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Multiple Endocrine Neoplasia Type 1

Synonyms: MEN1, MEN1 Syndrome, Multiple Endocrine Adenomatosis, Wermer Syndrome
, 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: December 14, 2017.

Summary

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 either 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.

Diagnosis/testing.

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 pathogenic variants are known to cause MEN1 syndrome, detects a heterozygous MEN1 pathogenic variant 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).

Management.

Treatment of manifestations: Hyperparathyroidism is treated with subtotal parathyroidectomy and cryopreservation of parathyroid tissue or total parathyroidectomy and autotransplantation of parathyroid tissue; calcimimetics are used to treat primary hyperparathyroidism in those for whom surgery is contraindicated or has failed; prior to surgery, bone antiresorptive agents are used to reduce hypercalcemia and limit bone resorption. Prolactinomas are treated with dopamine agonists (cabergoline being 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 pathogenic variant has been identified.

Pregnancy management: Women with primary hyperparathyroidism from any cause are at increased risk of developing preeclampsia; infants born to women with primary hyperparathyroidism should be monitored for postnatal hypocalcemia.

Genetic counseling.

MEN1 syndrome is inherited in an autosomal dominant manner. Approximately 10% of cases are caused by a de novo pathogenic variant. 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.

Diagnosis

Diagnostic criteria for MEN1 include the presence of two of three endocrine tumors – parathryoid, pituitary, or 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

The diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome should be suspected in individuals with endocrine tumors, although non-endocrine tumors may appear before the manifestations of hormone-secreting endocrine tumors (see Clinical Description).

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.
  • Thyroid-stimulating hormone (TSH)-secreting anterior pituitary tumors occur with the signs/symptoms of hyperthyroidism.
  • Adrenocorticotrophic hormone (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) [Thakker et al 2012] 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]. Pancreatic gastrinomas are usually evaluated by CT, MRI, and/or EUS [Yates et al 2015].

Non-endocrine tumors associated with MEN1 syndrome include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.

Cutaneous manifestations may be helpful in the diagnosis of individuals with MEN1 syndrome even before manifestations of hormone-secreting tumors appear.

Establishing the Diagnosis

The diagnosis of MEN1 syndrome is established in a proband by identification of ONE OR BOTH of the following:

  • Two of three endocrine tumors (i.e., parathryoid, pituitary, and well-differentiated endocrine tumors of the gastro-entero-pancreatic [GEP] tract)
  • A heterozygous pathogenic variant in MEN1 on molecular testing (see Table 1)

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of MEN1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes MEN1 and other genes of interest (see Differential Diagnosis) may also be used. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may also be consided. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in MEN1 Syndrome

Gene 1Test MethodProportion of Probands with a Germline Pathogenic Variant 2 Detectable by This Method
MEN1Sequence analysis 3Familial: 80%-90% 4, 5
Simplex: 65% 6, 7, 8
Gene-targeted deletion/duplication analysis 91%-4% 10

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

1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.
5.

The likelihood of detecting an MEN1 pathogenic variant increases when an individual has 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].

6.
7.

The likelihood of detecting anMEN1 pathogenic variant increases in simplex cases with the presence of pancreatic lesions or with the presence of two main manifestations of MEN1 [Odou et al 2006].

8.

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

9.

Testing that identifies exon 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.

10.

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
ParathyroidNAYesPrimary hyperparathyroidism in 100% by age 50 yrs 1
Anterior pituitaryProlactinomaYesAnterior pituitary tumors in ~30%-40% 2Most commonly seen anterior pituitary tumor subtype, accounting for 60% of pituitary tumors 3
GH-secretingYesAccounts for 25% of anterior pituitary tumors 3
GH/PRL-secretingYes5% 3
TSH-secretingYesRare 4
ACTH-secretingYes<5% 3
Non-functioningNo<5% 3
Well-differentiated endocrineGastrinomaYesAccounts for 40% of well-differentiated endocrine tumors 5
InsulinomaYes10% 3
GlucagonomaYes<1% 3
VIPomaYes<1% 3
Non-functioning & PPomaNo20%-55% 3 of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs)
CarcinoidBrochopulmonaryNo2% 3
ThymicNo2% 3
GastricNo10% 3
AdrenocorticalCortisol-secretingRarely40% 3
Aldosterone-secretingRarely
PheochromocytomaRarely<1% 3

NA = not applicable

GH = growth hormone

PRL = prolactin

TSH = thyroid-stimulating hormone

ACTH = adrenocorticotrophic hormone

VIPoma = vasoactive intestinal peptide-secreting tumor

PPOMA = pancreatic polypeptide-secreting tumor

1.

