Pathophysiology
MEN 2 is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Inherited as an autosomal dominant disorder, MEN 2 has 3 distinct subtypes, including MEN 2A, MEN 2B, and familial medullary thyroid carcinoma-only (FMTC-only). The subtypes are defined by the combination of tissues affected. Developmental abnormalities may also be present. By age 70 years, the penetrance rate is 70%. Genetic testing and clinical surveillance beginning in childhood provide the opportunity to treat the devastating and sometimes fatal complications of this disorder.¹


The RET proto-oncogene is 80 kilobase (kb) long and encodes a putative tyrosine kinase receptor. Its endogenous ligand may be the glial cell line–derived neurotrophic factor (GDNF), which appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. Recent data suggest that an overrepresentation of mutant RET as an undefined second hit undefined event might trigger tumorigenesis. However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways.

Glandular hyperplasia begins with an increase of C cells located in the thyroid gland follicles and can progress to malignancy. Although they are benign, pheochromocytomas can cause a life-threatening hypertensive episode or arrhythmia.

Virtually all MEN 2A patients develop medullary thyroid carcinoma. This is often the first expressed abnormality and usually occurs in the second or third decade of life. The medullary thyroid carcinoma in MEN 2A patients is typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral.

Pheochromocytomas are present in approximately half of MEN 2A patients. They are bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as the medullary thyroid carcinoma or several years later (both primarily occurring in the second or third decade). The pheochromocytomas of MEN 2A patients are nearly all benign. Parathyroid hyperplasias are present in nearly half of patients but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, symptoms can often be elucidated following comprehensive questioning.


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