Medullary thyroid carcinoma may occur as part of several inherited cancer syndromes. In addition to medullary thyroid carcinoma, multiple endocrine neoplasia type 2A (MEN-2A) is characterized by pheochromocytoma and parathyroid gland hyperplasia or adenoma, while MEN-2B is associated with pheochromocytoma developmental anomalies, including marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gut. The only disease phenotype of familial medullary thyroid carcinoma is medullary thyroid carcinoma. These syndromes have an autosomal dominant pattern of inheritance with a high degree of penetrance and variable expression.
Medullary thyroid carcinoma originates in the calcitonin-producing cells (C-cells) of the thyroid gland. In patients with medullary thyroid carcinoma or its precursor, C-cell hyperplasia, supranormal plasma calcitonin levels result from various stimuli. In families with MEN-2, screening for abnormal plasma calcitonin responses has allowed surgery to be performed at an early stage, resulting in improved survival. In MEN-2 families, biochemical manifestations of medullary thyroid carcinoma generally occur between the ages of 5 and 25 years (mean, 15 years), before the development of pheochromocytoma. Thus, the predictive value of clinical tests depends on the age at which they are performed. Biochemical screening allows for early detection of tumors, but treatment even at this stage is not always curative. Knowledge of whether a person is a gene carrier creates the opportunity for possible preventive treatment.
In 1987, the MEN-2 gene was assigned to the pericentromeric region of chromosome 10 by linkage analysis; this permitted reliable determination of gene carrier state. In 1993, MEN-2 was shown to be associated with mutations in the RET proto-oncogene, and specific RET mutations were detected in MEN-2 families.
In order to validate DNA analysis as an early, reliable method for identification of MEN-2 gene carriers, the results of DNA analysis in four large MEN-2 families were compared with the results of biochemical, radiologic, and pathologic examinations. Histopathologic examination revealed that all young carriers who had normal plasma calcitonin test results and who underwent thyroidectomy had small foci of medullary thyroid carcinoma. Obviously, growth of carcinoma at a very young age is in accordance with the pathophysiologic function of the mutated oncogene. In contrast with biochemical tests, DNA analysis permits unambiguous identification of MEN-2 gene carriers and enables surgery to be performed before medullary thyroid carcinoma becomes incurable [1,2].
Little is known about the psychosocial implications of DNA analysis. In MEN-2 families, the youngest generation poses a particularly important clinical problem. Parents with MEN-2 are especially concerned about the future health and welfare of their children. Adaptation of applicants and their family to their newly acquired risk status is necessary to arrive at a well-considered decision about screening and treatment.
In the Netherlands, family members at-risk for MEN-2 can apply for presymptomatic DNA analysis at one of eight clinical genetics centers. During the first visit to the center, applicants are informed by a genetic counselor about the disease and its mode of inheritance, the counseling procedure, and the medical and psychosocial consequences of the test outcome. After (written) informed consent is obtained, blood is taken and sent to a laboratory. During a second appointment, the test outcome is disclosed and its implications discussed. Applicants with an unfavorable DNA test outcome can meet the attending physician after counseling.
The major objectives of the present study were to examine the psychosocial impact of DNA test results and to identify risk factors for maldadaptive reactions to those results. It was thought that the study findings would enable genetic counselors to anticipate psychosocial problems. This article describes the first results of the study.
In 1993, an evaluative study of individuals at risk for MEN-2 was started at the Utrecht University Hospital in cooperation with the Clinical Genetics Center, Utrecht. After the first visit to the genetics center, applicants and the person closest to them--usually the partner or sometimes a parent, if the applicant was an adolescent--were asked by the clinical geneticist to join the study. The minimum age of participation was 16 years. Information about children under age in whom DNA analysis was performed was obtained from the applying parents. This resulted in data on two groups: (1) subjects requesting DNA analysis for themselves and (2) parents applying for their children. Some results of the symptom checklist (SCL90) that are indicative of psychological distress are presented in this article.
Data collection was carried out by means of semistructured interviews and questionnaires 1 week after application (before disclosure of the test results) and 2 weeks and 1 year after disclosure.
Predisclosure Interview--The first interview (before disclosure) focused on the applicant's attitude toward DNA analysis. Topics of examination included: (1) the motivation for applying for testing; (2) expectations about which test outcome was thought to be most likely, and what the impact of the disclosure might be; (3) the perceived threat from genetic testing; (4) the defense against harmful consequences; and (5) knowledge about the test, disease, and its mode of inheritance.
First Postdisclosure Interview--In the first interview after test disclosure, the researcher examined participants' psychological reactions (eg, anxiety, depression, shock, guilt, relief, and disbelief) and social effects resulting from disclosure (eg, stigmatization and altered interpersonal relationships and socioeconomic position). The interviewer also explored how participants dealt with the test outcome, especially the way in which they communicated their feelings to others. Furthermore, participants were asked about what changes they expected in the near future, what options for further screening and treatment they favored, and what kind of support they needed.
Follow-up Interview--The same topics were examined in the follow-up interview (1 year after disclosure), using the same methods. At that time, participants also were asked about life events, changes in their life, and medical treatment they had received.