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
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
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 .
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
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,