Medullary Thyroid Carcinoma Associated with Germline RET K666N Mutation.

Medullary Thyroid Carcinoma Associated with Germline RET K666N Mutation.

Thyroid. 2016 Sep 27;

Authors: Xu JY, Grubbs EG, Waguespack SG, Jimenez C, Gagel RF, Sosa JA, Vassilopoulou-Sellin R, Dadu R, Hu MI, Trotter CS, Jackson M, Rich TA, Hyde SM, Sherman SI, Cote GJ

Abstract
BACKGROUND: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The K666N RET DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.
METHODS: The clinical features, genetic data, and family information of eight index MTC patients with a germline RET K666N variant were assessed.
RESULTS: Four probands presented with MTC and extensive nodal metastasis, one with biopsy confirmed distant metastasis. Two additional probands presented with localized disease; however, nodal status was not available. Of the final two probands one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had 2 foci of MTC (largest dimension of 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (ages 5-90), 11 have documented evaluation for MTC. Of these only 2 were found to have elevated basal serum calcitonin upon screening and the remaining patients were in the normal range. One elected to have a thyroidectomy at age 70 was confirmed to have MTC. The other, age 57, elected surveillance. Four prophylactic thyroidectomies were performed with one case of C-cell hyperplasia at 20 years, and 3 cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.
CONCLUSIONS: From this case series, the largest such experience to date, we conclude that the RET K666N variant is likely pathogenic and associated with low penetrance of MTC. However, we feel the findings are insufficient to clearly define its pathogenicity and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, we believe that 'at risk' individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

PMID: 27673361 [PubMed - as supplied by publisher]

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