Abstract
Since DNA tests have enabled reliable identification of asymptomatic RET (rearranged during transfection) gene carriers, myriads of publications have appeared on genotype-phenotype relationships. A comprehensive appraisal of this body of evidence using evidence-based methodology is pending. This study was based on systematic evaluation of the literature using evidence-based criteria. (1) There is a distinct age-related progression of hereditary medullary thyroid carcinoma (MTC) in carriers of RET mutations (grade C). (2) Among the high-risk RET mutations, those in codon 634 cause higher penetrance rates of the multiple endocrine neoplasia 2A phenotype (MTC, pheochromocytoma, and parathyroid hyperplasia/adenoma) than mutations in codons 609, 611, 618, and 620, irrespective of the amino acid substituting for cysteine (grade C). (3) DNA-based screening is superior to calcitonin-based screening in asymptomatic RET carriers (grade C). (4) Using a worst-case scenario, i.e., considering the earliest finding of MTC in asymptomatic RET carriers, pre-emptive thyroidectomy should be performed before that time (grade C) to be truly prophylactic. Specifically, for carriers of highest-risk mutations (codon 918): within the first year of life; for carriers of high-risk mutations (codon 609, 611, 618, 620, 630, and 634): before the age of 5 years; and for carriers of least-high risk mutations (codon 768, 790, 791, 804, and 891): before the age of 5-10 years. Strict adherence to these grade C recommendations can result in undertreatment of the former (codon 634) and overtreatment of the latter. These genotype-phenotype correlations provide a solid foundation on which to base surgical concepts, leaving little room for randomized controlled clinical trials.
Published Version
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