Chapter 13: Multiple Endocrine Neoplasia
The gene involved in the pathogenesis of multiple endocrine neoplasia (MEN) type 2 syndromes is
(B) MEN2 syndromes are characterized by the presence of medullary thyroid cancer (MTC) and pheochromocytomas. The MEN2A variant is further characterized by primary hyperparathyroidism (HPT). MEN2B, on the other hand, is notable for mucosal and musculoskeletal abnormalities, which include neuromas of the mouth and lips, “marfanoid” habitus, and ganglioneuromatosis of the bowel myenteric and submucosal plexus. Additional abnormalities associated with MEN2B include congenital hip dislocation, pes cavus, pectus excavatum, and kyphosis. Both MEN2 syndromes are inherited in an autosomal dominant fashion with nearly 100% penetrance but varying degrees of expressivity. Mutations in the RET (rearranged during transfection) proto-oncogene, which maps to chromosome 10, have been identified in individuals with MEN2 syndromes. This gene encodes a receptor tyrosine kinase important in transmembrane signal transduction.
MEN2A variants are characterized by mutations in one of five codons, which specify highly conserved cysteine residues in the extracellular domain (see Fig. 13-3).
FIGURE 13-3. Structure of the RET tyrosine kinase receptor. RET mutations in multiple endocrine neoplasia (MEN) type 2 (A) and sporadic medullary thyroid cancer (MTC) (B). CLA, cutaneous lichen amyloidosis; FMTC, familial medullary thyroid cancer. A Reproduced with permission from Wells S and Franz C: Medullary carcinoma of the thyroid. World J Surg 24:954, 2000, Springer-Verlag.
In the nonmutated RET gene, two cysteine residues are juxtaposed and a resultant disulfide bond is formed. When the RET gene is mutated such that one of these cysteine residue is replaced, the free remaining cysteine residue is available to form a disulfide bond with a cysteine residue of a neighboring receptor. When this aberrant disulfide bond is formed, dimerizing the two receptors, the result is a constitutively activated tyrosine kinase and unopposed signal transduction (see Fig. 13-4).
FIGURE 13-4. RET mutations in the cysteine-rich extracellular domain lead to dimerization and constitutive activation, whereas mutations in the intracellular domain result in changed substrate specificity.
In contrast to MEN2A, MEN2B variants are characterized by a single point mutation in the catalytic domain of the RET gene product. This mutation, specifying replacement of a methionine with a threonine residue at the tyrosine kinase domain, occurs most frequently at codon 918 and results in changed substrate specificity.
In both MEN2 syndromes, there seems to be a strong ...