{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:23:11Z","timestamp":1792174991522,"version":"4.4.0"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Odense University Hospital","award":["142-A5632"],"award-info":[{"award-number":["142-A5632"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung\u2019s disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3\u201392). Age-related penetrance at age 70 years for MTC was 98% (CI, 91\u2013100), for PHEO 24% (CI, 16\u201337), and for PHPT 10% (CI, 5\u201320). None had CLA or Hirschsprung\u2019s disease. The age-related progression of MTC was significant (p &lt; 0.001). The mean age at T0N0M0 was 16 years (CI, 12\u201320), at T1-4N0M0 38 years (CI, 34\u201342), at TxN1M0 45 years (CI, 38\u201353) and at TxNxM1 49 years (CI, 36\u201361). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59\u201384). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung\u2019s disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population.<\/jats:p>","DOI":"10.3390\/cancers17030374","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T12:24:09Z","timestamp":1737635049000},"page":"374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["RET C611Y Germline Variant in Multiple Endocrine Neoplasia Type 2A in Denmark 1930\u20132021: A Nationwide Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0604-6937","authenticated-orcid":false,"given":"Anders","family":"Hansen","sequence":"first","affiliation":[{"name":"Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vestergaard","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center North Denmark, Aalborg University Hospital, 9000 Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark"},{"name":"Department of Endocrinology, Aalborg University Hospital, 9000 Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-4767","authenticated-orcid":false,"given":"\u00c5se","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Endocrinology, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5903-3355","authenticated-orcid":false,"given":"Ulla","family":"Feldt-Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Endocrinology, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4269-7550","authenticated-orcid":false,"given":"Mette","family":"Madsen","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center North Denmark, Aalborg University Hospital, 9000 Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark"},{"name":"Department of Pediatrics and Adolescent Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rune","family":"N\u00e6raa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorte","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7259-1039","authenticated-orcid":false,"given":"Katharina","family":"Main","sequence":"additional","affiliation":[{"name":"Department of Growth and Reproduction, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery, Aalborg University Hospital, 9000 Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Londero","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Rolighed","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoffer","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Rask","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Maare","sequence":"additional","affiliation":[{"name":"Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Zealand University Hospital, 4000 Roskilde, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Gaustadnes","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rossing","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Copenhagen University Hospital, 2100 Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernille","family":"Hermann","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9770-3188","authenticated-orcid":false,"given":"Jes","family":"Mathiesen","sequence":"additional","affiliation":[{"name":"Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1089\/thy.2015.0673","article-title":"A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma","volume":"26","author":"Opsahl","year":"2016","journal-title":"Thyroid"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.2147\/CLEP.S174606","article-title":"Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901\u20132014: A nationwide study","volume":"10","author":"Mathiesen","year":"2018","journal-title":"Clin. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1097\/00005792-196809000-00001","article-title":"Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing\u2019s disease: Multiple endocrine neoplasia, type 2","volume":"47","author":"Steiner","year":"1968","journal-title":"Medicine"},{"key":"ref_4","first-page":"147","article-title":"Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: A new variant","volume":"37","author":"Donovan","year":"1989","journal-title":"Henry Ford Hosp. Med. J."},{"key":"ref_5","first-page":"603","article-title":"Hirschsprung\u2019s disease in a family with multiple endocrine neoplasia type 2","volume":"1","author":"Verdy","year":"1982","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_6","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":"Dou","year":"1993","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/363458a0","article-title":"Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A","volume":"363","author":"Mulligan","year":"1993","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1365-2796.1995.tb01208.x","article-title":"Genotype-phenotype correlation in multiple endocrine neoplasia type 2: Report of the International RET Mutation Consortium","volume":"238","author":"Mulligan","year":"1995","journal-title":"J. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1001\/jama.1996.03540190047028","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","year":"1996","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/humu.21385","article-title":"Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10","volume":"32","author":"Rybicki","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/cen.12978","article-title":"Variability in Penetrance of Multiple Endocrine Neoplasia 2A with Amino Acid Substitutions in RET Codon 634","volume":"84","author":"Machens","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1677\/ERC-08-0105","article-title":"Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation","volume":"15","author":"Milos","year":"2008","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/EJE-14-0818","article-title":"RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation","volume":"172","author":"Navarro","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1530\/EJE-13-0050","article-title":"The clinical spectrum of RET proto-oncogene mutations in codon 790","volume":"169","author":"Bihan","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1210\/jc.2016-3640","article-title":"Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study","volume":"102","author":"Mathiesen","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E92","DOI":"10.1210\/jc.2010-0375","article-title":"The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A","volume":"95","author":"Schulte","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","first-page":"926","article-title":"p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy","volume":"40","author":"Panarotto","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S2213-8587(18)30336-X","article-title":"Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: An international, multicentre, retrospective study","volume":"7","author":"Castinetti","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1530\/EC-18-0220","article-title":"The RET C611Y mutation causes MEN 2A and associated cutaneous","volume":"7","author":"Qi","year":"2018","journal-title":"Endocr. Connect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/humu.23430","article-title":"Genotype-specific progression of hereditary medullary thyroid cancer","volume":"39","author":"Machens","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Holm, M., Vestergaard, P., Poulsen, M.M., Rasmussen, \u00c5.K., Feldt-Rasmussen, U., Bay, M., Rolighed, L., Londero, S., Pedersen, H.B., and Hahn, C.H. (2023). Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930\u20132021: A Nationwide Population-Based Retrospective Study in Denmark 1930\u20132021. Cancers, 15.","DOI":"10.3390\/cancers15072125"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/thy.2016.0411","article-title":"Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994\u20132014: A Nationwide Study","volume":"27","author":"Mathiesen","year":"2017","journal-title":"Thyroid"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1089\/thy.2017.0404","article-title":"Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study","volume":"27","author":"Mathiesen","year":"2017","journal-title":"Thyroid"},{"key":"ref_24","unstructured":"Porta, M., Greenland, S., Hern\u00e1n, M., dos Santos Silva, I., and Last, M. (2014). A Dictionary of Epidermiology, Oxford University Press. [6th ed.]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1089\/thy.2014.0335","article-title":"Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma","volume":"25","author":"Wells","year":"2015","journal-title":"Thyroid"},{"key":"ref_26","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":"Endocrine-Related Cancer"},{"key":"ref_27","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."},{"key":"ref_28","unstructured":"Amin, M.B., Edge, S.B., Greene, F.L., Schilsky, R.L., Gaspar, L.E., Washington, M.K., Sullivan, D.C., Brierley, J.D., Balch, C.M., and Compton, C.C. (2017). AJCC Cancer Staging Manual, Springer. [8th ed.]."},{"key":"ref_29","unstructured":"Edge, S.B., Byrd, D.R., Compton, C.C., Fritz, A.G., Greene, F.L., and Trotti, A. (2010). AJCC Cancer Staging Manual, Springer. [7th ed.]."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1093\/bjs\/znab106","article-title":"Medullary thyroid cancer outcomes in patients with undetectable versus normalized postoperative calcitonin levels","volume":"108","author":"Fanget","year":"2021","journal-title":"Br. J. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00198-016-3716-2","article-title":"Primary hyperparathyroidism: Review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus","volume":"28","author":"Khan","year":"2017","journal-title":"Osteoporos. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1001\/jamasurg.2016.2310","article-title":"The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism","volume":"151","author":"Wilhelm","year":"2016","journal-title":"JAMA Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1056\/NEJMra1806651","article-title":"Pheochromocytoma and Paraganglioma","volume":"381","author":"Neumann","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_34","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. Le Groupe d\u2019Etude des Tumeurs a Calcitonine","volume":"60","author":"Schuffenecker","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1530\/EJE-12-1106","article-title":"High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients","volume":"168","author":"Imai","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s12020-021-02686-1","article-title":"Kidney malformations and Hirschsprung\u2019s disease in carriers of cysteine mutations in exon 10 of the RET proto-oncogene","volume":"73","author":"Machens","year":"2021","journal-title":"Endocrine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/gim.2012.93","article-title":"Survival among people with Down syndrome: A nationwide population-based study in Denmark","volume":"15","author":"Zhu","year":"2013","journal-title":"Genet. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:34:53Z","timestamp":1759919693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17030374"],"URL":"https:\/\/doi.org\/10.3390\/cancers17030374","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]}}}