DiagnosisClinical DiagnosisMultiple endocrine neoplasia type 1 (MEN1) syndrome occurs with a varying combination of more than 20 endocrine and non-endocrine tumors; consequently, no simple definition can encompass all index cases or affected families.Endocrine tumors associated with MEN1 syndrome. Diagnostic criteria are the presence of two of the following three endocrine tumors, which may become evident either by overproduction of polypeptide hormones or by growth of the tumor itself.Parathyroid tumors manifest as hypercalcemia (primary hyperparathyroidism [PHPT]) as the result of the overproduction of parathyroid hormone.Pituitary tumors manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males as a result of a prolactin-secreting anterior pituitary adenoma (prolactinoma).Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract (including tumors of the stomach, duodenum, pancreas, and intestinal tract) [Klöppel et al 2004] manifest as the following (from most to least frequent):Zollinger-Ellison syndrome (ZES) (i.e., peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)Hypoglycemia resulting from an insulin-secreting pancreatic tumor (insulinoma)Hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (necrolytic migratory erythema) resulting from a glucagon-secreting pancreatic tumor (glucagonoma)Watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) resulting from a vasoactive intestinal peptide (VIP)-secreting tumor (VIPoma)Familial MEN1 syndrome is defined as MEN1 syndrome in an individual who has either of the following:At least one first-degree relative with one or more of these endocrine tumors Single-organ involvement and an MEN1 disease-causing germline mutationNote: (1) Non-functioning pancreatic endocrine tumors that are difficult to diagnose by biochemical and imaging tests are the most frequently seen tumors in MEN1 syndrome [Jensen 1999]. (2) Type II gastric enterochromaffin-like (ECL) cell carcinoids are included in the well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract. They are common in MEN1 and are usually recognized incidentally during gastric endoscopy for ZES [Bordi et al 1998, Gibril et al 2000].Non-endocrine tumors associated with MEN1 syndromeSkinFacial angiofibromas. Benign tumors comprising blood vessels and connective tissue. They consist of acneiform papules that do not regress and may extend across the vermillion border of the lips.Collagenomas. Multiple, skin-colored, sometimes hypopigmented, cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs. They are typically asymptomatic, rounded, and firm-elastic, from a few millimeters to several centimeters in size.
Note: The rapid growth of protuberant multiple collagenomas after excision of multiple pancreatic masses including a pancreatic VIPoma has also been reported in an individual with MEN1 [Xia & Darling 2007].Lipomas. Multiple benign fatty tissue tumors found anywhere that fat is located. They can be subcutaneous or, rarely, visceral.Central nervous systemMeningioma in 8% of 74 individuals [Asgharian et al 2004]; the meningiomas were mainly asymptomatic and 60% showed no growth.Ependymoma in 1%Leiomyomas. Benign neoplasms derived from smooth (nonstriated) muscle [McKeeby et al 2001, Ikota et al 2004]In 32 consecutively ascertained individuals with MEN1 syndrome, Darling et al [1997] identified multiple facial angiofibromas in 88%, collagenomas in 72%, café au lait macules in 38%, lipomas in 34%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6%. Darling et al [1997] and Asgharian et al [2004] suggest that these cutaneous findings may be helpful in diagnosis of individuals with MEN1 syndrome before manifestations of hormone-secreting tumors appear.TestingBiochemical TestingSince several parameters may influence the biochemical assessment of the secreted hormones, it is reasonable to consider the upper limit of reference values as the referring value.Primary hyperparathyroidism (PHPT) is defined as increased serum concentrations of the following:Parathyroid hormone (PTH) (normal range: 10-60 pg/mL [Kratz & Lewandrowski 1998])Calcium (normal range: 8.5-10.5 mg/dL or 2.1-2.6 mmol/L [Kratz & Lewandrowski 1998])Note: Elevated urinary excretion of calcium may be observed, but is not required for a diagnosis of PHPT.Prolactinoma is characterized by increased serum concentrations of prolactin (PRL). Normal ranges for PRL [Kratz & Lewandrowski 1998]:Premenopausal females. 0-20 ng/mL or 0-2.0 µ5g/LPostmenopausal females. 0-15 ng/mL or 0-1.5 µ5g/LMales. 0-15 ng/mL or 0-1.5 µg/LNote: Increased serum concentrations of prolactin can be observed in pregnancy and with use of dopaminergic drugs.Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tractGastrinoma is characterized by elevated basal serum concentration of gastrin (normal: <100 ng/L [Kratz & Lewandrowski 1998]).
Intravenous provocative tests with either secretin (2U/kg) or calcium infusion (4 mg Ca ²⁺/kg/hr for 3 hours) are required to distinguish individuals with ZES from individuals with hypergastrinemia, such as those with antral G-cell hyperplasia [Thakker et al 2012].
Note: Elevated serum concentration of gastrin can also be observed in achlorhydria resulting from use of antacids such as proton pump inhibitors.Pancreatic insulinoma is characterized by fasting hypoglycemia with high plasma or serum concentration of insulin (reference values 2-20 U/mL or 14.35-143.5 pmol/L) and C-peptide (0.5-2.0 ng/mL or 0.17-0.66 nmol/L) or proinsulin [Brandi et al 2001, Marx 2001, Thakker et al 2012].
Note: The most reliable evaluation is a supervised 72-hour fast, where hypoglycemia occurs in association with increased plasma insulin concentration [Thakker et al 2012].VIPoma is characterized by high plasma concentration of VIP, as determined by immunoassay test (<75 pg/mL or <75 ng/L) [Kratz & Lewandrowski 1998].Adrenocortex tumors are generally non-functioning, but may be associated with elevated serum concentrations of cortisol. Reference values:Fasting 8am - noon. 5-25 µg/dL or 138-690 nmol/LFasting noon - 8pm. 5-15 µg/dL or 138-414 nmol/LFasting 8pm - 8am. 0-10 µg/dL or 0-276 nmol/LImaging StudiesParathyroid disease does not usually require imaging for diagnosis as (1) the underlying cause of primary hyperparathyroidism in MEN1 is usually multiglandular disease with enlargement of all the parathyroid glands rather than a single adenoma and (2) preoperative imaging does not influence the surgical approach.Prolactinoma. MRI is the imaging test of choice.Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract. Endoscopic ultrasound (EUS) examination is the most sensitive imaging procedure for the detection of small (≤10 mm) pancreatic endocrine tumors in asymptomatic individuals with MEN1 [Gauger et al 2003, Langer et al 2004, Kann et al 2006, Tonelli et al 2006]. Langer et al [2004] determined that somatostatin receptor scintigraphy (SRS) (performed using ¹¹¹Indium-diethylenetriamine pentaacetic acid-octreotide [¹¹¹In-DPTA octreotide]) is the procedure of choice for the identification of metastases of MEN1 pancreatic endocrine tumors (PETs). CT and MRI imaging are also helpful in localizing the tumor [Imamura et al 2011].CarcinoidCT and MRI are equally sensitive in detecting thymic carcinoid, at initial evaluation and during follow up for recurrence [Brandi et al 2001].
