Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN1) is a genetic condition that causes benign and malignant tumors in endocrine (hormone producing) and non-endocrine tissues. It occurs in approximately 1 in 30,000 individuals.

Endocrine tumors may arise in the:

• Parathyroid glands (small glands located next to the thyroid gland)
• Pituitary gland
• Stomach, bowel or pancreas (gastro-entero-pancreatic, or GEP tract)
• Adrenal glands (glands that sit on top of each kidney)

Non-endocrine tumors may include:

• Facial angiofibromas (acne-like lesions that form near the nose and mouth)
• Collagenomas (skin-colored nodules on the trunk, neck and extremities)
• Lipomas (benign fatty tissue tumors)
• Meningiomas and ependymomas (tumors of the central nervous system)
• Leiomyomas (benign smooth muscle tumors)

Because MEN1 is hereditary, the risk of developing the features associated with MEN1 may be passed from generation to generation in a family. However, the type and severity of disease can vary widely between family members.

MEN1 is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform different functions within our bodies.

In most patients with MEN1, the disorder develops as the result of alterations in a specific gene known as MEN1, which is located on chromosome 11 at position q13. MEN1 is the only gene known to be associated with MEN1. Normally, the protein produced by the MEN1 gene acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. It also plays a fundamental role in regulating DNA replication and repair. A person with MEN1 has one copy of the MEN1 gene that has lost its ability to carry out these duties.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the MEN1 gene. Patients with MEN1 generally carry a mutation of one copy of the MEN1 gene in all the cells of their body. Individuals who have MEN1 are born and develop normally, but are at an increased risk to develop specific types of tumors. These tumors are believed to develop because, over time, the working copy of the MEN1 gene may become altered within one or more cells. The loss of function of the second MEN1 gene copy leads to abnormal growth of the affected cells, increasing the chance of forming a tumor.

How is multiple endocrine neoplasia type 1 inherited?

Approximately 90 percent of patients with MEN1 inherit an altered copy of the MEN1 gene from a parent who also has MEN1. In the remaining 10 percent of patients, MEN1 results from the development of a “new” mutation in the MEN1 gene in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change.

A person with a mutation in one copy of the MEN1 gene in all the cells of their body have a 50 percent — or one in two — chance of passing this same alteration onto his children. Children who inherit the altered gene copy will have MEN1 and will be at risk of developing the features associated with this disorder.

An individual may be diagnosed as having MEN1 if he or she develops two of the three main MEN1-related endocrine tumors, including:

• Parathyroid tumors
• Pituitary tumors
• Tumors of the stomach, bowel or pancreas (GEP tract)

Alternatively, an individual who develops only one of these tumors may be diagnosed as having MEN1 when there is a family history consistent with the condition.

A careful and detailed review of an individual’s medical and family history may be performed to aid in the diagnosis of multiple endocrine neoplasia type 1.

A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed cancer, the types of cancer and the ages of onset, as well as the presence of any clinical manifestations. If the pattern of clinical features and/or cancers is suggestive of MEN1, the physician or counselor may recommend that genetic testing be performed. 

Genetic testing for MEN1

In order to confirm — on a molecular level — that an individual has MEN1, he or she can undergo genetic testing:

• Generally, a sample of blood is obtained from an affected individual.
• DNA is isolated from this sample, and the two copies of the MEN1 gene are analyzed and compared to the normal reference sequence for the MEN1 gene.
• If an alteration in one MEN1 gene copy is identified, the genetic counselor can examine whether the alteration has been previously reported in other individuals with MEN1.
• It is estimated that 80-90 percent of individuals carrying a diagnosis of familial MEN1 will have a detectable mutation involving MEN1. However, germline MEN1 mutations are found in only 65 percent of patients who are the first in their family to have the disorder. Therefore, it’s important to remember that the failure to identify an alteration in the MEN1 gene does not exclude the clinical diagnosis of MEN1.
• MEN1 genetic test results can provide important information for other family members. If a mutation in the MEN1 gene is identified, relatives can be tested for the presence of the same genetic alteration.

Reproductive options

A person with MEN1 who is concerned about passing this disorder onto future children has several options, including:

• Prenatal diagnosis: DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the MEN1 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation Genetic Diagnosis (PGD): For couples using in vitro fertilization (IVF) to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the MEN1 gene would be implanted.

Before one can proceed with prenatal testing or PGD, a MEN1 mutation must be identified in a parent with multiple endocrine neoplasia type 1.  

Individuals with MEN1 are at increased risk to develop endocrine and non-endocrine tumors. These tumors are often benign (non-cancerous); however, they may require removal or treatment as they can cause symptoms due to pressure on nearby organs or excess hormone secretion.

Endocrine tumors

• Parathyroid tumors — 100 percent of patients develop hyperparathyroidism (overactive parathyroid glands due to hormone-secreting parathyroid tumors) by age 50
• Pituitary tumors — 10-60 percent of patients develop tumors in the pituitary gland
• Adrenal tumors — 20-40 percent of patients develop tumors in the adrenal glands

Non-endocrine tumors

• Skin
  • Facial angiofibromas are identified in 80-90 percent of patients
  • Collagenomas are identified in 70 percent of patients
• Lipomas are identified in 34 percent of patients
• Other non-endocrine tumors that have been reported in patients with MEN1 include leiomyomas and tumors of the central nervous system (specifically meningiomas and ependymomas). The true incidence of these tumors in individuals with MEN1 is not currently known.

Risk of malignancy

In some cases, MEN1-associated tumors undergo malignant changes and behave more like cancers.

The two MEN1-related endocrine tumor types most likely to become malignant are:

• Carcinoid tumors — Approximately 10 percent of individuals with MEN1 develop carcinoid tumors. Typically, these form on the thymus (an immune system organ in the chest), the bronchus (an airway passage in the lungs), or on the membrane lining the inside of the stomach
• Tumors of the gastro-entero-pancreatic (GEP) tract — MEN1 patients are at risk to develop tumors along the GEP tract such as gastrinomas, which secrete a digestive hormone called gastrin. About 40 percent of individuals with MEN1 develop gastrinomas in a part of the small bowel known as the duodenum or, rarely, in the pancreas.

Almost all individuals with a germline MEN1 mutation will develop features of the condition. Approximately 50 percent of individuals with MEN1 will develop features associated with MEN1 by age 20, and more than 95 percent of individuals with MEN1 will develop features by age 50. 

There are currently no standard screening recommendations for patients with MEN1. Screening guidelines may vary between experts and may be dependent on factors such as the patient’s age and clinical history. Management of patients with MEN1 should be provided by specialists with expertise in this condition.

There are some annual screening recommendations that apply to all adults who have or are at risk for MEN1, including assessment of calcium, parathyroid hormone, gastrin, and prolactin levels. Occasionally, additional imaging tests such as ultrasound, CT or MRI may be necessary to screen for carcinoid, pancreatic, pituitary and other tumors. Screening recommendations may begin as early as age 5 for children at risk for MEN1.

If possible, individuals with MEN1 should avoid smoking cigarettes or cigars and should not be exposed to secondhand smoke, which is associated with an increased risk of developing thymic carcinoid tumors.

Adults who have MEN1 or who would like more information about MEN1 may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania.

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