Multiple endocrine neoplasia type 2 (RET)

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Multiple endocrine neoplasia type 2, usually shortened to MEN2, is an inherited condition that raises the risk of tumors in several hormone-producing glands. It is caused by a change in a single gene, RET. Nearly everyone with the condition develops medullary thyroid carcinoma, a cancer of the thyroid gland, and many also develop tumors of the adrenal glands or the parathyroid glands.

MEN2 stands apart from the other conditions in this section in two ways.

The first concerns the gene. Almost every hereditary cancer gene works by losing a protective function. RET works the opposite way: the inherited change switches the gene permanently on rather than off. That difference explains why medullary thyroid carcinoma appears so early and so consistently, and it is also why a drug can block the overactive protein directly.

The second concerns what is done about it. Because the thyroid can be removed and because the cancer is close to inevitable, preventive removal of the thyroid gland in childhood is standard. For the highest-risk gene changes, this is done within the first year of life. Few decisions in medicine are made this early, and the reasoning behind the timing is set out below.

This article is written for people who carry a RET change with or without a diagnosis of cancer, and for parents making decisions on behalf of a child.

What does the RET gene do?

RET carries instructions for a protein on the surface of certain cells that receives growth signals from outside. Under normal conditions, it switches on when a signal arrives and switches off again afterward. It is essential during development, particularly for the nervous system and the kidneys.

RET is a proto-oncogene, meaning the normal version is not harmful, but a change can make the protein overactive. This is the reverse of a tumor suppressor gene, where a change removes a protective brake. In MEN2, the inherited change locks the RET protein in the on position, so affected cells receive a continuous instruction to grow whether or not a signal has arrived.

Three practical consequences follow, and they run through the whole of this article:

Only one copy needs to change. Because the altered protein is actively harmful rather than simply absent, a single altered copy is enough. There is no need for a second event in a cell, which is why the cancer develops so early and in nearly everyone.
Where the change sits matters enormously. Different positions in the gene make the protein overactive to different degrees. This creates a tight link between the specific change and how the disease behaves, which is why management is based on the exact result rather than the diagnosis alone.
A drug can block the protein. An overactive protein is a target. Medications that block RET are now approved for advanced medullary thyroid carcinoma.

The cells most affected are the thyroid’s C cells, which normally produce a hormone called calcitonin. These cells give rise to medullary thyroid carcinoma, and the calcitonin they release provides a blood test that closely tracks the disease.

The two forms of MEN2

MEN2 is divided into two forms, which share the thyroid cancer but differ in almost everything else.

MEN2A

MEN2A accounts for roughly 95% of cases. It involves:

Medullary thyroid carcinoma — In nearly all carriers, usually appearing in childhood or early adulthood.
Pheochromocytoma — A tumor of the adrenal gland, in roughly 50% of carriers, often affecting both glands. These tumors release hormones that can cause episodes of high blood pressure, headache, sweating, and palpitations.
Overactive parathyroid glands — In roughly 20% to 30% of cases, usually caused by enlargement of one or more glands or a parathyroid adenoma, raising the level of calcium in the blood.

Some families with MEN2A have additional features: an itchy, thickened patch of skin between the shoulder blades caused by amyloid deposits, or Hirschsprung disease, a bowel condition present from birth. Families in which medullary thyroid carcinoma is the only feature were once classified separately as familial medullary thyroid carcinoma; they are now considered part of MEN2A.

MEN2B

MEN2B accounts for roughly 5% of cases and is the more severe form. It involves:

Medullary thyroid carcinoma — In essentially all carriers, and far earlier than in MEN2A. It has been found in infants only weeks old.
Pheochromocytoma — In roughly 50%, as in MEN2A.
No parathyroid involvement — Overactive parathyroid glands are not part of MEN2B.
Physical features present from early childhood — Small bumps called mucosal neuromas on the lips and tongue, thickened lips, a tall, slender build with long limbs and loose joints, and ganglioneuromas in the wall of the bowel, which cause constipation or other digestive problems from infancy.

These physical features usually appear before the cancer does, and recognizing them is one of the most valuable things a clinician can do in this condition. Roughly three-quarters of MEN2B cases arise from a new gene change rather than an inherited one, so there is generally no family history to prompt suspicion, and the physical signs are the only clue. More than 95% of MEN2B is caused by a single change, at a position in the gene known as M918T.

How risk is estimated and why the specific gene change matters

In most hereditary cancer syndromes, risk figures come as broad ranges and family history shifts them. MEN2 is different. The relationship between the specific RET change and disease behavior is tight enough that management is set almost entirely by the report result.