Note: Because both plain chest x-ray and SRS scan have lower sensitivity than CT and MRI in detecting either primary or recurrent thymic carcinoid, SRS scan is not the first imaging study of choice [Gibril et al 2003, Scarsbrook et al 2007, Goudet et al 2009].CT is useful in localizing occult bronchial carcinoid tumors and in follow up after their removal.Adrenocortical tumors. These are generally detected by CT.Molecular Genetic TestingGene. MEN1 is the only gene in which mutations are known to cause MEN1 syndrome.Clinical testing. Individuals who have a single MEN1-related tumor and no family history of MEN1 syndrome rarely have germline MEN1 mutations [Ellard et al 2005]. Although different mutation detection rates are reported in different series, the likelihood of detecting a MEN1 mutation increases in individuals with more main tumors (parathyroid, pancreatic, and pituitary), especially those from families with hyperparathyroidism and pancreatic islet tumors [Ellard et al 2005, Klein et al 2005].In simplex cases (i.e., a single occurrence in a family):Odou et al [2006] found that mutation detection frequency depended on the number and type of clinical manifestations: (1) pancreatic disease was significantly linked with the probability of detecting an MEN1 mutation; (2) the presence of two manifestations increased the probability of identifying an MEN1 mutation.Jäger et al [2006] suggest that MEN1 testing should also be offered to those with PHPT or gastrinomas, whereas simplex cases with carcinoid tumors or primary prolactinomas are rarely associated with germline MEN1 mutations. Approximately 5%-10% of people with MEN1 do not have a mutation in the coding region of MEN1 or in splicing sites. Such individuals may harbor a large gene deletion or a mutation of untranslated regions or introns, or they may represent phenocopies (i.e., MEN4 syndrome; see Differential Diagnosis). Table 1. Summary of Molecular Genetic Testing Used in MEN1 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMEN1Sequence analysis / mutation scanning 2 Sequence variants 3Familial 4Simplex 5Clinical 80%-90% 6 65% 6, 7Deletion / duplication analysis 8Exonic and whole-gene deletions1%-4% 9Linkage analysis 10Not applicableNot applicable 111. The ability of the test method used to detect a mutation in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies, although mutation scanning detection frequency may vary considerably among laboratories as it is highly dependent on the detailed methodology employed. 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Familial MEN1 syndrome is defined as a proband meeting the diagnostic criteria of MEN1 syndrome plus a minimum of one first-degree relative with at least one of these tumors. 5. Simplex MEN1 syndrome is defined as a single occurrence of MEN1 syndrome in a family.6. MEN1 germline mutations are identified in about 80% to 90% of probands with familial MEN1 syndrome [Brandi et al 2001] and about 65% of individuals with simplex MEN1 syndrome (i.e., a single occurrence of MEN1 syndrome in a family) [Guo & Sawicki 2001].7. The likelihood of detecting a germline mutation may be lower in the individual who is known to be the first affected individual in the family, possibly because a de novo mutation has resulted in somatic mosaicism that involves the germline in that individual [Klein et al 2005].8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Kishi et al [1998], Bergman et al [2000], Cavaco et al [2002], Ellard et al [2005], Klein et al [2005], Tham et al [2007], Fukuuchi et al [2006]10. Non-pathogenic single nucleotide polymorphisms have been described, which are potentially useful for segregation analysis in informative kindreds when MEN1 mutation is not found [Tham et al 2007, Lemos & Thakker 2008].11. MEN1 normal allelic variants are potentially useful for segregation analysis in informative kindreds when MEN1 mutation is not found by other molecular testing [Tham et al 2007, Lemos & Thakker 2008].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Confirmation of the diagnosis in a proband relies on detection of a MEN1 mutation. 1.Sequence analysis of MEN1 should be performed first.2.If no mutation is detected, follow with deletion/duplication analysis.Note: Without MEN1 molecular genetic testing, the diagnosis of MEN1 syndrome is likely to be delayed or missed in individuals presenting with ZES because of the later onset and milder manifestations of the other features of MEN1 syndrome.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Note: Linkage analysis may be used in certain families if a disease-causing mutation is not identified using sequence analysis or deletion/duplicaton analysis.Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersGermline MEN1 mutations. Familial isolated hyperparathyroidism (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies. MEN1 germline mutations have been reported in between 20% [Miedlich et al 2001, Villablanca et al 2002] and 57% [Pannett et al 2003] of families with FIHP. In families with FIHP caused by MEN1 mutation, 38% are missense mutations (p <0.01), in contrast to MEN1 syndrome, in which missense mutations account for 20% of cases [Lemos & Thakker 2008]. Nonsense mutations in MEN1 are found in only 5% of families with FIHP, whereas 23% of families with MEN1 syndrome have nonsense mutations. Of note, in one family with FIHP with an intronic MEN1 mutation and no clinical evidence of hyperparathyroidism-jaw tumor syndrome, the mother of the proband (whose genetic status was unknown, but who likely had the same mutation as the proband) died of parathyroid carcinoma [Carrasco et al 2004]. Thus, in contrast to MEN1 syndrome (in which the risk for parathyroid carcinoma does not appear to be increased), FIHP may be associated with an increased risk for parathyroid carcinoma (see also Differential Diagnosis).Somatic MEN1 mutations. Sporadic tumors (including parathyroid adenoma, gastrinoma, insulinoma, and bronchial carcinoid) occurring as single tumors in the absence of any other findings of MEN1 syndrome frequently harbor somatic MEN1 mutations that are not present in the germline; thus, predisposition to these tumors is not heritable [Carling 2005]. Somatic mutations are scattered throughout MEN1.Arnold et al [2002] identified specific clonal alterations involving somatic mutation and/or deletion of both MEN1 alleles in 15%-20% of sporadic parathyroid adenomas. In addition, 5%-50% of sporadic endocrine tumors have been found to have loss of heterozygosity (LOH) at the 11q13 locus, where MEN1 is found [Friedman et al 1992, Heppner et al 1997].}

Natural HistoryEndocrine tumors occurring in individuals with MEN1 syndrome are shown in Table 2.Table 2. Endocrine Tumor Types in MEN1 SyndromeView in own windowTumor TypeTumor SubtypeHormone SecretingPrevalence in MEN1 SyndromeParathyroidNA ¹ Yes100% have primary hyperparathyroidism by age 50 yrs ² Anterior pituitaryProlactinoma (PRLoma)Yes~10%-60% ³ have anterior pituitary tumorsMost commonly seen anterior pituitary tumor subtypeGrowth hormone (GH)-secretingYesAccounts for 5% of anterior pituitary tumors ⁴ GH/PRL-secretingYes5% ⁴ TSH-secretingYesRare ⁵ ACTH-secretingYes2% ^{4Well-differentiated endocrineGastrinomaYesAccounts for 40% of well-differentiated endocrine tumors 6 InsulinomaYes10% 4 GlucagonomaYes2% 4 VIPomaYes2% 4 CarcinoidBronchialNo10%ThymicNoAdrenocorticalCortisol-secretingRarely~20%-40% have adrenocortical tumorsRareAldosterone-secretingRarelyRarePheochromocytomaRarely<1% 4 1. Not applicable 2. First clinical manifestation of MEN1 in 90% of individuals 3. First clinical manifestation of MEN1 in 10% of familial cases and 25% of simplex cases 4. Brandi et al [2001] 5. Valdes-Socin et al [2003] 6. Manifest as Zollinger-Ellison syndrome (ZES)The endocrine tumors of MEN1 syndrome occur in varying combinations in individuals. The only specific clustering of tumors within the MEN1 phenotype is the Burin variant, a phenotype reported in four kindreds from Newfoundland and in one from Mauritius, in which the prevalence of prolactinoma is higher than average and the prevalence of gastrinoma is lower than average [Hao et al 2004].Of note, MEN1 tumors are often clinically distinct from sporadically occurring tumors of the same tissue type (i.e., as single tumors in the absence of other findings of MEN1 syndrome) (see Differential Diagnosis).Primary Hyperparathyroidism (PHPT)PHPT is often mild, with biochemical evidence of hypercalcemia often detected in the course of evaluation of asymptomatic individuals known to have or be at risk for MEN1 syndrome. PHPT is the main MEN1-associated endocrinopathy, being the first clinical expression of MEN1 syndrome in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 syndrome can be expected to have hypercalcemia by age 50 years [Thakker 2010]. Although PHPT is frequently asymptomatic for a long period of time, it may manifest as reduced bone mass in women who are hyperparathyroid as early as age 35 years [Burgess et al 1999].A study from Taiwan on MEN1-PHPT demonstrated that it was less aggressive than that reported in the