First clinical manifestation of MEN1 in 90% of individuals

2.

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

3.
4.
5.

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 as early as age 35 years who are hyperparathyroid [Kann et al 2012].

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 [Norton et al 2008].

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, Thakker et al 2012].

Cancer risk. Parathyroid carcinoma is rare in individuals with MEN1. To date only three people with germline MEN1 pathogenic variants have been reported to have parathyroid carcinoma [Shih et al 2009, del Pozo et al 2011, Thakker et al 2012].

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 (GH) and prolactin (PRL) with follicle-stimulating hormone (FSH), luteinizing hormone, or adrenocorticotropic hormone (ACTH) 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 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 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 [Thakker et al 2012].

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 tumors 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-ACTH.

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. No increased prevalence of pituitary carcinoma is observed in individuals with MEN1 [Thakker et al 2012].

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]. Twenty-five percent 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 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 pathogenic variants [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; 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].

Glucagonoma

  • Pathology. Glucagonomas can be associated with other tumors in MEN1 syndrome, but they are very rare. MEN1-associated glucagonomas are estimated to account for only about 3% of all diagnosed glucagonoma [Castro et al 2011]. Tumor size is often >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].

VIPoma

  • Pathology. It has been estimated that 17% of individuals 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 greater than 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 3% of individuals with MEN1 syndrome. CT is useful in localizing occult bronchial tumors while CT and MRI are equally sensitive in detecting thymic cardinoid tumors at initial evaluation [Thakker et al 2012]. 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].

Carcinoid tumors 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 and bronchial carcinoids occur predominantly in women (male/female ratio 1:4) [Thakker et al 2012]. Interestingly, among Japanese individuals with MEN1 thymic carcinoids have a less marked gender difference (male/female ratio 2:1) [Sakurai et al 2012]. Additionally, individuals with MEN1 who smoke have a higher risk of developing carcinoid tumors than individuals with MEN1 who do not smoke.

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 of 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, have been described in a variable percentage (20% to 73%) of individuals with MEN1, depending on the radiological screening methods employed. Adrenocortical tumors are most often detected during CT screening.

Most of these tumors include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; less than 10% of these tumors demonstrate hormonal hypersecretion, and among these Cushing syndrome is the most common [Thakker et al 2012].

Rarely, adrenaocortical 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 nonfunctional 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%. In individuals with MEN1 who have adrenal tumors larger than 1 cm, the risk of malignancy is about 13%. This risk may be higher in affected individuals whose tumor is greater than 4 cm in diameter.

Non-Endocrine Tumors Associated with MEN1 Syndrome

Skin findings may include [Darling et al 1997, Thakker et al 2012]:

  • Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [Thakker et al 2012]. They consist of acneiform papules that do not regress and may extend across the vermilion border of the lips.
  • Collagenomas, present in about 70% of affected individuals, frequently present as multiple, skin-colored, sometimes hypopigmented, cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [Thakker et al 2012]. They are typically asymptomatic, rounded, and firm-elastic measuring a few millimeters to several centimeters in size. 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 are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [Thakker et al 2012]. They can be subcutaneous or, rarely, visceral.
  • Other skin findings include café au lait macules in 38%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [Darling et al 1997].

Central nervous system tumors are rare in individuals with MEN1.

  • Meningioma was reported in 8% of 74 individuals [Asgharian et al 2004]; the meningiomas were mainly asymptomatic and 60% showed no growth.
  • Ependymoma is present in about 1% of affected individuals.

Leiomyomas are benign neoplasms derived from smooth (nonstriated) muscle [McKeeby et al 2001, Ikota et al 2004]. Sporadic uterine leiomyomas affect 20% to 30% of reproductive-age women. No data regarding the frequency of these tumors in women with MEN1 or comparing sporadic incidence vs incidence in women with MEN1 are available – nor are any data regarding multiple leiomyomas of the esophagus and lungs in individuals with MEN1.

