Endocrine diseases that occur in MEN2 are medullary thyroid carcinoma (MTC), a type of thyroid cancer, pheochromocytoma (PHEO), an adrenal tumor, and parathyroid adenoma or primary hyperparathyroidism (PHPT), an increased release of the parathyroid hormone. MTC due to RET mutations occurs earlier than MTC not based on a genetic alteration in the RET gene and affects around 25% of all MTC patients. PHEO, in the context of MEN2, often occurs on both sides.

Around 95% of MEN2A patients develop MTC, which typically manifests as a mass in the neck and localized pain. MTC usually occurs before the age of 35 and, in 70% of cases, has already spread to the cervical lymph nodes at the time of diagnosis.

PHEO usually co-occurs after MTC and is the first manifestation in 13-27% of MEN2A patients. In the context of MEN2A, PHEOs occur earlier, show less pronounced symptoms, and occur more frequently on both sides than tumors that are not based on a RET mutation. Around 4% of PHEOs become malignant tumors.

Hyperparathyroidism in the context of MEN2A is mild and often asymptomatic. With an average age at diagnosis of 38 years, PHPT occurs significantly later than MTC.

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

MTC occurs later and less frequently with FMTC than with MEN2A and MEN2B. FMTC is seen as a variant of MEN2A with a low probability of occurrence for PHEO and PHPT.

MEN2B is characterized by the early occurrence of aggressive MTC in all patients unless prophylactic thyroid gland removal has been performed.

PHEO occurs in about 50% of patients and is often localized on both sides.

The parathyroid glands are not affected in MEN2B.

In the context of MEN2B, mucosal neuromas can occur from infancy or early childhood. Prominent lips with small nodules characterize the characteristic facial features at the edge of the red lips. In addition, there may be neuromas (thickening of the nerve fibers) of the eyelids and thickened nerves of the cornea of the eyes. Furthermore, 75% of MEN2B patients have a so-called marfanoid habitus characterized by tall stature, a slender physique with a curved or twisted spine, lax joints, and little subcutaneous fatty tissue.

Around 40% of those affected have ganglioneuromatosis (a proliferation of nerve cells and their surrounding cells) of the gastrointestinal tract, the symptoms of which usually appear in infancy or early childhood.

The treatment recommendations for MEN2 depend on the disease in question:

• Standard therapy is the removal of the thyroid gland (thyroidectomy) with the removal of the surrounding lymph nodes (timing depends on the mutation; see early detection recommendations) and subsequent hormone replacement therapy with the thyroid hormone L-thyroxine.
• If removal is incomplete, additional radiation therapy may be considered.
• Certain drugs (kinase inhibitors) can stop the growth of tumors that cannot be removed entirely or have spread.

• Removal of the adrenal glands (only in exceptional cases prophylactic removal of the adrenal glands on both sides in the case of a unilateral tumor)
• Drug therapy may be necessary before surgery (alpha-adrenergic blockade in PHEO with catecholamine secretion)

• Asymptomatic: Initially, no surgical treatment is required under close monitoring
• Symptomatic: removal of the parathyroid glands, removal of the visibly enlarged parathyroid glands is preferred
• If PHEO is known, the adrenal glands should be removed before the parathyroid glands are removed.

Different screening tests are carried out for the various diseases that can occur in the context of MEN2:

• Removal of the thyroid gland is the treatment of choice. The timing of the operation and further diagnostics depend on the mutation present in the RET gene (a codon is a specific position on the gene):
  • “Highest risk” mutations (codon 918): Surgery in the first year of life
  • “High risk” mutations (codons 634 and 883): Surgery up to the age of 5, exact timing depends on the calcitonin level in the blood (calcitonin is a hormone that is secreted more frequently by an MTC)
    Annual ultrasound of the thyroid gland and calcitonin level in the blood from 3 years of age
  • “Moderate risk” mutations (all others with RET mutation): Surgery in childhood or young adulthood, depending on the blood calcitonin level and mutation
• Annual ultrasound of the thyroid gland and calcitonin level in the blood (start depends on mutation)
  In 50% of MTC patients, recurrence occurs despite complete removal of the thyroid gland and removal of the surrounding lymph nodes, so annual calcitonin checks are recommended postoperatively (higher frequency if recurrence is known)

• Annual laboratory checks (free metanephrine and normetanephrine in plasma or fractionated metanephrine in 24-hour urine)
  • “Highest risk” and “high risk” mutations: From age 11
  • “Moderate risk” mutations: From 16 years of age
    MRI (or CT) in case of abnormal laboratory values
• In women with MEN2, a pheochromocytoma should be ruled out before a planned pregnancy. If a woman is already pregnant, a diagnosis of pheochromocytoma should be made as soon as possible.

• Annual laboratory checks in patients who have not had their parathyroid glands removed (calcium, iPTH, 25-OH vitamin D)
  • “High risk” mutations: From 11 years
  • “Moderate risk” mutations: From the age of 16
  • “Highest risk” mutations/MEN2B: no screening required