literature [Lee et al 2006].Common clinical manifestations of hypercalcemia:Central nervous system. Altered mental status, including lethargy, depression, decreased alertness, confusion (rarely, obtundation and coma)Gastrointestinal. Anorexia, constipation, nausea, and vomitingRenal. Diuresis, impaired concentrating ability, dehydration, hypercalciuria, and increased risk for kidney stonesSkeletal. Increased bone resorption and increased fracture riskCardiovascular. Cause of and/or exacerbation of hypertension, shortened QT intervalHypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome [Marx 2001].Pathology. Multiglandular parathyroid disease with enlargement of all the parathyroid glands, rather than a single adenoma, is typical; adenomas are considered to be sporadic tumors of clonal origin [Marx 2001].Cancer risk. Malignant progression of parathyroid tumors is not a clinical feature of "classic" MEN1 syndrome despite six case reports of parathyroid carcinoma in persons with MEN1 [Sato et al 2000, Dionisi et al 2002, Agha et al 2007, Shih et al 2009, del Pozo et al 2011].Anterior Pituitary TumorsPituitary tumors are the first clinical manifestation of MEN1 syndrome in 25% of simplex cases (i.e., a single occurrence of MEN1 syndrome in a family) and in 10% of familial cases. Vergès et al [2002] reported that pituitary involvement was the initial manifestation of MEN1 syndrome in 17% of individuals and that pituitary adenomas occurred with significantly greater frequency in women than in men (50% vs 31%; P<0.001). The incidence of pituitary tumors in MEN1 syndrome varies from 15% to 55% in different series [Thakker et al 2012]. Prolactinoma is the most common pituitary tumor.Adenomas that produce more than one hormone occur more frequently than was originally thought. The association of growth hormone and prolactin with follicle-stimulating hormone, luteinizing hormone, or adrenocorticotropic hormone has been reported [Trouillas et al 2008].In spite of their high penetrance in MEN1, pituitary tumors are usually solitary; rarely has more than one pituitary tumor been observed simultaneously in an individual — an example being an individual with one gonadotrope macroadenoma and one corticotrope microadenoma [Al Brahim et al 2007].Symptoms depend on the pituitary hormone produced:Amenorrhea and galactorrhea occur in females with PRL-secreting tumors.Reduction of libido or impotence occurs in males with PRL-secreting tumors.Hypercortisolism occurs in ACTH-secreting tumors, as described in four children with MEN1 ages 11 to 13 years with Cushing’s disease as the first manifestation of MEN1 [Matsuzaki et al 2004, Rix et al 2004].Gigantism and acromegaly occur in children and adults, respectively, with growth hormone (GH)-secreting tumors [Stratakis et al 2000].A functioning FSH-secreting adenoma has been reported in a man [Sztal-Mazer et al 2008].Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [Carty et al 1998].Histology. Between 65% [Brandi et al 2001] and 85% [Vergès et al 2002] of pituitary tumors in MEN1 syndrome are macroadenomas.Trouillas et al [2008] confirmed the following regarding MEN1-associated turmors vs non-MEN1-associated tumors: Histologically, MEN1 tumors are significantly larger and more often invasive.Persons with MEN1 and large pituitary tumors are younger. Multiple adenomas are significantly more frequent in MEN1, especially with prolactin-adrenocorticotropic hormone. Genotype-phenotype correlation is lacking.Cancer risk. Although Vergès et al [2002] reported that 32% of pituitary macroadenomas were invasive, malignant degeneration of MEN1-associated pituitary tumors is infrequent. However, Benito et al [2005] reported a metastatic gonadotrophic pituitary carcinoma in a female with MEN1 and Gordon et al [2007] reported a metastatic prolactinoma that presented as a cervical spinal cord tumor.Well-Differentiated Endocrine Tumors of the Gastro-Entero-Pancreatic (GEP) TractGastrinoma. Approximately 40% of individuals with MEN1 syndrome have gastrinoma, which manifests as Zollinger-Ellison syndrome (ZES). Findings can include upper abdominal pain, diarrhea, esophageal reflux, and acid-peptic ulcers; if not properly diagnosed or treated, ulcer perforation can occur from hypergastrinemia, even without prior symptoms. Heartburn and weight loss occur, but are less commonly reported. ZES-associated hypergastrinemia may result in multiple duodenal ulcers; epigastric pain generally occurs two or more hours after meals or at night and may be relieved by eating. However, the pain may also be in the right upper quadrant, chest, or back. Vomiting may be related to partial or complete gastric outlet obstruction; hematemesis or melena may result from GI bleeding.ZES usually occurs before age 40 years [Gibril et al 2004]. 25% of individuals with MEN1 syndrome/ZES have no family history of MEN1 syndrome [Gibril et al 2004].Pathology. In general, endocrine pancreatic microadenomatosis is a feature of MEN1 syndrome [Anlauf et al 2006]. Typically, multiple small (diameter <1 cm) gastrinomas are observed in the duodenal submucosa. In particular, more than 80% of MEN1 gastrinomas are commonly found within the first and second portions of the duodenum [Hoffmann et al 2005]. MEN1 duodenal gastrinomas are associated with diffuse hyperplastic changes of gastrin cells and multicentric microtumors (<1 mm) that produce gastrin [Anlauf et al 2005].
About 50% of duodenal microgastrinomas have loss of heterozygosity (LOH) at the MEN1 locus and thus could represent the initial tumor [Anlauf et al 2007]. Multifocal duodenal endocrine tumors presumably arise by independent clonal events in individuals with a germline MEN1 mutation [Anlauf et al 2007]. Such precursor lesions are not reported in sporadic, non-MEN1 gastrinomas [Anlauf et al 2007].Cancer risk. The gastrinomas of MEN1 syndrome are frequently multiple and usually malignant. Half have metastasized before diagnosis [Brandi et al 2001, Anlauf et al 2005, Fendrich et al 2007]. Individuals with liver metastases have a poor prognosis for survival; this contrasts with nodal metastases, which do not seem to negatively influence prognosis.
Pancreatic gastrinomas, which are rare in MEN1 [Anlauf et al 2006], are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors (PETs), eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [Tonelli et al 2005], whereas four of 12 symptomatic individuals operated on at a mean age of 51 years had malignant tumors, from which two of the individuals subsequently died.Insulinoma. The age of onset of insulinoma associated with MEN1 is generally one decade earlier than the sporadic counterpart [Marx et al 1999].Pathology. Generally a single tumor occurs in the setting of multiple islet macroadenomas [Brandi et al 2001]. Tumors responsible for hyperinsulinism are usually about 1-4 cm in diameter.Cancer risk. Insulinomas are almost always benign. One individual with cervical metastasis of a glucagonoma recovered well from pancreatoduodenectomy and subsequently remained asymptomatic [Butte et al 2008].Non-secreting GEP tract tumors are frequent in MEN1 syndrome.A prospective endoscopic ultrasonographic evaluation of the frequency of non-functioning pancreatic tumors in MEN1 suggested that their frequency of 54.9% is higher than previously thought [Thomas-Marques et al 2006]. Moreover, the penetrance of 34% for these tumors at age 50 years in persons with MEN 1 from the French Endocrine Tumor Study Group indicates that they are the most frequent pancreaticoduodenal tumor in MEN 1. Average life expectancy of individuals with MEN1 with non-screting tumors was shorter than life expectancy of individuals who did not have pancreaticoduodenal tumors [Triponez et al 2006].A long-term follow-up study in MEN1 in affected individuals of Japanese heritage revealed that non-functioning pancreatic tumors smaller than 20 mm in diameter did not show any apparent growth over a long monitoring period and did not metastasize to regional lymph nodes or the liver [Sakurai et al 2007].Neuroendocrine tumors with immunohistochemical expression of gastrin but without signs of ZES are considered “functionally inactive NETs expressing gastrin,” not secreting neuroendocrine tumors or gastrinomas [Anlauf et al 2006].Preliminary results of a Japanese survey of neuroendocrine gastrointestinal tumors revealed that the incidence of MEN1 associated with pancreatic endocrine tumors (PETs) was 7.4% [Ito et al 2007].Carcinoid TumorsThymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 10% of individuals with MEN1 syndrome. These are the only MEN1 syndrome-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females [Teh et al 1997]; bronchial carcinoids are more prevalent in females than in males. Interestingly, thymic carcinoids have a less marked gender difference (male/female ratio 2:1) in Japanese individuals with MEN1 [Sakurai et al 2012]. The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy [Schnirer et al 2003]. Thymic, bronchial, and gastric carcinoids rarely oversecrete ACTH, calcitonin, or GHRH; similarly, they rarely oversecrete serotonin or