Changes are sorted into three categories, based on how early and how reliably medullary thyroid carcinoma develops:

Highest risk — The M918T change, which causes almost all MEN2B. Medullary thyroid carcinoma develops earliest, and spread to lymph nodes has been reported in the first year of life.
High risk — Changes at position 634, the most common cause of classic MEN2A, and the A883F change. Cancer typically develops in early childhood.
Moderate risk — All other RET changes. Cancer generally develops later, sometimes not until adulthood, and behaves less predictably.

Two qualifications belong alongside these categories.

Behavior varies within each group. Some people with moderate-risk changes develop cancer in childhood and others reach middle age without it, so the category sets a starting position rather than a fixed schedule. Recent work also suggests that once medullary thyroid carcinoma has developed, the age at which it is found predicts outcome better than the risk category does, which strengthens rather than weakens the argument for acting early.

The figures for medullary thyroid carcinoma also describe what happens without treatment. Preventive thyroid surgery has reduced deaths from this cancer in RET carriers from around 15% to 20% to roughly 5%. A carrier reading that the cancer is close to inevitable is reading about the natural course of a condition that current care is designed to interrupt.

Who should be tested?

Genetic testing for RET is offered when:

Medullary thyroid carcinoma is diagnosed at any age. Roughly a quarter of these cancers are hereditary, and testing is recommended for everyone diagnosed regardless of family history.
A parent, sibling, or child carries a RET change, or has been diagnosed with MEN2.
Pheochromocytoma is diagnosed, particularly at a young age or when it affects both adrenal glands.
The physical features of MEN2B are present, including mucosal neuromas, thickened lips, or unexplained bowel problems from infancy.
C-cell hyperplasia is reported on a thyroid specimen, meaning an increased number of the cells from which medullary thyroid carcinoma arises.

How the test is performed

Germline testing is done on a blood or saliva sample and examines the DNA a person was born with. The laboratory sequences the RET gene, usually as part of a panel, using next generation sequencing.

What matters most on the report is not simply whether a change was found, but which change. Because the position determines the risk category and therefore the timing of surgery, the report should state the specific codon. If your report names a change and you have not been told which risk category it falls into, ask that question.

Blood tests are used alongside the genetic result, not instead of it. Calcitonin measures C-cell activity and rises before cancer becomes visible, so it helps determine the timing of surgery within the window the genetic result defines. Blood or urine tests for hormones released by pheochromocytoma, and blood calcium for the parathyroid glands, make up the rest of the monitoring.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to make the RET protein overactive. This confirms MEN2, and the report should name the specific position.
Variant of uncertain significance — A change was found, but its effect is unknown. This is not a positive result. It is managed as though negative, with monitoring guided by family history, and it is never a basis for removing a child’s thyroid gland. Our article on variants of uncertain significance explains this result in detail.
Benign or likely benign variant — A harmless difference, usually not reported.
No variant identified — No change was found in the genes tested.

What the result means

A pathogenic or likely pathogenic variant confirms MEN2. The specific change determines the risk category, the age at which thyroid surgery is planned, and which other glands need monitoring. Each child, sibling, and parent has a 50% chance of carrying the same change.

A negative result means two different things:

True negative — A specific change is already known in your family, and you tested negative for that exact change. You did not inherit it, you do not need preventive surgery or monitoring, and your children cannot inherit it from you. For a child in an affected family, this result ends what would otherwise be a lifetime of surveillance.
Uninformative negative — No change has been identified in anyone in the family. In someone diagnosed with medullary thyroid carcinoma, this means the cancer is most likely not hereditary. When a family pattern is strong and no change is found, monitoring may still be offered based on family history.

Germline versus somatic RET changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. That is MEN2.

A somatic change arises within a tumor during life, exists only in the tumor cells, and cannot be inherited.

Roughly half of medullary thyroid carcinomas that are not hereditary carry a somatic RET change within the tumor, most often the same M918T change that causes MEN2B when inherited. The same change therefore means entirely different things depending on where it is found. A tumor sequencing report naming RET does not establish MEN2, and confirming that requires a separate germline test on blood or saliva. Because a quarter of all medullary thyroid carcinomas turn out to be hereditary, that test is recommended for everyone with this diagnosis.

RET is also involved in cancer in a third way that causes confusion. In some thyroid and lung cancers, part of the RET gene joins a different gene, forming what is called a fusion. These are somatic events with no inherited component, and our article on RET mutations and fusions in thyroid cancer covers them.

Surveillance and risk reduction

Preventive removal of the thyroid gland

This is the central intervention in MEN2, and the reasoning differs from preventive surgery in other hereditary syndromes. Medullary thyroid carcinoma develops in nearly every carrier, it can spread to lymph nodes very early, and once it has spread it is difficult to cure. Removing the gland before cancer develops is highly effective, and the thyroid hormone it produces can be replaced by a daily tablet.

