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Multiple Endocrine Neoplasia Type 1

Synonyms: MEN1, MEN1 Syndrome, Multiple Endocrine Adenomatosis, Wermer Syndrome

, MD, PhD, , PhD, and , MD, PhD.

Author Information
, MD, PhD
Department of Surgery and Translational Medicine
University of Florence and Regional Center for Hereditary Endocrine Tumors
Unit of Metabolic Bone Diseases
University Hospital of Careggi
Florence, Italy
, PhD
Department of Surgery and Translational Medicine
University of Florence and Regional Center for Hereditary Endocrine Tumors
Unit of Metabolic Bone Diseases
University Hospital of Careggi
Florence, Italy
, MD, PhD
Department of Surgery and Translational Medicine
University of Florence and Regional Center for Hereditary Endocrine Tumors
Unit of Metabolic Bone Diseases
University Hospital of Careggi
Florence, Italy

Initial Posting: ; Last Update: February 12, 2015.


Clinical characteristics.

Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of more than 20 endocrine and non-endocrine tumors.

Endocrine tumors become evident by overproduction of hormones by the tumor or by growth of the tumor itself.

  • Parathyroid tumors are the main MEN1-associated endocrinopathy; onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years; hypercalcemia causes lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis, dehydration, hypercalciuria, kidney stones, increased bone resorption/fracture risk, hypertension, and shortened QT interval.
  • Pituitary tumors include prolactinoma (the most common) which manifests as oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males.
  • Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract can manifest as Zollinger-Ellison syndrome (gastrinoma); hypoglycemia (insulinoma); hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting tumor).
  • Carcinoid tumors are non-hormone-secreting and can manifest as a large mass after age 50 years.
  • Adrenocortical tumors can be associated with primary hypercortisolism or hyperaldosteronism.

Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.


Clinical diagnostic criteria for MEN1 syndrome include the presence of two endocrine tumors that are parathyroid, pituitary, or GEP tract tumors. Biochemical testing detects an increased serum concentration of parathyroid hormone and calcium in primary hyperparathyroidism, increased serum concentrations of prolactin from a prolactinoma, and increased serum concentrations of gastrin, insulin, and VIP from tumors of the GEP tract. Prolactinomas are imaged by MRI, neuroendocrine tumors (NETs) are detected by somatostatin receptor scintigraphy, and pancreatic endocrine tumors are detected by endoscopic ultrasound. Molecular genetic testing of MEN1, the only gene in which mutation is known to cause MEN1 syndrome, detects MEN1 pathogenic variants in approximately 80%-90% of probands with familial MEN1 syndrome and in approximately 65% of simplex cases (i.e., a single occurrence of MEN1 syndrome in the family).


Treatment of manifestations: Hyperparathyroidism is treated with subtotal parathyroidectomy and cryopreservation of parathyroid tissue or total parathyroidectomy and autotransplantation of parathyroid tissue; recent studies suggest that long-acting release octreotide or calcimimetic could also be effective; prior to surgery, bone anti-resorptive agents are used to reduce hypercalcemia and limit bone resorption. Prolactinomas are treated with dopamine agonists (cabergoline is the drug of choice). Growth hormone-secreting tumors causing acromegaly are treated by transsphenoidal surgery; medical therapy for growth hormone-secreting tumors includes somatostatin analogs, octreotide, and lanreotide. ACTH-secreting pituitary tumors associated with Cushing syndrome are surgically removed; non-secreting pituitary adenomas are treated by transsphenoidal surgery. Proton pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas. Surgery is indicated for insulinoma and most other pancreatic tumors. Long-acting somatostatin analogs can control the secretory hyperfunction associated with carcinoid syndrome. Surgical removal of adrenocortical tumors that exceed 3.0 cm in diameter can prevent malignancy.

Prevention of primary manifestations: Thymectomy may prevent thymic carcinoid in males, particularly in smokers.

Prevention of secondary complications: Measure PTH and/or serum calcium to assess for hypoparathyroidism following subtotal or total parathyroidectomy. Measure urinary catecholamines prior to surgery to diagnose and treat a pheochromocytoma to avoid blood pressure peaks during surgery.

