Endocrine diseases occurring with MEN2 include medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and parathyroid adenoma / primary hyperparathyroidism (PHPT). MTCs due to RET mutations have an earlier onset than sporadic MTCs and affect approximately 25% of all MTC patients. PHEO associated with MEN2 is almost always located in the adrenal gland region and often occurs bilaterally.
An MTC develops in approximately 95% of all MEN2A patients and is usually manifested by a space-occupying lesion in the neck region which is associated with localized pain. MTC usually occurs before the age of 35 and has already metastasized into the cervical lymph nodes in 70% of the cases at 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 develop bilaterally more often than sporadic tumors. Approximately 4% of PHEOs become malignant.
Hyperparathyroidism associated with MEN2A exhibits a mild form and often progresses asymptomatically. 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. The simultaneous occurrence of MEN2A with Hirschsprung’s disease has also been described.
MTCs associated with FMTC occur later on in life, and the penetrance for MTCs is lower than for MEN2A and MEN2B. FMTC is considered to be a variant of MEN2A with lower penetrance for PHEO and PHPT.
MEN2B is characterised by early onset of aggressive MTCs in all patients if a prophylactic thyroidectomy has not been performed.
PHEOs occur in approximately 50% of patients and are often multiple and bilateral.
MEN2B does not affect the parathyroid glands.
Mucosal neuromas associated with MEN2B may occur starting in infancy or early childhood. The existing characteristic facies is marked by prominent lips with submucosal nodules at the edge of the vermilion border of the lips. In addition, there may be neuromas of the eyelids and thickened corneal nerves.
Furthermore, 75% of MEN2B patients have Marfanoid habitus with kyphoscoliosis or lordosis, lax joints, and minimal subcutaneous fatty tissue.
Approximately 40% of those affected have ganglioneuromatosis of the gastrointestinal tract, the symptoms of which usually occur during infancy or early childhood.