Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare, inherited disorder that causes tumors to develop in various endocrine glands throughout the body. Endocrine glands produce and release hormones, chemical messengers that regulate bodily functions like metabolism, growth, and reproduction. While most MEN1-related tumors are benign, meaning non-cancerous, they can still lead to health complications by causing the affected glands to produce an excess of hormones.
The Genetic Cause of MEN1
Multiple Endocrine Neoplasia Type 1 arises from a change in the MEN1 gene. The normal MEN1 gene produces a protein called menin, which functions as a tumor suppressor. Menin helps regulate cell growth and division, preventing uncontrolled cell multiplication, and also plays a part in DNA replication and repair.
A mutation in the MEN1 gene causes it to lose its ability to produce functional menin. This impairment in the tumor suppressor function allows cells, particularly in endocrine glands, to divide excessively and form tumors. MEN1 follows an autosomal dominant inheritance pattern, meaning an individual needs only one copy of the mutated gene from a single parent to develop the disorder. While most cases are inherited, spontaneous mutations can occur without a prior family history.
Commonly Affected Glands and Tumors
MEN1 most frequently affects three main endocrine glands: the parathyroid glands, pancreas (and duodenum), and pituitary gland. These are often referred to as the “3 Ps” due to their common involvement in the syndrome. Symptoms depend on which glands are affected and the hormones produced by the tumors.
Parathyroid Glands
Parathyroid gland tumors are the most common manifestation of MEN1, occurring in over 90% of affected individuals. These tumors, usually adenomas, lead to primary hyperparathyroidism, where the parathyroid glands produce too much parathyroid hormone. Excess parathyroid hormone results in elevated blood calcium levels, causing symptoms such as kidney stones, bone thinning, fatigue, muscle weakness, joint pain, depression, or difficulty concentrating.
Pancreas (and Duodenum)
Pancreatic neuroendocrine tumors (pNETs) and duodenal tumors affect 30% to 90% of MEN1 patients. These tumors can be “functional,” meaning they produce excess hormones, or “non-functional,” causing symptoms due to their size or spread. Gastrinomas are the most common functional pNETs in MEN1, often arising in the duodenum or pancreas. They secrete gastrin, leading to excessive stomach acid production, which can cause severe peptic ulcers and is known as Zollinger-Ellison syndrome.
Insulinomas are the second most common functional pancreatic tumor. These tumors produce an excess of insulin, resulting in low blood sugar (hypoglycemia). Symptoms of insulinomas can include fatigue, nervousness, dizziness, lightheadedness, fainting, and confusion. Other, less common functional tumors include glucagonomas, which can cause a skin rash and high blood sugar, and VIPomas, leading to watery diarrhea, dehydration, and low potassium.
Pituitary Gland
Pituitary adenomas occur in approximately 25% to 55% of individuals with MEN1. The pituitary gland, often called the “master gland,” regulates many bodily functions by releasing hormones. Prolactinomas, tumors producing too much prolactin, are the most frequent pituitary tumor associated with MEN1.
In women, excess prolactin can lead to irregular or absent menstrual cycles, milky discharge from the breasts (galactorrhea), and fertility issues. Men with prolactinomas may experience decreased libido, erectile dysfunction, or enlarged breasts. Other less common pituitary tumors in MEN1 can produce growth hormone (leading to acromegaly or gigantism), adrenocorticotropic hormone (causing Cushing disease), or thyroid-stimulating hormone (resulting in hyperthyroidism).
Diagnosis and Clinical Criteria
MEN1 diagnosis involves clinical evaluation, biochemical testing, and genetic analysis. A clinical diagnosis of MEN1 is established if an individual develops tumors in at least two of the three main affected glands: the parathyroid glands, pancreas, or pituitary gland. This helps identify the characteristic pattern of tumor development.
Biochemical testing analyzes blood and urine samples to detect abnormal hormone levels, indicating endocrine tumor presence and activity. For instance, high blood calcium levels coupled with elevated parathyroid hormone (PTH) suggest parathyroid tumors. Similarly, increased gastrin levels can point to gastrinomas, while elevated prolactin levels may indicate a prolactinoma. These tests provide valuable physiological evidence of tumor function.
Genetic testing confirms a MEN1 diagnosis by identifying a mutation in the MEN1 gene, typically through a blood test screening for specific alterations. It also identifies at-risk family members, allowing for early detection and intervention.
Management and Treatment Approaches
MEN1 management involves proactive, long-term care focused on early detection and targeted tumor treatment. Regular surveillance is foundational to MEN1 management, aiming to identify new or growing tumors before they cause significant health problems. This often includes annual biochemical testing to monitor hormone levels and periodic imaging (e.g., MRI or CT scans) to visualize endocrine glands.
Treatment strategies for MEN1 are individualized, depending on the type, size, and hormone production of each tumor. For hyperparathyroidism, surgical removal of overactive parathyroid glands normalizes calcium levels and prevents complications like kidney stones and bone loss. For gastrinomas, medications like proton pump inhibitors reduce stomach acid production and manage ulcers.
Pituitary tumors, particularly prolactinomas, are often managed with medications that shrink the tumor and reduce hormone levels. When surgery is needed for pancreatic neuroendocrine tumors, the approach varies: smaller, non-functional tumors may be observed, while larger or hormone-producing tumors might require partial pancreatic removal. The goal of these treatments is to effectively control tumors and their hormonal effects, improving patient well-being.