{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T20:45:24Z","timestamp":1769805924859,"version":"3.49.0"},"reference-count":62,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,17]]},"abstract":"<jats:p>\n                    Multiple endocrine neoplasia type 2 (MEN2) is caused by germline\n                    <jats:italic>RET<\/jats:italic>\n                    mutations and is characterized by the presence of medullary thyroid cancer (MTC) associated or not with other endocrine neoplasias. MEN2 is classified as MEN2A, including different variants, and MEN2B. The aim of the present study was to evaluate the impact of the\n                    <jats:italic>RET<\/jats:italic>\n                    genetic screening in redefining the prevalence of the different MEN2 variants inside the MEN2A group. This study included 223 MEN2 families: 202 MEN2A (55 MEN2A classical, 3 MEN2A + lichen cutaneous amyloidosis (CLA), 5 MEN2A + Hirschsprung disease (HD) and 139 FMTC variants) and 21 MEN2B.\n                    <jats:italic>RET<\/jats:italic>\n                    germline mutations found in MEN2A classical variant, as well as in MEN2A + CLA and MEN2A + HD, were the \u2018high-risk\u2019 category in most cases, while only 5\/139\n                    <jats:italic>RET<\/jats:italic>\n                    -mutated FMTC families showed a \u2018high-risk\u2019 category mutation. The most frequent mutation in the FMTC variant was the p.Val804Met (62\/139). Among all, 116 families had a known history of hereditary disease (group A) at diagnosis and 107 had an apparently sporadic form of MTC (group B). Different MEN2A variants and\n                    <jats:italic>RET<\/jats:italic>\n                    ATA risk level category mutations were observed in the two groups. In conclusion, we demonstrated that the FMTC is the most prevalent MEN2A variant; \u2018moderate-risk\u2019\n                    <jats:italic>RET<\/jats:italic>\n                    mutations, particularly non-cysteine mutations, are almost exclusively present in the FMTC variant; about 50% of hereditary MTC kindreds are primarily discovered by the\n                    <jats:italic>RET<\/jats:italic>\n                    genetic screening, confirming the clinical utility of performing this analysis in all cases of MTC.\n                  <\/jats:p>","DOI":"10.1530\/erc-25-0244","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T11:54:11Z","timestamp":1765972451000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Redefining the prevalence of different clinical variants in MEN2A and their correlation with RET germline mutations: a single-center series and experience"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5957-8902","authenticated-orcid":true,"given":"Cristina","family":"Romei","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Ramone","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Ciampi","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Casalini","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Prete","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Bottici","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Cappagli","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Agate","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Molinaro","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Gambale","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Brogioni","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Matrone","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Elisei","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Nature","first-page":"458","article-title":"Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A","volume":"363","author":"Mulligan LM","year":"1993","unstructured":"Mulligan LM\n, \nKwok JB\n, \nHealey CS\n, et al.\n Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. 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(https:\/\/doi.org\/10.1186\/s13053-024-00276-6)"},{"key":"bib13","series-title":"Clin Endocrinol","first-page":"892","article-title":"Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?","volume":"82","author":"Romei C","year":"2015","unstructured":"Romei C\n, \nTacito A\n, \nMolinaro E\n, et al.\n Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol 2015 82 892\u2013899. (https:\/\/doi.org\/10.1111\/cen.12686)"},{"key":"bib14","series-title":"Ann Endocrinol","first-page":"187","article-title":"Clinical utility of genetic diagnosis for sporadic and hereditary medullary thyroid carcinoma","volume":"80","author":"Elisei R","year":"2019","unstructured":"Elisei R\n, \nBottici V\n, \nCappagli V\n, et al.\n Clinical utility of genetic diagnosis for sporadic and hereditary medullary thyroid carcinoma. 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(https:\/\/doi.org\/10.1210\/jc.2011-2046)"},{"key":"bib17","series-title":"Am J Clin Oncol","first-page":"508","article-title":"Early, prophylactic thyroidectomy in hereditary medullary thyroid carcinoma: a 26-year monoinstitutional experience","volume":"38","author":"Pelizzo MR","year":"2015","unstructured":"Pelizzo MR\n, \nTorresan F\n, \nBoschin IM\n, et al.\n Early, prophylactic thyroidectomy in hereditary medullary thyroid carcinoma: a 26-year monoinstitutional experience. Am J Clin Oncol 2015 38 508\u2013513. (https:\/\/doi.org\/10.1097\/coc.0b013e3182a78fec)"},{"key":"bib18","series-title":"Case Rep Endocrinol","article-title":"A new MEN2 syndrome with clinical features of both MEN2A and MEN2B associated with a new RET germline deletion","volume":"2020","author":"Giani C","year":"2020","unstructured":"Giani C\n, \nRamone T\n, \nRomei C\n, et al.