from parathyroid adenomas. The son and daughter had been followed from childhood as cases of idiopathic epilepsy unresponsive to anticonvulsive therapy.

Guida et al. (1966) described pituitary adenoma and duodenal carcinoid in patients with this condition. Bronchial carcinoid was described as a feature of the disorder by Williams and Celestin (1962).

Some kindreds (e.g., Ballard et al., 1964; Wermer, 1954) have a high frequency of severe peptic ulcer disease with islet cell tumors, whereas other kindreds (e.g., Johnson et al., 1967) are devoid of peptic disease.

Bilateral pheochromocytomas occur in MEN2A and MEN2B and pancreatic islet cell tumors in MEN1. Tateishi et al. (1978) described a patient with both forms of endocrine neoplasia. They also reviewed 14 reported cases of MEN with features overlapping MEN I and II. For example, 7 patients with acromegaly (102200) due to pituitary adenoma had pheochromocytoma, 2 with Sipple syndrome (MEN2A) had pituitary adenoma, and so on.

Prosser et al. (1979) found 4 patients in 3 unrelated families who had prolactin-secreting pituitary adenomas.

Farid et al. (1980) observed 4 kindreds in the Burin Peninsula of Newfoundland, whose ancestors came from the same small community in the British Isles, with hyperparathyroidism and prolactinoma, but no documented pancreatic tumors. Two kindreds had carcinoid tumors at unusual sites, either thymus or peripheral lung parenchyma. In contrast to the benign course of the prolactinomas and the primary hyperparathyroidism, 2 persons with thymic carcinoid died from metastatic disease. Bear et al. (1985) referred to the disorder in these families as MEN1-Burin (see 613733.0016). Hershon et al. (1983) described a phenotypically similar but unrelated kindred from the Pacific Northwest, in which 6 of 7 living affected members had prolactinomas and none had pancreatic islet tumors. Farid (1994) reported that the Burin Peninsula families were in fact related. All 4 families had ancestors who lived in the Harbor Breton region a century earlier and all affected members of the 4 families carried the same PYGM (608455) allele segregating with the disorder. Petty et al. (1994) demonstrated by linkage studies that the gene in both the Newfoundland kindreds and the kindred from the Pacific Northwest mapped to 11q in the same region as the MEN1 gene. No recombinants were seen with PYGM in either kindred, but the PYGM allele associated with the disease was different in the 2 kindreds.

The Zollinger-Ellison syndrome (ZES) may present purely as hyperparathyroidism. For example, 1 member of the family described as having hereditary hyperparathyroidism by Cutler et al. (1964) was later reported to have a malignant schwannoma, pituitary adenomas, multiple pancreatic islet cell adenomas, and multiple adrenocortical adenomas. Snyder et al. (1972) reported 5 families and noted the previously described association of lipomas.

The Zollinger-Ellison syndrome is merely hypergastrinism and may have causes other than MEN I. For example, Long et al. (1980) reported the Zollinger-Ellison syndrome with ectopic production of gastrin by a mucinous cystadenoma of the ovary. McCarthy (1982) distinguished 2 common forms of the Zollinger-Ellison syndrome: the sporadic and usually malignant type, seen most often in later life, and the genetic variety that occurs as part of MEN I.

Stacpoole et al. (1981) observed a family in which 3 persons had A-cell pancreatic tumors (glucagonomas) as part of MEN I. Two had the classic glucagonoma syndrome with skin rash, glucose intolerance, and hypoaminoacidemia. Administered secretin and somatostatin gave anomalous metabolic responses.

Bahn et al. (1986) reported 25-year-old monozygotic twins with MEN I who had impressive differences in expression of the disorder. One had epigastric pain and diarrhea at presentation; was found to have primary hyperparathyroidism, Zollinger-Ellison syndrome, Cushing disease, and hyperprolactinemia; and underwent hypophysectomy. The second twin was asymptomatic but had primary hyperparathyroidism and hyperprolactinemia. A large, histologically benign pituitary adenoma 'that invaded dura and bone' was removed by a transsphenoidal approach 2 days after parathyroidectomy.

