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.
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:
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.
MEN2 is divided into two forms, which share the thyroid cancer but differ in almost everything else.
MEN2A accounts for roughly 95% of cases. It involves:
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 accounts for roughly 5% of cases and is the more severe form. It involves:
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.
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:
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.
Genetic testing for RET is offered when:
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.
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:
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.
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:
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.
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.
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.
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.
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.
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.