Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis

INTRODUCTION — 

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant predisposition to tumors of the parathyroid glands (which occur in the large majority of patients by age 50 years), anterior pituitary, and enteropancreatic endocrine cells; hence, the mnemonic device of the "3 Ps" (table 1) [1]. However, the clinical spectrum of this disorder has been expanded (figure 1). The duodenum is a common site of tumors (gastrinomas) in these patients, and many other tumor types are more common than in the general population (ie, bronchial and thymic neuroendocrine tumors (NETs), gastric carcinoid tumors, adrenal adenomas, cutaneous tumors [angiofibromas, collagenomas], adipose tissue tumors [lipomas, hibernomas], smooth muscle tumors [leiomyomas] and central nervous system [CNS] tumors [meningiomas, ependymomas]) [2,3]. The recognition of MEN1 is important as individuals who inherit a pathogenic variant in the MEN1 gene may be at risk of considerable morbidity and premature mortality due to MEN1-associated tumors. Indeed, previous studies have indicated that life expectancy in patients with MEN1 was reduced by 15 years compared with control populations, although outcomes have improved over time [4]. The risks of malignant disease related to functioning and nonfunctioning gastropancreatic NETs and, less frequently, to thymic NETs are leading causes of premature mortality in patients with MEN1.

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: Genetics" and "Multiple endocrine neoplasia type 1: Management" 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 (table 1) [1,5]. MEN1 also includes a predisposition to gastrinomas in the duodenum, bronchopulmonary and thymic neuroendocrine tumors (NETs), gastric NETs, adrenal tumors (primarily adenomas but occasionally carcinoma), angiofibromas, lipomas, and other tumors (figure 1). (See 'MEN1 tumors' below.)

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 (figure 1). It should be noted that these are clinical definitions and do not necessarily indicate that a pathogenic variant of the MEN1 gene (ie, a "mutation") will be identifiable or responsible (see "Multiple endocrine neoplasia type 1: Genetics"). In addition, for diagnosis of MEN1, there are situations where genetic criteria can be used. (See 'Diagnosis' below.)

MEN1 TUMORS — 

The clinical presentation of patients with multiple endocrine neoplasia type 1 (MEN1) is determined by the site and spectrum of tumor development and/or consequences of hormonal hypersecretion. Although MEN1-associated tumor development is unusual in early childhood (ie, <5 years of age), tumor penetrance progressively increases with age such that 20 to 70 percent of patients with MEN1 have evidence of at least one MEN1-associated tumor by the age of 18 to 21 years. Almost all patients will develop biochemical or clinical evidence of primary hyperparathyroidism by the fifth decade. Furthermore, almost all patients with MEN1 undergo at least one operation related to MEN1-associated tumors in their lifetime [4]. The increased use and improved sensitivity of surveillance imaging modalities has resulted in higher estimates of penetrance of several of the other MEN1-associated tumors (eg, pituitary adenomas, gastropancreatic neuroendocrine tumors (NETs), bronchial NETs), although in some instances tumors may remain subclinical and without clinical sequelae (eg, small nonfunctioning pituitary adenomas).

Primary hyperparathyroidism — Multiple parathyroid tumors causing hyperparathyroidism are the most common manifestation of MEN1, displaying almost 100 percent penetrance overall and at least 75 percent penetrance by age 50 years (figure 2) [1,5,6]. Primary hyperparathyroidism is typically the initial manifestation of MEN1 (eg, in 75 to 90 percent of patients), although clinical presentations are unusual before the age of 10 years. MEN1 accounts for a small proportion of the overall burden of primary hyperparathyroidism, but the possibility of MEN1 should be considered in patients who present at a young age (eg, <40 years of age), those with a past medical history or family history of relevant MEN1-associated tumor(s), and in those with multigland parathyroid disease. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Diagnostic evaluation'.)

●MEN1 versus sporadic form – Primary hyperparathyroidism in the setting of familial MEN1 has a number of different features from the common sporadic (nonfamilial) form of the disease [1,7]:

•An equal male-to-female ratio is observed in MEN1 in contrast to the female predominance in sporadic hyperparathyroidism.

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

•Multigland disease is typical in MEN1 and, given sufficient time, perhaps universal. Although all parathyroid glands are typically involved in MEN1, the emergence of clinically apparent parathyroid tumor development/hyperplasia may be asymmetric with different pathophysiological trajectories between glands. 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 [8]; 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: Management".)

●Signs and symptoms – Similar to sporadic primary hyperparathyroidism, the majority of patients are asymptomatic or minimally symptomatic, and hypercalcemia is detected by routine or surveillance-driven 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). Some studies have reported that MEN1-associated primary hyperparathyroidism is associated with a greater reduction in bone mineral density than sporadic hyperparathyroidism, as well as more significant damage to cancellous bone microarchitecture as assessed by trabeculae bone score [9,10]. Kidney stones are observed frequently in MEN1-associated hyperparathyroidism, and a higher incidence of chronic kidney disease has been reported compared with the general population [9]. The biochemical diagnosis of primary hyperparathyroidism is based, as it is in other patients, on the demonstration of hypercalcemia with inappropriately high serum parathyroid hormone (PTH) concentrations.

