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Sipple described pheochromocytoma associated with carcinoma of the thyroid gland in 1961.1 Seven years later, multiple endocrine neoplasia type 2 (MEN2) was recognized as a distinct entity from MEN type 1 (MEN1) after analysis of a family with cases of pheochromocytoma, medullary thyroid carcinoma (MTC), and parathyroid hyperplasia.

MEN2 is an autosomal dominant tumor susceptibility syndrome. There are several variants of MEN2, but they are all caused by an activating mutation in the rearranged during transfection (RET) proto-oncogene. The two main variants are MEN2A and MEN2B. More rare variants of MEN2 include familial MTC (FMTC), MEN2A with cutaneous lichen amyloidosis, and MEN2A or FMTC with Hirschsprung's disease (Table 22-1).

Table 22-1. Multiple Endocrine Neoplasia Type 2 and Its Clinical Syndromes

MEN2 has been identified to date in about 500 to 1000 kindreds.2,3 All variants of MEN2 show a high penetrance for MTC. In fact, more than 90% of MEN2 carriers eventually show evidence of MTC or its precursor, C-cell hyperplasia.4,5 MEN2A, which accounts for 75% of MEN2 cases, is a syndrome of MTC in more than 90% of adult gene carriers, unilateral or bilateral pheochromocytoma in 50%, and multigland parathyroid tumors in 20% to 30%.3–5 MTC is the first neoplastic manifestation in most MEN2 kindreds because of its earlier and overall higher penetrance. MEN2B is characterized by MTC and pheochromocytoma, decreased upper-to-lower body ratio, a marfanoid habitus, and mucosal and intestinal ganglioneuromatosis. Hyperparathyroidism (HPT) does not occur in individuals with MEN2B.6 Patients with FMTC only develop MTC; they do not develop any of the other tumors associated with MEN2A and 2B.

To be classified as having FMTC, a kindred must have more than 10 carriers displaying MTC; multiple affected members or carriers older than age 50 years; and an adequate medical history to exclude pheochromocytomas or HPT, especially in older members.3 These rigorous criteria are used to avoid misclassifying small MEN2A kindreds whose members may not yet have developed pheochromocytomas or HPT. Ultimately, 20% to 25% of MTC cases are recognized as hereditary (see Chapter 6).

Mutations in the RET gene, located near the centromere on chromosome 10, cause MEN2, and the affected protein is a receptor tyrosine kinase.7 Its extracellular portion contains four cadherin-like repeats, a calcium-binding site, and a cysteine-rich domain. The intracellular portion contains a typical tyrosine kinase domain. RET disruption ...

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