Gene test interpretation: MEN1 (multiple endocrine neoplasia)

INTRODUCTION — This monograph summarizes the interpretation of germline genetic testing of MEN1, the major gene associated with multiple endocrine neoplasia type 1 (MEN1). Affected individuals are heterozygous for a pathogenic variant in the MEN1 gene. Evaluation and management of MEN1 are discussed in detail separately [1]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors' and "Multiple endocrine neoplasia type 1: Management".)

MEN1 gene — The MEN1 gene encodes menin, a tumor suppressor associated with multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation [2]. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. Over 1000 MEN1 pathogenic variants that inactivate or disrupt menin function have been detected. Inactivation of menin results in loss of tumor suppression.

Transmission is autosomal dominant; heterozygosity for a pathogenic variant in the MEN1 gene results, with high penetrance, in MEN1. MEN1 is caused by a de novo pathogenic variant in 10 percent of patients. Thus, a negative family history cannot be used to exclude the diagnosis. (See "Multiple endocrine neoplasia type 1: Genetics", section on 'Genetics'.)

How to read the report — Confirm that 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. This and other caveats are summarized in the checklist (table 1).

Disease association — MEN1 is characterized by predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells. 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 (table 2 and figure 1). Other associated tumors include angiomyolipomas, spinal cord ependymomas, and a two- to threefold increased risk of breast cancer has been reported. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

The diagnosis of MEN1 may be suspected on clinical grounds and a genetic diagnosis established by DNA testing that identifies a pathogenic (or likely pathogenic) variant in the MEN1 gene. If such an MEN1 variant cannot be identified, the definition of MEN1 allows the diagnosis to be made clinically: as the occurrence of two or more primary MEN1 tumor types (parathyroid, enteropancreatic endocrine, and pituitary tumors), or in family members of a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors. Multiple parathyroid tumors causing primary hyperparathyroidism are the most common component of MEN1, occurring in the large majority of patients by age 50 years, and is the initial manifestation of the disorder in most patients. A diagnosis of MEN1 may also be established in individuals found to harbor a pathogenic MEN1 variant following genetic testing, but who do not yet manifest any clinical features of the disorder (ie, a genetic diagnosis). This situation most frequently arises following predictive genetic testing of "at risk" family members of an affected MEN1 patient who has an established pathogenic MEN1 variant.

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). Most patients are asymptomatic or minimally symptomatic, and hypercalcemia is detected by biochemical screening. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Primary hyperparathyroidism'.)

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. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Pituitary adenomas'.)

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. The most common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome (ZES), although insulinoma may occur at a young age and can be the first clinical presentation of MEN1. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Pancreatic islet cell/gastrointestinal endocrine tumors'.)

●Nonfunctioning tumors – Nonfunctioning pancreatic tumors are 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. (See 'Monitoring for tumors in MEN1' below and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

Other tumors — A number of additional endocrine and nonendocrine tumors may occur in patients harboring pathogenic/likely pathogenic MEN1 variants and include thymic and bronchopulmonary neuroendocrine tumors, adrenal tumors, and an increased relative risk of breast cancer in female individuals. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

MANAGEMENT

Pathogenic variant in MEN1 — Optimal management for individuals with 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 tumors in MEN1 — Patients with MEN1, including those with a clinical and/or genetic diagnosis, and those whose heightened risk has not been effectively eliminated by germline testing, 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 family and the MEN1 team. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

Monitoring consists of the following:

Clinical assessment — Annual clinical visits with patient education 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.

Biochemical testing — Annual measurement of serum calcium, parathyroid hormone (PTH), and prolactin to detect asymptomatic hyperparathyroidism and prolactinoma, respectively. The specific age to begin biochemical monitoring is not established, but it is often commenced in childhood or in young persons.

Surveillance imaging — Baseline imaging studies for enteropancreatic and pituitary neoplasia, favoring modalities and subsequent intervals that minimize radiation exposure (eg, endoscopic ultrasound, magnetic resonance imaging [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 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.

Treatment of MEN1-associated tumors

The treatment of each of the MEN1-associated tumors is outlined in detail separately. (See "Multiple endocrine neoplasia type 1: Management".) In brief:

●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 no therapy can be acceptable alternatives, as they are for patients with sporadic hyperparathyroidism. (See "Multiple endocrine neoplasia type 1: Management", section on 'Parathyroid tumors'.)

For patients with MEN1 and indications for initial parathyroidectomy, subtotal (three and one-half glands) parathyroidectomy is generally preferred. A cervical thymectomy is also generally performed in this setting.

●Pituitary adenomas – Pituitary adenomas in patients with MEN1 are managed in the same way as sporadic pituitary adenomas. (See "Multiple endocrine neoplasia type 1: Management", section on 'Pituitary adenomas'.)

●Enteropancreatic neuroendocrine tumors

•Zollinger-Ellison syndrome – Active Zollinger-Ellison syndrome as part of the MEN1 syndrome is treated primarily by proton pump therapy to limit the clinical manifestations and complications of peptic ulcer disease. The role of duodenal-pancreatic surgery to prevent metastatic disease is uncertain and controversial but could prove beneficial and requires further study. (See "Multiple endocrine neoplasia type 1: Management", section on 'Pancreatic islet cell/gastrointestinal tumors'.)

•Insulinoma – Surgery is indicated for patients with MEN1 and insulinoma. Because patients with MEN1 often have additional pancreatic tumors that may include other insulinomas, local excision of any tumors in the head of the pancreas plus a distal subtotal pancreatectomy is frequently performed. (See "Multiple endocrine neoplasia type 1: Management", section on 'Insulinoma'.)

