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Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis

Author: Andrew Arnold, MD

Section Editor: Marc K Drezner, MD
Deputy Editor: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2018. | This topic last updated: Jul 24, 2017.

INTRODUCTION — Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant predisposition to tumors of the parathyroid glands (which occur in nearly all patients by
age 50 years), anterior pituitary, and enteropancreatic endocrine cells; hence, the mnemonic device of the "3 Ps" [1]. However, the clinical spectrum of this disorder has been
expanded. The duodenum is a common site of tumors (gastrinomas) in these patients, and carcinoid tumors, adrenal adenomas, and lipomas are more common than in the
general population (table 1).

The clinical manifestations and diagnosis of MEN1 will be reviewed here. The genetics of this disorder, its distinction from other multiple endocrine neoplasia (MEN) syndromes,
and its treatment are discussed separately. (See "Multiple endocrine neoplasia type 1: Definition and genetics" and "Multiple endocrine neoplasia type 1: Treatment" and "Clinical
manifestations and diagnosis of multiple endocrine neoplasia type 2".)

DEFINITION OF MEN1 — Multiple endocrine neoplasia type 1 (MEN1) is a rare heritable disorder classically characterized by a predisposition to tumors of the parathyroid glands,
anterior pituitary, and pancreatic islet cells [1]. The presence of MEN1 is defined clinically as the occurrence of two or more primary MEN1 tumor types, or in family members of a
patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors (table 1). It should be noted that these are clinical definitions and do not
necessarily indicate that mutation of the MEN1 gene will be identifiable or responsible. (See "Multiple endocrine neoplasia type 1: Definition and genetics".)

CLINICAL MANIFESTATIONS

Primary hyperparathyroidism — Multiple parathyroid tumors causing hyperparathyroidism are the most common manifestation of multiple endocrine neoplasia type 1 (MEN1),
displaying almost 100 percent penetrance by age 40 to 50 years. In most cases, it is the initial manifestation of MEN1. Reliable incidence figures do not exist, but it has been
estimated that the incidence of MEN1 ranges from 1 to 18 percent in patients with primary hyperparathyroidism [1].

Primary hyperparathyroidism in the setting of familial MEN1 has a number of different features from the common sporadic (non-familial) form of the disease [1,2]:

● The male-to-female ratio is even in MEN1 in contrast to the female predominance in sporadic hyperparathyroidism.

● Hyperparathyroidism in MEN1 typically presents in the second to fourth decade of life, approximately two decades earlier than in sporadic hyperparathyroidism.

● Multiple gland disease is typical in MEN1 and, given sufficient time, perhaps universal. In comparison, approximately 80 to 85 percent of patients with sporadic disease have
single parathyroid adenomas. There can be marked asymmetry in size among the distinct glands and, upon initial neck exploration, some parathyroid glands in MEN1 may
appear to be grossly normal. However, even the smaller glands will generally exhibit hypercellularity on histologic examination.

● A strong and seemingly inexorable proliferative drive in parathyroid cells appears to exist in classical MEN1, as indicated by the high rate of recurrent hyperparathyroidism
after apparently successful subtotal parathyroidectomy. One report from the National Institutes of Health (NIH), as an example, found a recurrence rate above 50 percent at 12
years [3]; most other studies have had shorter follow-up periods. The high recurrence rate clearly distinguishes the hyperparathyroidism of MEN1 from that seen in sporadic
disease. It has also resulted in differences of opinion with respect to optimal surgical management of this disorder. (See "Multiple endocrine neoplasia type 1: Treatment".)

Similar to sporadic primary hyperparathyroidism, the majority of patients are asymptomatic, and hypercalcemia is detected by routine biochemical screening. If clinical
manifestations of primary hyperparathyroidism are present, they may include decreased bone mineral density, kidney stones, and symptoms of hypercalcemia (eg, polyuria,
polydipsia, constipation). The biochemical diagnosis of primary hyperparathyroidism is based, as it is in all patients with primary hyperparathyroidism, on the demonstration of
hypercalcemia with inappropriately high serum parathyroid hormone (PTH) concentrations. (See "Primary hyperparathyroidism: Clinical manifestations" and "Primary
hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Pituitary adenomas — Clinically apparent pituitary adenomas have been found in approximately 15 to 20 percent of patients with MEN1 when sought by computed tomography
(CT) or magnetic resonance imaging (MRI) [4] and 42 percent in a multicenter study of 324 MEN1 patients [5]. The pathological prevalence in one series was over 60 percent [6].
The pituitary cell type is similar to that found in sporadic pituitary adenomas. Thus, the most common type of pituitary adenoma in MEN1 is lactotroph, but somatotroph,
corticotroph, gonadotroph, and clinically nonfunctioning tumors can also occur (table 1). Multiple pituitary tumors are rarely present in MEN1.