Timing follows the risk category:

Highest risk (M918T, MEN2B) — Total thyroidectomy within the first year of life, and ideally in the first months. Calcitonin is naturally high in newborns, so it does not guide timing in this group.
High risk (codon 634, A883F) — Total thyroidectomy at or before age 5, and earlier if calcitonin rises.
Moderate risk — Calcitonin measured every six to twelve months from around age 5, with surgery in childhood or early adulthood, timed by when calcitonin begins to rise.

Whether lymph nodes in the neck are removed at the same time depends on the risk category and on the calcitonin level before surgery. Removing them adds risk to the operation, so it is done when the chance of involvement justifies it rather than routinely.

The consequences of the surgery are permanent and deserve plain description. You must take thyroid hormone daily for life, and your dose is adjusted based on blood tests. The parathyroid glands sit against the thyroid and can be injured or removed during the operation, which may leave a person needing calcium and vitamin D indefinitely. The nerve supplying the voice box runs alongside the thyroid and can be affected, altering the voice. In experienced hands, these complications are uncommon, and this is one of the clearest reasons a child’s surgery is done by a surgeon who performs it often.

Monitoring the adrenal glands

Screening for pheochromocytoma uses blood or urine tests measuring the hormones these tumors release, generally performed annually. It begins around age 11 for people in the highest- and high-risk categories, and around age 16 for the moderate-risk category.

Finding a pheochromocytoma before it causes symptoms matters for a specific reason: an undiagnosed pheochromocytoma can cause a dangerous rise in blood pressure during any operation or during pregnancy. Screening is therefore done before planning other surgery. Where a tumor is found, the adrenal gland is removed, and surgeons aim to preserve part of the gland when possible, since these tumors often affect both sides.

Monitoring the parathyroid glands

For MEN2A, blood calcium is checked annually from the same age as adrenal screening. Overactive parathyroid glands develop in a minority and are usually mild. Treatment is removal of the affected glands, often at the same operation as thyroid surgery if the problem is already present.

If cancer develops

Medullary thyroid carcinoma that is found early and confined to the thyroid is usually cured by surgery. Where it has spread or returns, drugs that block the RET protein, including selpercatinib and pralsetinib, are effective and are now the preferred treatment. These medications work particularly well in this setting because they target the precise abnormality driving the cancer. Calcitonin and a second blood marker are used afterward to monitor for disease recurrence.

Testing family members

MEN2 is inherited in an autosomal dominant pattern, meaning a single altered copy causes it. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change, and it passes through fathers as well as mothers.

Children are tested in infancy or early childhood, and this is not deferred. The reason is the same as for the surgery: for the highest-risk changes, an operation is planned in the first year of life, and for high-risk changes before age 5. Testing at birth or shortly after is standard where a parent is known to carry a change, and in a family with MEN2B a newborn may be tested within weeks. This is among the earliest ages at which genetic testing for cancer risk is offered, and the justification is that a child who tests positive needs surgery while a child who tests negative needs nothing at all.

Because roughly three-quarters of MEN2B arises from a new gene change, an affected child’s parents are usually unaffected. Testing may still be offered, since a parent can occasionally carry the change in only some of their cells.

Carriers planning a family sometimes ask whether they can avoid the change in their children. Preimplantation genetic testing, in which embryos created through IVF are tested before transfer, and prenatal testing are available in many places. A genetics service and a fertility specialist can work through these options together.

What happens next

For someone diagnosed with medullary thyroid carcinoma, germline testing is arranged promptly, because the result determines whether relatives need testing and whether the adrenal glands must be checked before any further surgery.

For a carrier identified through family testing, the work is planning thyroid surgery at the age the risk category indicates and establishing monitoring of the adrenal and parathyroid glands.

A team usually coordinates care, including endocrinology, endocrine surgery, and genetics; for children, a pediatric endocrinologist and pediatric surgeon. Referral to a center that regularly manages this condition is standard, since both timing decisions and the surgery itself benefit from experience.

Families carry a particular weight in this condition because parents make decisions for infants and young children, and they often carry the same gene change themselves. Psychological support is routine in experienced centers, and patient organizations for MEN2 connect families facing the same decisions.

Questions to ask your doctor

Which specific RET change was found, and which risk category does it fall into?
Do I have MEN2A or MEN2B, and what does that mean for which glands are affected?
At what age should thyroid surgery be done in my case, or in my child’s case?
What is my calcitonin level, and how will it be used to decide timing?
Will lymph nodes in the neck be removed at the same operation?
What are the risks of the surgery, and how many of these operations does the surgeon perform each year?
What will thyroid hormone replacement involve after surgery?
When should screening for pheochromocytoma start, and how often?
Should my adrenal glands be checked before any other operation or before pregnancy?
When should my parathyroid glands and blood calcium be checked?
Which of my relatives should be tested, and at what age should my children be tested?
Should we be seen at a center that specializes in this condition?
If cancer develops or returns, would a RET-blocking medication be an option?
Is psychological support or a patient organization available to my family?