Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family

Abstract

Background and objectivesGenetic testing of the RET proto-oncogene allows for early diagnosis of multiple endocrine neoplasia syndrome type 2 and establishes a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of early diagnosis with genetic testing followed by prompt surgery for curing medullary thyroid carcinoma (MTC) as compared to later diagnosis with serum calcitonin. Patients and methodA retrospective, descriptive study of 8 members of a family with MEN 2A due to C634Y mutation. We performed serum calcitonin screening until 1999, and subsequently RET genetic testing. The carriers underwent total thyroidectomy, periodic determination of calcitonin, urinary metanephrines, calcium, and phosphorus, and cervical and abdominal imaging techniques. ResultsFive patients were diagnosed by calcitonin familial screening and at the time of writing all of them had high calcitonin levels. Three patients were diagnosed by genetic testing (an adult and two children) and were free of disease. Calcitonin was closely monitored in the children, who underwent surgery when it started to rise at 6 and 10 years of age respectively, nodular C-cell hyperplasia having been found in both. Three of the eight carriers developed bilateral and asynchronous pheochromocytoma, half had normal urinary metanephrine levels and two also had MTC. No patient had biochemical data suggesting hyperparathyroidism although in one patient multiple parathyroid adenomas were found at thyroidectomy. ConclusionsRET genetic analysis allowed for early diagnosis and treatment with no development of MTC in our patients, gave early guidance about the type of surgery required, and allowed for genotype-phenotype correlation. It demonstrates how genetic change is associated with a pathology we can prevent and manage, thereby improving the prognosis of our patients.