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PubMed This is a summary of 15 peer-reviewed journal articles Updated
Endocrinology

The Genetic Link: Understanding ZES and MEN1

At a Glance

Most Zollinger-Ellison syndrome is sporadic, but about one in five cases is linked to inherited MEN1. Blood calcium and parathyroid hormone testing, tumor-pattern review, genetic counseling, and family surveillance can help identify MEN1 and guide care.

Zollinger-Ellison Syndrome (ZES) can occur in two distinct ways. For most people (about 80%), the condition is sporadic, meaning it happens by chance and is not passed down through families [1]. However, for approximately one in five people with ZES, the condition is part of a hereditary genetic syndrome called Multiple Endocrine Neoplasia type 1 (MEN1) [1][2]. (Conversely, about 30% of people with MEN1 develop ZES).

What is MEN1?

MEN1 is a genetic condition caused by a mutation in the MEN1 gene. This gene normally produces a protein called menin, which acts as a “tumor suppressor” to keep cells from growing out of control [3]. When this gene is faulty, it increases the risk of tumors forming in various hormone-producing (endocrine) glands [4].

MEN1 is autosomal dominant, which means if one parent has the mutation, there is a 50% chance they will pass the gene variant on to each of their children [5]. Having the mutation confers a high risk for developing tumors, but it does not mean every single patient will inevitably develop every possible tumor type. Because of this risk, a ZES diagnosis is sometimes the first clue that a family needs medical screening.

Sporadic vs. MEN1-Associated ZES

While both types of ZES cause high gastrin and stomach acid, they often behave differently:

Feature Sporadic ZES MEN1-Associated ZES
Number of Tumors Usually a single, solitary tumor [2]. Often multifocal (many small tumors) [6][2].
Tumor Location Can be in the pancreas or duodenum [7]. Almost always starts in the duodenum (small intestine) [6].
Typical Age Usually diagnosed in middle age (40s or 50s) [2]. Often diagnosed at a younger age (20s or 30s) [8].
Surgical Goal May be aimed at a complete cure if localized [9]. Surgery is more complex; observation is sometimes chosen [9].

The “Three Ps” of MEN1

Doctors look for the “Three Ps” when suspecting MEN1. If you have ZES, your care team may screen you for tumors in these other areas:

  1. Parathyroid Glands: This is the most common feature of MEN1, affecting a large majority of patients by age 50 [10]. Overactive parathyroid glands (hyperparathyroidism) lead to high blood calcium, which can cause kidney stones and bone thinning [11].
  2. Pancreas/Duodenum: This includes the gastrinomas that cause ZES, as well as other tumors that may or may not produce hormones [12].
  3. Pituitary Gland: About 40% of people with MEN1 develop a tumor in this gland at the base of the brain [3]. These can affect hormones that control growth, reproduction, or stress [13].

Why Calcium Testing Matters

One of the easiest ways your doctor screens for MEN1 is by checking your serum calcium and parathyroid hormone (PTH) levels [1]. If your calcium and PTH are high, it suggests your parathyroid glands are overactive. High calcium can actually aggravate your ZES symptoms by stimulating even more gastrin production [11]. While treating the parathyroid issue does not cure the gastrinoma, it can reduce an aggravating factor and make your acid levels easier to control.

Genetic Testing and Counseling

Because a ZES diagnosis can have implications for your siblings and children, many specialists recommend genetic counseling [5]. A genetic counselor can explain testing limits, interpret variants, and guide you on what it means for your relatives.

A negative MEN1 genetic test does not always rule out a familial pattern, but if a pathogenic variant is found, your relatives can choose to be tested. This allows them to start surveillance—regular blood work and imaging—to catch any tumors when they are small and easier to manage [14][15].