Thyroid tumors. Adenomas, colloid goiters, and carcinomas have been reported to occur in more than 25% of individuals with MEN1. The presence of thyroid abnormalities in persons with MEN1 may be incidental and not significant, considering that the prevalence of thyroid disorders is commonly high also in the general population [Thakker et al 2012].

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, Marini et al 2017].

Genotype-Phenotype Correlations

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

One study reported a twofold higher risk of death in individuals with a heterozygous MEN1 pathogenic variant that affects the JunD interacting domain of menin [Thevenon et al 2013] (see Molecular Genetics, Normal gene product). Another study by Thevenon et al [2015] showed a minor positive intrafamilial heritability only for pituitary adenomas, adrenal tumors, and thymic tumors that progressively decreases with the degree of the genetic relationship. However, both of these studies confirmed the absence of any direct genotype-phenotype correlation, suggesting the existence of other possible modifying genetic and epigenetic factors influencing MEN1 clinical phenotypes.

Although a trend (which did not reach statistical significance) suggested that the prevalence of truncating variants 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 pathogenic variants and specific phenotype.

Penetrance

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].

Prevalence

MEN1 has a prevalence of between 1:10,000 to 1:100,000 individuals. Geographic clustering as a consequence of founder effect has been reported [Carroll 2013].

Differential Diagnosis

Table 3.

Differential Diagnosis of MEN1 Syndrome: Other Disorders

DisorderGeneMOIClinical Features of the Disorder
Overlapping w/MEN1Distinguishing from MEN1
MEN2 syndrome 1RETADIn MEN2A 1:
  • PHPT in ~20%-30% of individuals
  • Hypercalciuria & renal calculi (in some)
In MEN2A 1:
  • Medullary thyroid carcinoma & pheochromocytoma
  • PHPT that is generally milder than in MEN1-associated PHPT
  • In most individuals w/MEN2A & PHPT, no PHPT symptoms
MEN4 syndrome
(OMIM 610755)
CDKN1BADAll featuresNo specific distinguishing clinical features
Pituitary adenoma predisposition (OMIM 605555)AIPPituitary adenomas
  • Earlier-onset pituitary tumors than in MEN1
  • MEN1-associated single pituitary tumors typically prolactinomas or macroadenomas
Sporadic PHPT 2NANAPHPT
  • Peak incidence in 6th decade 3 (onset of MEN1: 3 decades earlier, at ages 20-25 yrs) 4
  • Identified because of symptoms of hypercalcemia (in MEN1, affected/at-risk individuals often asymptomatic when evaluated for MEN1 manifestations)
FIHP 5MEN1 6ADParathyroid adenoma or hyperplasiaNot associated w/other endocrinopathies typical of MEN1
CASR 7AD, AR
CDC73 8AD

PHPT = primary hyperparathyroidism

FIHP = familial isolated hyperparathyroidism

1.

MEN2A is a clinical subtype of MEN2 syndrome.

2.

Sporadic PHPT, generally caused by a single parathyroid adenoma, refers to PHPT that is not inherited.

3.
4.
5.

FIHP is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies in two or more individuals in one family.

6.

MEN1 germline pathogenic variants have been reported in 20%-57% of families with FIHP [Miedlich et al 2001, Villablanca et al 2002, Pannett et al 2003] (see Genetically Related Disorders).

7.

Between 14% and 18% of families with FIHP have identifiable CASR pathogenic variants [Simonds et al 2002, Warner et al 2004]. CASR pathogenic variants have also been identified in individuals with familial hypocalciuric hypercalcemia (OMIM 601198) and neonatal severe primary hyperparathyroidism (OMIM 239200).

8.

Pathogenic variants in CDC73 are responsible for hyperparathyroidism-jaw tumor syndrome. Of note, Warner et al [2004] did not identify any CDC73 pathogenic variants in 22 individuals with FIHP. See CDC73-Related Disorders.

Table 4.