Surveillance: Serum concentrations of calcium from age eight years, gastrin from age 20 years, and prolactin from age five years; abdominal CT or MRI from age 20 years and head MRI from age five years. Consider fasting serum PTH concentration and yearly chest CT.

Evaluation of relatives at risk: Because early detection affects management, molecular genetic testing is offered to at-risk members of a family in which a germline MEN1 mutation has been identified.

Genetic counseling.

MEN1 syndrome is inherited in an autosomal dominant manner. Approximately 10% of cases are caused by de novo mutation. Each child of an individual with MEN1 syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in a family is known.


Diagnostic criteria for MEN1 include the presence of two of three endocrine tumors (i.e., parathryoid, pituitary, and well-differentiated endocrine tumors of the gastro-entero-pancreatic [GEP] tract), which may become evident either by overproduction of polypeptide hormones or by growth of the tumor itself.

Familial MEN1 syndrome is defined as MEN1 syndrome in an individual who has either of the following:

Note: Clinicians should keep in mind that a varying combination of more than 20 endocrine and non-endocrine tumors have been reported in MEN1 syndrome and no simple definition can encompass all index cases or affected families.

Suggestive Findings

Multiple endocrine neoplasia type 1 (MEN1) syndrome should be suspected in individuals with endocrine tumors or non-endocrine tumors which may appear before the manifestations of hormone-secreting endocrine tumors.

Endocrine Tumors Associated with MEN1 Syndrome

Parathyroid tumors manifest as hypercalcemia (primary hyperparathyroidism [PHPT]) as the result of the overproduction of parathyroid hormone. Imaging is not usually required for diagnosis of parathyroid disease, as the underlying cause of primary hyperparathyroidism in MEN1 syndrome is usually multiglandular disease with enlargement of all the parathyroid glands rather than a single adenoma.

Pituitary tumors

  • Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
  • Growth hormone-secreting anterior pituitary adenomas are tumors that occur with the signs and symptoms of acromegaly.
  • Growth hormone/prolactin-secreting (GH/PRL-secreting) anterior pituitary adenomas manifest as signs/symptoms of acromegaly, as oligomenorrhea/amenorrhea and galactorrhea in females, and as sexual dysfunction and (more rarely) gynecomastia in males.
  • TSH- secreting anterior pituitary tumors occur with the signs/symptoms of hyperthyroidism.
  • ACTH-secreting anterior pituitary adenomas are mostly associated with Cushing's syndrome.
  • Non-secreting pituitary tumors manifest as enlarging pituitary tumors, compressing adjacent structures such as the optic chiasm with visual disturbances, and/or hypopituitarism.

Note: The imaging test of choice for all types of pituitary tumors is MRI.

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 clinical presentations (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)

Note: (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 GEP tract. They are common in MEN1 syndrome and are usually recognized incidentally during gastric endoscopy for ZES [Bordi et al 1998, Gibril et al 2000]. (3) 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]. CT and MRI are also helpful in localizing the tumor [Imamura et al 2011].

Carcinoid tumors

  • Occult bronchial carcinoid tumors. CT is useful in localizing these tumors.
  • Thymic carcinoid tumors. CT and MRI are equally sensitive in detecting these tumors, at initial evaluation [Brandi et al 2001].
    Note: Because both plain chest x-ray and somatostatin receptor scintigraphy (SRS) scan have lower sensitivity than CT and MRI in detecting either primary or recurrent thymic carcinoid, neither is the first imaging study of choice [Gibril et al 2003, Scarsbrook et al 2007, Goudet et al 2009].

Adrenocortex tumors are generally non-functioning and usually detected during the screening by CT. These tumors can be non-functioning or manifest as hyperaldosteronism, ACTH-independent Cushing’s syndrome, or pheochromocytoma.

Non-Endocrine Tumors Associated with MEN1 Syndrome


  • Facial 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.

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.

Central nervous system

  • Meningioma 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]

Establishing the Diagnosis

The genetic diagnosis of MEN1 syndrome is established in a proband with identification of a heterozygous pathogenic variant in MEN1 (see Table 1). Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

Single-gene testing. Sequence analysis of MEN1 is performed first, followed by deletion/duplication analysis if no pathogenic variant is found.