histamine and rarely cause the carcinoid syndrome. Thymic carcinoids have been reported to produce growth hormone causing acromegaly [Boix et al 2002] and ACTH causing Cushing syndrome [Takagi et al 2006, Yano et al 2006]; however, others have not observed hormone secretion by these tumors [Gibril et al 2003].The retrospective study of Gibril et al [2003] supports the conclusion that thymic carcinoid tumors are generally a late manifestation of MEN1 syndrome as no affected individuals had thymic carcinoid as the initial MEN1 manifestation. Thymic carcinoid in MEN1 syndrome commonly presents at an advanced stage as a large invasive mass. Less commonly, it is recognized during chest imaging or during thymectomy as part of parathyroidectomy.The mean age at diagnosis of gastric carcinoids is 50 years. In up to 70% of individuals with MEN1 syndrome, gastric carcinoids are recognized incidentally during endoscopy [Berna et al 2008].Cancer risk. The thymic carcinoids of MEN1 syndrome tend to be aggressive [Gibril et al 2003]. Ferolla et al [2005] determined that thymic carcinoids are highly lethal, particularly in males who are smokers, a finding confirmed by Goudet et al [2009] in a study of 21 thymic neuroendocrine tumors in 761 French individuals with MEN1. Spinal metastasis of carcinoid tumor has been reported in an individual with MEN1 [Tanabe et al 2008] and synchronous thymoma and thymic carcinoid has been reported in a woman with MEN1 [Miller et al 2008].Bronchial carcinoids, often multicentric, may exhibit both synchronous and metasynchronous occurrence. In contrast to thymic carcinoids, most bronchial carcinoids usually behave indolently, albeit with the potential for local mass effect, metastasis, and recurrence after resection [Sachithanandan et al 2005].Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) — this in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death [Goudet et al 2010]. The median survival following the diagnosis a thymic tumor is reported to be approximately 9.5 years with 70% of affected individuals dying as a direct result of the tumor [Goudet et al 2009].Adrenocortical TumorsAdrenocortical tumors, involving one or both adrenal glands, are present in 20%-40% of individuals with MEN1 syndrome.Rarely, adrenal cortex tumors are associated with primary hypercortisolism or hyperaldosteronism [Honda et al 2004]. In a study of 67 individuals, Langer et al [2002] identified ten with non-functional benign tumors, eight with bilateral adrenal gland tumors, three with Cushing syndrome, and one with a pheochromocytoma. Four developed adrenocortical carcinomas, three of which were functional.Histology. Silent adrenal gland enlargement is a polyclonal or hyperplastic process that rarely results in neoplasm. In the study of Langer et al [2002], the median tumor diameter at diagnosis was 3.0 cm (range 1.2-15.0 cm), with most tumors being 3 cm or smaller.Cancer risk. In a study of 715 individuals with MEN1, Gatta-Cherifi et al [2012] estimated the overall incidence of adrenocortical carcinoma at 1%; however, those affected individuals with adrenal tumors larger than 1 cm had an approximately 13% incidence of adrenocortical carcinoma. Morbidity and Mortality of MEN1 SyndromeImproved knowledge of MEN1 syndrome-associated clinical manifestations, early diagnosis of MEN1 syndrome-associated tumors, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death. Nonetheless, individuals with MEN1 syndrome are at a significantly increased risk for premature death [Geerdink et al 2003]. MEN1 syndrome-associated malignancies currently account for approximately 30% of deaths in MEN1 syndrome.In a multicenter study of 258 heterozygotes for an MEN1 mutation, Machens et al [2007] found that “as a result of differential tumor detection, MEN1 carriers born during the second half of the 20th century tend to have their tumors diagnosed earlier than carriers of the same age born in the first half.” Note: Machens et al [2007] use the term “carriers” to refer to heterozygotes for an MEN1 mutation.}

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been identified in MEN1 syndrome [Kouvaraki et al 2002, Turner et al 2002, Wautot et al 2002, Lemos & Thakker 2008].Of note, a trend (which has not reached statistical significance) suggests that the prevalence of truncating mutations in MEN1-related thymic carcinoids is higher than in other MEN1-related tumors [Lim et al 2006].

Differential DiagnosisCDKN1B. The following findings suggest the existence of a rare and important phenocopy of classic MEN1 reported as MEN4 (OMIM 610755). However, more families need to be studied to understand the complete phenotype.A germline mutation of CDKN1B/p27, encoding the p27^kip protein, was reported in a small family that did not have an MEN1 mutation but met clinical diagnostic criteria for MEN1 based on the presence of somatotropinoma, parathyroid tumors, and renal angiomyolipoma [Pellegata et al 2006].A truncating germline mutation of CDKN1B/p27 was reported in one Dutch individual with suspected MEN1 because of a pituitary adenoma, carcinoid tumor, and hyperparathyroidism [Georgitsi et al 2007].Agarwal et al [2009a] reported that a rare germline mutation in any four (p15, p18, p21, and p27) of the seven cyclin-dependent kinase inhibitor genes may be a cause of MEN1 or of some related phenotypes. They found germline mutations of CDKN2B/p15 and CDKN1B/p27 in two individuals with Zollinger-Ellison syndrome [Agarwal et al 2009a].Molatore et al [2010] identified a variant in CDKN1B/p27 at codon 69 (p.Pro69Leu) resulting in extremely reduced to absent p27 expression in an individual with multiple typical bronchial carcinoids, primary hyperparathyroidism, papillary thyroid carcinoma with neck lymph node metastasis, microadenoma in the pituitary gland, and bilateral multiple lung metastasis. The most important and common disorders to consider in the differential diagnosis:Primary hyperparathyroidism (PHPT). Overall, PHPT has a prevalence of 3:1000 in the general population with a female-to-male ratio of approximately 3:1 [Bilezikian & Silverberg 2000].Sporadic PHPT, generally caused by a single parathyroid adenoma, refers to PHPT that is not inherited. The peak incidence of sporadic PHPT is in the sixth decade of life [Bilezikian & Silverberg 2000].
Note: Most individuals with sporadic PHPT are identified because of symptoms of hypercalcemia, in contrast to individuals known to have or to be at risk for MEN1 syndrome, who are often asymptomatic when identified during evaluation for manifestations of MEN1 syndrome.MEN1 syndrome-associated PHPT represents 2%-4% of all PHPT, does not exhibit sex prevalence, and has its onset three decades earlier (ages 20-25 years) than its sporadic counterpart [Marx 2001, Uchino et al 2000]. PHPT caused by multiglandular disease in individuals younger than age 40 years may represent the first manifestation of MEN1 syndrome regardless of family history [Langer et al 2003].Familial isolated HPT (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies in two or more individuals in one family. Germline mutations have been identified in the following genes in individuals with FIHP (other individuals with FIHP may have a mutation in an as-yet unknown gene):MEN1 in 20% [Miedlich et al 2001] to 23% of FIHP [Warner et al 2004]. Hannan et al [2008] also reported germline mutations of MEN1 in individuals with FIHP (also see Genetically Related Disorders).CASR, the gene encoding the calcium-sensing receptor, responsible for familial benign hypercalcemia (FBH), also called familial hypocalciuric hypercalcemia (FHH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT) [Brown 1997, Carling et al 2000]. Between 14% [Simonds et al 2002] and 18% [Warner et al 2004] of families with FIHP have identifiable CASR mutations.HRPT2, the gene encoding parafibromin, which is responsible for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome [Carpten et al 2002, Teh et al 1998a, Villablanca et al 2004]. Of note, Warner et al [2004] did not identify any HRPT2 mutations in 22 individuals with FIHP. See CDC73-Related Disorders.MEN2 syndrome, caused by mutations in RET, is genetically distinct from MEN1 syndrome. MEN2A, a clinical variant of MEN2 syndrome, is characterized by medullary thyroid carcinoma, pheochromocytoma, and PHPT. PHPT occurs in approximately 20%-30% of individuals with MEN2A syndrome and is generally milder than MEN1 syndrome-associated PHPT [Brandi et al 2001]. Although most individuals with MEN2A syndrome and PHPT have no symptoms, hypercalciuria and renal calculi may occur. Note: Co-occurrence of MEN1 syndrome and MEN2 syndrome has been reported in one family with both germline mutations in the RET protooncogene and MEN1 tumor suppressor gene. The presence of both germline mutations did not alter the typical phenotype of either MEN1 syndrome or MEN2 syndrome or the clinical course of the diseases [Frank-Raue et al 2005].Pituitary tumorsProlactinomas occur more commonly with MEN1 syndrome than they do sporadically.MEN1 syndrome-associated pituitary adenomas have later onset than sporadic