Differential Diagnosis of MEN1 Syndrome: Clinical Features

Clinical FeatureComments
Pituitary tumors
  • If single pituitary adenomas: (1) not likely to be associated w/MEN1 if no other findings of MEN1 1; (2) respond better to medical therapy than MEN1-associated pituitary tumors 2
  • If multiple pituitary adenomas: see Table 3, Pituitary adenoma predisposition
Zollinger-Ellison syndrome (ZES)
  • Sporadically occurring gastrinomas (1) more commonly pancreatic in origin 3; (2) occur 1 decade later than gastrinomas in MEN1 4
  • 2 individuals w/ZES & pathogenic variants in 2 cyclin-dependent kinase inhibitor genes (RPRD1A and CDKN1B) reported 5
  • Gastrinomas may also be present in MEN4, TSC, & NF1
Non-functioning neuroendocrine tumors (NF-NETs)
  • Affect ~20%-55% of individuals w/MEN1
  • May also be present in VHL (10%-17%) & NF1
Insulinoma
  • Peak age at onset ~1 decade later in individuals w/sporadic insulinomas 4
  • Insulinomas may also be present in NF1
Carcinoid tumors
  • When not associated w/MEN1: usually occur in derivatives of the midgut & hindgut; are argentaffin positive; secrete serotonin (5-hydroxytryptamine); & have less severe course than MEN1-associated thymic carcinoid tumors 4
  • Association of gastric carcinoids & hyperparathyroidism appears to constitute a distinct syndrome in genetically predisposed individuals; should not be regarded as "atypical" or "incomplete" expression of MEN1 6.
Facial angiofibromas
  • Also seen in TSC
  • Age of onset in TSC: 3-4 years (vs in MEN1: <40 years)
LeiomyomasMay also be seen in w/Alport syndrome

MEN4 = multiple endocrine neoplasia type 4

TSC = tuberous sclerosis complex

NF1 = neurofibromatosis 1

VHL = von Hippel-Lindau syndrome

1.
2.
3.
4.
5.
6.

Management

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 if they have not already been completed:

  • Multiglandular parathyroid disease
  • Prolactinoma
  • Gastrinoma and other entero-pancreatic neuroendocrine tumors
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

PHPT

Parathyroidectomy is the treatment of choice for individuals 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. Timing of surgery and type of parathyroid intervention should be tailored to the individual's specific clinical characteristics.

  • 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 affected individuals 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. The procedure is dependent on the vitality of cryopreserved cells, which declines with the time interval from cryopreservation to autotransplantation.
    • Intraoperative monitoring of parathyroid hormone (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 is recommended.
    • Recurrent hypercalcemia is present in more than 50% of affected individuals 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 individuals with hypercalcemia, in association with hypercalciuria, to prevent and/or reduce clinical consequences of high calcium levels.

Those with asymptomatic hypercalcemia usually can delay parathyroid surgery in favor of regular assessment for symptom onset and complications.

Parathyroidectomy is mandatory in individuals with MEN1 who have Zollinger–Ellison syndrome (ZES) to correct primary hyperparathyroidism and hypercalcemia and, subsequently, reduce gastric acid output and the risk of peptic ulcers.

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

Individuals with PHPT who are not considered candidates for parathyroidectomy, who failed a previous intervention, or who present with post-surgical recurrence and decline to undergo any further surgical interventions can also be treated by calcimimetics (i.e., cinacalcet), a class of calcium-sensing receptor agonists that are able to restore normal calcium homeostasis and control parathyroid cell growth. Cinacalcet is a well-tolerated, safe, and effective treatment for individuals with MEN1 [Moyes et al 2010, Giusti et al 2016].

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, Thakker et al 2012].
  • Transsphenoidal surgery and radiotherapy are reserved for drug-resistant tumors and for macroadenomas compressing adjacent structures and generating neuroophthalmologic complications that cannot be managed through pharmacologic therapy.