Parathyroid carcinoma, typically presenting with severe hypercalcemia, is extremely rare in MEN1. (See "Primary hyperparathyroidism: Clinical manifestations" and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

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

Pituitary adenomas have been reported in approximately 15 to 50 percent of patients with MEN1 and may be the first manifestation of disease in 10 to 20 percent of patients with MEN1 (figure 2) [11]. In one study of patients presenting with pituitary macroadenomas <30 years of age, approximately 3 percent had a pathogenic variant in the MEN1 gene [12].

Prevalence and age-related penetrance — Large cohort series report a prevalence of pituitary tumors in patients with MEN1 of approximately 35 to 50 percent, although frequency is influenced by median age of the studied cohort [13-15]. Tumors typically present in early adulthood and likely have a female predominance. Pituitary tumors are rarely observed in early childhood (ie, <10 years of age) but are not an infrequent finding in the second decade of life. For example, in a study of 160 children with manifestations of MEN1 presenting before the age of 21 years, approximately 35 percent had evidence of a pituitary adenoma.

Pituitary tumor size and subtypes — The majority of pituitary adenomas in MEN1 are microadenomas (approximately 60 to 70 percent). The most common subtypes of pituitary adenoma are prolactinomas (approximately 40 to 45 percent) and nonfunctioning adenomas (approximately 35 to 40 percent). Other secretory subtypes (eg, somatotroph, corticotroph, gonadotroph adenomas) occur but at lower frequency (ie, each <10 percent of cases). In contrast to earlier reports, more recent studies indicate that prolactinomas respond well to dopamine agonist therapy. Most pituitary tumors, particularly nonfunctioning microadenomas, follow an indolent course and only rarely demonstrate aggressive behavior. Pituitary carcinoma is extremely rare in patients with MEN1. Pituitary tumors are often detected by surveillance imaging, including nonfunctioning microadenomas that only occasionally grow during short- to medium-term follow-up and are frequently without clinical consequence [14]. Whether routine and lifelong surveillance by imaging decreases morbidity from pituitary disease in MEN1 remains unknown.

Pancreatic islet cell/gastrointestinal endocrine tumors — Duodenopancreatic neuroendocrine tumors (NETs) may be the presenting feature of MEN1 in 10 to 20 percent of patients. Marked heterogeneity in tumor subtypes is evident; functioning and nonfunctioning tumors may be present and may coexist synchronously or asynchronously. While functioning tumors typically present with clinical features, nonfunctioning tumors are most commonly asymptomatic and detected on surveillance imaging. Tumor behavior exhibits marked variability, and although many pancreatic NETs display indolent growth rates, approximately 10 to 30 percent of clinically apparent NETs develop distant metastases (eg, approximateley15 to 20 percent for nonfunctioning pancreatic NETs and 15 to 25 percent for gastrinoma) [9,16]. Although some prognostic markers are available (eg, tumor size, grade, rate of growth for nonfunctioning tumors), improving risk stratification remains a priority for the field. The diagnosis and evaluation of MEN1-associated duodenopancreatic NETs requires a multidisciplinary approach.

●Malignant potential – The malignant potential of enteropancreatic NETs is now the primary life-threatening manifestation of MEN1. This is because effective treatment is usually available for the hyperparathyroidism and pituitary disease in MEN1. However, subclinical presentation of enteropancreatic NETs is more common; anatomic and/or intensive biochemical studies demonstrate evidence of duodenopancreatic tumors in up to 80 percent of patients with MEN1 (figure 1).

●Functioning tumors – Functioning pancreatic islet cell or gastrointestinal endocrine cell tumors become clinically apparent in one-third to two-thirds of patients with MEN1 (figure 2). The most common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome (ZES), leading to multiple peptic ulcers or diarrhea. (See 'Zollinger-Ellison syndrome' below.)

An estimated 60 percent of patients with MEN1 have either ZES or asymptomatic elevation in serum gastrin concentrations, and MEN1 is present in approximately 25 percent of patients with ZES [17,18]. Symptomatic insulinomas also occur with moderate frequency, while vasoactive intestinal peptide-secreting tumors (VIPomas) and glucagonomas are rare. (See "Clinical presentation, diagnosis, and management of VIPoma" and "Glucagonoma and the glucagonoma syndrome".)

●Nonfunctioning tumors – The prevalence of radiographically confirmed, nonfunctioning tumors is similar to that of gastrinomas, ranging from 30 to 80 percent [19-22]. Like hormonally active enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic NETs may be malignant and capable of causing liver metastases. Nonfunctioning tumors now represent the leading cause of premature mortality in MEN1. (See 'Nonfunctioning pancreatic tumors' below.)

●Diagnosis and localization – The diagnosis and localization of MEN1-associated pancreatic tumors may be confounded by the presence of multiple synchronous tumors, and one cannot assume that a tumor visualized on imaging studies represents the source of any coexisting pancreatic hormone excess (eg, gastrin, insulin). For example, it is likely that patients previously identified with one or more pancreatic lesions assumed to be gastrinomas may instead have had nonfunctioning pancreatic lesions with coexistent microscopic duodenal gastrinomas. Likewise, in those patients with evidence of metastatic disease, it cannot be assumed that the largest observable pancreatic tumor represents the source of metastases.