pituitary adenomas.MEN1 syndrome-related pituitary tumors are more likely to be macroadenomas than sporadic pituitary adenomas.Sporadic pituitary adenomas respond better to medical therapy than MEN1 syndrome-associated pituitary tumors [Beckers et al 2003].Note: Single pituitary adenomas in the absence of any other findings of MEN1 syndrome are not frequently associated with somatic MEN1 mutations [Agarwal et al 2009b], although some data suggest that somatic MEN1 gene mutations and deletions play a causative role in the development of a subgroup of sporadic pituitary adenomas [Agarwal et al 2009b].Familial pituitary adenomas are usually somatotrophinomas and lack MEN1 germline mutations [Tanaka et al 1998, Tsukada et al 2001]. MEN1 mutations have been identified in fewer than 1% of index cases with familial pituitary tumor [Vierimaa et al 2006].Germline mutations in AIP, encoding aryl hydrocarbon receptor-interacting protein, have been reported to cause pituitary adenoma predisposition (PAP) in studies in Northern Finland [Vierimaa et al 2006]. Daly et al [2007] confirmed this in a large series with germline AIP mutations in 15% of kindreds with familial isolated pituitary adenoma (FIPA).Linkage to 11q13 has been reported in kindreds with isolated familial somatotrophinoma [Gadelha et al 2000, Luccio-Camelo et al 2004].Note: Although CDKN1B/p27 mutations have been associated with an MEN1 syndrome-related phenotype that includes pituitary tumors [Georgitsi et al 2007, Pellegata et al 2006, Molatore et al 2010], Agarwal et al [2009b] did not identify pituitary tumors in individuals with CDKN1B/p27 germline mutations.Zollinger-Ellison syndrome (ZES)MEN1 syndrome-associated ZES is typically associated with multiple tumors in the duodenal mucosa, often surrounded by hyperplasia of gastrin cells. Twenty-five percent of all ZES can be attributed to MEN1 [Brandi et al 2001]. Moreover, 25% of individuals with MEN1 syndrome/ZES have no family history of MEN1 syndrome [Gibril et al 2004].Two individuals who have ZES along with a mutation in two cyclin-dependent kinase inhibitor genes (CDKN2B/p15 and CDKN1B/p27) have been reported [Agarwal et al 2009a].Sporadically occurring gastrinomas are more commonly pancreatic in origin [Norton et al 2001, Tonelli et al 2005]. Symptoms generally occur one decade earlier in MEN1 syndrome-associated gastrinomas than in sporadic gastrinomas [Brandi et al 2001].Insulinoma. MEN1 syndrome accounts for 10% of all sporadic and hereditary cases of hypoglycemia. MEN1 syndrome-associated hypoglycemia is generally caused by one tumor in the setting of multiple islet macroadenomas [Brandi et al 2001]. The peak age at onset of insulinoma in MEN1 syndrome is approximately one decade earlier than in sporadic insulinomas [Marx et al 1999, Brandi et al 2001].Carcinoid tumorsCarcinoid tumors not associated with MEN1 syndrome usually occur in derivatives of the midgut and hindgut, are argentaffin positive, and secrete serotonin (5-hydroxytryptamine).MEN1 syndrome-associated thymic carcinoid has a more severe course than sporadic thymic carcinoid, especially in smokers [Brandi et al 2001].The association of gastric carcinoids and hyperparathyroidism appears to constitute a distinct syndrome in genetically predisposed individuals and should not be regarded as 'atypical' or 'incomplete' expression of MEN1 syndrome [Christopoulos et al 2009].Facial angiofibromas are seen in tuberous sclerosis complex.Leiomyomas can be seen in association with Alport syndrome.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with multiple endocrine neoplasia type 1 (MEN1), evaluation for the following most common MEN1 syndrome-associated tumors (as described in Differential Diagnosis) is recommended:Multiglandular parathyroid diseaseGastrinoma and other entero-pancreatic neuroendocrine tumorsProlactinomaTreatment of ManifestationsClinical practice guidelines for MEN type 1 have been developed [Thakker et al 2012; click for full text].PHPTConsider the use of bone anti-resorptive agents prior to surgery to reduce hypercalcemia and limit PTH-dependent bone resorption, thus reducing future risk of osteoporosis.The optimal surgical approach in MEN1 syndrome-associated PHPT is controversial. Approaches include either subtotal parathyroidectomy (removal of 7/8 of the parathyroid tissue) with cryopreservation of parathyroid tissue, or total parathyroidectomy and autotransplantation of parathyroid tissue [Carling & Udelsman 2005].Marx [2001] determined that PHPT recurred in as many as 50% of euparathyroid individuals with MEN1 syndrome eight to twelve years after successful subtotal parathyroidectomy. Such recurrence was likely the result of either new neoplasia arising in residual normal tissue, or neoplasia progressing in the residual tissue.Elaraj et al [2003] showed that subtotal and total parathyroidectomy resulted in longer recurrence-free intervals compared with lesser resection. Cumulative recurrence rates for procedures that were less than subtotal parathyroid resection were 8%, 31%, and 63% at one, five, and ten years, respectively. For subtotal or total parathyroid resection, the cumulative recurrence rates were 0%, 20%, and 39% at one, five, and ten years, respectively.The high incidence of severe hypoparathyroidism after total parathyroidectomy supports the use of subtotal parathyroidectomy as the initial procedure of choice in MEN1 syndrome [Elaraj et al 2003].In a study from Taiwan selective parathyroidectomy (selective removal of the enlarged glands with or without biopsy of a normal-appearing gland) achieved optimal outcomes [Lee et al 2006].A European study determined that, when correctly performed, subtotal parathyroidectomy could be considered a surgical treatment that minimizes the risk of permanent hypocalcemia and facilitates future surgery [Hubbard et al 2006].16 years’ experience of surgical treatment of 51 persons with MEN1-PHPT from Italy revealed that total parathyroidectomy guided by intraoperative PTH monitoring and followed by autograft (to the forearm) is the best surgical option. Persistent hypoparathyroidism occurred in 25%, with a higher incidence in individuals undergoing a second surgery for cervical recurrence than in individuals undergoing the first surgery. At follow up, 10% of recurrences in the parathyroid autografted to the forearm were observed after a mean time of seven years ±5 (SD) years. Moreover, no cervical recurrence was documented [Tonelli et al 2007].Some studies have reported that treatment of MEN1-associated hyperparathyroidism by calcimimetics (which act on the calcium-sensing receptor) or octreotide LAR could be also effective, particularly for individuals in whom surgery either failed or was contraindicated [Faggiano et al 2008, Falchetti et al 2008, Moyes et al 2010].Pituitary TumorsPRL-secreting tumors (prolactinomas)Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment of PRL-secreting tumors.Cabergoline can be considered the current treatment of choice because of its reduced side effects and greater potency [Tichomirowa et al 2009].Growth hormone-secreting tumorsTranssphenoidal surgery, the first treatment of choice in growth hormone-secreting tumors causing acromegaly, is effective in 50%-70% of cases.Somatostatin analogs are the medical therapy of choice for the treatment of growth hormone-secreting tumors. Octreotide and lanreotide normalize serum concentration of hGH and IGF1 in more than 50% of treated individuals [Beckers et al 2003].Dopamine agonists are only rarely effective in treatment of growth hormone-secreting tumors causing acromegaly, although they can be effective in mixed GH-PRL-secreting adenomas and 10%-20% of tumors resistant to somatostatin analogs [Colao et al 1997, Marzullo et al 1999, Freda 2002].ACTH-secreting tumorsIn most ACTH-secreting pituitary tumors associated with Cushing syndrome, the treatment is excision of an adenoma. In the series of Beckers et al [2003], 92% of individuals with an identified microadenoma and 67% with a macro-adenoma were considered to be cured immediately after surgery.For those ACTH-secreting pituitary tumors associated with Cushing syndrome that are not cured neurosurgically, radiotherapy may be necessary to reduce the production of ACTH.Non-secreting pituitary adenomasIn non-secreting pituitary adenomas, surgical treatment using a transsphenoidal approach is the treatment of choice. However, in rare cases of very large adenomas with considerable extracellar extension, the transfrontal approach is the only possibility [Beckers 2002].In 5%-15% of cases, medical treatment with potent dopaminergic agonists or with somatostatin analogs may shrink the adenoma before surgery [Colao et al 1998].Published data are not sufficient to compare the treatment of sporadic versus MEN1 syndrome-associated pituitary tumors. Although general agreement on this topic does not exist, Beckers et al [2003] suggested that aggressive therapy is more frequently needed in MEN1-associated pituitary tumors than in sporadic tumors.Well-Differentiated Tumors of the Gastro-Entero-Pancreatic (GEP) TractGastrinomaMedications that