Clinical Significance

The primary utility of genetic testing for RET mutations is to confirm the diagnosis of MEN2, to provide predictive risk-assessment testing for family members, and to facilitate prenatal diagnosis of MEN2. Early detection of a pathogenic RET mutation improves the prognosis for presymptomatic individuals by offering an opportunity for therapeutic intervention prior to advanced disease, metastasis, or both.45-47 There is reduced morbidity and mortality achieved by increased clinical monitoring, prophylactic thyroidectomy (followed by thyroid hormone replacement therapy plus autotransplantation of the parathyroids), or both.1,37 This can be a very effective treatment to prevent disease metastasis. Resected thyroid tissue from children and adults with positive genetic findings demonstrates C cell hyperplasia or microscopic foci of malignancy in the absence of biochemical screening abnormalities or clinical symptoms.47 Thus, genetic testing for RET mutations is a more sensitive and specific screening tool than either physiological testing or pathology examination for assessing familial cancer risk for MEN2 in these families.45-47

The clinical significance of a positive finding of a RET mutation is considerable, given that there is virtually 100% penetrance of these mutations for MTC. But genetic findings cannot predict the age of disease onset; thus, continued surveillance for residual or recurrent MTC plus adrenal tumors is included in the follow-up care of MEN2 patients and asymptomatic carriers. About 50% of MEN2 patients (both subtypes A and B) will develop pheochro-mocytoma, while 20% to 30% of MEN2A patients may develop parathyroid hyperplasia.1 Patients with FMTC typically develop only MTC and none of the other clinical manifestations of MEN2A or MEN2B. Each subtype appears to "breed true" within a family. Genetic screening and mutation identification are currently recommended by 5 years of age for children who are at risk in MEN2A families. Children should be screened even earlier if MEN2B has been diagnosed in close relatives, due to the earlier age of onset and aggressive clinical course of this variant.45,46 Some of the other advantages of DNA testing in MEN2 are that the test is relatively noninvasive and low risk, it is usually better tolerated by the patient than biochemical screening by metabolic challenge,37 genotype results are not subject to physiologic status, and serial genotype testing is not necessary. Individuals in MEN2 families who are not carriers of the familial RET mutation have the lower, general population risk for sporadic incidence of these endocrine neoplasias and do not require the same frequent monitoring for abnormal thyroid or adrenal function in the absence of clinical symptoms. Several tyrosine kinase inhibitors that inhibit RET are being tested in clinical trials for treatment of MEN2 neoplasms.48,49

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