Although different mutation detection rates are reported in different series, the likelihood of detecting a MEN1 pathogenic variant increases in the following:

  • 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]
  • Simplex cases with the presence of pancreatic lesions or with the presence of two main manifestations of MEN1 [Odou et al 2006]

Individuals who have a single MEN1-related tumor and no family history of MEN1 syndrome rarely have germline MEN1 mutations [Ellard et al 2005].

A multi-gene panel that includes MEN1 and other genes of interest (see Differential Diagnosis) may also be used. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of MEN1, genomic testing may be considered. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Notes regarding WMitoSeq. (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively

Table 1.

Summary of Molecular Genetic Testing Used in MEN1 Syndrome

Gene 1Test MethodProportion of Probands with a Germline Pathogenic Variant Detectable by This Method
MEN1Sequence analysis 2 Familial: 80%-90% 3
Simplex: 65% 4
Deletion/duplication analysis 51%-4% 6

Familial = a proband meeting the diagnostic criteria of MEN1 syndrome plus a minimum of one first-degree relative with at least one of these tumors.

Simplex = a single occurrence of MEN1 syndrome in a family


See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Brandi et al [2001]


Guo & Sawicki [2001]


Testing that identifies exonic or whole-gene deletions/duplications not 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.


Kishi et al [1998], Bergman et al [2000], Cavaco et al [2002], Ellard et al [2005], Klein et al [2005], Fukuuchi et al [2006], Tham et al [2007]

Clinical Characteristics

Clinical Description

Endocrine tumors occurring in individuals with MEN1 syndrome are shown in Table 2.

Table 2.

Endocrine Tumor Types in MEN1 Syndrome

Tumor TypeTumor SubtypesHormone SecretingPrevalence in MEN1 Syndrome
ParathyroidNA 1 YesPrimary hyperparathyroidism in 100% by age 50 yrs 2
Anterior pituitaryProlactinoma (PRLoma)YesAnterior pituitary tumors in ~10%-60% 3Most commonly seen anterior pituitary tumor subtype
Growth hormone (GH)-secretingYesAccounts for 5% of anterior pituitary tumors 4
GH/PRL-secretingYes5% 4
TSH-secretingYesRare 5
ACTH-secretingYes2% 4
Well-differentiated endocrineGastrinomaYesAccounts for 40% of well-differentiated endocrine tumors 6
InsulinomaYes10% 4
GlucagonomaYes2% 4
VIPomaYes2% 4
AdrenocorticalCortisol-secretingRarelyAdrenocortical tumors in ~20%-40%Rare
PheochromocytomaRarely<1% 4

Not applicable


First clinical manifestation of MEN1 in 90% of individuals


First clinical manifestation of MEN1 in 10% of familial cases and 25% of simplex cases


Brandi et al [2001]


Socin et al [2003]


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 vomiting
  • Renal. Diuresis, impaired concentrating ability, dehydration, hypercalciuria, and increased risk for kidney stones
  • Skeletal. Increased bone resorption and increased fracture risk
  • Cardiovascular. Cause of and/or exacerbation of hypertension, shortened QT interval

Hypercalcemia 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 Tumors

Pituitary 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%). 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].
  • Reduced libido and erectile dysfunction was described in a man with a functioning FSH-secreting adenoma [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].

Pathology. 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 pituitary turmors vs non-MEN1-associated pituitary tumors:

  • Histologically, MEN1 tumors are significantly larger and more often invasive.
  • Multiple adenomas are significantly more frequent in MEN1, especially with prolactin-adrenocorticotropic hormone.

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 gonadotropic 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) Tract

Gastrinoma. 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 multifocal 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 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 appear 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 ~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].


  • Pathology. Glucagonomas can be associated with other tumors in MEN1 syndrome, but they are very rare. MEN1-associated glucagonoma are estimated to account for only about 3% of all diagnosed glucagonoma [Castro et al 2011] Tumor size is often greater than 3 cm and visceral metastases are frequent.
  • Cancer risk. About 80% of MEN1-associated glucagonomas are malignant and frequently spread to the liver [Castro et al 2011].


