Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated?

RET proto-oncogene mutations are associated with medullary thyroid carcinomas usually requiring preventive thyroidectomy in gene carriers. We present a large kindred with the Y791F mutation in the RET proto-oncogene that did not have medullary thyroid carcinomas.

Eight members of a Danish family with the Y791F mutation participated. All gene carriers underwent pentagastrin testing, and measurements of serum calcitonin. In the index person, exons 10, 11, and 13-16 of the RET proto-oncogene were screened. In the rest of the individuals only exon 13 was analysed. Mutation analysis was done by direct bidirectional sequencing of PCR products on an ABI 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA).

The index person was screened genetically due to goitre at a young age. A total of 27 members of the family underwent genetic testing. Twelve (44.4%, 95% CI: 25.5%-64.7%) had the mutation (age range 13-84 years). None of these had abnormal pentagastrin tests (0%, 95% CI: 0%-26.5%). We found no significant differences in basal serum calcitonin concentrations between gene carriers (mean +/- SD: 0.16 +/- 0.54 pmol/l, n = 11) and non-gene carriers (0.55 +/- 0.86 pmol/l, n = 6, 2 P = 0.29). None showed signs of primary hyperparathyroidism or phaeochromocytoma.

The Y791F RET proto-oncogene mutation may have a low penetrance. In selected cases, prophylactic thyroidectomy may be replaced by watchful waiting with repeated pentagastrin testing, provided careful evaluation of risks and benefits is performed.