Maton et al. (1986) suggested that the Cushing syndrome is more common in patients with the Zollinger-Ellison syndrome than previously reported, occurring in 8% of all cases. Three of 16 patients with the Zollinger-Ellison syndrome and MEN1 had the Cushing syndrome due to pituitary overproduction of ACTH. In all sporadic cases of ZES, Cushing syndrome was due to ectopic production of ACTH by the gastrinoma. Gaitan et al. (1993) described mother and daughter who, in addition to other manifestations of MEN1, had Cushing disease due to ACTH-secreting tumors.

Yu et al. (1999) reported on the long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors in whom the excess hormone state was controlled. They studied 212 patients with Zollinger-Ellison syndrome. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up of 13.8 years (range, 0.1 to 31 years). Death had occurred in 31% of patients, all from non-acid-related causes. One-half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. Yu et al. (1999) concluded that in ZES, gastrinoma growth is the main single determinant of long-term survival, with 50% of patients dying a gastrinoma-related death and none an acid-related death.

Bordi et al. (2001) identified carcinoid tumors in the antropyloric mucosa of 4 patients with MEN1/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic ZES (p less than 0.001), indicating a prominent role for the MEN1 gene defects in tumor development. Immunohistochemically, the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, 2 of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT2; 193001), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In 1 of these patients, a second antral VMAT2-positive carcinoid was seen 21 months after the first diagnosis. The authors concluded that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least 2 cases, were identified as ectopic ECL cell carcinoids.

Skogseid et al. (1992) reviewed adrenocortical lesions in 31 MEN I patients. In 12 (37%), they found adrenal enlargement, which was bilateral in 7. One person developed unilateral adrenocortical carcinoma manifested by rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 years of observation for bilateral minor adrenal enlargement. In the other patients, adrenal enlargement was not associated with ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis. Pancreatic endocrine tumors were significantly overrepresented in the patients with adrenal lesions, being present in all 12. In agreement with findings in sporadic cases, the MEN1 adrenocortical carcinoma showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN1 locus at 11q13. Skogseid et al. (1992) concluded that the pituitary-independent adrenocortical proliferation is not the result of the primary lesion in MEN I but may represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor.

Verges et al. (2002) analyzed data on pituitary adenomas in 324 MEN1 patients from a French and Belgian multicenter study. Data on pituitary disease were compared with those from 110 non-MEN1 patients with pituitary adenomas, matched for age, year of diagnosis, and follow-up period. In the authors' MEN1 series, pituitary disease occurred in 136 of 324 (42%), less frequently than hyperparathyroidism (95%, p less than 0.001) and endocrine enteropancreatic tumors (54%, p less than 0.01). Mean age of onset of pituitary tumors was 38.0 +/- 15.3 years (range, 12 to 83 years). Pituitary disease was associated with hyperparathyroidism in 90% of cases, with enteropancreatic tumors in 47%, with adrenal tumors in 16%, and with thoracic neuroendocrine tumors in 4%. Pituitary disease was the initial lesion of MEN1 in 17% of all MEN1 patients. MEN1 pituitary adenomas were significantly more frequent in women than in men (50% vs 31%, p less than 0.001). Eighty-five percent of MEN1-related pituitary lesions were macroadenomas, including 32% of invasive cases. Among secreting adenomas, hormonal hypersecretion was normalized, after treatment, in only 42%, with a median follow-up of 11.4 years. No correlation was found between the type of MEN1 germline mutation and the presence or absence of pituitary adenoma. The authors concluded that their study shows that pituitary adenomas occur in 42% of cases and are characterized by a larger size and a more aggressive presentation than without MEN1.

Darling et al. (1997) performed a complete cutaneous evaluation on 32 consecutive patients with established diagnoses of MEN1. They observed multiple facial angiofibromas in 88%, collagenomas in 72%, cafe-au-lait macules in 38%, lipomas in 34%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% of these individuals. Darling et al. (1997) noted that there is considerable overlap between the cutaneous findings in MEN1 and those in tuberous sclerosis (see 191100). However, facial angiofibromas in MEN1 tend to be smaller and fewer and to occur in different areas (upper lip and vermilion border) in comparison to those seen in tuberous sclerosis. Darling et al. (1997) suggested that these cutaneous findings may be helpful in presymptomatic diagnosis of MEN1 patients.

