Chapter 42

## Abstract

Abstract

1. Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal disorder of tumor formation and developmental abnormalities which affects about 1 in 30,000 individuals. It is characterized by the occurrence of C-cell tumors of the thyroid (medullary thyroid carcinoma), often in association with tumors of the adrenal medulla (pheochromocytoma) and parathyroid hyperplasia or adenoma. Developmental abnormalities, which occur in a minority of cases, principally affect the autonomic nerve plexuses of the intestine. The thyroid C cells, adrenal medulla, and intestinal autonomic plexuses but not the parathyroid glands are derived from neural ectoderm.

2. Distinct clinical subtypes of MEN 2 are defined by the combination of tissues affected and the presence or absence of developmental abnormalities. In MEN 2A, thyroid C cells, adrenal medulla, and parathyroids may all be involved, but developmental abnormalities are rare. In familial MTC (FMTC), only thyroid C-cell tumors are seen; there are no developmental abnormalities. In MEN 2B, thyroid C cells and adrenal medullary tumors are common, but parathyroid abnormality is uncommon; there are constant developmental abnormalities involving hyperplasia of the intestinal autonomic nerve plexuses and disorganized growth of peripheral nerve axons in the lips, oral mucosa, and conjunctiva, giving rise to a characteristic facies. The onset of thyroid and adrenal tumors in MEN 2B tends to occur early, and their behavior may be more aggressive.

3. The gene for MEN 2 was identified by positional cloning. It lies on chromosome 10q11.2. This gene, ret, is a previously known receptor tyrosine kinase. Mutations in ret in MEN 2A and FMTC result in constitutive activation of the receptor; in MEN 2B, the extent of activation is unclear, but the substrate specificity of the tyrosine kinase may be altered. There are clear correlations between specific mutations in ret and the phenotypes that result. Loss-of-activity mutations in ret result in Hirschsprung disease of the colon and rectum (HSCR), in which there is an absence of intestinal autonomic nerve plexuses, in distinction to the hyperplasia in MEN 2B. In a few families, MEN 2A and HSCR coexist, apparently as a result of the same ret mutation; the mechanism for this is not understood. ret is unusual among tumor-predisposing genes in that MEN 2 mutations result in gain of function; it is not a tumor-suppressor gene.

4. The tumors characteristic of MEN 2 also occur in a nonhereditary form. Somatic mutations of ret are found in these tumors, but almost all are of the same type as the germ-line mutations characteristic of MEN 2B, which alter the substrate specificity of the tyrosine kinase. This may imply that ret mutations of the type seen in MEN 2A and FMTC, which result in activation of a normal tyrosine kinase domain, are for the most part effective in tumorigenesis only during a restricted period in development.

5. MEN 2 is a good example of an inherited cancer syndrome in which screening of family members leads to early diagnosis and effective treatment by thyroidectomy and adrenalectomy. Since each of the tissues involved in tumor formation secretes a characteristic product (calcitonin, epinephrine, parathyroid hormone), biochemical monitoring of family members at risk provides a sensitive means of early detection. This can now be refined by predictive genetic testing for the characteristic ret mutations.

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