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 bronchial and thymic neuroendocrine tumors, gastric carcinoid tumors, adrenal adenomas, and lipomas are more common than in the general population.

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 [1,2]. MEN1 also includes a predisposition to gastrinomas in the duodenum, bronchopulmonary and thymic neuroendocrine tumors, gastric carcinoids, adrenal adenomas (occasionally carcinomas), angiofibromas, lipomas, and other tumors (figure 1). (See 'Clinical manifestations' 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.)

CLINICAL MANIFESTATIONS

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) [1-3]. In most cases, it is the initial manifestation of MEN1, although clinical presentations are unusual before the age of 10 years. 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] and probably much closer to the lower end of this range [4].

Primary hyperparathyroidism in the setting of familial MEN1 has a number of different features from the common sporadic (non-familial) form of the disease [1,5]:

●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 [6]; 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".)

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). 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 — 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) [7] and 42 percent in a multicenter study of 324 MEN1 patients (figure 2) [8]. The pathologic prevalence in one series was over 60 percent [9]. Pituitary tumors have been reported to be the first manifestation of MEN1 in 13 percent of patients [10]. The range of pituitary cell types 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 (figure 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 [7,11]. 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 [12].

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 [8]:

●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 six years), showed that such screening primarily detected nonfunctioning microadenomas that grew only occasionally and without clinical consequence; detected prolactinomas responded well to medical treatment [13].

Thus, it seems likely that functioning and nonfunctioning pituitary microadenomas represent the most common type of pituitary abnormality in MEN1, and they are frequently detected on routine biochemical and/or radiologic surveillance with macroadenomas accounting for 25 to 35 percent of tumors.

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 are similar to that in patients with sporadic adenomas. (See "Causes, presentation, and evaluation of sellar masses", section on 'Pituitary adenomas'.)

Pancreatic islet cell/gastrointestinal endocrine tumors — Effective treatment is usually available for the hyperparathyroidism and pituitary disease in MEN1; as a result, the malignant potential of enteropancreatic neuroendocrine tumors (NETs) is now the primary life-threatening manifestation of MEN1. However, subclinical involvement is more common; anatomic or intensive biochemical studies reveal evidence of enteropancreatic 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). 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 approximately 25 percent of patients with ZES [14,15]. Symptomatic insulinomas also occur with moderate frequency, while VIPomas and glucagonomas are rare. (See "VIPoma: Clinical manifestations, diagnosis, and management" 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 [16-19]. 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.)

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 — Historically, attempts at surgical cure of the hypergastrinemia in ZES in patients with MEN1 were uniformly unsuccessful. It is now apparent that 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 [14,20,21]; in comparison, in MEN1, the tumors that are found in the pancreas do not usually secrete gastrin [14]. Gastrinomas in MEN1 usually present in adulthood with a typical age of onset of 30 to 50 years. A previous history of H. pylori infection is reported to be associated with an increased prevalence and severity of hypergastrinemia.

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, reported in up to 80 percent of patients but are not necessarily associated with a poor prognosis or a high likelihood that clinically important metastases will occur [22]. 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 [23].

In one large series, investigators at the National Institutes of Health (NIH) prospectively followed 107 patients with MEN1 and ZES and reviewed 1009 cases from the literature [24]. 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 only 8 percent of patients with MEN1/ZES if careful testing was done.

●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 [22,25,26] (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 [27].

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 [28].

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 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 [29]. Like hormonally active enteropancreatic tumors in MEN1, clinically "nonfunctioning" pancreatic neuroendocrine tumors may be malignant and can metastasize to the liver. Nonfunctioning pancreatic NETs have been detected as early as ages 12 to 14 in asymptomatic children with MEN1 [30,31].

Nonfunctioning pancreatic NETs are among the most common tumor of the pancreaticoduodenal region in patients with MEN1 [16-19]. In a report of 579 MEN1 patients, 108 patients with isolated nonfunctioning pancreatic NETs were identified with the following clinical characteristics and course [17]:

●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).

The recognition of nonfunctioning pancreatic tumors is important as they now represent the leading cause of premature mortality in MEN1 [32]. The risk of metastases is reported to be associated with tumor size, such that attempts to diagnose such tumors should focus on detecting those most likely to be clinically relevant. However, the best way to detect these nonfunctioning tumors is unclear. Assays for tumor markers like chromogranin A have low sensitivity [33,34]. 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 [2,31]. ⁶⁸Gallium-DOTATATE positron emission tomography (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 [35]. Such sensitive imaging methods increase detection of indolent tumors as well as potentially aggressive lesions. In a retrospective study, ¹⁸F-fludeoxyglucose (FDG) PET/CT imaging was useful for predicting the malignant potential of pancreatic NETs in MEN1 [36]. The methods used for tumor detection should account for the ionizing radiation dose, particularly when serial imaging is being performed. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Imaging studies for disease localization'.)

