Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation.
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.
Machens
Andreas
A
Department of General Surgery, Internal Medicine, Division of Endocrinology, Martin-Luther-University Halle-Wittenberg, D-06097 Halle/Saale, Germany.
Schneyer
Ulrich
U
Holzhausen
Hans-Jürgen
HJ
Raue
Friedhelm
F
Dralle
Henning
H
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
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