Schussheim et al. (2001) reviewed new clinical features of MEN1. These included multiple facial angiofibromas, previously considered pathognomonic for tuberous sclerosis; these had been reported in approximately 90% of MEN1 patients, with 50% having 5 or more. MEN1-related angiofibromas differ from those associated with tuberous sclerosis in that they are smaller, fewer, and located on the upper lip and vermilion border of the lip, areas that appear to be spared in tuberous sclerosis patients. Collagenomas had also been identified in more than 70% of MEN1 cases. These lesions can be subtle, and diagnosis might require consultation and biopsy by a dermatologist. Lipomas, both cutaneous and visceral, had been described in up to one-third of MEN1 patients compared with 6% of controls. This moderately high prevalence of lipoma in the general population made it difficult to use this lesion as a marker for MEN1 disease. In contrast to pheochromocytoma in MEN2 (171400), pheochromocytoma occurring in association with MEN1 is rare. In all cases the tumors were unilateral, and it was malignant in only one patient. Leiomyomas had been observed in patients with MEN1. Adrenal cortical lesions were common in MEN1, occurring in up to 40% of patients. The majority of these tumors were bilateral, hyperplastic, and nonfunctional, and caused minimal morbidity; however, tumors that cause hypercortisolemia and hyperaldosteronism had been reported. Thyroid tumors, which include follicular adenomas, goiters, and carcinoma, had long been observed in more than 25% of MEN1 patients.

Asgharian et al. (2004) prospectively assessed the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status, dermatologic evaluation, and tumor imaging studies. Combinations of the occurrence of angiofibromas, collagenomas, and lipomas were analyzed. The combination criterion of more than 3 angiofibromas or any collagenoma had the highest sensitivity (75%) and specificity (95%). Asgharian et al. (2004) concluded that this diagnostic criterion has greater sensitivity for MEN1 than pituitary or adrenal disease and has comparable sensitivity to hyperparathyroidism reported in some studies of patients with MEN1 with gastrinoma.

Hao et al. (2004) examined 2 large kindreds with a MEN1 variant that were followed up for 20 to 30 years, with MEN1 tumors in 30 members. Cases from the 2 kindreds had parathyroid adenomas (93%), pituitary tumors (40%) (always prolactinoma), and enteropancreatic endocrine tumors (27%). The latter included insulinoma (10%) and nonfunctioning islet tumor (7%), but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs 42%, p less than 0.01) and higher prevalence of prolactinoma (40% vs 22%, p less than 0.01) defined this variant. DNA showed no characteristic MEN1 mutation in these 2 kindreds.

Reviews

Wolfe and Jensen (1987) reviewed diagnosis and treatment of the Zollinger-Ellison syndrome. For a review of MEN1, see Thakker (1998).

Guo and Sawicki (2001) reviewed the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors.

Clinical Management

Brandi et al. (2001) authored a consensus statement covering the diagnosis and management of MEN1 and MEN2, including important contrasts between them. The most common tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of enteropancreatic hormones, except insulin. The roles for surgery of most enteropancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention.

Biochemical Features

Brandi et al. (1986) cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with type I MEN. Whereas normal plasma stimulated incorporation of labeled thymidine to the same extent as did plasma-free culture medium, the plasma from the patients increased mitogenic activity 2400% over the control value. Bovine parathyroid cells were stimulated to proliferation, whereas plasma from normal subjects inhibited proliferation of the bovine parathyroid cells. The mitogenic activity had an apparent molecular weight of 50,000 to 55,000.

Inheritance

MEN I is an autosomal dominant disorder. Chandrasekharappa et al. (1997) suggested that affected individuals inherit one altered copy of the MEN1 gene from an affected parent, but the tumors lose the remaining copy (the wildtype allele) as a somatic event. Thus, the inheritance pattern is autosomal dominant, but the mechanism of tumorigenesis is recessive.