Common questions in this guide

Does Zollinger-Ellison syndrome always mean I have MEN1?
No. About 80% of people with Zollinger-Ellison syndrome have the sporadic form, which occurs by chance, while about 20% have ZES associated with MEN1. A younger age at diagnosis, multiple tumors, or a relevant family history may prompt evaluation for MEN1.
What is MEN1, and how can it run in a family?
MEN1 is an inherited condition caused by a change in the MEN1 gene, which normally helps control cell growth. It is autosomal dominant, so a parent with the gene change has a 50% chance of passing it to each child. Inheriting the change raises tumor risk but does not guarantee that every possible tumor will develop.
Why are calcium and parathyroid hormone checked with ZES?
High blood calcium and parathyroid hormone levels can indicate overactive parathyroid glands, a common feature of MEN1. High calcium can stimulate more gastrin and make ZES-related acid problems harder to control. Treating the parathyroid problem does not remove the gastrin-producing tumor, but it may reduce this aggravating factor.
How is MEN1-associated ZES different from sporadic ZES?
Sporadic ZES usually involves one tumor and may arise in the pancreas or duodenum, with diagnosis often in middle age. MEN1-associated ZES often involves multiple small tumors in the duodenum and is diagnosed at a younger age. Because tumors may be multifocal, surgery can be more complex and observation may sometimes be considered.
When should someone with ZES consider MEN1 genetic counseling or testing?
Genetic counseling may be especially useful when ZES is diagnosed at a younger age, when imaging shows multiple tumors, or when relatives have MEN1-related tumors or unexplained high calcium. A genetic counselor can explain what testing can and cannot show, interpret results, and discuss implications for siblings and children.
What other problems are doctors looking for when they screen for MEN1?
MEN1 screening commonly looks at the parathyroid glands, the pancreas and duodenum, and the pituitary gland. These areas can develop tumors or hormone problems, such as high calcium from overactive parathyroid glands. Screening may use blood tests and imaging to find changes when they are small.
What does a positive or negative MEN1 genetic test mean for my family?
If a disease-causing MEN1 variant is found, siblings and children can choose testing to learn whether they inherited it and whether surveillance is appropriate. A negative test does not always rule out a familial pattern, so doctors may still consider the person's history and family history. Regular blood work and imaging can help detect MEN1-related tumors early in people at risk.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Should I have my serum calcium and parathyroid hormone (PTH) levels checked to screen for MEN1?
  2. 2.Based on my age and the number of tumors found, do you recommend genetic counseling and testing for the MEN1 gene?
  3. 3.Does my imaging show a single tumor or multiple tumors (multifocal) in my duodenum or pancreas?
  4. 4.If I have MEN1, how does that change our plan for surgery versus long-term medication?
  5. 5.Are there other specialists, such as a genetic counselor or an endocrinologist, who should be part of my care team?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (15)
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    Assessing for Multiple Endocrine Neoplasia Type 1 in Patients Evaluated for Zollinger-Ellison Syndrome-Clues to a Safer Diagnostic Process.

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    The American journal of medicine 2017; (130(5)):603-605 doi:10.1016/j.amjmed.2016.11.035.

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    [Comparison of clinical characteristics between sporadic gastrinoma and multiple endocrine neoplasia type 1-related gastrinoma].

    Guo Y, Chen LH, Liu M, et al.

    Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 2021; (24(10)):875-882 doi:10.3760/cma.j.cn.441530-20210719-00291.

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    Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells.

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    Gastroenterology 2017; (153(6)):1555-1567.e15 doi:10.1053/j.gastro.2017.08.038.

    PMID: 28859856
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    Multiple endocrine neoplasia type 1 (MEN1): recommendations and guidelines for best practice.

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    How to treat gastrinomas in patients with multiple endocrine neoplasia type1: surgery or long-term proton pump inhibitors?

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    Surgery today 2023; (53(12)):1325-1334 doi:10.1007/s00595-022-02627-z.

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    All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update.

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    Intraoperative Decision-Making and Technical Aspects of Parathyroidectomy in Young Patients With MEN1 Related Hyperparathyroidism.

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This page is for informational purposes only and does not constitute medical advice. Ask your healthcare team whether calcium and PTH testing, genetic counseling, or MEN1 surveillance are appropriate for you.

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