Growth hormone-secreting tumors

  • Transsphenoidal surgery is the surgical treatment of choice for GH-secreting tumors causing acromegaly and is effective in 50%-70% of cases.
  • Somatostatin analogs are the medical therapy of choice for the treatment of GH-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 GH-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 macroadenoma 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, surgery 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] 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

Gastrinoma

  • 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 treatment of gastrinoma in MEN1 syndrome is controversial because these tumors are usually microscopic and scattered over the entire neuroendocrine tissue, making successful surgical outcome rare. Surgical ablation of gastrinoma is suggested only in the presence of concomitant non-functioning NETs that either double their size in a six-month interval, or approach or exceed 2 cm in diameter [Thakker et al 2012, Falconi et al 2016]. There are no controlled trials comparing the efficacy of gastrinoma surgery with respect to medical treatment.
  • 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 >~0.5 cm in 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. Individuals with MEN1 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 the affected individual's preferences, as such approaches may improve the cure rate. However, given the common multiple microadenomatose nature of these tumors in individuals with MEN1, surgery is often not effective.
    • Whipple pancreaticoduodenectomy provides the greatest likelihood of cure for gastrinoma in individuals with MEN1, but can be associated with an increased operative mortality and long-term morbidity unless performed by an experienced surgeon.
  • Unresectable tumors or advanced metastatic cancer can be treated with somatostatin analogs (SSAs), cytotoxic chemotherapy, inhibitors of thyrosin kinase receptors (sunitinib), or inhibitors of mammalian target of rapamycin (mTOR; everolimus). All these therapies have demonstrated an increase in the median progression-free survival in individuals with sporadic pNETs; however, no specific trials have been performed in individuals with MEN1 who have GEP-NET [Marini et al 2017].
  • Treatment for non-functioning pancreatic NETs is controversial; some centers consider surgical resection for lesions >1 cm in size, while other centers recommend surgery only for tumors >2 cm.
  • Occult metastatic disease (i.e., tumors not detected by imaging investigations) may be present in a substantial proportion of affected individuals 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 greater than 4 cm in diameter, for tumors 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 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 postoperatively 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 to both 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 and thus avoid dangerous and potentially lethal blood pressure peaks during surgery.

Surveillance

Routine surveillance using biochemical testing and imaging is recommended for asymptomatic individuals with a heterozygous 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

Notes:

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

2. 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]

3. 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. Yearly biochemical investigations, 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

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the MEN1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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.

Pregnancy Management

Since MEN1 is a rare condition, there are no specific guidelines regarding the clinical management and follow up of affected pregnant women.

Maternal primary hyperparathyroidism from any cause can increase the risk of developing preeclampsia during prengnacy [Hultin et al 2009]. Approximately 50% of infants born to women with primary hyperparathyroidism experience neonatal hypocalcemia [Kort et al 1999]. Other neonatal complications may include intrauterine growth restriction, preterm birth, and permanent hypoparathyroidism [Diaz-Soto et al 2013].

There is one report of a 29-year-old woman with molecularly confirmed MEN1 who underwent total parathyroidecotomy seven years prior to conception and was maintained on calcium and vitamin D supplementation throughout pregnancy with monthly serum calcium monitoring. She also had an asymptomatic pituitary micoradenoma and pancreatic islet cell tumors. Pregnancy proceeded without further complications and resulted in the delivery of a healthy infant at term. The infant did not have any neonatal complications [Daglar et al 2016].

Therapies Under Investigation

Pituitary tumors. In an 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 (SSAs) may be used to control proliferation of enterochromaffin-like cells:
    • Two clinical trials (PROMID and CLARINET) in individuals who did not have MEN1 demonstrated that treatment with SSAs had a significant positive effect on the prolongation of progression-free survival [Caplin et al 2014, Rinke et al 2009].
    • One study on octreotide LAR therapy has demonstrated the same effect in individiuals with MEN1. The authors suggest initiating early therapy with SSAs in those with MEN1 who had NETs to reduce malignant progression and reduce morbility [Ramundo et al 2014].
    • The European Neuroendocrine Tumor Society (ENETS) is designing a prospective randomized controlled multicenter study to clarify possible benefits of SSA treatment vs no treatment on tumor progression in individuals with MEN1 who have pNETs. The study start date was in June 2016 with an estimated study completion date of June 2022 [Selberherr A, Niederle B, and participating ENENS Centers of Excellence].
    • ENENS is also conducting a prospective randomized controlled multicenter study in ENENS Centers of Excellence to evaluate non-functioning pancreatic neuroendocrine tumors in MEN1: Somatostatin Analogs Versus NO Treatment (SANO).
  • Peptide receptor radionuclide therapy (PRRT), with radio labeled SSAs, takes advantage of the SSA specificity for somatostatin receptors to deliver cytotoxic doses of a radioactive isotope (i.e., yttrium-90 or luteticium-177) selectively to GEP-NET cells.
    Response rates, reported to be 15%-35%, may vary based on the type of tumor and the radionuclide used [Kwekkeboom et al 2011, Nicolas et al 2011, Ezziddin et al 2014]. There are no studies specifically focusing on NETs associated with MEN1.

