{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:18:57Z","timestamp":1777875537940,"version":"3.51.4"},"reference-count":27,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      proto-oncogene. The\n                      <jats:italic toggle=\"yes\">\n                        RET\n                        <jats:sup>K666N<\/jats:sup>\n                      <\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      The clinical features, genetic data, and family information of eight index MTC patients with a germline\n                      <jats:italic toggle=\"yes\">\n                        RET\n                        <jats:sup>K666N<\/jats:sup>\n                      <\/jats:italic>\n                      variant were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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\u2009mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3\u2009cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5\u201390 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      From this case series, the largest such experience to date, it is concluded that the\n                      <jats:italic toggle=\"yes\">\n                        RET\n                        <jats:sup>K666N<\/jats:sup>\n                      <\/jats:italic>\n                      variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly 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, \u201cat risk\u201d individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2016.0374","type":"journal-article","created":{"date-parts":[[2016,9,27]],"date-time":"2016-09-27T12:16:26Z","timestamp":1474978586000},"page":"1744-1751","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":10,"title":["Medullary Thyroid Carcinoma Associated with Germline\n                    <i>\n                      RET\n                      <sup>K666N<\/sup>\n                    <\/i>\n                    Mutation"],"prefix":"10.1177","volume":"26","author":[{"given":"Jian Yu","family":"Xu","sequence":"first","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"},{"name":"Baylor College of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth G.","family":"Grubbs","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven G.","family":"Waguespack","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilo","family":"Jimenez","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Gagel","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie A.","family":"Sosa","sequence":"additional","affiliation":[{"name":"Duke University Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rena V.","family":"Sellin","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramona","family":"Dadu","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mimi I.","family":"Hu","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chardria S.","family":"Trotter","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Jackson","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thereasa A.","family":"Rich","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel M.","family":"Hyde","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven I.","family":"Sherman","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilbert J.","family":"Cote","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2016,12,1]]},"reference":[{"key":"e_1_3_3_2_2","unstructured":"The University of Utah Department of Pathology MEN2 Database. 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