title: Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation.
abstract: BACKGROUND
  Individual germline mutations in the RET (REarranged during Transfection) proto-oncogene may set the time window for malignant progression from C-cell hyperplasia to familial medullary thyroid carcinoma. Owing to the close genotype-phenotype correlation, genetic information may lend to individual timing of prophylactic thyroidectomy according to RET genotype. Limited information exists on the Cys630 RET genotype. Most of the few published carriers of this genotype who developed medullary thyroid carcinomas (MTCs) were in their mid-30s.
  
  
  METHODS
  This case series of a German RET family with the Cys630Arg genotype was assembled to study malignant progression of MTC in this rare RET genotype.
  
  
  RESULTS
  There was considerable variability of malignant progression from C-cell hyperplasia to MTC in carriers of the Cys630Arg genotype. In these persons, MTCs had developed by the age of 32 years (index patient, pT2bN0M0), and 15 years and 1 year (non-index patients; pT1apN1bM0 and pT1bpN0M0, respectively). The Cys630Arg genotype always segregated with the familial medullary thyroid carcinoma phenotype.
  
  
  CONCLUSIONS
  The Cys630 RET genotype may have a more vigorous transforming activity than currently thought and can cause MTC in RET gene carriers within the first year of life. Starting in early infancy, identified RET gene carriers should be scrutinized until stimulated serum calcitonin levels become positive or, when these remain normal, should undergo prophylactic thyroidectomy before they reach 5 years of age.
authors.affiliation: Department of General Surgery, Internal Medicine, Division of Endocrinology, Martin-Luther-University Halle-Wittenberg, D-06097 Halle/Saale, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Machens
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schneyer
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Holzhausen
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Raue
authors.forename: Henning
authors.initials: H
authors.lastname: Dralle
mesh_terms: D001120:Arginine; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000473:pathology; D003545:Cysteine; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010375:Pedigree; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D001120:Arginine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D003545:Cysteine