Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.
BACKGROUND
Missense mutations of the ret proto-oncogene on chromosome 10q11.2 are the underlying cause of hereditary medullary thyroid carcinoma (MTC), either as familial MTC only (FMTC) or as a part of multiple endocrine neoplasia type 2 syndrome (MEN 2). This study presents our experience with direct presymptomatic DNA screening in MEN 2 and FMTC kindreds.


METHODS
Twenty one families with MEN 2 or FMTC were considered in the study. One hundred three individuals had been analyzed; 56 were at risk. The ret mutations were detected by DNA analysis of exons 10, 11, and 16 by using nonradioactive labeling method based on digoxigenin DNA sequencing technique. Serum calcitonin evaluation was carried out in all individuals at risk. Thyroidectomy was performed in those who had to undergo surgery.


RESULTS
The ret mutations were identified in all 21 families. In MEN 2A and FMTC families mutations occurred in exons 10 and 11. MEN 2B families had mutations in exon 16. The most frequent mutation in MEN 2A and FMTC affected codon 634. Twenty one gene carriers were identified in unaffected individuals at risk. Ten of 21 gene carriers had elevated calcitonin levels, and 11 had normal levels. MTC or C-cell hyperplasia was found in six gene carriers with pathologic calcitonin values who underwent operation. In a 5-year-old gene carrier with normal calcitonin values C-cell hyperplasia was evident.


CONCLUSIONS
Direct predictive DNA analysis allows us to identify MEN 2 or FMTC gene carriers and offer them prophylactic treatment.
D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000601:surgery; D002879:Chromosomes, Human, Pair 10; D004252:DNA Mutational Analysis; D004076:Digoxigenin; D029721:Drosophila Proteins; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D006801:Humans; D008197:Lymph Node Excision; D008297:Male; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000601:surgery; D010375:Pedigree; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000601:surgery; D013965:Thyroidectomy
D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D004076:Digoxigenin