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 neuroendocrine tumors

●Thymic NETs – Thymic 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 [37,38]. 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) [38-40]. Heavy smoking may be a risk factor [39].

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 (carcinoid) tumors", 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 somatostatin receptor scintigraphy [SRS]) reported the following results [41]:

•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 [42]. 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 [43].

Some have recommended regular screening, by chest imaging studies, for this tumor in males with MEN1 [1,38,39]. Given the rarity of these tumors and the unproven survival benefits of this approach, we consider such routine surveillance reasonable but not mandatory. 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 [40,44]. (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 MEN1 patients) with a female preponderance. However, the increased use of thoracic imaging in MEN1 patients has demonstrated that bronchopulmonary NETs (based on suggestive radiologic appearances) are likely to occur in at least 20 to 30 percent of MEN1 patients with equal sex distribution [37,42,45,46].

Most tumors are small and hormonally inactive, and many patients remain asymptomatic. 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 be associated with a rapidly progressive disease-course [46]. 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 very low numbers of directly attributable deaths [42].

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) and possible benefits should be discussed with the patient to allow a fully informed decision to be made.

Gastric carcinoids — Gastric carcinoids and ECL cell proliferation (a precursor lesion of gastric carcinoid) occur with substantial frequency in patients with MEN1 and ZES. In a prospective study of 57 patients with MEN1 and ZES, advanced ECL cell proliferation and gastric carcinoid (ie, ECLomas) were detected in 53 and 23 percent, respectively [47]. 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. 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 [48]. Such patients may benefit from regular monitoring for gastric carcinoid. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Stomach' and "Multiple endocrine neoplasia type 1: Management".)

Adrenal tumors — Adrenocortical tumors are reported to occur in 20 to 75 percent of MEN1 patients, although the majority are small and clinically nonfunctioning. A minority of patients have hormone-secreting tumors, with primary hyperaldosteronism or ACTH-independent Cushing syndrome most commonly observed. Presentations with adrenocortical carcinoma (approximately 1 percent of MEN1 patients) or pheochromocytoma are only very occasionally reported. The investigation and diagnosis of adrenal tumors in MEN1 does not differ from that of their sporadic counterparts [49]. (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", section on 'Primary adrenal CS (suppressed ACTH)'.)

Cutaneous tumors — Cutaneous tumors are common in MEN1 (figure 1) [1,2,50]; 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 [51]:

●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 [24].

Similarly, the presence of angiofibromas or collagenomas can be helpful clinically in suggesting the diagnosis of MEN1 in selected patients with primary hyperparathyroidism. Melanoma and hibernoma have also been reported in MEN1 patients [2], but this association and potential menin-related pathogenesis require further investigation.

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 [52,53]. Early screening (eg, beginning at age 40) has been reasonably suggested, but evidence for effectiveness remains to be demonstrated.

MEN1 in children — Several cohort studies have focused on the clinical expression of 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 [31,37,54,55].

Primary hyperparathyroidism is the most frequently encountered manifestation during childhood, although pituitary and pancreatic tumors are reported in 20 to 40 percent of patients (comprising 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 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 radiologic abnormalities associated with tumor development. (See 'Genetic testing' below and 'Index patient' below and 'Family members in MEN1 kindreds' 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 clinical to an underlying unifying diagnosis. There should be a particularly high suspicion of MEN1 in patients presenting with endocrine tumors at a young age (eg, primary hyperparathyroidism, insulinoma) or in those with synchronous or asynchronous presentations of multiple tumors affecting the same or different endocrine tissues.

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 MEN1 patients.

GENETIC TESTING

Potential benefits — The optimal role of genetic testing in the context of multiple endocrine neoplasia type 1 (MEN1) is not clear cut, 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 [1,56]. However, 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.

Although the decision to undertake genetic testing should be carefully considered and fully discussed with the patient, it is generally recommended in patients considered to be at high risk of MEN1. (See 'Index patient' below and 'Family members in MEN1 kindreds' below.)

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 [56,57]:

●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

●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 irrespective of whether they express any clinical manifestations of MEN1 or remain asymptomatic

●Individuals with suspicious or atypical MEN1 (eg, early-onset [<30 years] and or multiple parathyroid tumors, gastrinoma, or multiple pancreatic neuroendocrine tumors)

It is estimated that 5 to 30 percent of patients with a clinical diagnosis of MEN1 (eg, ≥2 MEN1-associated tumors) do not harbor a pathogenic MEN1 variant, and although 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), some patients may represent the chance occurrence of two sporadic tumors (eg, parathyroid and pituitary adenoma). It is notable that patient cohorts with a clinical diagnosis of MEN1 but no detectable MEN1 mutation, are reported to run a different clinical course, developing clinical features at an older age, not developing a third tumor type, and have normal life-expectancy [37,58,59]. 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. 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 — DNA testing for MEN1 has been proposed in different clinical settings (eg, patients presenting with a clinical diagnosis of MEN1 [two or more MEN1-associated tumors], atypical expressions of possible MEN1, early onset primary hyperparathyroidism with multigland involvement, or in patients presenting with MEN1-associated endocrine tumors who have a relevant family history).

We make determinations regarding MEN1 DNA testing on a case-by-case basis, but discussions with the patient and genetic counselor more often than not lead to pursuit of such testing. 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 'Family members in MEN1 kindreds' below and 'Monitoring for MEN1-associated tumors' below.)

DNA testing can be particularly useful when the diagnosis of MEN1 is unable to be clearly established on clinical grounds. Examples may include some patients with a suggestive family history who present with isolated primary hyperparathyroidism [56] 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: Management".)

The likelihood that a patient with MEN1 clinical features harbors an underlying MEN1 mutation can be estimated based on the spectrum of clinical features and presence or absence of family history. 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 [60]. 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 [61].

It is also important to recognize that 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. Current genetic testing for MEN1 should include techniques to detect structural variants including partial or whole gene deletions. DNA sequencing costs have generally dropped but can remain substantial in some settings (and are variably covered by insurance in the United States).

Family members in MEN1 kindreds

Whom to test — 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. (See 'Pretest genetic counseling' above.)

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. The optimal age to being screening has not been established. Some advocate starting early in childhood (ie, <5 years of age), while others suggest this can be deferred until the individual is able to decide for themselves whether to undergo testing. It is reported that delays in identifying affected family members of a MEN1 proband may result in potentially avoidable morbidity and mortality [62].

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 pathogenic variant, the presence or absence of this family-specific mutation 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 mutation and therefore do not need regular surveillance (keeping in mind that technical issues can rarely confound the results of genetic testing [63]). 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 'Monitoring for MEN1-associated tumors' below.)

●Pathogenic MEN1 variant identified – The presence of the MEN1 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/imaging tests) on these individuals. It is possible that asymptomatic individuals' knowledge that they definitely carry the MEN1 disease 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 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 [64].

Alternative to DNA screening — If DNA testing is not employed for screening asymptomatic family members in known or suspected MEN1 kindreds, one low-cost option is measurement of serum calcium [7]. 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.

MONITORING FOR MEN1-ASSOCIATED TUMORS — For patients with MEN1, known MEN1 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 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 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 [32]. We try to individualize surveillance protocols to minimize lifetime radiation exposure, particularly in younger individuals.

•Often we will initially perform baseline imaging studies for enteropancreatic and pituitary neoplasia, favoring modalities and subsequent intervals that minimize radiation exposure (eg, endoscopic ultrasound [EUS], MRI), with a follow-up study one or two years later, and address factors like patient anxiety. Decisions regarding the possible benefits of imaging for thymic and bronchopulmonary neuroendocrine tumors (NETs) are more nuanced 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.

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 [1,65]. 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 [1,60]. 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 [13,32,65].

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 [1,32].

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 MEN1 patients 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 potential 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 [16].

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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●General principles – 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. 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 MEN1 patients. (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 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 radiologic abnormalities associated with tumor development. (See 'Genetic testing' above.)

●Primary hyperparathyroidism – In most cases, multiple parathyroid tumors causing primary hyperparathyroidism are the initial manifestation of MEN1, and they are found 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 is a lactotroph adenoma, but somatotroph, corticotroph, gonadotroph, and clinically nonfunctioning 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 imagining techniques as sensitive blood-based tumor markers are not currently available. (See 'Pancreatic islet cell/gastrointestinal endocrine tumors' above.)

●Genetic testing – DNA testing for a pathogenic variant of the MEN1 gene 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. For those declining genetic testing or in those kindreds without a detectable MEN1 mutation, 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 in MEN1 kindreds' above.)

●Monitoring for MEN-1 associated tumors – 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 (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. 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 'Monitoring for MEN1-associated tumors' above.)