\n A new MEN2 syndrome with clinical features of both MEN2A and MEN2B associated with a new RET germline deletion. 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(https:\/\/doi.org\/10.1210\/jc.2018-02102)"},{"key":"bib23","series-title":"J Clin Endocrinol Metab","first-page":"770","article-title":"A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A","volume":"83","author":"Berndt I","year":"1998","unstructured":"Berndt I\n, \nReuter M\n, \nSaller B\n, et al.\n A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 1998 83 770\u2013774. (https:\/\/doi.org\/10.1210\/jc.83.3.770)"},{"key":"bib24","series-title":"Clin Lab","first-page":"273","article-title":"Change in the spectrum of RET mutations diagnosed between 1994 and 2006","volume":"53","author":"Frank-Raue K","year":"2007","unstructured":"Frank-Raue K\n, \nRondot S\n, \nSchulze E\n, et al.\n Change in the spectrum of RET mutations diagnosed between 1994 and 2006. 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(https:\/\/doi.org\/10.3390\/cancers13215554)"},{"key":"bib1","series-title":"Nature","first-page":"458","article-title":"Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A","volume":"363","author":"Mulligan LM","year":"1993","unstructured":"Mulligan LM\n, \nKwok JB\n, \nHealey CS\n, et al.\n Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993 363 458\u2013460. (https:\/\/doi.org\/10.1038\/363458a0)"},{"key":"bib2","series-title":"Hum Mol Genet","first-page":"237","article-title":"Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours","volume":"3","author":"Eng C","year":"1994","unstructured":"Eng C\n, \nSmith DP\n, \nMulligan LM\n, et al.\n Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 1994 3 237\u2013241. (https:\/\/doi.org\/10.1093\/hmg\/3.2.237)"},{"key":"bib3","series-title":"JAMA","first-page":"1575","article-title":"The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis","volume":"276","author":"Eng C","year":"1996","unstructured":"Eng C\n, \nClayton D\n, \nSchuffenecker I\n, et al.\n The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996 276 1575\u20131579. (https:\/\/doi.org\/10.1001\/jama.1996.03540190047028)"},{"key":"bib4","series-title":"Recent Results Cancer Res","first-page":"139","article-title":"Hereditary medullary thyroid cancer genotype-phenotype correlation","volume":"204","author":"Frank-Raue K","year":"2015","unstructured":"Frank-Raue K\n & \nRaue F\n\n. Hereditary medullary thyroid cancer genotype-phenotype correlation. Recent Results Cancer Res 2015 204 139\u2013156. (https:\/\/doi.org\/10.1007\/978-3-319-22542-5_6)"},{"key":"bib5","series-title":"GeneReviews","article-title":"Multiple endocrine neoplasia type 2","author":"Eng C","year":"1993","unstructured":"Eng C\n & \nPlitt G\n\n. Multiple endocrine neoplasia type 2. In GeneReviews. Seattle, WA, USA: University of Washington, 1993. (http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1257\/)"},{"key":"bib6","series-title":"Endocr Relat Cancer","first-page":"T29","article-title":"A comprehensive review on MEN2B","volume":"25","author":"Castinetti F","year":"2018","unstructured":"Castinetti F\n, \nMoley J\n, \nMulligan L\n, et al.\n A comprehensive review on MEN2B. Endocr Relat Cancer 2018 25 T29\u2013T39. (https:\/\/doi.org\/10.1530\/erc-17-0209)"},{"key":"bib7","series-title":"J Oncol","first-page":"705036","article-title":"Genetic and clinical features of multiple endocrine neoplasia types 1 and 2","volume":"2012","author":"Romei C","year":"2012","unstructured":"Romei C\n, \nPardi E\n, \nCetani F\n, et al.\n Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. J Oncol 2012 2012 705036. (https:\/\/doi.org\/10.1155\/2012\/705036)"},{"key":"bib8","series-title":"Br J Surg","first-page":"278","article-title":"Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity","volume":"73","author":"Farndon JR","year":"1986","unstructured":"Farndon JR\n, \nLeight GS\n, \nDilley WG\n, et al.\n Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986 73 278\u2013281. (https:\/\/doi.org\/10.1002\/bjs.1800730411)"},{"key":"bib9","series-title":"Thyroid","first-page":"567","article-title":"Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma","volume":"25","author":"Wells SA","year":"2015","unstructured":"Wells SA\n, \nAsa SL\n, \nDralle H\n, et al.\n Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015 25 567\u2013610. (https:\/\/doi.org\/10.1089\/thy.2014.0335)"},{"key":"bib10","series-title":"Genes","first-page":"698","article-title":"Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations","volume":"10","author":"Elisei R","year":"2019","unstructured":"Elisei R\n, \nTacito A\n, \nRamone T\n, et al.\n Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations. Genes 2019 10 698. (https:\/\/doi.org\/10.3390\/genes10090698)"},{"key":"bib11","series-title":"Curr Opin Oncol","first-page":"212","article-title":"The role of genetic testing in prostate cancer screening, diagnosis, and treatment","volume":"34","author":"de la Calle CM","year":"2022","unstructured":"de la Calle CM\n, \nBhanji Y\n, \nPavlovich CP\n, et al.\n The role of genetic testing in prostate cancer screening, diagnosis, and treatment. Curr Opin Oncol 2022 34 212\u2013218. (https:\/\/doi.org\/10.1097\/cco.0000000000000823)"},{"key":"bib12","series-title":"Hered Cancer Clin Pract","first-page":"4","article-title":"Current prospects of hereditary adrenal tumors: towards better clinical management","volume":"22","author":"Ohmoto A","year":"2024","unstructured":"Ohmoto A\n, \nHayashi N\n, \nTakahashi S\n, et al.\n Current prospects of hereditary adrenal tumors: towards better clinical management. Hered Cancer Clin Pract 2024 22 4. 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