{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:15:11Z","timestamp":1781777711214,"version":"3.54.5"},"reference-count":38,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Progetti di Ricerca di Ateneo, University of Pisa","award":["PRA_2022_51"],"award-info":[{"award-number":["PRA_2022_51"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Hereditary medullary thyroid carcinoma (MTC) is an inherited syndrome accounting for 25% of MTC cases. It is caused by germline RET mutations, which can be inherited or occur de novo.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>This study aimed to define the prevalence and genetics of de novo MEN2 syndromes, which are not yet fully understood, and to characterize the parental origin of the RET de novo mutation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We selected 152 of 215 families with hereditary MTC. In de novo cases, we sequenced the wild-type and mutated alleles of the index cases and compared their single nucleotide polymorphism profiles with those of their parents. Digital droplet PCR was performed to determine the presence of mosaicism in both the index case and the parents.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In 24 of 152 (15.78%) families, the index case had a de novo mutation. Single nucleotide polymorphism analysis demonstrated that in all cases, the mutation occurred on the paternal allele. The absence of mosaicism supported the hypothesis that the mutation occurred during spermatogenesis. The mean age of fathers at the time of conception was, in some cases but not all, relatively advanced.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The prevalence of de novo hereditary MEN2 syndromes was approximately 16%, including MEN2B, and around 9% for other phenotypes. All de novo cases were of paternal origin and likely resulted from an acquired alteration in sperm DNA. The possible role of advanced paternal age in promoting de novo mutations could not be ruled out.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf171","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T01:41:09Z","timestamp":1743212469000},"page":"e3559-e3565","source":"Crossref","is-referenced-by-count":7,"title":["Prevalence and genetics of \u201cde novo\u201d MEN2 syndromes"],"prefix":"10.1210","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6017-5166","authenticated-orcid":false,"given":"Roberta","family":"Casalini","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5957-8902","authenticated-orcid":false,"given":"Cristina","family":"Romei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Bottici","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Cappagli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tascini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Matrone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-6916","authenticated-orcid":false,"given":"Alessandro","family":"Prete","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6345-9343","authenticated-orcid":false,"given":"Raffaele","family":"Ciampi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Ramone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5333-9257","authenticated-orcid":false,"given":"Rossella","family":"Elisei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa , 56100 Pisa ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"issue":"6","key":"2025101519591192000_dgaf171-B1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/00005792-198411000-00001","article-title":"Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients","volume":"63","author":"Saad","year":"1984","journal-title":"Medicine (Baltimore)"},{"key":"2025101519591192000_dgaf171-B2","doi-asserted-by":"crossref","first-page":"705036","DOI":"10.1155\/2012\/705036","article-title":"Genetic and clinical features of multiple endocrine neoplasia types 1 and 2","volume":"2012","author":"Romei","year":"2012","journal-title":"J Oncol"},{"issue":"8","key":"2025101519591192000_dgaf171-B3","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1210\/js.2018-00178","article-title":"Update on multiple endocrine neoplasia type 2: focus on medullary thyroid carcinoma","volume":"2","author":"Raue","year":"2018","journal-title":"J Endocr Soc"},{"issue":"3","key":"2025101519591192000_dgaf171-B4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF03347719","article-title":"Identification of the Cys634-&gt;Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis","volume":"17","author":"Ceccherini","year":"1994","journal-title":"J Endocrinol Invest"},{"issue":"6","key":"2025101519591192000_dgaf171-B5","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.3390\/clinpract14060179","article-title":"Endocrine perspective of cutaneous lichen amyloidosis: RET-C634 pathogenic variant in multiple endocrine neoplasia type 2","volume":"14","author":"Florescu","year":"2024","journal-title":"Clin Pract"},{"issue":"2","key":"2025101519591192000_dgaf171-B6","doi-asserted-by":"crossref","first-page":"T29","DOI":"10.1530\/ERC-17-0209","article-title":"A comprehensive review on MEN2B","volume":"25","author":"Castinetti","year":"2018","journal-title":"Endocr Relat Cancer"},{"issue":"6","key":"2025101519591192000_dgaf171-B7","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1089\/thy.2014.0335","article-title":"American thyroid association guidelines task force on medullary thyroid carcinoma. Revised American thyroid association guidelines for the management of medullary thyroid carcinoma","volume":"25","author":"Wells","year":"2015","journal-title":"Thyroid"},{"issue":"7","key":"2025101519591192000_dgaf171-B8","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1093\/hmg\/2.7.851","article-title":"Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC","volume":"2","author":"Donis-Keller","year":"1993","journal-title":"Hum Mol Genet"},{"issue":"3","key":"2025101519591192000_dgaf171-B9","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1007\/s12020-020-02332-2","article-title":"MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives","volume":"69","author":"Amodru","year":"2020","journal-title":"Endocrine"},{"issue":"6","key":"2025101519591192000_dgaf171-B10","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/S1470-2045(14)70154-8","article-title":"Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study","volume":"15","author":"Castinetti","year":"2014","journal-title":"Lancet Oncol"},{"issue":"8","key":"2025101519591192000_dgaf171-B11","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1210\/jc.2013-1204","article-title":"Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update","volume":"98","author":"Wells","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2025101519591192000_dgaf171-B12","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13059-016-1110-1","article-title":"New insights into the generation and role of de novo mutations in health and disease","volume":"17","author":"Acuna-Hidalgo","year":"2016","journal-title":"Genome Biol"},{"issue":"6","key":"2025101519591192000_dgaf171-B13","first-page":"1076","article-title":"Parent-of-origin effects in multiple endocrine neoplasia type 2B","volume":"55","author":"Carlson","year":"1994","journal-title":"Am J Hum Genet"},{"issue":"9","key":"2025101519591192000_dgaf171-B14","doi-asserted-by":"crossref","first-page":"698","DOI":"10.3390\/genes10090698","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","year":"2019","journal-title":"Genes (Basel)"},{"issue":"1","key":"2025101519591192000_dgaf171-B15","first-page":"233","article-title":"Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. 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