PROGRESS IN GENETIC SCREENING OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A- IS CALCITONIN TESTING OBSOLETE

Background. Recent identification of RET mutations in multiple endocri ne neoplasia type 2A (MEN 2A) allows a DNA-based approach to diagnosis in lieu of calcitonin sampling. To prospectively evaluate the efficac y of mutational analysis, genetic screening was performed in 124 patie nts (53 male, 71 female; age, 1 month to 80 years) at risk for MEN 2A referred over 3 months. Methods, Analysis used genomic DNA and a polym erase chain reaction-based denaturing gradient gel electrophoresis str ategy for mutation detection at RET codons 609 611, 618, 620, and 634. Ninety-three of 124 patients were from established MEN 2A kindreds (g roup A), and screening replaced calcitonin testing. Twenty-one of 124 patients (group B) represented index cases of medullary thyroid carcin oma (MTC), and DNA analysis was performed to distinguish sporadic from hereditary disease. Ten patients (group C) had modest calcitonin elev ations or had undergone thyroidectomy without confirming pathologic re sults, and testing was undertaken to clarify, status. Results. Group A : RET mutations occurred in 29 (median age, 10 years) of 93 patients, 14 of whom underwent thyroidectomy. No false-positive results were obs erved. Group B: Five (24 %) of 21 patients with seemingly sporadic MTC had RET mutations at codons 618 (one), 620 (one), or 634 (three). Gro up C: Nine of 10 patients with alleged MEN 2A had genetically negative results. Conclusions. Denaturing gradient gel electrophoresis reliabl y detects MEN 2A. Modest calcitonin elevations may bad to a false-posi tive diagnosis of MTC. DNA testing is the optimal approach to evaluati ng MEN 2A. Index cases of sporadic MTC should also undergo DNA analysi s.