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Psychosocial Consequences of DNA Analysis for MEN Type 2

Psychosocial Consequences of DNA Analysis for MEN Type 2

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.

Grosfeld and associates provide the first report of the impact of DNA-based genetic counseling in patients who are RET germ-line carriers, as well as the myriad psychosocial problems they may experience. Even those who are negative for the RET mutation may have emotional reactions (survivor guilt). Because of the possibly early age of onset of medullary thyroid carcinoma in MEN-2 (patients as young as age 3 have had metastatic medullary thyroid carcinoma), children at increased risk require testing, given approval of their parents.

The authors' extensive experience with MEN-2 will undoubtedly be useful to physicians and genetic counselors who deal with this disease and also the more than 4,000 hereditary disorders affecting humans that require genetic counseling [1].

The authors describe an extremely well-conceived approach to high-risk subjects. Each participant underwent a pretest interview and was thoroughly educated about the potential problems of knowing his or her DNA risk status, including psychological distress and economic penalties (ie, insurance restrictions, employer concerns). At another interview session following disclosure, the authors explored how participants dealt with the test results and how they expressed their feelings about those results with others. Attention was given to options for further screening and therapy. One year follow-up was repeated in a similar manner.

With the current advances in DNA technology, it has become mandatory that physicians be knowledgeable about both DNA testing, including its diagnostic significance and limitations, and genetic counseling. Particular concern must be given to how DNA findings impact on patients at high risk for all the various diseases for which this technology is available, including, of course, cancer. Unfortunately, relatively few genetic counselors are sufficiently knowledgeable about hereditary cancer, and in many cases physicians must continue to assume major responsibility for the counseling process.

RET Test Permits Unparalled Diagnostic Precision

Genetic counseling notwithstanding, the RET test has enabled unparalleled precision in diagnosis. For example, prior to 1993, when the RET proto-oncogene was found to be responsible for MEN-2, identification of at-risk patients required biochemical testing, particularly pentagastrin 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 develop this deadly cancer. Thus, in these cases, a false sense of security may have led to a fatal outcome. False-positive results also occurred with the pentagastrin stimulation test, and these often led to unnecessary total thyroidectomies. The RET test has abrogated these problems and, when available, should be the diagnostic procedure of choice.

DNA testing for MEN-2 will be the panacea for preventing malignancy in persons with this disorder. Clearly, children will require testing, given that small foci of medullary thyroid carcinoma were found in most of the young (4 to 18 years old) MEN-2 family members investigated by Grosfeld et al. This factor necessitates total thyroidectomy at a young age in RET-positive patients. Importantly, DNA testing for the RET proto-oncogene should reduce the uncertainty of cancer risk status and clearly provide opportunities for surgical prevention (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.

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