Zollinger-Ellison syndrome

●Biological features – Gastrin-secreting tumors are reported in approximately 20 to 60 percent of patients with MEN1. In contrast to sporadically occurring gastrinomas, the gastrinomas in MEN1 patients are frequently multifocal and often exceedingly small, with most (>90 percent) occurring within the duodenum [17,23,24]. In MEN1, tumors in the pancreas do not usually secrete gastrin [17]. Gastrinomas in MEN1 usually present in adulthood with a typical age of onset of 30 to 50 years while earlier presentations (ie, in children, persons <21 years of age) are uncommon. Therefore, it is rarely the presenting feature of MEN1 (<10 percent of cases). A previous history of Helicobacter pylori infection is reported to be associated with an increased prevalence and severity of hypergastrinemia.

●Mortality – The risk of death from malignant spread of MEN1-associated gastrinoma appears to be less than that for sporadic gastrinoma. However, local lymph node metastases are reported in up to 70 to 80 percent of patients with MEN1 with clinically apparent gastrinoma(s)/ZES. However, the presence of such local lymph node involvement is not necessarily associated with an adverse prognosis or a high likelihood of clinically important metastases (eg, hepatic metastases) [25]. However, approximately 15 to 25 percent of patients with ZES manifest an aggressive disease course with the development of distant metastases [9,16]. The reported 5- and 10-year survival of patients with MEN1-associated gastrinoma in a recent study was reported to be approximately 80 and 65 percent, respectively, with reduced survival observed in those with gastrin levels >20 times the upper limit of normal, a coexisting pancreatic tumor >2 cm, and/or presence of liver metastases or multiple synchronous tumors [26].

●When to suspect – Hypersecretion of gastrin in ZES in MEN1 may be suspected clinically by the presence of multiple peptic ulcers (image 1) or symptoms like diarrhea or steatorrhea. The diagnosis is confirmed by the same biochemical and gastric acid output criteria as are used in the sporadic cases [25,27,28] (see "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis"). However, the diagnosis of gastrinoma can be challenging, and other causes of hypergastrinemia need to be considered. Several imaging modalities (eg, endoscopic ultrasound, computed tomography [CT], magnetic resonance imaging [MRI], somatostatin receptor scintigraphy [SSRS]) may be used to localize the gastrinoma(s), although many tumors will remain occult due to their small size and duodenal location. Imaging also may identify coexisting (frequently nonfunctioning) pancreatic NETs. 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 [29].

●Associated Cushing syndrome – The incidence of Cushing syndrome has been reported to be increased in patients with ZES. When Cushing 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 syndrome usually have a corticotroph adenoma of the pituitary and relatively mild symptoms of cortisol excess [30].

Insulinoma — Insulin-producing pancreatic islet cell adenomas in MEN1 are often small and solitary but may be multiple in up to 30 percent of patients, and they can occur throughout the pancreas. Coexisting, nonfunctioning pancreatic tumors may be observed. Insulinoma in MEN1 is reported in 10 to 30 percent of patients and 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]. Insulinoma may present in children and young persons with MEN1 and is the first presentation of disease in 10 percent of patients. 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. Localization/regionalization of insulinoma is important to guide surgical treatment and, as for sporadic insulinoma, may require a range of imaging approaches and/or use of other regionalization techniques. (See "Insulinoma".)

Other functioning pancreatic NETs — Glucagonomas (ie, glucagon-secreting pancreatic neuroendocrine tumors [NETs]) occur in a low percentage (<5 percent) of patients with MEN1. However, some nonfunctioning pancreatic NETs may either stain for glucagon or lead to modest elevations in plasma glucagon levels without any associated clinical features. The classical clinical features of glucagonomas (eg, anemia, stomatitis, weight loss and necrolytic migratory erythema) may be absent, although patients may have glucose intolerance. VIPomas have been reported in only a few patients with MEN1. VIPomas are associated with the development of watery diarrhea, hypokalemia, and achlorhydria. MEN1-associated growth hormone-releasing hormone (GHRH) secreting tumors (ie, GHRHomas) and somatostatin secreting tumors have been reported very rarely.

Nonfunctioning pancreatic tumors

●Clinical features – Pancreatic NETs 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 [31]. Like hormonally active enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic NETs may be malignant and can metastasize to the liver.

Microscopic pancreatic NETs develop almost universally in patients with MEN1, but clinically detectable nonfunctioning tumors are reported in 30 to 60 percent of patients. Nonfunctioning pancreatic NETs have been detected as early as ages 12 to 14 years in asymptomatic children with MEN1 [32,33] with an estimated penetrance of 20 percent by approximately 20 years of age. Most tumors are detected through surveillance imaging and are only rarely associated with symptoms (ie, relating to local mass effects).

Nonfunctioning pancreatic tumors represent the leading cause of premature mortality in MEN1 [34]. However, distinguishing nonfunctioning tumors that follow an aggressive disease course from those with more indolent behavior remains a challenge. No reliable biomarkers allow the accurate prediction of disease course, and recommendations for intervention are primarily based on tumor size, as increased rates of metastases are reported with larger tumors (>2 to 3 cm). Other potential adverse prognostic markers include higher tumor growth rates on serial imaging, increased tumor grade (≥2), high Ki67 index, and higher uptake values on ¹⁸F-fludeoxyglucose-positron emission tomography (FDG-PET)/CT. Patients with MEN1 with truncating/deleterious pathogenic MEN1 variants occurring in exons 2, 9, or 10 may have a higher risk of metastatic pancreatic NETs and benefit from closer surveillance and follow-up. However, none of these genotype-phenotype associations are proven unequivocally and therefore do not typically guide patient management [35].

