Age-related disease penetrance in a large medullary thyroid cancer family with a codon 609 RET gene mutation

Background: Familial medullary thyroid cancer (MTC) is a form of type 2 multiple endocrine neoplasia in which individuals develop MTC as the sole phenotypic manifestation of their disease. A previous study has suggested that patients with familial MTC may have a later age of onset (and more indolent course) of MTC than is observed in individuals with multiple endocrine neoplasia type 2A. Methods and Results: The age-related penetrance nf MTC, C-cell hyperplasia, and a positive pentagastrin test for carriers of a codon 609 mutation of the RET gene in a large MTC family was determined. Pentagastrin testing and surgical pathology findings for patients who had thyroidectomies were correlated with RET sequence analysis findings. The penetrance of this mutation for the development of MTC was 0% at age 20, 10% at age 30, 50% at age 45, and approximately 100% at age 60. The ages of onset of C-cell hyperplasia and a positive pentagastrin stimulation test were similar, and both preceded the age of onset of MTC. Carriers of the mutated gene in this family had a later age of onset of disease than has been reported for families with multiple endocrine neoplasia type 2A and 2B syndromes. Conclusions: These results may have implications for the clinical management of MTC families with a 609 mutation.