Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A
C J Lips1, R M Landsvater, J W Höppener
1Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
Background:
Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene.
Methods:
Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene.
Results:
Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia.
Conclusions:
Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.
Insights
DNA analysis definitively identifies carriers of the Multiple Endocrine Neoplasia type 2A (MEN-2A) gene, unlike less reliable biochemical tests. This genetic testing is crucial for early detection and management of MEN-2A related conditions.
Area of Science:
- Genetics
- Oncology
- Endocrinology
Background:
- Multiple Endocrine Neoplasia type 2A (MEN-2A) is a hereditary condition associated with medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma.
- Missense mutations in the RET proto-oncogene are the known cause of MEN-2A.
- Genetic testing for RET mutations allows for the identification of individuals at high risk for developing medullary thyroid carcinoma.
Purpose of the Study:
- To compare the diagnostic accuracy of biochemical tests with DNA analysis for identifying carriers of the MEN-2A gene.
- To evaluate the reliability of plasma calcitonin and urinary catecholamine measurements versus genetic testing in MEN-2A families.
Main Methods:
- Screening of 300 subjects from four MEN-2A families from 1975 onwards.
- Biochemical testing included plasma calcitonin stimulation tests and urinary catecholamine/metabolite excretion.
- Carrier status was determined by DNA analysis, including linkage analysis and RET gene mutation analysis.
Main Results:
- Of 80 confirmed MEN-2A gene carriers, 66 presented with abnormal calcitonin levels and medullary thyroid carcinoma.
- Fourteen young carriers had normal calcitonin tests, but 8 were found to have early-stage medullary thyroid carcinoma upon thyroidectomy.
- DNA analysis identified 68 individuals without the MEN-2A gene, none of whom developed MEN-2A associated tumors.
Conclusions:
- DNA analysis provides unambiguous identification of MEN-2A gene carriers.
- Biochemical tests can yield false-negative results in carriers, particularly in younger individuals.
- Genetic testing is superior to biochemical screening for accurate diagnosis and management of MEN-2A.