In a report of 579 patients with MEN1, 108 patients with isolated nonfunctioning pancreatic NETs were identified with the following clinical characteristics and course [20]:

•The penetrance of nonfunctioning pancreatic NETs 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 NETs was similar to that for gastrinoma patients (69 to 70 years) and shorter than that for patients without pancreatic tumors (77 years).

●Diagnosis and localization – The diagnosis of nonfunctioning tumors is primarily based on imaging, although the optimal schedule for the detection, characterization, and follow-up of nonfunctioning pancreatic NETs remains uncertain. Decisions regarding use of conventional and molecular/functional imaging should account for the clinical context and also the cumulative ionizing radiation dose, particularly when serial imaging is required.

Existing blood-based tumor markers such as chromogranin A, pancreatic polypeptide, and glucagon appear to have low diagnostic utility. Although multiple imaging modalities are available for the detection of nonfunctioning pancreatic tumors, their optimal use remains to be defined. Pancreatic MRI is often used for periodic surveillance of asymptomatic patients without known pancreatic tumors because it does not expose patients to ionizing radiation. Both MRI and CT have good sensitivity for tumors >1 cm. Once nonfunctioning tumors are identified, additional staging and/or tumor characterization/risk stratification may employ other imaging techniques including functional imagining (eg, somatostatin receptor [SSTR] PET/CT). Some experts have advocated use of SSTR PET/CT as part of the surveillance schedule of patients with MEN1 [36,37].

Limited data suggest that endoscopic ultrasound (EUS) has better sensitivity for detecting nonfunctioning tumors (particularly small tumors) compared with other cross-sectional imaging modalities (eg, CT scanning), and a combination of MRI plus EUS has been recommended by some experts [5,33]. However, EUS may miss tumors in the pancreatic tail, while the value of detecting small (<1 cm), nonfunctioning tumors remains uncertain SSTR (PET)/CT scanning may have especially high sensitivity for detecting NETs in MEN1, at times leading to a change in management [38]. One study reported that SSTR PET/CT was equivalent to MRI but superior to CT for the detection of pancreatic NETs in patients with MEN1 but frequently added additional benefit over conventional imaging for assessing lymph node or distant metastases [39]. A further study in 58 patients with MEN1 in whom SSTR PET/CT was used as a screening tool or to characterize known pancreatic NETs reported that SSTR PET/CT detected three times as many pancreatic tumors as conventional imaging and changed management in nearly one-half of patients. Furthermore, in patients with MEN1 in whom SSTR PET/CT was negative, no pancreatic NETS were identified by conventional imaging during 38 months of follow-up [40]. 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 NETs in MEN1 [41]. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Diagnostic and staging evaluation'.)

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

Thymic and bronchopulmonary NETs

●Thymic NETs – Thymic neuroendocrine tumors (NETs; formerly known as thymic carcinoid tumors) occur with increased frequency in MEN1 (2.6 to 8 percent in retrospective series of patients with MEN1) and typically run an aggressive disease course, such that they account for up to 20 percent of MEN1-related deaths, with an overall 10-year survival of approximately 30 percent [9,42]. Thymic NETs occur mostly in adult males (median age of onset approximately 40 to 45 years), although the male predominance is reported to be less pronounced in Asian cohorts (compared with those of European descent) [42-44]. Cigarette smoking may be a risk factor [43].

Thymic NETs, the most common cause of anterior mediastinal masses in MEN1, are typically nonfunctional (in contrast to the substantial incidence of ectopic Cushing syndrome in patients with sporadic thymic carcinoid) and tend to be aggressive, with approximately 50 percent of patients having metastases at diagnosis. (See "Thymic neuroendocrine neoplasms", section on 'Clinical presentation'.)

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 SRS) reported the following results [45]:

•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.

A subsequent study evaluating 294 patients with pathogenic germline variants in MEN1 identified thymic tumors in 14 patients including 12 with thymic NETs and 2 with thymomas [46]. The majority of tumors demonstrated loss of heterozygosity at the MEN1 locus, although transcriptome analysis demonstrated that the thymic NETs had a molecular signature distinct from thymomas and normal thymic tissue [47].

Some have recommended regular screening for thymics NETs by chest imaging studies in patients with MEN1 [1,42,43]. Given the rarity of these tumors and the unproven survival benefits of this approach, we consider such routine surveillance reasonable but not mandatory and should be discussed with the patient. Targeting surveillance to those at highest risk (eg, males aged >30 years, cigarette use, positive family history of MEN1-associated thymic NETs) may be appropriate. If surveillance imaging is performed, chest MRI or low-dose CT scanning every one to three years has been suggested. Certainly, it seems prudent to strongly advise males with definite or possible MEN1 against smoking, to take into consideration a strong family history of thymic tumors, and to perform prophylactic thymectomy in patients undergoing parathyroidectomy, although even this measure does not fully prevent subsequent development of thymic neoplasia [44,48]. One guideline has suggested preventative total thymectomy (ideally using a minimally invasive approach) in male patients with MEN1 aged >30 years in whom at least one family member has had a thymic NET [15]. Evaluation is always warranted in patients with any symptoms suggestive of thymic NET including new chest pain, cough, shortness of breath or features suggestive of superior vena cava (SVC) obstruction. (See "Multiple endocrine neoplasia type 1: Management".)

●Bronchopulmonary NETs – Bronchopulmonary NETs were previously considered rare tumors in MEN1 (histologically proven tumors occurring in <5 percent of patients with MEN1) with a female preponderance. However, the increased use of thoracic imaging in patients with MEN1 has demonstrated that bronchopulmonary NETs (based on suggestive radiologic appearances) are likely to occur in at least 20 to 30 percent of patients with MEN1 with equal sex distribution [9,46,49,50].