The phenotypic presentation of pituitary disease is variable. In one large kindred, as an example, lactotroph adenomas predominated, and none of the 165 patients had
acromegaly [4,7]. Furthermore, the distribution of lactotroph adenomas was not even; the prevalence was more than 50 percent in some branches of the kindred and very low in
others [8].

A multicenter study of 324 MEN1 patients (42 percent of whom had pituitary tumors), compared with 110 non-MEN patients with pituitary adenomas, revealed that [5]:

● Of the 136 MEN1 patients with pituitary adenomas, 85 percent had macroadenomas (versus 42 percent in non-MEN1 patients).

● In the same patients, hormonal hypersecretion was normalized in 42 percent after treatment versus 90 percent in non-MEN1 patients, reflecting the finding that the MEN1
patients had adenomas that were larger and more aggressive than those in non-MEN patients.

In contrast, another study, which examined the results of systematic presymptomatic screening for pituitary adenomas over a significant follow-up period (median 6 years), showed
that such screening primarily detected nonfunctioning microadenomas that grew only occasionally and without clinical consequence; detected prolactinomas responded well to
medical treatment [9].

Whether a program of routine and lifelong surveillance by imaging would decrease morbidity from pituitary disease in MEN1 remains unknown.

The clinical manifestations, approach to diagnosis, and therapy of pituitary adenomas in patients with MEN1 is similar to that in patients with sporadic adenomas. (See "Causes,
presentation, and evaluation of sellar masses", section on 'Pituitary adenomas'.)

Pancreatic islet cell/gastrointestinal tumors — Effective treatment is usually available for the hyperparathyroidism and pituitary disease in MEN1; as a result, the malignant
potential of enteropancreatic neuroendocrine tumors is now the primary life-threatening manifestation of MEN1.

Functioning pancreatic islet cell or gastrointestinal endocrine cell tumors become clinically apparent in approximately one-third of patients with MEN1 (table 1). The most common
cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome (ZES), leading to multiple peptic ulcers. It has been estimated that 60 percent of patients with MEN1
have either ZES or asymptomatic elevation in serum gastrin concentrations; on the other hand, MEN1 is present in 20 to 60 percent of patients with ZES [10]. Symptomatic
insulinomas also occur with moderate frequency, while VIPomas and glucagonomas are rare (table 1). (See "VIPoma: Clinical manifestations, diagnosis, and management" and
"Glucagonoma and the glucagonoma syndrome".)

The prevalence of radiographically confirmed, nonfunctioning tumors is similar to that of gastrinomas, ranging from 30 to 80 percent [11-14]. Like hormonally active
enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic neuroendocrine tumors may be malignant and capable of causing liver metastases. (See 'Nonfunctioning
pancreatic tumors' below.)

Zollinger-Ellison syndrome — Historically, attempts at surgical cure of the hypergastrinemia in ZES in patients with MEN1 were uniformly unsuccessful. It is now apparent that

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the basis for the failure of these approaches, namely resection of palpable tumors and/or partial pancreatectomy, is due to the biological nature and characteristics of the tumors in
MEN1. In contrast to sporadically occurring gastrinomas, the gastrinomas in MEN1 patients are multifocal, often exceedingly small, and easily overlooked. In addition, the
duodenum is a common site of gastrinomas both in MEN1 and in sporadic gastrinoma [10,15,16]; in comparison, in MEN1, the tumors that are found in the pancreas do not usually
secrete gastrin [10].

The risk of death from malignant spread of MEN1-associated gastrinoma appears to be less than that for sporadic gastrinoma. Local lymph node metastases are common but are
not necessarily associated with a poor prognosis or a high likelihood that clinically important metastases will occur [17].