•Nonfunctioning pancreatic neuroendocrine tumors (NETs) – Surgery is indicated for patients with MEN1 and nonfunctioning pancreatic NETs ≥2 cm or smaller tumors (1 to 2 cm) considered to be at higher risk of progression (eg, rapid growth on serial imaging or higher-grade tumors). The majority of small nonfunctioning tumors (<1 cm) run 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 – The management of other MEN1-associated tumors is discussed in detail separately. (See "Multiple endocrine neoplasia type 1: Management", section on 'Thymic neuroendocrine tumors' and "Multiple endocrine neoplasia type 1: Management", section on 'Bronchopulmonary neuroendocrine tumors' and "Multiple endocrine neoplasia type 1: Management", section on 'Gastric neuroendocrine tumors' and "Multiple endocrine neoplasia type 1: Management", section on 'Adrenal tumors'.)

Variants of uncertain significance or negative genetic testing — Management of individuals with inconclusive or negative genetic testing depends on the likelihood of disease.

●Negative genetic testing for a known familial pathogenic variant – Negative testing for a known familial pathogenic variant in MEN1 very likely excludes MEN1, with caveats noted above (see 'How to read the report' above). However, if there is a strong clinical suspicion of MEN1 in an individual despite the apparent absence of the familial variant, or even in an asymptomatic person, discussion with the accredited genetics laboratory may be indicated to consider genetic testing by an alternate method as there may be very rare occasions where laboratory methodological issues result in a false-negative test result [3].

●Negative genetic testing if the familial variant is unknown – If MEN1 is suspected based on personal or family history and a familial variant has not been characterized, then negative testing of MEN1 cannot be used to exclude the disorder. Consultation with a genetics expert and the MEN1 team is advised to determine the next steps, which may include a gene panel testing for other genes or more extensive testing of MEN1. Some pathogenic variants, eg, in noncoding regions of/near MEN1, could remain undetected by methodology used in commercial testing laboratories. Similarly, somatic and germline mosaicism has been reported in patients with MEN1 and may not be detected by all methods currently used in commercial assays. Also, genetic variants in the MEN1 gene are not responsible for all individuals, or even kindreds, with an MEN1 phenotype. Pathogenic variants in CDKN1B or other CDK inhibitor genes are responsible for a small proportion of patients with MEN1-like phenotypes, sporadic or familial, in the absence of an MEN1 pathogenic variant. (See "Multiple endocrine neoplasia type 1: Genetics", section on 'Other genes'.)

Clinical and biochemical assessment and surveillance imaging can also be performed to detect MEN1-related tumors. (See 'Monitoring for tumors in MEN1' above and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Genetic testing'.)

●Variant of uncertain significance (VUS) – A VUS means the pathogenicity of the variant is inconclusive and the variant has not been determined to be pathogenic or benign. Management is based on personal and family history of MEN1 manifestations. Individuals with a VUS may benefit from consultation with an expert in MEN1 or a genetics expert to assist in determining the pathogenicity of the variant. Where possible, additional steps should be taken to facilitate reclassification of the variant (eg, upgrading to likely pathogenic/pathogenic or downgrading to benign/likely benign status). This may involve a number of additional approaches (eg, genetic testing of additional affected family members, genetic testing of parents) and frequently requires multidisciplinary discussion between clinical and genetic teams in partnership with the patient [4].

First-degree relatives

●Timing of genetic testing – MEN1 is autosomal dominant. All first-degree relatives of an individual with a pathogenic variant in MEN1 should be offered genetic counseling and, at the appropriate time, DNA testing for the variant irrespective of whether they express any clinical manifestations of MEN1 or remain asymptomatic. The parents of the proband should be offered testing if future childbearing is possible. It is possible that a parent may be affected but undiagnosed. It is also possible that the affected individual has a de novo pathogenic variant and the parent may be unaffected. In addition, somatic and germline mosaicism have been reported in MEN1, which may make interpretation of genetic test results more challenging and may require specialist discussion. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Family members in MEN1 kindreds'.)

Each child of an affected parent has a 50 percent chance of inheriting the MEN1 variant and being at risk for developing MEN1. The optimal age for genetic testing has not been established. Some advocate starting early in childhood (ie, <5 years of age), as clinical manifestations are occasionally reported in young children, while others suggest this can be deferred until a later time point (eg >12 years, or even to the age of majority), thereby allowing the child/young person to be better involved in the decision-making process with regard to genetic testing, or to even make the decision for themselves. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Family members in MEN1 kindreds'.)

Reproductive counseling should be provided to discuss reproductive options. Some may elect to conceive using 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 – For those declining genetic testing or in those kindreds without a detectable MEN1 mutation, regular clinical assessment and biochemical surveillance (eg, for primary hyperparathyroidism) should be pursued. The decision as to whether to undertake any surveillance imaging in this setting should be guided by discussion with the patient together with the information from clinical and biochemical surveillance. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Alternative to DNA screening'.)

RESOURCES

Information about MEN1

●UpToDate topics

•Genetics – (See "Multiple endocrine neoplasia type 1: Genetics".)

•Clinical features and diagnosis – (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

•Treatment – (See "Multiple endocrine neoplasia type 1: Management".)

•Guidelines – (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

●MEN1 resources

•Locating genetic testing laboratories

Locating an expert

●Clinical geneticists with expertise in endocrine disorders – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide online or telephone access to a genetic counselor.

●National Institutes of Health (NIH) Cancer Genetics Services Directory