  • Pathology. It has been estimated that about 17% of patients with MEN 1 develop VIPomas at some stage of their disease. MEN1-associated VIPomas represent about 5% of all diagnosed VIPomas [Yeung & Tung 2014]. Tumor size is often >3 cm.
  • Cancer risk. VIPomas are malignant and have usually metastasized at the time of diagnosis. Metastases occur most frequently in the liver.

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-secreting tumors was shorter than life expectancy of individuals who did not have pancreaticoduodenal tumors [Triponez et al 2006].

Carcinoid Tumors

Thymic, 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 with a male/female ratio of 20:1 [Teh et al 1997]. Interestingly, among Japanese individuals with MEN1 thymic carcinoids have a less marked gender difference (male/female ratio 2:1) [Sakurai et al 2012]. Bronchial carcinoids are more prevalent in females than in males.

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 in 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].

Pathology. Carcinoids tend to be multifocal, and may occur synchronously or over time.

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 multifocal, may occur synchronously or over time. 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 Tumors

Adrenocortical 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.

Pathology. 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.

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 <1 cm had an approximately 13% incidence of adrenocortical carcinoma.

Morbidity and Mortality of MEN1 Syndrome

Improved 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 pathogenic variant, 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 pathogenic variant.

Quality of life. In 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified in MEN1 syndrome [Kouvaraki et al 2002, Turner et al 2002, Wautot et al 2002, Lemos & Thakker 2008].

Although a trend (which did not reach statistical significance) suggested that the prevalence of truncating mutations in MEN1-related thymic carcinoids is higher than in other MEN1-related tumors [Lim et al 2006], a review by Lips et al [2012] found no association between single mutations and specific phenotype.


The age-related penetrance for all clinical features surpasses 50% by age 20 years and 95% by age 40 years [Bassett et al 1998, Marx et al 1998, Thakker et al 2012].


Anticipation has not been reported.


A prevalence of approximately one in 30,000 has been reported [Marx 2001].

Differential Diagnosis

MEN4 syndrome. An inherited syndrome presenting a panel of clinical manifestations overlapping those of MEN1 has been described and associated to inactivating mutations of CDKN1B encoding for the p27kip1 inhibitor of cell cycle progression. This novel syndrome has been named MEN4 (OMIM 610755) and it represents a very rare phenocopy of classic MEN1. Currently, nine different CDKN1B pathogenic variants have been identified worldwide. No specific clinical features distinguish MEN4 from MEN1.

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 [Uchino et al 2000, Marx 2001]. 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 pathogenic variant in an as-yet unknown gene):

MEN2 syndrome, caused by pathogenic variants in RET, is genetically distinct from MEN1 syndrome. MEN2A, a clinical subtype 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 germline mutations in both the RET protooncogene and the 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 tumors. 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 mutations and deletions play a causative role in the development of a subgroup of sporadic pituitary adenomas [Agarwal et al 2009b].

  • Prolactinomas 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].

Familial pituitary adenomas are usually somatotrophinomas and lack MEN1 germline mutations [Tanaka et al 1998, Tsukada et al 2001]. MEN1 pathogenic variants have been identified in fewer than 1% of index cases with familial pituitary tumor [Vierimaa et al 2006].

Zollinger-Ellison syndrome (ZES). 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].

MEN1 syndrome-associated ZES is typically associated with multiple tumors in the duodenal mucosa, often surrounded by hyperplasia of gastrin cells; 25% 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 and mutation of two cyclin-dependent kinase inhibitor genes (CDKN2B/p15 and CDKN1B/p27) have been reported [Agarwal et al 2009a].

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 tumors. Carcinoid 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 SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 1 (MEN1), evaluation for the following most common MEN1 syndrome-associated tumors (as described in Clinical Description) is recommended:

  • Multiglandular parathyroid disease
  • Prolactinoma
  • Gastrinoma and other entero-pancreatic neuroendocrine tumors
  • Medical genetics consultation

Treatment of Manifestations

Clinical practice guidelines for MEN type 1 have been developed [Thakker et al 2012] (full text).