can control some of the GEP hormone excess-dependent features of MEN1 syndrome and thus prevent severe and sometimes life-threatening morbidity in MEN1 syndrome include proton pump inhibitors or H₂-receptor blockers to reduce gastric acid output [Jensen 1999].Surgical (versus nonsurgical) management of gastrinoma in MEN1 syndrome is controversial as successful outcome of surgery is rare.Because MEN1 syndrome gastrinomas occur most commonly in the first and second portions of the duodenum, and less commonly the third and fourth portions of the duodenum and the first jejunal loop, it is important that all these sites be examined during preoperative imaging, intraoperative exploration, and pathologic examination of surgical specimens [Tonelli et al 2005].A case of a primary lymph node gastrinoma in an individual with MEN1 has been reported and a review of similar cases in the international literature reveals that some gastrinomas in lymph nodes are not the result of metastastic spread. A long-term symptom-free follow up after the excision of a lymph node gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. Thus, the findings of Zhou et al [2006] supported the possibility that any gastrinoma in persons with MEN1 syndrome should be surgically resected for cure if possible. Lately, Anlauf et al [2008] reported the presence of a primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a person with MEN1 syndrome, confirming the need for a systematic search for the primary tumor.Pancreatic tumors. Pancreatic surgery for asymptomatic individuals with MEN1 syndrome is controversial.Surgery is usually indicated for insulinoma and most of the other pancreatic tumors observed in MEN1 syndrome. According to Tonelli et al [2005], the best surgical approach for an MEN1 insulinoma is intraoperative localization of nodules greater than approximately 0.5 cm diameter by palpation or intraoperative ultrasound followed either by enucleation (removal) of these nodules or by pancreatic resection if multiple large deep tumors are present.A retrospective analysis considering the clinical characteristics, surgical treatment, and clinical outcome of persons with MEN1 syndrome with pancreatic endocrine tumors (PETs) revealed functioning PETs in 64% and non-functioning tumors in 36%. Pancreatic surgery was performed in 69% of individuals. Recurrent disease developed in the residual pancreas in 20% of at-risk individuals a median of 7.8 years after the first operation; distant metastases occurred in 14% of surgically treated individuals who did not have distant metastasis at the time of initial surgery at a median of 2.7 years following surgery. At follow up, 29% of individuals with PETs had died, 22% were alive with disease, 47% were alive without evidence of disease, and 2% were lost to follow up. The median overall survival was 19.5 years (range 13-26 years) and was significantly longer for those with functioning PETs versus those with non-functioning tumors, for those who underwent surgical resection of their PETs versus those who did not, and for those with localized versus metastatic PETs at the time of diagnosis. Younger age, hormonal function, and PET resection were independently associated with longer overall survival [Kouvaraki et al 2006]. These findings supported that early diagnosis and surgical excision of MEN1-related PETs improved survival even considering the potential morbidity of pancreatic resection and the risk of long-term insulin dependence.A German study suggested that an early and aggressive surgery of PETs in those with MEN1 prevents development of liver metastases, the most life-threatening complication. Pylorus-preserving pancreaticoduodenectomy (PPPD) could be the procedure of choice for MEN1/ZES, although it remains to be proven in large-scale studies [Bartsch et al 2005].In an Italian study of 16 individuals with MEN1 syndrome who underwent pancreatoduodenectomy (PD), total pancreatectomy (TP), or distal pancreatectomy for hypergastrinism, 81% had ZES, hypoglycemia, and/or pancreatic endocrine neoplasias larger than 1 cm. Patients were followed three and six months postoperatively and yearly thereafter with measurement of fasting serum gastrin concentration and serum concentrations of other entero-hormones, and a secretin provocative test. In addition, an abdominal US and/or a CT scan were obtained once every two years or when hormone concentrations were high. At follow up of those who had been hypergastrinemic preoperatively, 77% were eugastrinemic with a negative secretin provocative test and 23% had recurrence of the disease. The authors concluded that PD was superior to less radical surgical approaches in providing a cure with limited morbidity for gastrinoma and pancreatic neoplasia. The authors suggest that a rapid intraoperative gastrin measurement (IGM) may be of value in the assessment of surgical cure [Tonelli et al 2006]. All individuals with insulinoma were cured.
Note: Limited resection or simple enucleation of nodules is more frequently followed by persistence or recurrence of the disease [Lo et al 1998, Simon et al 1998, Jordan 1999].Eleven individuals with MEN1 presenting with metastatic duodenal gastrinomas or developing them during follow up were treated by somatostatin analogs (63.6%) and chemotherapy (27.3%). Such non-surgical treatment seemed to stabilize the disease [Nikou et al 2005]. Further and larger studies are needed.In summary, when surgery is controversial or not possible, the medical treatment of MEN1 endocrine pancreatic tumors, as with sporadic nonsyndromictumors, may include somatostatin analogs, chemotherapy, and interferon-alpha. Somatostatin analogs may improve symptoms and provide an antiproliferative effect. Chemotherapy is indicated when the tumors tend to grow. Interferon-alpha produces a symptomatic response in 40%-60% of patients, a biochemical response in 30%-60%, and tumor shrinkage in 10%-15% [Libé & Chanson 2007].Carcinoid TumorsLong-acting somatostatin analogs can control the secretory hyperfunction associated with carcinoid syndrome [Tomassetti et al 2000]; however, the risk for malignant progression of the tumor remains unchanged [Schnirer et al 2003]. Therefore, the treatment of choice for carcinoid is surgical removal, if resectable.Thymic carcinoid recurred in all individuals with MEN1 syndrome who were followed for more than one year after resection of the tumor [Gibril et al 2003].For unresectable tumors and those individuals with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g. cisplatin, etoposide) may be used [Oberg et al 2008].Adrenocortical TumorsConsensus guidelines for the management of MEN1-associated non-functioning tumors do not exist. The risk for malignancy is increased if the tumor has a diameter greater than 4 cm, although adrenocortical carcinomas have been identified in tumors smaller than 4 cm [Thakker et al 2012]. Surgery is suggested for adrenal tumors >4 cm in diameter, for tumors that are 1-4 cm in diameter with atypical or suspicious radiologic features, or for tumors that show significant measurable growth over a six-month interval [Langer et al 2002, Schaefer et al 2008, Gatta-Cherifi et al 2012]. Prevention of Primary ManifestationsThe organs in MEN1 syndrome at highest risk for malignant tumor development — the duodenum, pancreas, and lungs (bronchial carcinoids) — are not suitable for ablative surgery.The only prophylactic surgery possible in MEN1 syndrome is thymectomy to prevent thymic carcinoid [Brandi et al 2001]. Prophylactic thymectomy should be considered at the time of neck surgery for primary hyperparathyroidism in males with MEN1 syndrome, particularly those who are smokers or have relatives with thymic carcinoid [Ferolla et al 2005].Prevention of Secondary ComplicationsPostoperative hypoparathyroidism. Measurement of serum concentration of parathyroid hormone (PTH) on the first day following subtotal or total parathyroidectomy may be a good predictor of residual parathyroid function [Debruyne et al 1999, Mozzon et al 2004]. Repeated measurements of serum calcium concentration are also useful and less expensive than measurement of the serum concentration of PTH [Debruyne et al 1999].After autotransplantation of the parathyroid glands, the serum concentration of PTH should be assessed no earlier than two months post-operatively and then once a year thereafter; serum concentration of PTH should be measured in separate but simultaneous blood samples, one from the arm without a parathyroid autotransplant and one from the arm with the parathyroid autotransplant. This procedure allows the physician both to assess the function of the transplanted parathyroid tissue and monitor for possible recurrence of hyperparathyroidism.Intraoperative hypertensive crisis. Although pheochromocytoma occurs rarely in MEN1 syndrome, it is appropriate to measure urinary catecholamines prior to surgery to diagnose and treat a pheochromocytoma to avoid dangerous and potentially lethal blood pressure peaks during surgery.SurveillanceRoutine surveillance using biochemical testing and imaging is recommended for asymptomatic