In one large series, investigators at the NIH prospectively followed 107 patients with MEN1 and ZES and reviewed 1009 cases from the literature [18]. Their findings were as
follows:

● Approximately 25 percent of MEN1/ZES patients had no family history of MEN1.

● ZES was the initial clinical manifestation of MEN1 in 40 percent of patients with MEN1/ZES.

● The onset of ZES symptoms preceded the diagnosis of hyperparathyroidism in 45 percent of patients.

● The diagnosis of ZES was delayed for three to six years after its onset.

● Pituitary disease occurred in 60 percent of patients.

● In patients without a family history of MEN1, ZES and other MEN1 manifestations occurred later and were less severe.

Hypersecretion of gastrin in ZES in MEN1 may be suspected clinically by the presence of multiple peptic ulcers (image 1) or symptoms like diarrhea. The diagnosis is confirmed by
the same biochemical and gastric acid output criteria as are used in the sporadic cases [17,19,20] (see "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and
diagnosis"). Hypercalcemia from coexisting hyperparathyroidism can significantly exacerbate the symptoms of ZES, and parathyroidectomy to correct hypercalcemia can reduce
fasting and secretin stimulated gastrin levels and basal acid secretion [21].

The incidence of Cushing's syndrome has been reported to be increased in patients with ZES. When Cushing's syndrome occurs in patients with nonfamilial gastrinoma, the usual
cause is ectopic corticotropin (ACTH) release from the islet-cell tumor. These cases are associated with severe symptoms. In contrast, patients with familial MEN1 and ZES who
develop Cushing's syndrome usually have a corticotroph adenoma of the pituitary and relatively mild symptoms of cortisol excess [22].

Insulinoma — Insulin-producing pancreatic islet cell adenomas in MEN1 are often small, may be multiple, and may be associated with the simultaneous presence of other islet
cell tumors. Insulinoma in MEN1 typically presents in the second to fourth decade of life, earlier than in sporadic insulinoma, which usually occurs in individuals older than 40 years
[1]. The diagnosis of insulinoma depends, as in nonfamilial causes, upon the documentation of hypoglycemia with characteristic symptoms that are rapidly reversed by the
administration of glucose, and inappropriately high serum insulin concentrations. (See "Insulinoma".)

Nonfunctioning pancreatic tumors — It is important to recognize that pancreatic neuroendocrine tumors in MEN1 often synthesize multiple hormones. But hormone synthesis
does not always have clinical consequences, suggesting that many such tumors may be defective in their peptide hormone processing apparatus or have an inefficient secretory
mechanism [23]. Like hormonally active enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic neuroendocrine tumors may be malignant and can metastasize to
the liver. Nonfunctioning pancreatic neuroendocrine tumors have been detected as early as ages 12 to 14 in asymptomatic children with MEN1 [24,25].

Nonfunctioning pancreatic neuroendocrine tumors are among the most common tumor of the pancreaticoduodenal region in patients with MEN1 [11-14]. In a report of 579 MEN1
patients, 108 patients with isolated nonfunctioning pancreatic neuroendocrine tumors were identified with the following clinical characteristics and course [12]:

● The penetrance of nonfunctioning pancreatic neuroendocrine tumors was 34 percent at age 50 years.

● The risks of metastasis and death were low for patients with tumors ≤20 mm.

● Average life expectancy for patients with nonfunctioning pancreatic neuroendocrine tumors was similar to that for gastrinoma patients (69 to 70 years) and shorter than that for
patients without pancreatic tumors (77 years).

The best way to detect these nonfunctioning tumors is unclear. A limited amount of data suggests that endoscopic ultrasound (EUS) outperforms CT scanning in this setting, and a
combination of MRI plus EUS has been recommended [25]. 68Gallium-DOTATATE PET/CT scanning has been reported to have especially high sensitivity for detecting
neuroendocrine tumors in MEN1, at times leading to a change in management [26]. Such sensitive imaging methods increase detection of indolent tumors as well as potentially
aggressive lesions. In a retrospective study, 18F-FDG PET/CT imaging was useful for predicting the malignant potential of pancreatic neuroendocrine tumors in MEN1 [27]. (See
"Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Endoscopic ultrasonography'.)

