Familial medullary thyroid carcinoma with noncysteine RET mutations: Phenotype-genotype relationship in a large series of patients

Familial medullary thyroid carcinoma only is related to germ. line mutation s in the protooncogene RET, mainly in exons 10, whereas noncysteine mutatio ns (exons 13-15) are considered infrequent. We analyzed 148 patients from 4 7 familial medullary thyroid carcinoma only families, and we found noncyste ine RET mutations in 59.5% of these families. Of the index cases with noncy steine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference i n size, bilaterality, presence of C cell hyperplasia, or nodal metastases w as found. Gene carriers with noncysteine RET mutations had a lower incidenc e of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized a t an older age. In conclusion, familial medullary thyroid carcinoma with no ncysteine RET mutations are not infrequent and are overrepresented in presu med sporadic medullary thyroid carcinoma, suggesting that RET analysis shou ld routinely be extended to exons 13,14, and 15. The phenotype is character ized by a late onset of the disease, suggesting a delayed appearance of C c ell disease rather than a less aggressive form. In familial medullary thyro id carcinoma gene carriers, the optimal timing for thyroidectomy remains co ntroversial. Based on these data, we propose that surgery should be perform ed before elevation of the basal calcitonin level, potentially as soon as t he pentagastrin test becomes abnormal.