Most tumors are small and hormonally inactive, and many patients remain asymptomatic. Symptoms may include cough, hemoptysis, or shortness of breath, and such symptoms should be investigated promptly. Onset is typically in adulthood, and some patients harbor multiple/bilateral tumors. Although the majority of tumors assessed histologically have features of well-differentiated typical and atypical carcinoid tumors, a small proportion are malignant, including large cell and small cell lung NETs, and may occasionally be associated with a rapidly progressive disease course [50]. However, the majority of MEN1-associated bronchopulmonary NETs (which are reported to represent a distinct entity from their sporadic counterparts) are reported to run an indolent course with low growth rates (approximately 6 percent per year) and excellent long-term survival with low numbers of directly attributable deaths [46].

Given the generally favorable outcomes of those with bronchopulmonary NETs, the value of undertaking periodic thoracic surveillance imaging of asymptomatic "at-risk" patients (ie, those harboring pathogenic MEN1 variants) remains uncertain, and the risks (eg, exposure to potentially high cumulative doses of ionizing radiation if employing CT scanning) and possible benefits should be discussed with the patient to allow a fully informed decision to be made. When surveillance imaging is performed, low-dose thoracic CT or MRI is suggested.

Gastric NETs/gastric "carcinoids" — "Type 2" Gastric neuroendocrine tumors (NETs) and ECL cell proliferation (a precursor lesion of gastric carcinoid) occur with substantial frequency in patients with MEN1 and ZES. They typically occur as small lesions in the gastric fundus or body and may be multiple [51]. In a prospective study of 57 patients with MEN1 and ZES, advanced ECL cell proliferation and gastric NETs (ie, ECLomas) were detected in 53 and 23 percent, respectively [52]. 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 NETs. Another study of 38 patients with MEN1 reported a lower frequency of ECL tumors occurring in only 2 out of 16 patients with ZES, although approximately 60 percent demonstrated some ECL hyperplasia [53]. Such patients may benefit from regular monitoring for gastric NETs. (See "Clinical characteristics of well-differentiated neuroendocrine tumors arising in the gastrointestinal and genitourinary tracts", section on 'Stomach' and "Multiple endocrine neoplasia type 1: Management".)

Adrenal tumors — Adrenal tumors are reported to occur in 20 to 60 percent of patients with MEN1, although the majority are small and clinically nonfunctioning. A minority of patients have hormone-secreting tumors (approximately 15 percent of those with adrenal tumors), which may result in primary hyperaldosteronism, ACTH-independent Cushing syndrome, or hyperandrogenism. Pheochromocytoma is rarely observed in MEN1. Adrenocortical carcinoma is also only rarely reported (approximately 1 percent of patients with MEN1) but should be considered based on imaging characteristics, tumor size, and growth rates. The investigation and diagnosis of adrenal tumors in MEN1 does not differ from that of their sporadic counterparts [54,55]. (See "Diagnosis of primary aldosteronism" and "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approach to initial evaluation' and "Establishing the cause of Cushing syndrome".)

Additional MEN1-associated tumors — Cutaneous tumors are common in multiple endocrine neoplasia type 1 (MEN1) (figure 1) [1,5,56]; 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 [57]:

●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 [58].

Similarly, the presence of angiofibromas or collagenomas can be helpful clinically in suggesting the diagnosis of MEN1 in selected patients with primary hyperparathyroidism. Melanoma has also been reported in patients with MEN1 [5], but this association and potential menin-related pathogenesis require further investigation. Adipose tissue tumors (ie, lipomas, hibernomas) and smooth muscle tumors (ie, leiomyomas) are also observed [2].

Central nervous system (CNS) tumors including meningioma and ependymomas have been reported in patients with MEN1, although whether these are part of the MEN1 tumor spectrum remains uncertain [2,3].

Breast cancer — The risk of breast cancer in female patients with MEN1 has been reported to be almost double, and with earlier mean onset, compared with the general population [59,60]. Early screening (eg, beginning at age 40) has been suggested by some experts, but evidence for effectiveness remains to be demonstrated.

MEN1 in children — Several cohort studies have focused on the clinical expression of multiple endocrine neoplasia type 1 (MEN1) in children and young persons, in part reflecting recommendations suggesting periodic clinical, biochemical, and radiologic surveillance in this age group. Taken together, these heterogeneous studies indicate that 20 to 70 percent of children and young persons with MEN1 manifest clinical, biochemical, or radiologic abnormalities by the age of 18 to 21 years [9,33,61,62].

Primary hyperparathyroidism is the most frequently encountered manifestation during childhood, while 20 to 40 percent of children and young persons (ie, < 18 to 21 years of age) expressing manifestations of MEN1-associated tumors have pancreatic and or pituitary tumors (both functioning and nonfunctioning tumors). The high prevalence of tumors emphasizes the importance of regular clinical assessment (eg, history, examination) to establish the presence of symptoms or signs suggestive of clinically important tumors. The value of periodic biochemical and radiologic surveillance in otherwise asymptomatic children remains uncertain. While malignant presentations are rare in this age group, clinically important nonfunctioning pancreatic tumors (ie, >1 to 2 cm) are reported in the second decade of life, prompting some experts to commence radiologic screening between 12 to 16 years of age. (See 'Monitoring for MEN1-associated tumors' below.)