Other tumors — A number of other tumors also occur with increased frequency in MEN1. These include carcinoid, cutaneous tumors, adrenal tumors (especially nonfunctional
adrenocortical adenomas), gastric enterochromaffin-like cell carcinoids, pheochromocytoma (very rarely), angiomyolipomas, meningiomas, and spinal cord ependymomas (table
1).

Carcinoid tumors — Thymic carcinoid tumors occur with increased frequency in MEN1 (2.6 to 5 percent in retrospective series of patients with MEN1), mostly in men [28,29].
Heavy smoking may be a risk factor [28]. Carcinoids in women with MEN1 are most often bronchial [30].

Thymic carcinoids, the most common cause of anterior mediastinal masses in MEN1, are typically nonfunctional (in contrast to the substantial incidence of ectopic Cushing's
syndrome in patients with sporadic thymic carcinoid) and tend to be aggressive. (See "Pathology of mediastinal tumors".)

A prospective study of thymic carcinoids in 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed for a mean of eight years (with serial chest CT, MRI, and
somatostatin receptor scintigraphy [SRS]) reported the following results [31]:

● Seven patients (8 percent) developed thymic carcinoids, all of which were hormonally inactive.

● All seven patients were male, and ZES was present in six.

● Five of the seven were asymptomatic, one had cough, and one had chest pain.

● CT and MRI were more sensitive than SRS for detecting the tumors initially or with recurrence.

● All patients underwent surgical resection. All four patients followed for more than one year postoperatively had tumor recurrence.

Some have recommended regular screening, by chest imaging studies, for this tumor in men with MEN1 [1,28]. However, given the rarity of these tumors and the unproven survival
benefits of this approach, we consider such routine screening reasonable but not mandatory. Certainly, it seems prudent to strongly advise men with definite or possible MEN1
against smoking, to take into consideration a strong family history of carcinoid tumors, and to perform prophylactic thymectomy in patients undergoing parathyroidectomy, although
even this measure does not fully prevent subsequent development of thymic neoplasia [29,32]. (See "Multiple endocrine neoplasia type 1: Treatment".)

Gastric carcinoids and enterochromaffin-like cell proliferation (a precursor lesion of gastric carcinoid) have been reported in patients with MEN1 and ZES. In a prospective study of
57 patients with MEN1 and ZES, advanced enterochromaffin-like cell proliferation and gastric carcinoid were detected in 53 and 23 percent, respectively [33]. Long duration of
ZES, long duration of medical treatment, high fasting serum gastrin levels, and the presence of gastric nodules on gastroscopy were associated with a higher risk of gastric
carcinoid. Such patients may benefit from regular monitoring for gastric carcinoid. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in
the tubular digestive tract, lung, and genitourinary tract", section on 'Stomach' and "Multiple endocrine neoplasia type 1: Treatment".)

Cutaneous tumors — Cutaneous tumors are common in MEN1 (table 1) [1,34]; their presence in patients with pancreatic endocrine tumors suggest the diagnosis of MEN1.
This was illustrated in a prospective study of 110 consecutive patients with gastrinoma (48 with MEN1 and 62 without MEN1) with the following findings [35]:

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● Angiofibromas and collagenomas were more common in MEN1 patients than in those without MEN1 (64 versus 8 percent, and 62 versus 5 percent, respectively).

● These cutaneous tumors were multiple in 77 to 81 percent of MEN1 patients; lipomas were present in 17 percent.

● The combination criterion of more than three angiofibromas and any collagenomas had a sensitivity of 75 percent and a specificity of 95 percent for the diagnosis on MEN1.
The sensitivity and specificity of this criterion compares favorably to the finding of hyperparathyroidism in patients who present initially with gastrinomas [18].

Similarly, the presence of angiofibromas or collagenomas can be helpful clinically in suggesting the diagnosis of MEN1 in selected patients with primary hyperparathyroidism.

DIAGNOSIS — The clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) is based upon the occurrence of two or more primary MEN1 tumor types (parathyroid gland,
anterior pituitary, and enteropancreatic). In family members of a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors is consistent with
familial MEN1 [1].

