What is multiple endocrine neoplasia type 2?

Multiple endocrine neoplasia type 2 (MEN2) combines three diseases: multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC), and multiple endocrine neoplasia type 2B (MEN2B). All three diseases are characterized by hormonal disorders, which is why they are called “endocrine.” They are caused by mutations – or genetic changes – in the RET gene, and those affected have a much higher risk of medullary thyroid carcinoma (MTC), a form of thyroid cancer, and pheochromocytoma (PHEO), a tumor of the adrenal glands. In addition, MEN2A can lead to the enlargement or tumors of the parathyroids, with an increased release of the parathyroid hormone parathormone, referred to as primary hyperparathyroidism (PHPT). Certain genetic changes exhibit a combination of MEN2A and cutaneous lichen amyloidosis, a skin disease, or Hirschsprung’s disease, an intestinal disease.

How is multiple endocrine neoplasia type 2 diagnosed?

Clinical Diagnostic Criteria

MEN2A:

Occurrence of at least two specific endocrine tumors (MTC, PHEO, parathyroid adenoma / PHPT) in one person or in close relatives

FMTC:

At least four people with MTC without the occurrence of PHEO or parathyroid adenoma / PHPT in a family

MEN2B:

Early-onset MTC, mucosal neuromas of the lips and tongue, thickened nerve fibers of the cornea, characteristic facial features with a widened vermilion border of the lips and a large, slender physique.

Genetic Diagnostics

Genetic diagnostics should be conducted for all people with medullary thyroid carcinoma or with clinically diagnosed MEN2. Evidence of a genetic change in the RET gene can genetically confirm the diagnosis of MEN2. Since this examination also allows the exact location of the mutation to be determined, it is possible to narrow down the disease more precisely.

What is the risk of cancer?

Endocrine, or hormonal diseases, occurring with MEN2 are medullary thyroid carcinoma (MTC), a certain thyroid cancer, pheochromocytoma (PHEO), an adrenal tumor, and parathyroid adenoma, or primary hyperparathyroidism (PHPT), an increased release of the parathyroid hormone parathormone. Due to RET mutations, MTCs occur earlier than MTCs not caused by a genetic change in the RET gene, and they affect around 25% of all MTC patients. PHEOs associated with MEN2 commonly occur on both sides.

MEN2A

An MTC develops in around 95% of all MEN2A patients and is typically manifested by a space-occupying lesion in the area of the neck with localized pain. The MTC usually occurs before the age of 35 and has already spread into the cervical lymph nodes in 70% of the cases by the time of diagnosis.

A PHEO usually occurs after or at the same time as the MTC; it is the first manifestation in 13-27% of MEN2A patients. PHEOs associated with MEN2A occur earlier, exhibit milder symptoms, and occur on both sides more often than tumors not caused by a RET mutation. Around 4% of PHEOs become malignant tumors.

Hyperparathyroidism associated with MEN2A exhibits a mild form and often progresses without symptoms. PHPT occurs much later than the MTC, with an average age of 38 at the time of diagnosis.

In some families, MEN2A occurs in combination with cutaneous lichen amyloidosis, a skin disease. The simultaneous occurrence of MEN2A and Hirschsprung’s disease, an intestinal disease, is also known.

FMTC

MTCs occur later and less frequently with FMTC than with MEN2A and MEN2B. FMTC is considered to be a variant of MEN2A with lower probability of occurrence for PHEO and PHPT.

MEN2B

What is characteristic of MEN2B is the early onset of aggressive MTCs in all patients if a prophylactic removal of the thyroid has not been performed.

PHEOs occur in around 50% of patients and are often located on both sides

The parathyroids are not affected with MEN2B.

Mucosal neuromas associated with MEN2B may occur starting in infancy or early childhood. The existing characteristic facial features are marked by prominent lips with small nodules at the edge of the vermilion border of the lips. In addition, there may be neuromas (thickening of the nerve fibers) of the eyelids and thickened corneal nerves. Furthermore, 75% of MEN2B patients have what is called Marfanoid habitus, which is characterized by excessive tallness, a slender physique with a bent or twisted spine, lax joints, and minimal subcutaneous fatty tissue.

Around 40% of those affected have ganglioneuromatosis (tumor made up of nerve cells and the cells surrounding them) of the gastrointestinal tract, the symptoms of which usually occur during infancy or early childhood.

What causes multiple endocrine neoplasia type 2?