Mapping

Bale et al. (1987, 1989) studied linkage with multiple markers in a single large kindred with MEN I. INT2 (164950), which is located at 11q13, was found to be closely linked to MEN1. In studies of 3 families, Thakker et al. (1989) established linkage with INT2; peak lod score = 3.30 at theta = 0.00.

Larsson et al. (1988) mapped the MEN1 locus to chromosome 11 by demonstrating linkage to a DNA probe derived from the PYGM locus (608455), which, in turn, has been mapped to 11q13-qter.

By comparing constitutional and tumor tissue genotypes of insulinomas from 2 brothers who had inherited the disorder from their mother, Larsson et al. (1988) demonstrated loss of the linked locus in tumor tissue. Tumors in both showed loss of 1 constitutional allele at all informative loci on chromosome 11. The informative markers extended from HRAS1, located at 11p15.5, to APOA1 (107680), located at 11q13. (Larsson et al. (1988) quoted a paper in press indicating that the APOA1 locus is in band q23.) In 3 families, the authors observed a total maximum lod score of 4.37 at theta = 0.00. Larsson et al. (1989) and Nordenskjold et al. (1989) both provided linkage data for markers at 11q13 with multiple endocrine neoplasia type I.

Nakamura et al. (1989) identified 6 closely linked markers in the vicinity of 11q13 which are useful for identification of carriers in MEN I families. The target region containing the gene was narrowed to about 12 cM. Friedman et al. (1989) and Thakker et al. (1989) demonstrated loss of heterozygosity (LOH) for chromosome 11 alleles in parathyroid tumors from patients with MEN I. Friedman et al. (1989) found such loss in 10 of 16 tumors from 14 patients. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included 1 copy of the MEN I locus.

Bale et al. (1989) studied the DNA from 66 tumors removed from patients with MEN I. They demonstrated allelic loss of chromosome 11 RFLPs in 10 of 16 parathyroid tumors from MEN I patients and in 9 of 34 sporadic parathyroid adenomas. The smallest consistent region of loss was between INT2 and D11S149. Bystrom et al. (1990) showed that the pathogenesis of MEN1-associated parathyroid lesions involves unmasking of a recessive mutation at the disease locus and that sporadic primary hyperparathyroidism shares the same mechanisms. By examination of allele losses in MEN1-associated lesions, they defined deletions of chromosome 11 and mapped the MEN1 locus to a small region within 11q13, telomeric to PYGM.

Richard et al. (1991) created a high-resolution radiation hybrid map of the proximal long arm of chromosome 11 containing the MEN1 and BCL1 (168461) gene loci. By statistical analysis of the cosegregation of markers in radiation hybrids, they arrived at the following most likely order of loci: C1NH (606860)--OSBP (167040)--CD5 (153340)/CD20(112210)--PGA (169710)--FTH1 (134770)--COX8 (123870)--PYGM--SEA (165110)--KRN1 (148021)--HSTF1 (164980)/INT2--GST3 (134660)--PPP1A (176875). They suggested that the localization of the protooncogene SEA between PYGM and INT2, 2 markers that flank MEN1, makes SEA a potential candidate for the MEN1 locus. The positions of PPP1A and GST3 are such that neither is likely to be directly involved in CLL (151400) or MEN1. Fujimori et al. (1992) placed the MEN1 locus within an 8-cM region between D11S480 and D11S546.

Larsson et al. (1992) found that 13 marker systems tested with 17 DNA probes were located within a region on chromosome 11 spanning a 14% meiotic recombination region, with the MEN1 locus in the middle: based on meiotic crossovers, 4 systems were on the telomeric side and 4 on the centromeric side of MEN1. The remaining 5 were closely linked to MEN1, with no crossovers in their set of 6 families including 59 affected persons. The calculated accuracy of prediction of MEN1 was more than 99.5% when 3 of the marker systems were informative.

