{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:56:00Z","timestamp":1789152960238,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200388"],"award-info":[{"award-number":["HG200388"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in <jats:italic>AKT1<\/jats:italic>. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55\u2010year\u2010old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19\u2009years of age. We report the identification of the <jats:italic>AKT1<\/jats:italic> c.49G\u2009&gt;\u2009A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating <jats:italic>AKT1<\/jats:italic> variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the <jats:italic>AKT1<\/jats:italic> variant. The tumor also contained two likely pathogenic variants in <jats:italic>PIK3R1<\/jats:italic>, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K\/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder.<\/jats:p>","DOI":"10.1002\/ajmg.a.62761","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T09:40:56Z","timestamp":1650447656000},"page":"2766-2771","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>Late\u2010onset<\/scp> Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1012-5152","authenticated-orcid":false,"given":"Emily W.","family":"Modlin","sequence":"first","affiliation":[{"name":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Slavotinek","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas N.","family":"Darling","sequence":"additional","affiliation":[{"name":"Department of Dermatology Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Lipkowitz","sequence":"additional","affiliation":[{"name":"Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic G.","family":"Barr","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela N.","family":"Munster","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-1621","authenticated-orcid":false,"given":"Christopher A.","family":"Ours","sequence":"additional","affiliation":[{"name":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2009.12.012"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201638"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a005181"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2014.08.017"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4274\/tdd.2246"},{"issue":"5","key":"e_1_2_7_7_1","first-page":"260","article-title":"Understanding Proteus syndrome, unmasking the elephant man, and stemming elephant fever","volume":"1","author":"Cohen M. M.","year":"1988","journal-title":"Neurofibromatosis"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01211-z"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320570117"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912735"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-74237-z"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2020.02.002"},{"issue":"4","key":"e_1_2_7_13_1","first-page":"469","article-title":"Morphological characterization of the breast in Proteus syndrome complicated by ductal carcinoma in situ","volume":"36","author":"Iqbal J.","year":"2006","journal-title":"Annals of Clinical and Laboratory Science"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-020-0150-6"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37737"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a004036"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.234"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz116"},{"issue":"2","key":"e_1_2_7_19_1","first-page":"172","article-title":"Mild and delayed\u2010onset Proteus syndrome","volume":"17","author":"Luo S.","year":"2007","journal-title":"European Journal of Dermatopathology: EJD"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1001-9294(14)60040-7"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.034942.112"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-86029-0"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.10.018"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.140.8.947"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3880510"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31744"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12506265"},{"issue":"4","key":"e_1_2_7_28_1","first-page":"E16","article-title":"Recurrent cerebriform connective tissue nevus on the foot of a patient with Proteus syndrome","volume":"98","author":"Wu J.","year":"2016","journal-title":"Cutis"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62761","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62761","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62761","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T05:15:43Z","timestamp":1692681343000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,20]]},"references-count":27,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/ajmg.a.62761"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62761","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,20]]},"assertion":[{"value":"2022-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}