title: Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This study was based on systematic evaluation of the literature using evidence-based criteria.
  
  
  RESULTS
  (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.
  
  
  CONCLUSIONS
  These genotype-phenotype correlations provide a solid foundation on which to base surgical concepts, leaving little room for randomized controlled clinical trials.
authors: Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06097, Halle/Saale, Germany. AndreasMachens@aol.com
authors: Andreas
authors: A
authors: Machens
authors: Henning
authors: H
authors: Dralle
mesh_terms: D000367:Age Factors; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D003062:Codon; D018450:Disease Progression; D019317:Evidence-Based Medicine; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics / Q000473:pathology / Q000601:surgery; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D013965:Thyroidectomy
chemical_list: D003062:Codon; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human