Sawicki et al. (1992) reported loss of heterozygosity on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors had LOH for markers flanking the MEN1 region. LOH on chromosome 11 had previously been found in 3 types of tumors that occur in patients with the MEN I syndrome: sporadic pituitary adenomas, sporadic and familial parathyroid neoplasms, and pancreatic endocrine tumors including insulinoma, glucagonoma, vasointestinal peptide tumor, and nonfunctional tumors. Although gastrinomas account for the majority of both sporadic and familial pancreatic endocrine tumors, LOH had not previously been demonstrated for this form.

Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel. The location of MEN1 was narrowed to a 2-Mb region beginning centromeric to COX8 and extending to approximately CAPN1.

Guru et al. (1997) mapped and sequenced the MEN1 genomic region. They produced a precisely ordered map of 33 transcribed genes within this 2-Mb region.

The European Consortium on MEN1 (1997) constructed a 1.2-Mb sequence-ready contig encompassing the MEN1 region. They described 3 gene clusters, including the central cluster which contains the MEN1 gene.

From a comparative mapping analysis of 10q and the pericentric region of 11q in the human and mouse chromosome 19, Rochelle et al. (1992) concluded that the murine homolog of the MEN1 locus may lie in the proximal segment of chromosome 19. By FISH, Guru et al. (1999) mapped the mouse Men1 gene to chromosome 19 in a region showing homology of synteny to human chromosome 11q13.

Molecular Genetics

Chandrasekharappa et al. (1997) identified several MEN1 candidate genes in a previously identified minimal interval on 11q13. Chandrasekharappa et al. (1997) identified mutations in one of these genes, designated MEN1, in 14 probands from 15 families. Twelve different heterozygous mutations (613733.0001-613733.0012) were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism.

Lemmens et al. (1997) independently identified the MEN1 gene, which they had designated SCG2, and found 9 different heterozygous mutations in 10 unrelated MEN1 families.

Agarwal et al. (1997) extended their mutation analysis to 34 more unrelated familial MEN1 probands (to a total of 50 kindreds) and to 2 related disorders, sporadic MEN1 and familial hyperparathyroidism (145000). In 8 of 11 cases of sporadic MEN1, they found heterozygous germline MEN1 mutations (e.g., 613733.0014); such mutations were found in 47 of 50 familial MEN1 probands. They proved that the mutation was new in 1 case of sporadic MEN1. Among the familial MEN1 cases, 8 mutations were observed more than once. In all, 40 different mutations (32 familial and 8 sporadic) were distributed across the MEN1 gene. A predicted loss of function of the encoded menin protein supported the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutations were found in 5 probands with familial hyperparathyroidism, suggesting that this disorder is often caused by mutation in another gene.

In affected members of the 4 families with MEN1 from the Burin peninsula in Newfoundland, who were previously described by Farid et al. (1980) and Bear et al. (1985), Olufemi et al. (1998) identified a mutation in the MEN1 gene (613733.0016).

Bassett et al. (1998) investigated 63 unrelated MEN1 kindreds (195 affected and 396 unaffected members) for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. They identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice site mutation, and 6 missense mutations) that were scattered throughout the coding region, together with 6 polymorphisms that had heterozygosity frequencies of 2 to 44%. More than 10% of the mutations arose de novo, and 4 mutation hotspots accounted for more than 25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected more than 85% of the mutations. MEN1 mutant-gene carrier status was detected in 201 individuals (155 affected and 46 unaffected). By analysis of these cases, they defined the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. The number of disease alleles and the frequent occurrence of de novo mutations, often at hotspots with short repeat sequences, suggested that haplotype analysis is of limited use for the diagnosis of MEN1.

Tanaka et al. (1998) studied germline mutations of the MEN1 gene in 5 cases of familial and 4 cases of sporadic multiple endocrine neoplasia type I, 6 cases in 3 independent pedigrees of familial pituitary adenoma without MEN1, and 3 cases of familial primary hyperparathyroidism in Japanese patients. Eight different types of germline mutations in all 9 MEN1 cases were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all 9 tumors of the cases with microsatellite analysis. No germline mutation of the MEN1 gene was detected in 3 pedigrees of familial pituitary adenoma and 3 cases of familial primary hyperparathyroidism. LOH on 11q13 was detected in 2 cases in 1 pedigree of familial pituitary adenoma, and 1 of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in 3 cases of familial primary hyperparathyroidism. The authors concluded that the loss of function of MEN1 causes familial or sporadic MEN1, but does not cause familial primary hyperparathyroidism or most familial pituitary adenoma without MEN1.