individuals with an MEN1 disease-causing mutation and others at risk for MEN1 syndrome-associated tumors (i.e., those known to have MEN1 syndrome and those with an affected parent who have not undergone molecular genetic testing); surveillance should begin in early childhood and continue for life. Early detection and treatment of the potentially malignant neuroendocrine tumors should reduce the morbidity and mortality of MEN1 syndrome. Such screening can detect the onset of the disease about ten years before symptoms develop, thereby providing an opportunity for earlier treatment [Bassett et al 1998].MEN1 Minimal Surveillance Program [Brandi et al 2001, Thakker et al 2012]For individuals known to have MEN1 syndrome or a family-specific mutation in MEN1 1, 2Biochemical investigationsYearly, beginning at the specified age:Serum concentration of prolactin from age five years ¹ Fasting total serum calcium concentration (corrected for albumin) and/or ionized-serum calcium concentration from age eight years ¹ Fasting serum gastrin concentration from age 20 years ^{1To be considered: fasting serum concentration of intact (full-length) PTH ImagingEvery three to five years beginning at the specified age; the interval depending on whether there is biochemical evidence of a neoplasia and/or signs and symptoms of an MEN1-related tumor 1: Head MRI from age five years 1Abdominal CT or MRI from age 20 years 1To be considered: yearly chest CT, somatostatin receptor scintigraphy (SRS) octreotide scan1. According to the International Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2 [Brandi et al 2001], and Clinical Practice Guidelines for MEN Type 1 [Thakker et al 2012] 2. Can be modified according to clinical suspicion and/or findings in an individualFor individuals at 50% risk of having MEN1 syndrome in whom genetic status is unknownBiochemical investigations. Yearly, beginning at the specified age:Serum concentration of prolactin from age five years Fasting total serum calcium concentration (corrected for albumin) and/or ionized-serum calcium concentration from age ten years Fasting serum concentration of intact (full-length) PTH from age ten years Fasting serum gastrin concentration if individual has symptoms of ZES (reflux or diarrhea) from age 20 yearsEvaluation of Relatives at RiskMolecular genetic testing should be offered to at-risk members of a family in which a germline MEN1 mutation has been identified in an affected relative [Lairmore et al 2004].When molecular genetic testing for an MEN1 mutation is not possible or is not informative, individuals at 50% risk (i.e., first-degree relatives of an individual with MEN1 syndrome) should undergo routine evaluation (see Surveillance).See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationPrimary hyperparathyroidism (PHPT). An Italian group described preliminary results of the use of cinacalcet (a calcimimetic drug) over a 12-month period in an individual with local recurrence of MEN1-PHPT. A dose of 30 mg daily was well tolerated. Serum concentration of calcium and PTH rapidly normalized and bone mass increased over pre-treatment with a return to normal bone turnover in the absence of antiresorptive agents [Falchetti et al 2008]. Another group followed eight individuals with MEN1-PHPT for a range of ten to 35 months. All were commenced on cinacalcet at a dose of 30 mg. Significant reductions were observed in serum calcium and PTH measurements; and cinacalcet was well tolerated [Moyes et al 2010].Another Italian group treated eight individuals with MEN1-PHPT for six months with octreotide-LAR at a dose of 30 mg every four weeks in order to stabilize the duodenum-pancreatic neuroendocrine tumor before parathyroidectomy [Faggiano et al 2008]. Hypercalcemia and hypercalciuria normalized in 75% and 62.5%, respectively. Serum concentrations of PTH decreased significantly in all treated individuals and normalized in 25%. However, larger studies are needed before introducing cinacalcet and/or octreotide-LAR as a cure for MEN1-PHPT.Ablation using ethanol injection has been suggested as an alternative to reoperation of recurrent primary hyperparathyroidism [Veldman et al 2008].Pituitary tumors. In a MEN1 animal model with a pituitary PRL-secreting adenoma, monotherapy with the anti-VEGF-A monoclonal antibody (mAb) G6-31 was studied. Tumor growth was evaluated by MRI and vascular density in tissue sections was assessed. Significant inhibition of the growth of the pituitary adenoma leading to an increased mean tumor doubling-free survival and lowering of serum prolactin concentration were observed in treated animals but not controls. Additionally, the vascular density in pancreatic islet tumors was significantly reduced by the treatment. Such findings suggest that VEGF-A blockade may represent a nonsurgical treatment for benign tumors of the endocrine system, including those associated with MEN1 syndrome [Korsisaari et al 2008].Well-differentiated tumors of the gastro-entero-pancreatic (GEP) tract. Somatostatin analogs may be used to control proliferation of enterochromaffin-like cells. In one study, long-term administration of octreotide resulted in regression of a type II gastric carcinoid tumor [Tomassetti et al 2000]. As for MEN1-primary hyperparathyroidism, more extensive studies are needed to establish the efficacy of such molecules for clinical use in individuals with MEN1-ZES.Inhibitors of tyrosine kinase receptors (TKRs) and of the mammalian target of rapamycin (mTOR) signaling pathway have been reported to be effective in treating pancreatic neuroendocrine tumors (NET) [Raymond et al 2011, Yao et al 2011] because pancreatic NET may express TKRs. Treatment of individuals who have advanced, well-differentiated pancreatic NET with sunitimib malate, which inhibits TKRs, led to increased overall survival and a doubling in progression-free survival when compared to affected individuals receiving placebo. Treatment of individuals who have advanced, low-grade, or intermediate-grade pancreatic NET with everolimus, an mTOR inhibitor, also led to a doubling of median progression-free survival when compared to affected individuals who received placebo [Yao et al 2011]. These two studies mainly included individuals without MEN1; in fact, in the sunitimib study (comprising 171 individuals), only two individuals had MEN1 and neither was in the treatment arm [Raymond et al 2011]. In the everolimus study (410 individuals), details of MEN1 status were not provided. However, it seems highly plausible that these results can be extrapolated to individuals with MEN1 harboring pancreatic NET [Thakker et al 2012].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherIn a qualitative study of 29 Swedish individuals with MEN1 syndrome, the participants described physical, psychological, and social limitations in their daily activities and the effect of these limitations on their quality of life. A majority had adjusted to their situation, describing themselves as being healthy despite physical symptoms and treatment. The participants received good care in a clinical follow-up program [Strømsvik et al 2007].}

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Multiple Endocrine Neoplasia Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMEN111q13​.1MeninCatalogue of Somatic Mutations in Cancer (COSMIC)
MEN1 @ LOVD
Multiple endocrine neoplasia and MEN1MEN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Multiple Endocrine Neoplasia Type 1 (View All in OMIM) View in own window 131100MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1 613733MEN1 GENE; MEN1Molecular Genetic PathogenesisSince the cloning of the gene in 1997 [Chandrasekharappa et al 1997], 1336 mutations (1,133 germline and 203 somatic) and 24 non-pathogenic polymorphisms have been described [Lemos & Thakker 2008]. Specifically, mutations have been reported in 1091 families, more than 70% leading to truncated forms of menin, 4% consisting of large deletions, but no genotype/phenotype correlations were found.The inactivating germline MEN1 mutation is inherited from the affected parent or has its origin in an inactivating de novo mutation at an early embryonic stage, while the second MEN1 mutation occurs in the remaining MEN1 allele in a somatic cell. These findings are from loss of heterozygosity (LOH) studies in tumor tissues of individuals with MEN1 syndrome which revealed that most of the associated neoplasms had lost the MEN1 allele derived from the unaffected parent. The findings indirectly indicate a clonal outgrowth with an acquired loss of the MEN1 allele derived from the unaffected parent, confirming MEN1 as a tumor suppressor that follows the expected mutagenesis pattern predicted by Knudson’s two-hit model. Normal allelic variants. Twenty-four normal variants (polymorphisms) have been described [Lemos & Thakker 2008]: 12 in the coding region (10 synonymous and 2 non-synonymous), 9 in the introns, and 3 in the untranslated regions.Pathologic allelic variants. More than 1000 germline MEN1 mutations are scattered in and around the open reading frame without significant clustering that