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Multiple Endocrine Neoplasia type 2A
The first step in the management of a kindred with MEN-2A or FMTC is to perform a ret protooncogene analysis on the index-case 1,2 (Figure 1). As all known mutations are located in 7 exons, polymerase chain reaction amplification of the appropriate ret gene exons and direct DNA sequencing are straightforward and practical. When a mutation is found, it is screened in all first-degree relatives to determine which individuals are gene carriers. This analysis is performed after informed consent has been obtained and should be repeated twice on separate blood samples to exclude the possibility of a sample mix-up or laboratory errors.
In a family with an identified mutation, 50 % of first-degree relatives do not carry the mutated gene and their risk of developing the disease is similar to that of the general population. These subjects are reassured and require no further evaluation. In gene carriers, two approaches have been utilized to guide further management. The first approach advocates annual pentagastrin testing, starting before the age of 6. Total thyroidectomy should be performed when the pentagastrin test becomes abnormal, and this occurs around the age of 10 to 13 years. Approximately 50 % of these children had microscopic MTC at the time of pentagastrin test conversion. The interpretation of borderline results of the pentagastrin test has posed a problem, repeated testing over a period of months to years has been proposed as a solution to this problem but it is both inconvenient and costly, and thus should lead to surgery. About 90 % of children managed in this way exhibit evidence of long-term cure (as shown by negative pentagastrin testing). Recurrences have been observed in about 5 % of cases, and may be due to undetected metastases in neck lymph nodes at the time of initial surgery. Another plausible explanation is that thyroidectomy was not complete, leaving a few residual C cells, which would then be the origin of recurrent MTC. An alternative approach to management of MEN-2A, which is gaining momentum, is to decide to perform thyroidectomy exclusively on the basis of the genetic test result. A positive genetic test signifies that the affected child has a 90 % or greater probability of developing MTC at some point during life. Atotal thyroidectomy before the age of 6 years should ideally remove normal and malignant C cells before the development of metastases. In experienced hands, the morbidity caused by total thyroidectomy is not worse in children than in adults and treatment with thyroxine is simple and devoid of long-term side effects. The obvious advantages of this approach are the simplicity of the decision-making process, avoidance of inconvenient repeated pentagastin testing and the highest probability that any transformed C cell will be removed before the development of metastatic disease. Furthermore, there is usually a positive attitude of family members towards genetic testing in kindreds with hereditary MTC, and early surgery in an affected child is usually well accepted by parents 30,31. At this point in time however, it is not clear whether long-term studies of children who are thyroidectomized at an earlier age, based exclusively on genetic testing will result in a cure rate greater than the 90 % found in children in whom the decision was based on pentagastrin testing. Familial medullary thyroid carcinoma In families with mutations in exons 13 or 14, C-cell disease may emerge later in life, usually during the third or fourth decade and MTC then has an indolent course. It was therefore suggested that pentagastrin testing should be performed every other year in gene carriers, starting around the age of 10 years, and that thyroidectomy only be performed when the pentagastrin test becomes abnormal. Multiple Endocrine Neoplasia type 2B In the face of phenotypic abnormalities associated with gastro-intestinal disorders in a child, the physician should promptly consider the diagnosis of MEN-2B. The diagnosis should then be confirmed by a ret proto-oncogene analysis. A total thyroidectomy may be decided during the first year of life or at the time of diagnosis. Other screening studies Prospective annual screening for pheochromocytoma in gene 2A and 2B carriers by measurement of plasma or of 24-hour urinary normetanephrines and metanephrines allows early detection of pheochromocytoma. In subjects with a codon 634 mutation, calcium and PTH 1-84 concentrations are measured yearly. Patients with apparently sporadic MTC Approximately 5 % of patients with apparently sporadic MTC have germline mutations of the ret proto-oncogene, and consequently hereditary MTC. Cases discovered include several de novo germline mutations and members of previously unidentified kindreds. A consensus is being formulated in favor of a peripheral blood ret proto-oncogene analysis for all patients with apparently sporadic MTC. If the test is negative, the probability that this individual might be a member of a kindred with hereditary MTC without ret proto-oncogene mutation is less than 5 %. Despite a negative ret proto-oncogene analysis, pentagastrin screening is usually performed in first-degree relatives, particularly for young age at diagnosis of the MTC or histological features suggestive of a hereditary tumor (bilateral and multifocal tumor, presence of C cell hyperplasia). If pentagastrin test results are normal in 3 first-degree relatives aged more than 30 years, the probability of hereditary MTC drops to an insignificant level. |
