Abstract
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor of the thyroid parafollicular C-cells associated with activating mutations in the rearranged during transfection (RET) kinase proto-oncogene. We report the clinical outcomes of a family with a rare germline RET K666N pathogenic variant discovered incidentally by genetic testing performed for breast cancer risk stratification in an asymptomatic 24-year-old woman. Subsequent genetic testing identified the same pathogenic variant in her 21-year-old sister, 60-year-old father, and 84-year-old paternal grandmother. The proband and her sister had no biochemical or imaging evidence of MTC. The 60-year-old father had mildly elevated serum calcitonin and multiple thyroid nodules on ultrasound. Fine-needle aspirate thyroid biopsy cytology suggested MTC so he underwent total thyroidectomy. Surgical pathology demonstrated bilateral subcentimeter foci of MTC and C-cell hyperplasia. The 84-year-old grandmother was also found to have multiple thyroid nodules and elevated calcitonin but declined further evaluation. There was no biochemical evidence of other multiple endocrine neoplastic type 2 (MEN2)-associated tumors (ie, parathyroid adenoma, pheochromocytoma) in the family. These data, along with prior rare reports in the literature, suggest that monoallelic germline RET K666N pathogenic variants carry a risk of familial MTC that demonstrate age-dependent expressivity but low penetrance of other MEN2 tumors in affected individuals.