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 pathogenic MEN1 variant 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 radiologic abnormalities associated with tumor development. (See 'Genetic testing' below and 'Index patient' below and 'Family members' below.)

Establishing a timely diagnosis of MEN1 requires a high index of suspicion and is frequently delayed. Thus, the possibility of MEN1 should be considered in all patients presenting with any of the associated endocrine tumors. Undertaking a full clinical history and examination together with establishing any relevant family history may alert the clinician to an underlying unifying diagnosis. There should be a particularly high suspicion of MEN1 in patients presenting with endocrine tumors (eg, primary hyperparathyroidism, insulinoma) at a young age, in those with synchronous or asynchronous presentations of multiple tumors affecting the same or different endocrine tissues, and in those presenting with relevant clinical features with a family history of tumors in the MEN1 spectrum.

Given the complexity of decision-making and specialized skills needed in the diagnosis, management, and treatment of MEN1, it is strongly recommended that this be done in centers with established multidisciplinary teams experienced in the care of patients with MEN1.

GENETIC TESTING

Potential benefits — The optimal role of genetic testing in multiple endocrine neoplasia type 1 (MEN1) is not clear, as there is a lack of high-quality data to demonstrate that preclinical detection of MEN1-related tumors leads to interventions that improve morbidity or mortality. Despite this lack of evidence, it seems likely that identifying those at risk of MEN1-associated tumors (ie, pathogenic MEN1 variant carriers) and earlier tumor detection may improve outcomes. Thus, MEN1 genetic testing is generally recommended in settings where an increased likelihood of MEN1 is suspected. Country-specific guidance and indications for testing have been established [1,63]. In addition, the increased availability and application of genetic testing in the clinical setting and falling deoxyribonucleic acid (DNA) sequencing costs have removed some of the previous barriers to genetic testing.

Direct DNA testing for pathogenic variants in the MEN1 gene is available in academic and commercial laboratories (ie, Genetic Testing Registry). Generally speaking, DNA testing can have utility in several linked ways, including [63,64]:

●Confirming the clinical diagnosis of the syndrome in a proband

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

●Determining whether or not asymptomatic or other relatives of a proband carry the specific pathogenic MEN1 variant

●Prenatal/preimplantation genetic testing

Based upon these potential benefits, guidelines from an international group of endocrinologists recommend offering germline MEN1 genetic testing to [1]: any index patient with clinical MEN1 (two or more primary MEN1 tumor types); all first-degree relatives of known pathogenic MEN1 variant carriers irrespective of whether they express any clinical manifestations of MEN1 or remain asymptomatic; and individuals with clinical features suspicious for MEN1 (eg, early-onset and/or multigland parathyroid disease, gastrinoma or multiple pancreatic NETs) or atypical MEN1 presentations (eg, hyperparathyroidism with adrenal tumor). However, the specific indications for MEN1 genetic testing may vary between regions and are often determined by the comprehensive regional/national genetic testing guidelines.

An estimated 5 to 30 percent of patients with a clinical diagnosis of MEN1 (eg, ≥2 MEN1-associated tumors) do not harbor a pathogenic MEN1 variant. Some of these patients may have disruption to the MEN1 gene not detected by DNA testing methods (eg, noncoding variants) or alternate hereditary syndromes (eg, MEN4), and some patients may represent the chance occurrence of two sporadic tumors (eg, parathyroid and pituitary adenoma). Patient cohorts with a clinical diagnosis of MEN1 but no detectable pathogenic MEN1 variant appear to have a different clinical disease course, as they develop clinical features at an older age, do not develop a third tumor type, and have normal life-expectancy [9,65,66]. Establishing that such individuals do not harbor a detectable pathogenic MEN1 variant is not definitive but is helpful in assessing risk to first-degree relatives.

Pretest genetic counseling — Pretest genetic counseling should discuss the implications of a "positive" (identifying a pathogenic MEN1 variant and confirming a genetic diagnosis of MEN1) or "negative" (no pathogenic MEN1 variant identified) test result. This should include the potential implications of a positive result for other family members (and the mechanisms for such information to be shared). Consent for genetic testing should also cover the potential for uncertain tests results (eg, variants of uncertain significance) that can lead to diagnostic confusion for both patient and clinician. (See "Genetic counseling: Family history interpretation and risk assessment".)

Index patient — We consider it reasonable to consider MEN1 genetic testing in:

●All possible index cases (ie, ≥2 of the main MEN1-associated endocrine tumors).

●Patients with atypical MEN1 presentations (ie, ≥1 MEN1-related endocrine tumors and ≥1 nonendocrine MEN1-related tumor).

●Patients presenting with at least one MEN1-associated endocrine tumor and a first-degree relative with an MEN1-associated tumor.

●Patients with multigland parathyroid disease (adenomas and/or hyperplasia) presenting at a young age (eg, <35 years).

●Patients with early-onset relevant endocrine tumors (eg, pituitary adenomas or insulinoma (eg, <20 years of age).

We make determinations regarding MEN1 DNA testing on a case-by-case basis, but discussions with the patient and genetic counselor often lead to pursuit of such testing. Beyond assessing whether detection of a pathogenic MEN1 variant 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 for the prospective surveillance for MEN1-related tumors in the proband and family. (See 'Family members' below and 'Monitoring for MEN1-associated tumors' below.)