Parathyroidectomy is the treatment of choice for patients with MEN1, but it is controversial whether to perform subtotal (3.5 glands) or total parathyroidectomy, and whether surgery should be performed at an early or late stage of the disease.

  • Subtotal parathyroidectomy (i.e. removal of ≤3.5 glands) has resulted in persistent or recurrent hypercalcemia within ten to 12 years after surgery in 40%-60% of patients with MEN1, and in hypocalcemia requiring long-term therapy with vitamin D or its active metabolite calcitriol in 10%-30% [Thakker et al 2012].
  • Total parathyroidectomy with autotransplantation in the forearm may use both fresh and cryopreserved parathyroid tissue. Procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
    • Intraoperative monitoring of PTH by rapid assay during surgery to determine successful removal of hyperfunctioning parathyroid tissue, and to help with the decision to implant parathyroid tissue in the forearm.
    • Recurrent hypercalcemia is present in more than 50% of patients with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful.

Subtotal parathyroidectomy is suggested as the initial treatment of primary hyperparathyroidism in MEN1; total parathyroidectomy with autotransplantation may also be reserved for those with extensive disease either at first or at repeat surgery [Thakker et al 2012].

Parathyroidectomy may be reserved for symptomatic hypercalcemic patients with MEN1 while asymptomatic hypercalcemic patients with MEN1 do not undergo parathyroid surgery but have regular assessment for symptom onset and complications.

Bone anti-resorptive agents administered prior to surgery help to reduce hypercalcemia and limit PTH-dependent bone resorption, thus reducing future risk of osteoporosis.

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 has failed or is contraindicated [Faggiano et al 2008, Falchetti et al 2008, Moyes et al 2010].

Pituitary Tumors

PRL-secreting tumors (prolactinomas)

  • Dopamine agonists such as cabergoline, bromocriptine, pergolide, and quinagolide are the preferred treatment for PRL-secreting tumors.
  • Cabergoline may be considered the current treatment of choice because of its limited side effects and greater potency [Tichomirowa et al 2009].

Growth hormone-secreting tumors

  • Transsphenoidal 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 tumors

  • In 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 adenomas

  • In 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 opinion on this issue differs, Beckers et al [2003] have 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) Tract


  • Medications 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. 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.
  • The optimal therapy of gastrinoma is controversial.
    • In non-metastasizing gastrinoma within the pancreas, surgery may be curative and should be performed by an experienced endocrine surgeon. MEN1 patients will have multiple small submucosal duodenal gastrinomas and in experienced surgical centers local excision of these tumors with lymph node dissection, duodenectomy, or less commonly duodenopancreatectomy may be also considered together with patient preferences, as such approaches may improve the cure rate.
    • Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in patients with MEN1, but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
  • Non-resectable tumor mass can be treated with somatostatin analogs, biotherapy, targeted radionuclide therapy, locoregional treatments and chemotherapy.
  • Inoperable or metastatic pancreatic neuroendocrine tumors (NETs) may be subjected to a chemotherapy. Sunitinib and everolimus may be used for patients with advanced (inoperable or metastatic) progressive well differentiated pancreatic NETs. [Thakker et al 2012].
  • Treatment for non-functioning pancreatic NETs is controversial, some centers considered surgical resection for lesions that are >1cm in size, although other centers recommend surgery only if the tumor is >2cm.
  • Occult metastatic disease (i.e. tumors not detected by imaging investigations) may be present in a substantial proportion of these patients at the time of initial presentation.

Carcinoid Tumors

Long-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 Tumors

Consensus 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 Manifestations

The 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 Complications

Postoperative 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 once a year thereafter; serum concentration of PTH should be measured simultaneously in separate 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.