Targeted molecular therapies

  • Everolimus is an oral mTOR pathway inhibitor, used in individuals with advanced, low-grade, or intermediate-grade pNETs. mTOR regulates cell survival, proliferation, and motility. A recent international multicenter double-blind Phase III study on 410 persons with pNETs has shown that treatment with mTOR pathway inhibitors leads to an increase of median progression-free survival. This study did not provide any information about the clinical and/or genetic status of MEN1 in those who underwent treatment [Yao et al 2011].
  • Sunitinib, an oral tyrosine-kinase inhibitor, targets the VEGF receptor. It is used for the treatment of advanced pNETs, since they express high levels of VEGF receptors. A multinational randomized double-blind placebo-controlled Phase III clinical trial comprising 171 individuals showed that treatment with sunitinib increases the median progression-free survival. However, the study included only two individuals with MEN1, both of whom received placebo [Raymond et al 2011].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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% of individuals diagnosed with MEN1 syndrome have the disorder as the result of a de novo MEN1 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
  • Approximately 90% of individuals diagnosed with MEN1 syndrome have an affected parent; however, the family history of some individuals diagnosed with MEN1 syndrome 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. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

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, the risk to the sibs is 50%.
  • If the parents have been tested for the MEN1 pathogenic variant identified in the proband and:
    • A parent of the proband has the MEN1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. A high clinical variability has been described between affected members of the same families (bearing the same MEN1 pathogenic variant) and even between homozygous twins.
    • If the MEN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrance risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
  • If the parents have not been tested for the MEN1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for MEN1 syndrome because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has the MEN1 pathogenic variant, his or her family members may be 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.

Testing of at-risk asymptomatic individuals. Molecuar genetic testing of at-risk asymptomatic family members is strongly recommended for all first-degree relatives of an affected person with an identified MEN1 pathogenic variant. Molecular genetic testing should be performed in at-risk asymptomatic individuals as soon as possible so that individuals with an MEN1 pathogenic variant can receive the appropriate clinical surveillance (see Management). Education and genetic counseling of all at-risk individuals and their families prior to genetic testing is appropriate.

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 (typically extracted from white blood cells) 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 and Preimplantation Genetic Diagnosis

Once the MEN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MEN1 syndrome are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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
    Email: info@amend.org.uk
  • Associazione Italiana Neoplasie Endocrine Multiple (AIMEN 1 & 2)
    Corso Francia, 220/a
    Italy
    Phone: 39 800 177 526
    Fax: 39 0331 983343
    Email: info@aimen.it
  • Medline Plus
  • My46 Trait Profile
  • 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
    Email: endoandmeta@info.niddk.nih.gov
  • 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
    Email: jo.grey@amend.org.uk

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
MEN111q13​.1MeninMEN1 databaseMEN1MEN1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Multiple Endocrine Neoplasia Type 1 (View All in OMIM)

131100MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1
613733MEN1 GENE; MEN1

Molecular Genetic Pathogenesis

The inactivating inherited or de novo MEN1 pathogenic variants in combination with an aquired somatic variant results in clonal outgrowth, confirming MEN1 as a tumor suppressor that follows 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.

Pathogenic variants. More than 1,000 MEN1 germline variants – more than 200 of which are pathogenic – have been reported throughout the gene [Lemos & Thakker 2008, Concolino et al 2016]; pathogenic variants include:

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]. Pathogenic variants that prevent translocation to the nucleus have been described [Tala et al 2006].

Menin is expressed in all tissues, presumably playing tissue-specific roles in 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:

  • Directly interacting with transcription factors (e.g., JunD, NF-kB, PPARgamma, VDR) that induce or suppress gene transcription;
  • Interacting with various histone-modifying enzymes (MLL; HDACs and EZH2); and
  • Directly interacting with gene promoters and acting as a transcription factor itself.

Menin inhibits JunD-mediated transcription and, 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.

