Zollinger-Ellison syndrome

In most people with Zollinger-Ellison syndrome (ZES), the cause is not known. However, in about 25-30% of cases, it occurs with an inherited condition called multiple endocrine neoplasia type 1 (MEN1). This condition is caused by changes (mutations) in the MEN1 gene and is inherited in an autosomal dominant manner. Most, but not all, individuals with an MEN1 gene mutation will develop symptoms of multiple endocrine neoplasia type 1.^[1][2]

The MEN1 gene normally regulates the body's production of a protein thought to play a role in preventing the development of tumors (a tumor suppressor gene). Mutations that affect the function of this gene therefore affect the body's ability to prevent the growth of tumors, thus leading the the signs and symptoms of multiple endocrine neoplasia type 1.^[2]

Zollinger-Ellison syndrome (ZES) usually occurs sporadically, for unknown reasons in a person with no history of the condition in the family. In about 25-30% of people with ZES, it is associated with an inherited condition called multiple endocrine neoplasia type 1 (MEN1).^[1]

MEN1 is inherited in an autosomal dominant manner and is caused by mutations in the MEN1 gene. Most affected people inherit the mutated gene from a parent, and a few cases result from a new mutation that was not inherited. Unlike most autosomal dominant conditions, both copies of the MEN1 gene must have a mutation to cause symptoms of the condition. The mutation in the second copy of the gene occurs during a person's lifetime. Because of this, most, but not all, people born with an MEN1 gene mutation will develop signs and symptoms of the condition.^[3] This phenomenon is known as reduced penetrance. A person with an MEN1 gene mutation has a 50% (1 in 2) risk to pass on the mutated gene to each child.

There is not a genetic test specifically for Zollinger-Ellison syndrome (ZES), which usually occurs sporadically as a result of a tumor that secretes gastrin (a gastrinoma). However, genetic testing is available for multiple endocrine neoplasia type 1 (MEN1), which is a genetic condition present in about 25-30% of people with ZES.

People who have a single MEN1-related tumor (such as one gastrinoma) and no family history of multiple endocrine neoplasia type 1 are rarely born with MEN1 gene mutations. Generally, the chance of detecting a MEN1 gene mutation increases in people with more main tumors (parathyroid, pancreatic, and pituitary).^[4]

Genetic testing is most informative for asymptomatic family members when the affected family member has genetic testing first. The person with symptoms of MEN1 typically first has sequencing analysis of the gene to look for changes; if no mutation is found, they may have duplication/deletion analysis (a test that detects extra or missing parts of the gene).^[4]

Predictive testing for at-risk, asymptomatic, adult family members requires first finding the disease-causing mutation in the affected family member. It is important to note that in people with a MEN1 gene mutation, the chance to develop symptoms by age 20 is over 50%. The chance to develop symptoms by age 40 is 95%.^[4] Therefore, as a person ages and does not have signs or symptoms, the chance to have a MEN1 gene mutation decreases significantly.

The Genetic Testing Registry (GTR) provides information about the genetic tests for multiple endocrine neoplasia type 1. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Predictive genetic testing may be available to people with a family history of a genetic condition who have a potential risk of eventually developing the condition. Depending on the condition, a predictive test may show whether a person will definitely develop the condition (pre-symptomatic testing) or has an increased chance to develop the condition (susceptibility testing).^[5] Predictive testing may be considered if:^[5][6]

• the condition can be prevented or its symptoms can be treated
• the condition cannot be prevented or treated, but knowing the chance of getting the condition may help with important life decisions (such as decisions about health care, employment, or having children)
• a person can lower the risk to develop the condition by making lifestyle changes, having regular screening, taking preventative drugs, or having preventative surgery (e.g., for some hereditary cancer syndromes)
• a person prefers to live with certainty rather than uncertainty regarding knowing whether they will develop the condition

Even when a predictive test result is positive, it is usually not possible to predict the exact age that symptoms will develop, how fast symptoms will progress, or how a person will be affected. Because there is no going back after a person gets results, it is important to think through some of the main issues before deciding whether to have testing.^[5] Each person may have specific concerns relevant to their own situation.

Some questions to think about before making a decision may include:^[5]

• How might the test results affect me emotionally?
• How might I react if the result reveals that I carry the changed gene? For some people, even a result which shows that they have the changed gene is preferable to the stress and anxiety caused by not knowing.
• How might I react if the result reveals that I do not carry the changed gene?
• What might the test results mean for my children (or future children)? The results of a genetic test will not only tell you about your risk of developing the condition, it will also tell you more about your children's risk.
• What are the implications for other family members? Many family members share the same genes, so testing for one family member may have implications for others.

People who are considering having a predictive genetic test should speak with a genetics professional. Genetics professionals can provide the information needed in order for each person to make the decision that is right for them. They can explain the advantages and disadvantages of having the test; help to discuss any emotions that may arise; and address questions or concerns, including those about reproductive decision-making, privacy, and insurance.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.