Routine surveillance using biochemical testing and imaging is recommended for asymptomatic individuals with an MEN1 pathogenic variant 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 1

For individuals known to have MEN1 syndrome or a family-specific pathogenic variant in MEN1 2, 3

  • Biochemical investigations
    • Yearly, beginning at the specified age:
      • Serum concentration of prolactin, IGF-1, fasting glucose and insulin from age five years 2
      • Fasting total serum calcium concentration (corrected for albumin) and/or ionized-serum calcium concentration, chromogranin–A, pancreatic polypeptide, glucagon, vasocative intestinal peptide for other pancreatic NET from age eight years 2
      • Fasting serum gastrin concentration from age 20 years 2
    • To be considered: fasting serum concentration of intact (full-length) PTH
  • Imaging
    • Every 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 2:
      • Head MRI from age five years 2
      • Abdominal CT or MRI from age 20 years 2
    • To be considered: yearly chest CT, somatostatin receptor scintigraphy (SRS) octreotide scan



Brandi et al [2001], Thakker et al [2012]


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]


Can be modified according to clinical suspicion and/or findings in an individual

For individuals at 50% risk of having MEN1 syndrome in whom genetic status is unknown

  • Biochemical 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 years

Evaluation of Relatives at Risk

Molecular 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 pathogenic variant 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 Investigation

Primary 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 for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MEN1 syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 90% of individuals diagnosed with MEN1 syndrome have an affected parent.
  • Approximately 10% have de novo MEN1 mutations.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing.
    Note: Approximately 90% of individuals diagnosed with MEN1 syndrome have an affected parent; however, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with MEN1 has a 50% chance of inheriting the MEN1 pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations could also be explored; these may include alternate paternity or maternity (e.g., with assisted reproduction), undisclosed adoption, or desire on the part of family members to preserve privacy.

Testing of at-risk asymptomatic individuals. Consideration of molecular genetic testing of at-risk asymptomatic family members is appropriate for surveillance (see Management). Molecular genetic testing can only be used for testing at-risk relatives if a pathogenic variant has been identified in an affected family member. Because early detection of at-risk individuals affects medical management, testing of individuals during childhood who have no symptoms is beneficial [American Society of Clinical Oncology 2003]. Education and genetic counseling of at-risk individuals younger than age 18 years and of their parents prior to genetic testing is appropriate.

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the MEN1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like MEN1 syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the MEN1 pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Multiple Endocrine Neoplasia Disorders (AMEND)
    The Warehouse
    No 1 Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: + 44 (0)1892 516076
  • Associazione Italiana Neoplasie Endocrine Multiple (AIMEN)
    Phone: 39 800 177 526
    Fax: 39 0331 983343
  • Medline Plus
  • National Endocrine and Metabolic Diseases Information Service
    A service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    6 Information Way
    Bethesda MD 20892–3569
    Phone: 888-828-0904 (toll-free); 866-569-1162 (toll-free TTY)
    Fax: 703-738-4929
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • AMEND Research Registry
    The Warehouse
    Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: +44 1892 516076

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MEN111q13​.1MeninMEN1 databaseMEN1

Data 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)

613733MEN1 GENE; MEN1

Molecular Genetic Pathogenesis

Since the cloning of the gene in 1997 [Chandrasekharappa et al 1997], 1336 pathogenic variants (1,133 germline and 203 somatic) and 24 benign variants (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 none indicating a genotype/phenotype correlation.

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.

Gene structure. MEN1 has ten exons; exon 1 and parts of exons 2 and 10 are not translated to menin protein. MEN1 encodes a primary mRNA transcript of 2.8 kb. Less common mRNA transcripts have been described, presenting variations of the 5’-untranslated region but not of the coding region [Owens et al 2008]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Twenty-four benign variants have been described [Lemos & Thakker 2008]: 12 in the coding region (10 synonymous and 2 nonsynonymous), nine in the introns, and three in the untranslated regions.

Pathogenic allelic variants. More than 1000 germline MEN1 pathogenic variants are scattered in and around the open reading frame without significant clustering [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, Cebrián 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 are frameshifts, 6% in-frame deletions/insertions, 20% missense, and 23% nonsense [Lemos & Thakker 2008]. Intronic mutations, representing splicing-affecting genomic variants, have been detected in approximately 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 pathogenic variants (1,133 germline and 203 somatic), 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 is encoded by sequences that are essential for the regulation of gene expression and that overlap with NLSs [La et al 2007]. Nonsense mutations and most of the frameshift mutations generate a truncated menin protein that lacks the NLSs and is unable to move to the nucleus and be functional. It has also 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 NLSs necessary for normal menin translocation to the nucleus [Tala et al 2006].