Menin directly regulates the expression of the cyclin-dependent kinase-inhibiting (CDKI) genes, CDKN1b (encoding p27) and CDKN2C (encoding p18) 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]. Knockout mice [Scacheri et al 2006] with simultaneous loss of p18 and p27 develop a spectrum of tumors similar to that in humans with MEN1 and MEN2 with much more rapid tumor onset than in mice with either deficiency alone. Hundreds of menin-occupied genomic sites have been identified in promoter regions, near the 3' end of genes or within genes as well as outside known gene regions [Agarwal et al 2007], suggesting additional targets of transcription regulation.

Interaction between microRNA miR-24-1 and MEN1 mRNA has been described [Luzi & Brandi 2011]. Luzi et al [2012a] found an inverse correlation between menin and miR-24-1 expression in MEN1 parathyroid adenoma tissues with a conserved MEN1 wild-type allele. Moreover, ChIP analysis demonstrated the direct association of menin protein with the miR-24-1 promoter. Several studies have found evidence of 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 [Luzi et al 2012a, Vijayaraghavan et al 2014].

Additionally, Ouyang et al [2015] reported that Men1 mRNA is targeted and negatively regulated by microRNA-29b (miR-29b) and demonstrated that miR-29b represses translation of Men1 mRNA to menin protein, affecting intestinal epithelial homeostasis by reducing apoptosis in intestinal epithelial cells.

A physiologic role for menin has been shown in other processes:

  • Bone development
    • Regulation of early differentiation of osteoblasts (through interactions with Smad1 and Smad5 proteins) [Sowa et al 2003]
    • Inhibition of osteoblast late differentiation (by negatively regulating the BMP2-Smad1/5-Runx2 cascade, through the TGFβ-Smad3 pathway) [Sowa et al 2004]
    • Direct modulation of 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]
  • Hematopoiesis. Regulation of lymphoid progenitors [Naito et al 2005, Chen et al 2006, Caslini et al 2007, Maillard et al 2009]

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 [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. Nonsense pathogenic variants and most of frameshift germline or somatic pathogenic variants in MEN1 predict truncation of the protein with the absence of one, two, or all three NLSs and the blocking of menin translation to the nucleus with consequent loss of menin functionality.

Splice site pathogenic variants result in aberrant processed mRNA, often leading to a frameshift with a premature termination codon.

Missense variants 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 variants 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 variants and/or deletion of both MEN1 alleles in 15%-20% of sporadic parathyroid adenomas; these pathogenic variants 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 at the 11q13 locus, where MEN1 is found [Friedman et al 1992, Heppner et al 1997].

References

Published Guidelines / Consensus Statements

  • American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. 2003.
  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 4-25-18.
  • 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. 2012. Accessed 4-25-18. [PubMed: 22723327]

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  • Zhou H, Schweikert HU, Wolff M, Fischer HP. Primary peripancreatic lymph node gastrinoma in a woman with MEN1. J Hepatobiliary Pancreat Surg. 2006;13:477–81. [PubMed: 17013727]

Suggested Reading

  • 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]
  • Calendar A. Multiple endocrine neoplasia type 1 (MEN1). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2005. Accessed 4-25-18.
  • Daly AF, Tichomirow MA, Beckers A. Update on familial pituitary tumors: from multiple endocrine neoplasia type 1 to familial isolated pituitary adenoma. Horm Res. 2009;71 Suppl 1:105–11. [PubMed: 19153518]
  • 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]
  • 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;179:89–92. [PubMed: 18036394]
  • 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]
  • 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]
  • Vierimaa O, Villablanca A, Alimov A, Georgitsi M, Raitila A, Vahteristo P, Larsson C, Ruokonen A, Eloranta E, Ebeling TM, Ignatius J, Aaltonen LA, Leisti J, Salmela PI. Mutation analysis of MEN1, HRPT2, CASR, CDKN1B and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition. J Endocrinol Invest. 2009;32:512–8. [PubMed: 19474519]

Chapter Notes

Acknowledgments

This paper has been supported by Cofin MIUR 2003 (FM), by AIRC 2000 (MLB), and by the Fondazione Ente Cassa di Risparmio di Firenze (MLB).

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

  • 14 December 2017 (ma) Comprehensive update posted live
  • 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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