The likelihood that a patient with MEN1 clinical features harbors an underlying MEN1 pathogenic variant can be estimated based on the spectrum of clinical features and presence or absence of family history. For example, while a pathogenic MEN1 variant 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 [67]. Approximately 10 percent of kindreds with familial isolated hyperparathyroidism have a detectable MEN1 pathogenic variant, and yields can be even lower when less stringent criteria are selected, such as sporadic isolated hyperparathyroidism with age under 40 years [68].

Importantly, a "negative" result (ie, no pathogenic MEN1 variant detected) does not rule out the diagnosis of MEN1 nor the possibility that unidentified pathologic disruption of the MEN1 gene is responsible. Genetic testing for MEN1 should include techniques to detect structural variants including partial or whole MEN1 gene deletions and have sufficient depth of sequencing coverage of the MEN1 gene to detect mosaicism. DNA sequencing costs have generally dropped and are usually covered by insurance in the United States.

Family members

Whom to test — We discuss DNA testing with the index patient and appropriate family members (eg, first-degree relatives of the affected individual) and individualize testing decisions. Involvement of a genetic counselor can be very helpful. Full informed consent must be obtained for each individual to be tested. (See 'Pretest genetic counseling' above.)

We generally recommend genetic testing of potential index cases, as well as predictive genetic testing of "at risk" family members (eg, first-degree relatives of those with a known pathogenic MEN1 variant). In general, the primary purpose of such predictive testing is that it can guide clinical surveillance of at-risk individuals in an attempt to prevent disease-related morbidity and mortality. Although there is a lack of strong evidence that early, preclinical detection of MEN1-associated tumors reduces overall morbidity or mortality in MEN1 in many settings, benefit seems likely. Establishing the genetic status of relatives may also be helpful in other ways (eg, aiding reproductive decision-making). The optimal age for predictive genetic testing has not been established. Some advocate genetic testing early in childhood (ie, <5 years of age) due to the potential for early-onset tumors, while others suggest this can be deferred until the individual is able to decide for themselves whether to undergo testing. Delays in identifying affected family members of a MEN1 proband may result in potentially avoidable morbidity and mortality [69].

Genetic testing approach — Potential index cases undergoing genetic testing require high-fidelity DNA sequence analysis of the MEN1 gene, usually from a sample of peripheral blood or buccal cells. This is typically performed using next-generation DNA sequencing methodology, and testing of the MEN1 gene may be part of a wider disease-targeted gene panel. Analysis should also allow the detection of structural variants including whole or partial MEN1 gene deletions. If gene sequencing identifies a pathogenic MEN1 variant in the affected patient, the presence of this family-specific variant can then be determined in at-risk relatives.

●Pathogenic MEN1 variant not identified – A significant potential benefit of such testing is the identification of family members who do not have the familial MEN1 variant and therefore do not need regular surveillance. Nonetheless, technical issues rarely can confound the results of genetic testing [70]. (See 'Monitoring for MEN1-associated tumors' below.)

●Pathogenic MEN1 variant identified – The presence of the MEN1 variant in an asymptomatic family member does not usually indicate the need for immediate intervention but facilitates the introduction of regular surveillance for tumor detection (eg, assessment of symptoms, signs, biochemical/imaging tests). It is also possible that asymptomatic individuals' knowledge that they carry the MEN1 gene may increase compliance with surveillance visits and testing. (See 'Monitoring for MEN1-associated tumors' below.)

One potential barrier to genetic testing in asymptomatic relatives may stem from concerns over the possible implications of a "positive" genetic test on the ability to obtain health-related insurance or other financial products and possible implications for future employment. Although several countries have legislation in place that attempts to avoid such genetic discrimination based on the outcome of predictive genetic testing (eg, Genetic Information Nondiscrimination Act [GINA] of 2008 in the United States), this can remain a potential concern. Approaches to DNA testing and screening can vary in different nations.

Finally, knowledge of a family's specific MEN1 variant 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 variant [71].

Alternatives to DNA screening — If predictive DNA testing is not employed for asymptomatic family members in known or suspected MEN1 kindreds (eg, declined by kindred members), "at risk" individuals should be offered regular clinical review to assess for the possibility of tumor development and discuss the extent of surveillance. One low-cost option to determine the likelihood of MEN1 in an "at risk" individual is measurement of serum calcium with parathyroid hormone [11] given the high penetrance of hyperparathyroidism in MEN1.The presence of angiofibromas or collagenomas can also be useful in this context.

MONITORING FOR MEN1-ASSOCIATED TUMORS — 

For patients with a clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1), known pathogenic MEN1 variant carriers, and family members whose risk has not been eliminated by DNA testing, we monitor for MEN1-associated tumors as follows:

●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 commence regular clinical review in early childhood given the potential for early-onset tumor development.

●We typically measure serum calcium, parathyroid hormone (PTH), and prolactin annually to detect asymptomatic hyperparathyroidism and prolactinoma, respectively. The specific age to begin biochemical monitoring is not established, but it is often commenced in children or young persons.

●We tend more towards conservatism in the frequency of 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 [34]. We try to individualize surveillance protocols to minimize lifetime radiation exposure, particularly in younger individuals.