Menin is expressed in all tissues, preasumably playing tissue-specific roles. 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 demonstrated the existence of interacting regions in both 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 pathogenic variant 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 (mixed-lineage leukemia protein), 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.

Recently, Vijayaraghavan et al [2014] demonstrated that miR-24 negatively regulates menin expression in the endocrine pancreas as well, evidencing a feedback loop similar to that identified in the parathyroid glands by Luzi et al [2012a]. They also demonstrated that this mechanism affects the production of the cell cycle inhibitors p27kip1 and p18ink4c, regulating endocrine pancreas cell growth.

More recently, Ouyang et al [2015] reported that Men1 mRNA is targeted and negatively regulated by microRNA-29b (miR-29b) in rat intestinal epithelial cells. They demonstrated that induced overexpression of miR-29b, via transfection of a specific precursor, modestly reduced the expression of Men1 mRNA, but robustly reduced the expression of menin protein. Conversely, the inhibition of miR-29b, by a specific antagomir, enhanced menin protein expression. The silencing of miR-29b resulted in an increase in the level of menin associated with increased sensitivity to apoptosis, suggesting that miR-29b represses translation of Men1 mRNA to menin protein, affecting intestinal epithelial homeostasis by reducing apoptosis in intestinal epithelial cells.

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 shown 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 MLL protein, a histone methyltransferase that is mutated in acute lymphoid and myeloid leukemias. This MLL-menin complex is associated with 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) 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].

Cancer and Benign Tumors

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, these mutations were scattered along the entire MEN1 coding region without showing any hot spot. 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].


Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available online. 2003. Accessed 8-15-14.
  2. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Available online (registration or institutional access required). 2012. Accessed 8-15-14.

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Suggested Reading

  1. Burgess J. How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol (Oxf) 2010;72:13–6. [PubMed: 19552677]
  2. Calendar A. Multiple endocrine neoplasia type 1 (MEN1). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2005. Accessed 2-10-15.
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  4. Falchetti A, Brandi ML. Multiple endocrine neoplasia type I variants and phenocopies: more than a nosological issue? J Clin Endocrinol Metab. 2009;94:1518–20. [PubMed: 19420274]
  5. Ghataorhe P, Kurian AW, Pickart A, Trapane P, Norton JA, Kingham K, Ford JM. A carrier of both MEN1 and BRCA2 mutations: case report and review of the literature. Cancer Genet Cytogenet. 2007 Dec;179(2):89–92. [PubMed: 18036394]
  6. Marini F, Carbonell Sala S, Falchetti A, Caramelli D, Brandi ML. The genetic ascertainment of multiple endocrine neoplasia type 1 syndrome by ancient DNA analysis. J Endocrinol Invest. 2008;31:905–9. [PubMed: 19092297]
  7. McCallum RW, Parameswaran V, Burgess JR. Multiple endocrine neoplasia type 1 (MEN 1) is associated with an increased prevalence of diabetes mellitus and impaired fasting glucose. Clin Endocrinol (Oxf) 2006;65:163–8. [PubMed: 16886955]
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Chapter Notes


This paper has been supported by Cofin M.I.U.R. 2003 (F. T.), by A.I.R.C. 2000 (M. L. B.) and by the Fondazione Ente Cassa di Risparmio di Firenze (M. L. B.).

Author History

Maria Luisa Brandi, MD, PhD (2005-present)
Alberto Falchetti, MD; University Hospital of Careggi (2005-2012)
Francesca Giusti, MD (2012-present)
Francesca Marini, PhD (2005-present)

Revision History

  • 12 February 2015 (me) Comprehensive update posted live
  • 6 September 2012 (me) Comprehensive update posted live
  • 2 March 2010 (me) Comprehensive update posted live
  • 31 August 2005 (me) Review posted to live Web site
  • 9 September 2004 (mlb) Original submission
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