{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:17:31Z","timestamp":1784557051077,"version":"3.55.0"},"reference-count":10,"publisher":"Bioscientifica","content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,11,25]]},"abstract":"\n Mutations of the rearranged during transfection (\n RET<\/jats:italic>\n ) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other\n RET<\/jats:italic>\n mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other\n RET<\/jats:italic>\n polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in\n RET<\/jats:italic>\n . Sanger sequencing of the entire\n RET<\/jats:italic>\n -coding region and exon\u2013intron boundaries was performed. Five family members were C609Y mutation positive: 3\/5 initially presented with phaeochromocytoma, but only 1\/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S\n RET<\/jats:italic>\n polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a\n RET<\/jats:italic>\n C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of\n RET<\/jats:italic>\n polymorphisms for the purposes of risk stratification.\n <\/jats:p>\n \n Learning points:<\/jats:title>\n \n \n \n C609Y\n RET<\/jats:italic>\n mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.\n <\/jats:p>\n <\/jats:list-item>\n \n \n C609Y\n RET<\/jats:italic>\n mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.\n <\/jats:p>\n <\/jats:list-item>\n \n \n There may be a role for the routine screening of\n RET<\/jats:italic>\n polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.1530\/edm-16-0093","type":"journal-article","created":{"date-parts":[[2016,11,25]],"date-time":"2016-11-25T05:40:42Z","timestamp":1480052442000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":1,"title":["Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A"],"prefix":"10.1530","volume":"2016","author":[{"given":"Rowena","family":"Speak","sequence":"first","affiliation":[{"name":"1Departments of Oncology and Metabolism, University of Sheffield"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie","family":"Cook","sequence":"additional","affiliation":[{"name":"4Department of Genetics, Sheffield Children\u2019s Hospital, Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barney","family":"Harrison","sequence":"additional","affiliation":[{"name":"3Endocrine Surgery, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Newell-Price","sequence":"additional","affiliation":[{"name":"1Departments of Oncology and Metabolism, University of Sheffield"},{"name":"2Endocrinology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"key20161202145827819_bib1","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1245\/s10434-009-0524-3","article-title":"When is prophylactic thyroidectomy indicated for patients with the RET codon 609 mutation?","volume":"16","author":"Calva","year":"2009","journal-title":"Annals of Surgical Oncology"},{"key":"key20161202145827819_bib2","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1530\/EJE-14-0084","article-title":"Role of RET genetic variants in MEN2-associated phaeochromocytoma","volume":"170","author":"Siqueira","year":"2014","journal-title":"European 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