•Typically, we initially perform baseline imaging studies for enteropancreatic and pituitary neoplasia, favoring modalities and subsequent intervals that minimize radiation exposure (eg, endoscopic ultrasound [EUS], MRI). For the detection of enteropancreatic tumors, we typically perform a follow-up study one or two years later. Decisions regarding the possible benefits of imaging for thymic and bronchopulmonary neuroendocrine tumors (NETs) are more nuanced (eg, taking into account patient-specific factors such as sex, age, family history of thymic tumors) and should be fully discussed with the patient.

•If tumors are identified on surveillance imaging, their subsequent management should be determined as described elsewhere (see "Multiple endocrine neoplasia type 1: Management"). If surveillance indicates that the patient remains tumor free, ongoing annual clinical and biochemical assessment is recommended, while the interval between imaging modalities individualized based on joint discussion between the clinician and patient. For example, in individuals who remain asymptomatic and tumor-free, we typically suggest enteropancreatic imaging every two to three years and pituitary imaging every three to five years.

The specific strategy for biochemical and radiologic surveillance can be debated since evidence for improving outcomes is not strong [1,72]. 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 [1,67]. A 2012 paper, for example, while acknowledging weaknesses in available supporting data, suggested routine annual measurement of serum calcium, 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 (MRI of the pituitary and MRI/CT scan/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 [14,34,72].

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 [1,34].

However, it is also important to bear in mind that the main purpose of screening should be the detection of clinically important manifestations either requiring immediate treatment or closer monitoring. For example, almost all patients with MEN1 will develop multiple small, nonfunctioning pancreatic NETs (eg, 0.5 to 5 mm), but their detection using highly sensitive imaging modalities is generally unlikely to alter treatment decisions or patient prognosis. Thus, the surveillance approach will also be reasonably informed by one's criteria for intervention for MEN1-associated tumors (eg, use of tumor size criteria in the decision to operate on enteropancreatic endocrine tumors) (see "Multiple endocrine neoplasia type 1: Management", section on 'Pancreatic islet cell/gastrointestinal tumors'). 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 [19].

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: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

●General principles – Multiple endocrine neoplasia type 1 (MEN1) is a rare heritable (autosomal dominant) disorder classically characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells. Given the complexity of decision-making and specialized skills needed in the diagnosis, monitoring, and treatment of MEN1, it is strongly advised that patients are evaluated and managed in centers with established multidisciplinary teams experienced in the care of patients with MEN1. (See 'Definition of MEN1' above.)

●MEN1 diagnosis – The clinical diagnosis of 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 (figure 1). (See 'Diagnosis' above.)

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 pathogenic MEN1 variant 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 biochemical or radiologic abnormalities associated with tumor development. (See 'Genetic testing' above.)

●Primary hyperparathyroidism – Primary hyperparathyroidism, which occurs as a consequence of variably sized tumor development in all parathyroid glands, is most frequently the initial manifestation of MEN1 and is observed in the large majority of patients by age 50 years (figure 2). Similar to sporadic adenomas causing primary hyperparathyroidism, most patients are asymptomatic or minimally symptomatic, and hypercalcemia is detected by routine (or surveillance-based) 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.)

●Pituitary adenomas – The most common type of pituitary adenoma in MEN1 are lactotroph and nonfunctioning adenomas, but somatotroph, corticotroph, gonadotroph adenomas can also occur (figure 1). 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'.)

●Pancreatic islet cell/gastrointestinal endocrine tumors

•Functioning tumors – Functioning pancreatic islet cell or gastrointestinal endocrine tumors become clinically apparent in approximately one-third of patients with MEN1 (figure 2). The most common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome (ZES) (figure 1), although insulinoma may occur at a young age and can be the first clinical presentation of MEN1. (See 'Pancreatic islet cell/gastrointestinal endocrine tumors' above.)

•Nonfunctioning tumors – Nonfunctioning pancreatic tumors are now recognized as the most common pancreatic tumor type in MEN1 and are responsible for considerable morbidity and premature mortality. The detection of clinically relevant nonfunctioning pancreatic tumors is usually dependent on one of several imaging techniques as sensitive blood-based tumor markers are not currently available. The optimal use of the respective conventional and functional/molecular imaging modalities for tumor detection and surveillance has not been established. (See 'Pancreatic islet cell/gastrointestinal endocrine tumors' above.)

●Genetic testing – DNA testing for a pathogenic variant of the MEN1 gene is widely available through accredited genetic testing laboratories and is typically recommended for potential index MEN1 cases, as well as for predictive testing of "at risk" relatives of individuals with a known a pathogenic MEN1 variant. However, the decision to undertake genetic testing in these settings should be fully discussed with the individual and requires informed consent. Genetic counseling is critical, particularly for predictive testing in asymptomatic individuals. For those declining genetic testing or in those kindreds without a detectable pathogenic MEN1 variant, regular clinical and/or biochemical/radiologic assessment may alert the clinician to the onset of relevant tumors. (See 'Genetic testing' above and 'Index patient' above and 'Family members' above.)

●Monitoring for MEN-1 associated tumors – We carefully monitor all patients with MEN1, known pathogenic MEN1 variant carriers, and at-risk family members with unknown carrier status for symptoms or signs of MEN1-associated tumors, such as nephrolithiasis, amenorrhea (females), galactorrhea, erectile dysfunction (males), 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 typically perform additional, periodic biochemical and radiologic surveillance although the specific strategy is tailored to the individual based on patient preferences with the goal of minimizing the potential for iatrogenic harms (eg, from high cumulative doses of ionizing radiation). 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 'Monitoring for MEN1-associated tumors' above.)