MEN2 is caused by a mutation – or genetic change – in the RET gene. This gene encodes for the RET protein, which is a receptor (a tyrosine kinase receptor) at the surface of the cells of our body. It is via this receptor that cell growth and differentiation signals are transmitted. Now if the RET gene is altered, this leads to an overactive RET protein, i.e. increased activity of the receptor, which results in excessive cell growth and therefore the development of a tumor.

All in all, MEN2 occurs in approx. one in 35,000-40,000 people and is usually passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease. The remaining cases (around 9% with MEN2A and 50% with MEN2B) are due to a spontaneous or new mutation, called a de novo mutation.

Is there a treatment?

Treatment recommendations for MEN2 depend on the existing disease:

Medullary Thyroid Carcinoma

  • Standard treatment is to remove the thyroid (thyroidectomy) along with removal of the surrounding lymph nodes (the timing of this intervention will depend on the type of mutation, see the surveillance recommendations) and subsequent hormone replacement therapy with thyroid hormone L-thyroxin.

  • If the removal is incomplete, supplementary radiotherapy may need to be considered.

  • Certain medications (kinase inhibitors) may halt the growth of tumors that have not been completely removed or that have spread.

Pheochromocytoma

  • Removal of the adrenal glands (only in exceptional cases should adrenal glands on both sides be removed prophylactically when the tumor is on one side)

  • Medicinal therapy may need to be administered before an operation (alpha-adrenergic blockers for PHEO with catecholamine secretion).

Thyroid Adenoma or Enlargement

  • Without symptoms: With close monitoring, no surgical treatment is initially necessary.

  • Symptomatic: Removal of the parathyroids, with removal of the visibly enlarged parathyroids being preferable

  • If PHEO has been previously diagnosed, the adrenal glands should be removed before the parathyroids are removed.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Different surveillance examinations are conducted with regard to the various diseases that can occur as part of MEN2:

Medullary Thyroid Carcinoma

  • Removing the thyroid is the treatment of choice. The timing of the surgery and further diagnostics depends on which mutation in the RET gene is involved (a codon is a specific point on the gene):

    • Highest risk mutations (codon 918): operation during the first year of life
    • High risk mutations (codons 634 and 883): operation by the age of 5, with the exact time dependent upon the calcitonin level in the blood (calcitonin is a hormone that is released in greater amounts by an MTC)
      Annual ultrasound of the thyroid and calcitonin level in the blood as of the age of 3
    • Moderate risk mutations (all others with a RET mutation): operation in childhood or early adulthood, depending on the calcitonin level in the blood and the mutation
      Annual ultrasound of the thyroid and calcitonin level in the blood (with the start depending on the mutation)
  • A relapse occurs in 50% of MTC patients despite a complete removal of the thyroid and removal of the surrounding lymph nodes; for this reason, annual calcitonin checkups are recommended following the operation (even more frequently when there is a known relapse).

Pheochromocytoma

  • Annual laboratory checks (free metanephrine and normetanephrine in the plasma or fractionated metanephrine in 24-hour urine)

    • Highest-risk and high-risk mutations: from the age of 11
    • Moderate-risk mutations: from the age of 16
  • MRI (or CT) whenever there are abnormal laboratory values

  • For women with MEN2, a pheochromocytoma should be ruled out prior to a planned pregnancy. If pregnancy has already commenced, diagnostics to detect a pheochromocytoma should be conducted as soon as possible.

Thyroid Adenoma and Hyperplasia

  • Annual laboratory checks for patients who have not had their parathyroids removed (calcium, iPTH, 25-OH, vitamin D)

    • High-risk mutations: from the age of 11
    • Moderate-risk mutations: from the age of 16
    • Highest-risk mutations / MEN2B: no screening necessary

Self-Care and Support

What should I pay special attention to?

Different symptoms can occur depending on the disease involved. It is important to see a doctor if you become aware of any one of these symptoms.

The medullary thyroid carcinoma can manifest through swellings in the throat, hoarseness, or swallowing disorders.

A pheochromocytoma is characterized by elevated blood pressure and heart palpitations. In addition, there are rather non-specific signs such as headaches, outbreaks of sweating, dizziness, pale skin, and weight loss.

Hyperparathyroidism may present itself through bone pain. In addition, kidney or gall stones may occur and cause pain in the area of the flanks and/or upper abdomen.

Support Groups and Additional Information