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.
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.
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.
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.