corresponds to functional domains of the protein [Agarwal et al 1997, Chandrasekharappa et al 1997, Heppner et al 1997, Lemmens et al 1997, Bassett et al 1998, Carling et al 1998, Farnebo et al 1998, Giraud et al 1998, Sato et al 1998, Teh et al 1998b, Vortmeyer et al 1998, Cebrian et al 1999, Morelli et al 2000, Tahara et al 2000, Guo & Sawicki 2001, Pannett & Thakker 2001, Sato et al 2001, Turner et al 2002, Vergès et al 2002, Wautot et al 2002, Park et al 2003, Lemos & Thakker 2008]. Approximately 41% of germline mutations in the coding region of MEN1, detected by sequence analysis, are frameshift mutations, 6% are in-frame deletions/insertions, 20% are missense mutations, and 23% are nonsense mutations [Lemos & Thakker 2008]. Intronic mutations, representing splicing-affecting genomic variants, have been detected in about 9% of individuals with MEN1 syndrome who do not have coding region mutations [Lemos & Thakker 2008]. The most recent mutation update by Lemos and Thakker [2008] reported 1,336 different MEN1 mutations (1,133 germline and 203 somatic mutations), about 70% of them leading to a truncated form of menin protein. Normal gene product. Menin, a protein of 610 amino acids, has three nuclear localization signals (NLSs) near the carboxyl terminus. Menin does not show similarity with any other known human protein.Menin is mainly located in the nucleus [Agarwal et al 2004, La et al 2007]; the C-terminal part of menin contains sequences that are essential for the regulation of gene expression and that overlap with nuclear localization domains [La et al 2007]. Nonsense mutations and most of the frameshift mutations generate a truncated menin protein lacking the NLSs and thus unable to move to the nucleus and to be functional. Moreover it has been demonstrated that a splicing mutation of MEN1 alters the splice acceptor site of intron 9, which promotes an incorrect splicing, generating aberrant proteins lacking the nuclear localization signals necessary for the normal menin translocation to the nucleus [Tala et al 2006]. Menin is widely expressed and may play different roles in different tissues. It is probably involved in the regulation of several cell functions, including DNA replication and repair, and in transcriptional machinery. Menin is suspected to repress tumorigenesis through the repression of cell proliferation, principally via three main mechanisms: (1) directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription; (2) interacting with various histone-modifying enzymes (MLL; HDACs and EZH2); and (3) directly interacting with gene promoters and acting as a transcription factor itself. Menin may inhibit JunD-mediated transcriptional activation, as studies of deletion mutants have shown the existence of interacting regions of both the proteins.Menin could inhibit JunD-mediated transcription by modification of chromatin structure recruiting a specific histone deacetylase targeted to a promoter by binding JunD. Moreover, when compared to controls, lymphocytes from individuals with a heterozygous MEN1 mutation show both premature division of the centromere and hypersensitivity to alkylating agents. Thus, menin could be a negative regulator of cell proliferation after DNA damage.Several studies have demonstrated that menin directly regulates the expression of the cyclin-dependent kinase-inhibiting (CDKI) genes, CDKN1b (encoding p27) and CDKN2C (encoding p18), via interaction with MLL, thus negatively regulating cell proliferation.It has been hypothesized that menin may mediate its tumor suppressor action by regulating histone methylation in promoters of CDKN1b and CDKN2C, and possibly other CDK inhibitors [Karnik et al 2005, Milne et al 2005]. Consistent with this hypothesis, H3 K4 methylation and expression of p18 and p27 were shown to be dependent on menin in pancreatic islets [Karnik et al 2005]. Additional evidence of a role for p18 and p27 in MEN1 pathophysiology comes from studies in knockout mice [Scacheri et al 2006] in which the simultaneous loss of p18 and p27 leads to a tumor spectrum similar to that in human patients with MEN1 and MEN2, including tumors in the pituitary, parathyroid, thyroid, endocrine pancreas, stomach, and duodenum, and with much more rapid tumor onset than in mice with either deficiency alone. However, through serial analysis of chromatin occupancy (SACO), a method combining chromatin immuno-precipitation (ChIP) with serial analysis of gene expression (SAGE), hundreds of menin-occupied genomic sites were identified in promoter regions, near the 3' end of genes or within genes, extending other data about menin recruitments to many sites of transcriptional activity. Moreover, a large number of menin-occupied sites were located outside known gene regions [Agarwal et al 2007]. However, what determines the tissue-specific activities of menin remains to be delineated. Recently, the possible involvement of microRNA in MEN1-associated neoplasia has been hypothesized through interaction between microRNA with MEN1 mRNA and negative regulation of menin protein expression [Luzi & Brandi 2011]. miR-24-1 is able to bind to the 3'UTR of MEN1 mRNA. A recent study [Luzi et al 2012a] has found an inverse correlation between menin and miR-24-1 expression in MEN1 parathyroid adenoma tissues that conserved the MEN1 wild-type allele. Moreover, ChIP analysis demonstrated the direct association of menin protein with the miR-24-1 promoter. These findings suggest that MEN1-associated neoplasia could be controlled by a “negative feedback loop” between miR-24-1 and menin protein that mimics the second hit hypothesis of Knudson, providing an explanation for tissue-specific tumorigenesis in MEN1 syndrome.Moreover, a physiologic role for menin has been postulated in bone development. Menin intervenes both in early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [Sowa et al 2003] and in inhibition of their late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGFβ-Smad3 pathway) [Sowa et al 2004]. Murine menin promotes the commitment of multipotential mesenchymal stem cells into the osteoblast lineage through the interaction with the BMP-2-Smad1/5-Runx2 cascade [Sowa et al 2003]. Menin has been demonstrated to directly modulate both SMAD1 protein and microRNA 26a expression during the commitment of human adipose tissue-derived stem cells to the osteoblast lineage [Luzi et al 2012b].Menin is also involved in hematopoiesis, regulating lymphoid progenitors [Naito et al 2005, Chen et al 2006, Caslini et al 2007, Maillard et al 2009]. Menin interacts with the mixed-lineage leukemia (MLL) protein, a histone methyltransferase that is mutated in acute lymphoid and myeloid leukemias. This MLL-menin complex possesses a histone methyltransferase activity specific for histone H3 lysine 4 (H3K4) and it exerts epigenetic transcriptional activity resulting in activation of target genes, such as the clustered homeobox genes Hoxa9, Hoxc6, and Hoxc8. MLL-menin interaction is crucial for differential arrest, immortalization, and oncogenic properties of MLL-transformed leukemic blasts [Caslini et al 2007]. Menin is an essential oncogenic cofactor for MLL-mediated hematopoietic tumors; thus, inhibition of the MLL-menin interaction could be an effective therapeutic strategy in leukemias with MLL rearrangements. However, it remains to be clarified whether the menin–MLL–Hox pathway also plays a role in suppressing tumorigenesis in endocrine organ.Interestingly, it has been shown that wild-type menin (but not MEN1 disease-derived mutants) physically interacts with p53 and that ectopic menin expression in insulinoma cells enhances gamma irradiation-induced apoptosis, p21 expression, and proliferation inhibition. As activated p53 normally stimulates transcription of p21, inhibitor of the cyclin-dependent kinase and cell proliferation, and also multiple BH-domain-containing proapoptotic proteins such as PUMA, these findings could explain how menin, at least in part, regulates proliferation and apoptosis of endocrine cell through interaction with p53 [Bazzi et al 2008]. However, although many menin-interacting pathways have been described, it is highly likely that only a few basilar molecular pathways are involved in menin-dependent tumorigenesis.Abnormal gene product. Most (nonsense and frameshift mutations) germline or somatic mutations in MEN1 predict truncation of the protein with the absence of NLSs and the blocking of menin translation to the nucleus with consequent loss of menin functionality.Splice-site mutations result in aberrant processed mRNA often leading to a frameshift with a premature termination codon. Missense mutations may lead to alteration of the interaction sites of menin and its protein partners and, thus, to disruption of menin tumor suppressor activity [Luzi & Brandi 2011]. Other missense mutations may result in a reduction of protein stability and enhanced proteolytic degradation.Neither the finding of a tumor suppressor mechanism nor the identification of binding partners has established the ultimate pathways of menin action in normal tissues or in tumors [Agarwal et al 2004].