The diagnosis of MEN1 (or at least a determination that an individual is genetically predisposed to developing MEN1 clinically) can also be made by identifying a germline MEN1
mutation in an individual in whom the clinical diagnosis of MEN1 is not clearly established or in an asymptomatic family member who has not yet developed the serum biochemical
or radiological abnormalities associated with tumor development. (See 'Confirming the diagnosis of MEN1' below and 'Screening of family members in MEN1 kindreds' below.)

MEN1 MUTATIONAL ANALYSIS

Potential benefits — The optimal role of DNA testing in the context of multiple endocrine neoplasia type 1 (MEN1) is not clear cut [1,36]. In large part, this is due to a dearth of
solid data showing that preclinical detection of MEN1-related tumors leads to interventions that improve morbidity or mortality. This situation contrasts, for example, with the
established value of RET DNA testing in multiple endocrine neoplasia type 2 (MEN2) kindreds (table 2) (see "Clinical manifestations and diagnosis of multiple endocrine neoplasia
type 2"). Nonetheless, there are circumstances in which DNA testing for MEN1 can be helpful, and this option should be seriously considered. We make determinations regarding
MEN1 DNA testing on a case-by-case basis.

Direct DNA testing for MEN1 gene mutations is available in academic and commercial laboratories (ie, Genetic Testing Registry). Generally speaking, DNA testing can have utility
in several linked ways including [36,37]:

● Confirming the clinical diagnosis of the syndrome in a proband

● Examining a clearly affected proband to determine if mutation-specific carrier testing can be offered to relatives in that family

● Definitively determining whether or not asymptomatic or other relatives of a proband carry the mutant gene

● Prenatal/preimplantation diagnosis

Based upon these potential benefits, guidelines from an international group of endocrinologists recommend offering MEN1 mutational analysis to [1]:

● Any index patient with clinical MEN1 (two or more primary MEN1 tumor types)

● All first-degree relatives of known MEN1 mutation carriers

● Individuals with suspicious or atypical MEN1 (eg, multiple parathyroid tumors, gastrinoma, or multiple pancreatic neuroendocrine tumors)

Confirming the diagnosis of MEN1 — We make determinations regarding multiple endocrine neoplasia type 1 (MEN1) DNA testing on a case-by-case basis, but discussions with
patient and genetic counselor more often than not lead to pursuit of such testing. Situations in which DNA testing can be helpful may arise when the diagnosis of MEN1 is unable to
be clearly established on clinical grounds and would alter management. Examples may include some patients with a suggestive family history who present with isolated primary
hyperparathyroidism [36] or those with apparently sporadic Zollinger-Ellison syndrome (ZES), some of whom will have MEN1 mutation and would therefore be managed differently.
(See "Multiple endocrine neoplasia type 1: Treatment".)

Relevant factors to consider in these situations include the expected yield of testing, or likelihood of a positive result, which can vary markedly depending on the specific clinical
presentation. For example, while MEN1 gene mutation is detectable in approximately 70 percent of kindreds with classic familial MEN1, the yield of testing drops to 7 percent in
individuals with a sporadic presentation of combined hyperparathyroidism and pituitary adenoma [38]. Approximately 10 percent of kindreds with familial isolated
hyperparathyroidism have a detectable MEN1 mutation, and yields can be even lower when less stringent criteria are selected, such as sporadic isolated hyperparathyroidism with
age under 40 [39].

Cost-benefit considerations can importantly influence decision-making. Sequencing costs remain substantial (and variably covered by insurance in the United States). It is also
important to recognize that a negative result (mutation not detected) does not rule out the diagnosis of MEN1 nor the possibility that unidentified pathologic disruption of the MEN1
gene is responsible. Beyond assessing whether detection of an MEN1 mutation would impact a patient's immediate clinical management, factors influencing the decision to test
include an examination of the potential utility of a positive finding for the purposes of family screening and one's approach to the prospective surveillance for MEN1-related tumors
in the proband and family. (See 'Screening for MEN1-associated tumors' below.)

Screening of family members in MEN1 kindreds

Candidates for screening — We have a discussion about DNA testing with the index patient and appropriate family members, making decisions on a case-by-case basis.
Involvement of a genetic counselor can be very helpful. Proper informed consent must be obtained for each individual to be tested.