Both alleles of the MEN1 gene at 11q13 are mutated in the majority of MEN1 tumors. Hessman et al. (2001) performed a genomewide LOH screening of 23 pancreatic lesions, 1 duodenal tumor, and 1 thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6 to 75% (mean 31%). All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. The authors concluded that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability.

Lipomatous tumors are known to occur in a relatively high proportion of patients with MEN1. By fluorescence in situ hybridization analysis of lipomas from 2 patients with MEN1, Vortmeyer et al. (1998) demonstrated deletion of 1 MEN1 allele in 53% of cells examined from case 1 and in 63% of cells examined from case 2. In both cases, both MEN1 gene copies were visualized in normal cellular constituents.

Giraud et al. (1998) studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families.

Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (613733.0032) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed.

Sato et al. (1998) studied 8 unrelated Japanese families. These included 5 with familial MEN1, 2 with sporadic MEN1, and 1 with familial hyperparathyroidism. Six different mutations were identified, including 1 missense mutation, 3 deletions, and 2 nonsense mutations. In 1 proband with familial MEN1, no mutation was identified.

In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype.

The observation of LOH involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis.

Perren et al. (2007) hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Perren et al. (2007) concluded that the frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development.

By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, Wautot et al. (2002) identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype.

Turner et al. (2002) ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516 (613733.0028) accounts for 36.6% of all mutations.

In 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs.

Park et al. (2003) investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma.

Using church records and MEN1 family information for the 2 founder MEN1 mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC (613733.0033), Ebeling et al. (2004) traced back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and found 67 probable carriers born between 1728 and 1929, among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age of death of affected males was 61.1 years versus 65.8 years for unaffected males, and for affected females was 67.2 years versus 67.7 years for unaffected females. The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex matched life expectancy estimates derived from Finnish national statistics. The authors concluded that obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 years.

Lemos and Thakker (2008) provided a detailed review of the clinical aspects and molecular genetics of MEN1. The majority of the 1,336 mutations reported to date are predicted to result in truncated forms of menin and are scattered throughout the gene. There were no apparent genotype/phenotype correlations.

Familial Primary Isolated Hyperparathyroidism, MEN1 Variant

In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism (see 145000), Teh et al. (1998) found that affected members had a germline missense mutation in the MEN1 gene (613733.0020). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1. The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model.

In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas. Fujimori et al. (1998) identified a missense mutation in the MEN1 gene (613733.0021).

Warner et al. (2004) screened 22 unrelated patients with FIHP for mutations in the MEN1, CASR (601199) and HRPT2 (CDC73; 607393) genes. They identified 5 patients with MEN1 mutations, 4 with CASR mutations, and none with HRPT2 mutations. All 9 patients in whom mutations were found had multiglandular hyperparathyroidism. The patients with CASR mutations did not have biochemical findings of hypocalciuric hypercalcemia. Warner et al. (2004) recommended MEN1 and CASR genotyping in patients with multiglandular FIHP, regardless of urinary calcium excretion.

MEN1 Somatic Mutations

Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (613733.0013) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). Heppner et al. (1997) suggested that many of these tumors likewise may have MEN1 somatic mutations.

Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (168450) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism.

Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors.

By comparative genomic hybridization, Farnebo et al. (1999) screened DNAs from 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases for sequence copy number alterations. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or LOH of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene, in agreement with a role of the MEN1 gene in genomic stability. The authors concluded that the frequent occurrence of MEN1 mutations in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in post-irradiation patients.

Prezant et al. (1998) screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis.

Heppner et al. (1999) studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH.

To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient.

To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, Kjellman et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity. The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (160980) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.

Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading