Version July 2025
INTRODUCTION —
This monograph summarizes the interpretation of germline genetic testing of MEN1, the major gene associated with the syndrome multiple endocrine neoplasia type 1 (MEN1).
Indications for testing, clinical evaluation, tumor testing, and management of MEN1 are discussed in detail separately [1]. (See 'Information about MEN1' below.)
Interpretation of genetic testing for RET, the disease gene for MEN2, is also discussed separately. (See "Gene test interpretation: RET (multiple endocrine neoplasia type 2 gene)".)
MEN1 gene — MEN1 encodes the tumor suppressor menin, a scaffold protein in histone modification and epigenetic gene regulation [2]. It is thought to regulate several pathways and processes by altering chromatin structure.
Over 1000 MEN1 pathogenic variants that inactivate or disrupt menin function have been detected.
Transmission is autosomal dominant; heterozygosity for a germline pathogenic variant in the MEN1 gene results in MEN1 with high penetrance that increases with age (figure 1). Somatic and germline mosaicism have been reported; this may make the interpretation of genetic testing results challenging and require specialist discussion.
In 10 percent of MEN1 patients, the MEN1 pathogenic variant arises de novo rather than being inherited. Thus, a negative family history cannot be used to exclude the diagnosis (algorithm 1). (See "Multiple endocrine neoplasia type 1: Genetics", section on 'Genetics'.)
Consistent with tumor suppressor function, MEN1-associated tumors typically demonstrate biallelic inactivation of MEN1 (the germline MEN1 variant plus somatic inactivation of the wild-type MEN1 allele). Loss of heterozygosity is frequently observed in MEN1 tumors.
How to read the report — Confirm the result applies to the tested individual and determine whether testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory); if this is not the case, testing should be repeated in a certified laboratory.
The table summarizes these and other caveats (table 1).
Disease associations
Overview of MEN1 — MEN1 confers predisposition to the following tumors (table 2 and figure 2) [3]:
●Parathyroid adenomas or hyperplasia
●Anterior pituitary adenomas, which may be clinically functioning (lactotroph, somatotroph adenomas) or nonfunctioning
●Pancreatic neuroendocrine tumors (NETs; functioning or nonfunctioning)
●Gastrinomas in the duodenum
●Bronchopulmonary and thymic NETs
●Gastric NETs
●Adrenal adenomas (functioning or nonfunctioning), occasionally carcinomas
●Angiofibromas
●Lipomas
●Leiomyomas
●Hibernomas
●Collagenomas
●Central nervous system tumors including meningiomas and spinal cord ependymomas
●Breast cancer (twofold to threefold increased risk)
Diagnosis may be clinical and/or genetic:
●Clinical diagnosis – Two or more of the main endocrine components of MEN1 (parathyroid, pituitary, duodenal-pancreatic endocrine tumors), with or without a pathogenic variant in MEN1.
or-
One of the main components of MEN1 in a relative of a patient with a clinical diagnosis of MEN1.
●Genetic diagnosis – A pathogenic variant in MEN1, with or without associated clinical features (algorithm 1). This situation most frequently arises following predictive genetic testing of relatives of an affected individual.
Details are discussed separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
Primary hyperparathyroidism — Multiple parathyroid tumors causing primary hyperparathyroidism and hypercalcemia are the most common (and often the first) manifestation of MEN1 (figure 1); they occur in nearly all patients by age 50 years. Most patients are asymptomatic or minimally symptomatic. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Primary hyperparathyroidism'.)
Pituitary adenomas — The most common pituitary adenoma in MEN1 is a lactotroph adenoma, followed by clinically nonfunctioning adenomas. Somatotroph, corticotroph, and gonadotroph adenomas can also occur. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Pituitary adenomas'.)
Duodeno-pancreatic neuroendocrine tumors — Enteropancreatic NETs are found in up to 80 percent of patients. They may have malignant potential and are responsible for considerable morbidity and premature mortality. Functioning and nonfunctioning pancreatic NETs may coexist in the same patient.
●Nonfunctioning tumors – Nonfunctioning pancreatic tumors are the most common MEN1 pancreatic tumor and the leading cause of premature mortality in MEN1. They are typically asymptomatic (unless large and causing local mass effect) and are usually identified on pancreatic imaging (magnetic resonance imaging [MRI], computed tomography [CT], endoscopic ultrasound [EUS], or somatostatin receptor scintigraphy [SSRS]). (See 'Monitoring for MEN1 tumors' below and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)
●Functioning tumors – Functioning duodeno-pancreatic NETs become symptomatic in approximately one-third to two-thirds of patients with MEN1, most commonly as Zollinger-Ellison syndrome (ZES) due to duodenal gastrinoma(s). Insulinoma may occur at a young age and can be the first manifestation of MEN1. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Pancreatic islet cell/gastrointestinal endocrine tumors'.)
Other tumors — Additional tumors may include thymic and bronchopulmonary NETs, adrenal tumors, and female breast cancer. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
MANAGEMENT
Individuals with a pathogenic variant in MEN1 — Optimal management for individuals with either a clinical diagnosis of MEN1 or a pathogenic/likely pathogenic variant in MEN1 involves a multidisciplinary team. (See 'Locating an expert' below and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)
Monitoring for MEN1 tumors — Patients with MEN1 (clinical and/or genetic diagnosis), and those for whom increased risk has not been effectively excluded (eg, individuals not wishing to undergo genetic testing for a known familial pathogenic variant in MEN1), can be monitored for MEN1-associated tumors.
The age to initiate monitoring for MEN1 tumors in asymptomatic individuals (eg, children with normal growth) is controversial and should be individualized based on discussion between the family/caregivers and MEN1 team. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)
Clinical assessment — Annual visits with patient education for symptoms or signs attributable to MEN1-associated tumors, including:
●Primary hyperparathyroidism – Thirst, polyuria, symptoms of nephrolithiasis.
●Pituitary adenomas – Amenorrhea, galactorrhea, erectile dysfunction, abnormal growth, Cushing syndrome, acromegaly, headaches, visual field changes.
●Duodeno-pancreatic neuroendocrine tumors (NETs) – Indigestion/heartburn, diarrhea, weight loss, peptic ulcer disease, neuroglycopenic or sympathoadrenal symptoms from hypoglycemia.
●Other tumors/manifestations – Chest pain, cough, wheeze, dyspnea, hemoptysis (relating to thymic and bronchial NETs), skin changes, breast lumps.
Biochemical testing — In symptomatic or asymptomatic patients, annual screening for:
●Primary hyperparathyroidism – Serum calcium and parathyroid hormone (PTH)
●Prolactinoma – Serum prolactin
Additional biochemical and radiologic investigations are recommended to evaluate other symptoms depending on specific clinical features.
The specific age to begin biochemical monitoring is not established; it is often started in childhood or in young adulthood.
Surveillance imaging — Baseline imaging studies for enteropancreatic and pituitary neoplasia, favoring intervals and modalities that minimize radiation exposure (MRI, endoscopic ultrasound [EUS]).
The optimal age to commence surveillance imaging and choice of surveillance strategy in asymptomatic children is debated and should be discussed with the individual and/or their parents or guardians.
Decisions regarding the possible benefits of imaging for thymic and bronchopulmonary NETs in asymptomatic MEN1 patients are more nuanced and should be fully discussed with the patient.
Typically, surveillance imaging for pancreatic NETs is suggested every two to three years and pituitary tumors every three to five years (although some advocate more frequent imaging).
Any relevant symptoms or signs should be investigated promptly. (See 'Clinical assessment' above.)
Treatment of MEN1-associated tumors
The treatment of MEN1-associated tumors is outlined in detail separately. (See "Multiple endocrine neoplasia type 1: Management".)
●Parathyroid tumors – The indications for parathyroidectomy are similar to those in patients with sporadic adenomas causing primary hyperparathyroidism and include symptomatic hypercalcemia, nephrolithiasis, and evidence of bone disease, such as diminished bone density or fracture. For asymptomatic or minimally symptomatic hyperparathyroidism, surgery or observation is used; declining kidney function may favor surgery. (See "Multiple endocrine neoplasia type 1: Management", section on 'Parathyroid tumors'.)
For patients with MEN1 and indications for initial parathyroidectomy, subtotal parathyroidectomy (3.5 glands) is generally preferred. Cervical thymectomy is also generally performed.
Medical management may be an option for individuals who cannot undergo surgery. (See "Multiple endocrine neoplasia type 1: Management", section on 'Medical management'.)
●Pituitary adenomas – Pituitary adenomas in patients with MEN1 are managed the same as sporadic pituitary adenomas. (See "Multiple endocrine neoplasia type 1: Management", section on 'Pituitary adenomas'.)
●Enteropancreatic neuroendocrine tumors (NETs)
•Zollinger-Ellison syndrome (ZES) – Active ZES in MEN1 is treated primarily by proton pump inhibitor (PPI) therapy. The role of duodenal-pancreatic surgery to prevent distant metastatic disease is uncertain and requires ongoing study; it may be beneficial in some patients. (See "Multiple endocrine neoplasia type 1: Management", section on 'Pancreatic islet cell/gastrointestinal tumors'.)
•Insulinoma – Surgery is indicated for MEN1-associated insulinoma. The approach is tailored to the tumor site(s) and presence of other nonfunctioning pancreatic tumors. (See "Multiple endocrine neoplasia type 1: Management", section on 'Insulinoma'.)
•Nonfunctioning pancreatic NETs – Surgery is generally indicated for MEN1-associated nonfunctioning pancreatic NETs ≥2 cm and tumors 1 to 2 cm considered at higher risk of progression (rapid growth on serial imaging or higher-grade tumors). Most small nonfunctioning tumors (<1 cm) have an indolent course with low growth rates such that surveillance is often appropriate. (See "Multiple endocrine neoplasia type 1: Management", section on 'Clinically nonfunctional pancreatic neuroendocrine tumors'.)
●Other MEN1-associated tumors – Management of adrenal tumors and thymic, bronchopulmonary, and gastric NETs is discussed separately. (See "Multiple endocrine neoplasia type 1: Management".)
Individuals with no pathogenic MEN1 variant identified — Management depends on the clinical setting and pretest probability of disease.
●Known familial variant – The absence of a known familial pathogenic MEN1 variant essentially excludes MEN1, with caveats noted above. (See 'How to read the report' above.)
If there is a strong suspicion of MEN1 despite absence of the familial variant (possible false negative result), further discussion with the genetics laboratory may be indicated [4].
●Familial variant unknown – If MEN1 is suspected and a familial variant has not been characterized, then negative testing of MEN1 does not exclude MEN1. Consultation with a genetics expert and MEN1 team is advised to determine next steps (gene panel for other genes such as CDKN1B, the disease gene for MEN4), MEN1 noncoding variants, structural variants such as deletions, or germline mosaicism. (See "Multiple endocrine neoplasia type 1: Genetics", section on 'Other genes'.)
Clinical and biochemical assessment and surveillance imaging for MEN1-related tumors can be performed if there is deemed to be an ongoing or uncertain risk. (See 'Monitoring for MEN1 tumors' above and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Genetic testing'.)
●Variant of uncertain significance (VUS) – A variant is classified by the laboratory as a VUS when there is insufficient evidence to facilitate classification as pathogenic or benign.
Additional information should be sought, such as:
•Genetic testing of affected relatives to determine if the variant cosegregates with phenotype.
•Testing of parental deoxyribonucleic acid (DNA) samples to determine if the variant has arisen de novo.
•Additional clinical data from the patient (eg, analysis of tumor samples for evidence of loss of heterozygosity (LOH) or a somatic pathogenic variant within MEN1).
These approaches require multidisciplinary discussion between clinical and genetic teams in partnership with the patient [5]. Ultimately, VUS reclassification is the remit of the testing laboratory, but it may be initiated or facilitated by physician input.
Multidisciplinary discussion may help guide future management. Decision‐making and management of the patient and relatives is based on personal and family history of MEN1 manifestations. As additional information becomes available over time, variant reclassification is possible. Physicians should request periodic variant reevaluation.
At-risk relatives
●Whom to test – All first-degree relatives of an individual with a pathogenic variant in MEN1, including parents, should be offered genetic counseling and, at the appropriate time, DNA testing, regardless of clinical findings (algorithm 1). A parent may be affected but undiagnosed. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Family members'.)
Each child of an affected parent has a 50 percent chance of inheriting the MEN1 variant. The optimal timing for testing children is unclear, as discussed separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Family members'.)
●Reproductive testing and counseling – Reproductive counseling should be provided. Some may elect to use donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination" and "Preimplantation genetic testing".)
●Individuals who decline genetic testing – Regular clinical assessment and biochemical surveillance are pursued. Use of surveillance imaging is individualized. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Alternatives to DNA screening'.)
RESOURCES
Information about MEN1
●Genetics – (See "Multiple endocrine neoplasia type 1: Genetics".)
●Diagnosis – (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
●Treatment – (See "Multiple endocrine neoplasia type 1: Management".)
●Guidelines – (See "Society guideline links: Neuroendocrine neoplasms".)
Locating an expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide access to a genetic counselor.