When a patient is diagnosed as having MEN1, the issue of screening family members who are at risk often arises. In general, the primary and most compelling purpose of such
screening in human tumor predisposition syndromes is to prevent disease-related morbidity and mortality that would otherwise occur. However, there is at present little evidence
that early, preclinical detection actually reduces overall morbidity or mortality in MEN1. Nonetheless, because benefit seems likely in some instances and because other helpful
information can potentially result, screening may be pursued and DNA-based testing merits serious consideration.

Screening approach — If DNA-based family screening is to be pursued, the initial step is to test the MEN1 gene, usually from a sample of peripheral blood or buccal cells, from
the affected index case, if not already performed. If MEN1 sequencing of the affected patient does reveal a pathologic mutation, the presence or absence of this family-specific
mutation can then be determined in at-risk relatives. Thus, a significant potential benefit of such testing is the identification of family members who do not have the mutation and
therefore do not need regular surveillance. The value of this benefit is enhanced to the extent that the clinician tends to opt for one of the more costly or intensive approaches to
surveillance to detect MEN1-associated conditions in at-risk individuals. (See 'Screening for MEN1-associated tumors' below.)

The presence of the mutation in an asymptomatic family member does not indicate the need for a major intervention but does focus the need for regular surveillance (eg,
assessment of symptoms, signs, biochemical tests) on these individuals. It is possible that an asymptomatic individual's knowledge that he/she definitely carries the disease gene
may increase compliance with surveillance visits and testing. Other issues include genetic discrimination, which, in the United States, remains a potential concern, despite certain
protections in the Genetic Information Nondiscrimination Act of 2008. Approaches to DNA testing and screening can vary in different nations.

Finally, knowledge of a family's specific MEN1 mutation can resolve the small potential for diagnostic confusion attributable to rare MEN1 phenocopies within MEN1 kindreds,
namely individuals who can initially be classified as having the syndrome when they develop a typical tumor (eg, prolactinoma) but may then be proven by DNA testing to have not
inherited the pathologic mutation [40].

Alternative to DNA screening — DNA-based screening can yield useful information, although it is certainly not mandatory. If DNA testing is not employed for screening
asymptomatic family members, one low-cost option is measurement of serum calcium [4]. This approach exploits the high penetrance of hyperparathyroidism in MEN1. In addition,
adding measurements of serum parathyroid hormone (PTH) and/or ionized calcium and assuring the absence of vitamin D deficiency may improve sensitivity and specificity of
screening. Also, as noted above, the presence of angiofibromas or collagenomas can be useful in this context.

SCREENING FOR MEN1-ASSOCIATED TUMORS — For patients with multiple endocrine neoplasia type 1 (MEN1), known MEN1 carriers, and family members whose risk has
not been eliminated by DNA testing, we screen for MEN1-associated tumors as follows:

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● We maintain clinical vigilance for symptoms or signs that could be due to MEN1-associated tumors. These include symptoms of nephrolithiasis, amenorrhea, galactorrhea,
growth abnormalities, cushingoid changes, headache, vision issues, cough, erectile dysfunction, peptic ulcer disease, diarrhea, and neuroglycopenic or sympathoadrenal
symptoms from hypoglycemia.

● We typically measure serum calcium, PTH, and prolactin annually to detect asymptomatic hyperparathyroidism and prolactinoma, respectively.

● We tend toward conservatism in performing imaging studies, given the absence of prospective evidence for improved survival outcomes, and taking patient preferences into
account regarding the frequency and nature of such imaging is reasonable. Often we will initially perform an imaging study for enteropancreatic neoplasia, favoring modalities
and subsequent intervals that minimize radiation exposure (eg, endoscopic ultrasound) and address factors like patient anxiety.

