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Multiple endocrine neoplasia type 2 (MEN-2) is known to be associated with missense mutations in the RET proto-oncogene, and specific RET mutations have been detected in families. This disease can be deadly since more than half of patients who harbor the genetic susceptibility present with metastatic medullary thyroid carcinoma. About 50% of patients affected with MEN-2 will develop pheochromocytoma (often bilateral), and 10% to 20% will develop functioning parathyroid adenomas.
Multiple endocrine neoplasia type 2 (MEN-2) is known to be associatedwith missense mutations in the RET proto-oncogene, and specificRET mutations have been detected in families. This disease canbe deadly since more than half of patients who harbor the geneticsusceptibility present with metastatic medullary thyroid carcinoma.About 50% of patients affected with MEN-2 will develop pheochromocytoma(often bilateral), and 10% to 20% will develop functioning parathyroidadenomas.
Grosfeld and associates provide the first report of the impactof DNA-based genetic counseling in patients who are RET germ-linecarriers, as well as the myriad psychosocial problems they mayexperience. Even those who are negative for the RET mutation mayhave emotional reactions (survivor guilt). Because of the possiblyearly age of onset of medullary thyroid carcinoma in MEN-2 (patientsas young as age 3 have had metastatic medullary thyroid carcinoma),children at increased risk require testing, given approval oftheir parents.
The authors' extensive experience with MEN-2 will undoubtedlybe useful to physicians and genetic counselors who deal with thisdisease and also the more than 4,000 hereditary disorders affectinghumans that require genetic counseling .
The authors describe an extremely well-conceived approach to high-risksubjects. Each participant underwent a pretest interview and wasthoroughly educated about the potential problems of knowing hisor her DNA risk status, including psychological distress and economicpenalties (ie, insurance restrictions, employer concerns). Atanother interview session following disclosure, the authors exploredhow participants dealt with the test results and how they expressedtheir feelings about those results with others. Attention wasgiven to options for further screening and therapy. One year follow-upwas repeated in a similar manner.
With the current advances in DNA technology, it has become mandatorythat physicians be knowledgeable about both DNA testing, includingits diagnostic significance and limitations, and genetic counseling.Particular concern must be given to how DNA findings impact onpatients at high risk for all the various diseases for which thistechnology is available, including, of course, cancer. Unfortunately,relatively few genetic counselors are sufficiently knowledgeableabout hereditary cancer, and in many cases physicians must continueto assume major responsibility for the counseling process.
RET Test Permits Unparalled Diagnostic Precision
Genetic counseling notwithstanding, the RET test has enabled unparalleledprecision in diagnosis. For example, prior to 1993, when the RETproto-oncogene was found to be responsible for MEN-2, identificationof at-risk patients required biochemical testing, particularlypentagastrin stimulation of calcitonin. This test, unfortunately,was plagued by false-negative results.
Specifically, a subset of patients received the "good news"that their test was "negative," only to eventually developthis deadly cancer. Thus, in these cases, a false sense of securitymay have led to a fatal outcome. False-positive results also occurredwith the pentagastrin stimulation test, and these often led tounnecessary total thyroidectomies. The RET test has abrogatedthese problems and, when available, should be the diagnostic procedureof choice.
DNA testing for MEN-2 will be the panacea for preventing malignancyin persons with this disorder. Clearly, children will requiretesting, given that small foci of medullary thyroid carcinomawere found in most of the young (4 to 18 years old) MEN-2 familymembers investigated by Grosfeld et al. This factor necessitatestotal thyroidectomy at a young age in RET-positive patients. Importantly,DNA testing for the RET proto-oncogene should reduce the uncertaintyof cancer risk status and clearly provide opportunities for surgicalprevention (prophylactic total thyroidectomy) for germ-line carriers.
1. McKusick VA(ed): Medelian Inheritance in Man, 11th ed, vols.1 and 2. Baltimore and London, The Johns Hopkins University Press,1994.