The extent to which additional surveillance for endocrine tumors, employing biochemical and/or radiographic methods, should be used can be debated since evidence for their
efficacy in improving outcomes is not strong [1,41]. Nevertheless, some published guidelines have opted for pointing the clinician to a more aggressive screening protocol for
MEN1-associated risks beginning at very early ages [1,38]. A 2012 paper, for example, while acknowledging weaknesses in available supporting data, suggested routine annual
measurement of serum calcium, parathyroid hormone (PTH), gastrin, fasting glucose, insulin, insulin-like growth factor-1 (IGF-1), prolactin, and chromogranin-A, starting in
childhood and continuing for life. Imaging tests (magnetic resonance imaging [MRI] of the pituitary and MRI/computed tomography [CT] scan/endoscopic ultrasound (EUS) to
evaluate for enteropancreatic tumors) were suggested every one to three years [1]. Others have recommended more limited biochemical testing and somewhat different imaging
approaches [9,41].

We believe that cost-effectiveness and risk-benefit considerations (including those related to diagnostic radiation exposure) can be taken into account in determining the
prospective preclinical surveillance program of an individual with MEN1 or a family member at risk, beyond the maintenance of disease-focused clinical vigilance. For example,
annual measurement of serum calcium offers the opportunity to inexpensively detect asymptomatic hyperparathyroidism, which might be treated surgically. Other combinations of
biochemical and imaging surveillance, including those in published protocols, can reasonably be used but are not mandatory given the absence of support by high-quality evidence
[1]. New advances in treatment could dramatically alter these recommendations; for example, a future demonstration that an aggressive surgical approach to gastrinoma clearly
improves disease-related mortality would provide a rationale for intensive biochemical and anatomic screening, which is capable of detecting gastrointestinal or pancreatic disease
in asymptomatic family members [11].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See
"Society guideline links: Multiple endocrine neoplasia type 1" and "Society guideline links: Pancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

● Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant predisposition to tumors of the parathyroid glands, anterior pituitary, and enteropancreatic endocrine
cells. MEN1 is defined as the presence of two of the three main MEN1 tumor types, or in family members of a patient with a clinical diagnosis of MEN1, the occurrence of one
of the MEN1-associated tumors (table 1). (See 'Definition of MEN1' above.)

● In most cases, multiple parathyroid tumors causing primary hyperparathyroidism are the initial manifestation of MEN1, displaying almost 100 percent penetrance by age 40 to
50 years (table 1). Similar to sporadic adenomas causing primary hyperparathyroidism, the majority of patients are asymptomatic or minimally symptomatic, and
hypercalcemia is detected by routine biochemical screening. The biochemical diagnosis of primary hyperparathyroidism is based, as it is in all patients with primary
hyperparathyroidism, upon the demonstration of hypercalcemia with inappropriately high serum parathyroid hormone (PTH) concentrations. (See 'Primary
hyperparathyroidism' above.)

● The most common type of pituitary adenoma in MEN1 is a lactotroph adenoma, but somatotroph, corticotroph, gonadotroph, and clinically nonfunctioning adenomas can also
occur. The approach to diagnosis and therapy of pituitary adenomas in patients with MEN1 is similar to that in patients with sporadic adenomas. (See 'Pituitary adenomas'
above and "Causes, presentation, and evaluation of sellar masses", section on 'Evaluation of a sellar mass'.)

● Functioning pancreatic islet cell or gastrointestinal endocrine cell tumors become clinically apparent in approximately one-third of patients with MEN1. The most common
cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome (ZES) (table 1). (See 'Pancreatic islet cell/gastrointestinal tumors' above.)

● DNA testing for MEN1 gene mutations is available commercially and can provide valuable information in specific situations, although its results generally do not dictate use of
a major intervention established to improve morbidity or mortality. We make determinations regarding MEN1 DNA testing on a case-by-case basis, but discussions with patient
and genetic counselor more often than not lead to pursuit of such testing. Biochemical screening (ie, serum calcium) of family members can be considered as a less costly
alternative to genetic screening, given the high penetrance of primary hyperparathyroidism in MEN1, although its negative predictive value at younger ages is limited. (See
'MEN1 mutational analysis' above and 'Screening of family members in MEN1 kindreds' above.)

● We carefully monitor all patients with MEN1, known MEN1 mutation carriers, and at-risk family members with unknown carrier status for symptoms or signs of MEN1-
associated tumors, such as nephrolithiasis, amenorrhea (women), galactorrhea, erectile dysfunction (men), peptic ulcer disease, diarrhea, and neuroglycopenic or
sympathoadrenal symptoms from hypoglycemia. We typically measure serum calcium, PTH, and prolactin annually to detect asymptomatic hyperparathyroidism and
prolactinoma, respectively. Often, we perform additional surveillance using biochemical and imaging modalities. Others routinely use more aggressive screening protocols for
MEN1-associated risks, beginning at very early ages. Differences in approaches to surveillance in large part relate to the poor quality of supportive evidence in this area. (See
'Screening for MEN1-associated tumors' above.)

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GRAPHICS

Expressions of MEN1 with estimated penetrance (in parentheses) at age 40 years

Endocrine features Nonendocrine features

Primary hyperparathyroidism (90%) Lipomas (30%)

Entero-pancreatic tumor (30 to 70%) Facial angiofibromas (85%)

Gastrinoma (30 to 40%) Collagenomas (70%)

Insulinoma (10%)

NF* including pancreatic polypeptide (20 to 55% ¶ ) Rare, maybe innate, endocrine or nonendocrine features

Other: glucagonoma, VIPoma, somatostatinoma, etc (2%)

Foregut carcinoid

Thymic carcinoid NF (2%) Pheochromocytoma (<1%)

Bronchial carcinoid NF (2%) Ependymoma (1%)

Gastric enterochromaffin-like tumor NF (10%)

Anterior pituitary tumor adenoma (30 to 40%)

Prolactinoma (20%)

Other: GH + PRL, GH, NF (each 5%)

ACTH (2%), TSH (rare)

Adrenal cortical tumor NF (40 percent)

MEN1: multiple endocrine neoplasia type 1; NF: nonfunctioning; GH: growth hormone; PRL: prolactin; ACTH: corticotropin; TSH: thyroid-stimulating hormone.
* May synthesize a peptide hormone or other factors (such as small amine) but does not usually oversecrete enough to produce a hormonal expression.
¶ Omits nearly 100% prevalence of NF and clinically silent tumors, some of which are detected incidental to pancreatico-duodenal surgery in MEN1.

Reproduced with permission from: Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86:5658. Copyright © 2001 The
Endocrine Society.
Updated using:
1. Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg 2006; 243:265.
2. Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg 2006; 30:643.
3. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012; 97:2990.

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Zollinger-Ellison syndrome: Appearance of gastric ulcers

on upper GI series

Upper GI series performed in a patient with intractable epigastric pain

demonstrates severe manifestations of Zollinger-Ellison syndrome with three
different-sized ulcers (arrows) in the wall of the stomach. The patient had a high
fasting serum gastrin concentration consistent with Zollinger-Ellison syndrome
and a small duodenal wall gastrinoma was identified at surgery.

GI: gastrointestinal.

Courtesy of Jonathan Kruskal, MD, PhD.

Graphic 57632 Version 5.0

Normal upper GI series

Normal air-contrast upper GI study showing normal gastric folds and small
intestinal anatomy, and no masses.

GI: gastrointestinal.

Courtesy of Paul C Schroy III, MD.

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Features of MEN1 versus RET germline mutation tests

Test feature MEN1 gene RET gene

Information to patient and clinician Yes Yes

Guides intervention to prevent cancer No Yes

Guides intervention to cure cancer No Yes

Recommended for child Maybe* Yes

Chromosomal locus of gene 11q13 10cen ¶

Mutation type to cause tumor Inactivate Activate

Genotype/phenotype correlation No Yes

Mutation test shortcuts No Yes

False-negative rate 10 to 20% 2 to 5%

MEN1: multiple endocrine neoplasia type 1.

* Use in child depends partly on philosophy about using a nonessential genetic test in a subject that is not old enough to make an important long-term decision.
¶ 10 cen, chromosome 10, centromeric region.

Reproduced with permission from: Brandi, ML, Gagel, RF, Angeli, A, et al. Consensus: Guidelines for diagnosis and therapy of MEN type 2. J Clin Endocrinol Metab 2001; 86:5668. Copyright © 2001 the
Endocrine Society.

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Contributor Disclosures
Andrew Arnold, MD Nothing to disclose Marc K Drezner, MD Nothing to disclose Jean E Mulder, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through
requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

Conflict of interest policy

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