{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T19:01:49Z","timestamp":1757703709287,"version":"3.40.5"},"reference-count":24,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Loss\u2010of\u2010function pathogenic variants in somatic and germline cells in <jats:italic>SMAD4<\/jats:italic> may cause cancer and juvenile polyposis\u2010Hereditary Hemorrhagic Telangiectasia (<jats:italic>SMAD4\u2010<\/jats:italic>JP\u2010HHT), respectively. In a similar manner, gain\u2010of\u2010function somatic and germline pathogenic variants in <jats:italic>SMAD4<\/jats:italic> can cause various forms of cancer as well as Myhre syndrome. The different <jats:italic>SMAD4<\/jats:italic> molecular mechanisms result in contrasting clinical phenotypes demonstrated by <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT and Myhre syndrome. We report an additional patient with <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT and aortopathy, and expand the phenotype to include severe valvulopathy, cutaneous, ophthalmologic, and musculoskeletal features consistent with an inherited disorder of connective tissue. We compared this 70\u2010year\u2010old man with <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT to 18 additional literature cases, and also compared patients with <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT to those with Myhre syndrome. In contrast to aorta dilation, hypermobility, and loose skin in <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT, Myhre syndrome has aorta hypoplasia, stiff joints, and firm skin representing an intriguing phenotypic contrast, which can be attributed to different molecular mechanisms involving <jats:italic>SMAD4<\/jats:italic>. We remind clinicians about the possibility of significant cardiac valvulopathy and aortopathy, as well as connective tissue disease in <jats:italic>SMAD4<\/jats:italic>\u2010JP\u2010HHT. Additional patients and longer follow\u2010up will help determine if more intensive surveillance improves care amongst these patients.<\/jats:p>","DOI":"10.1002\/ajmg.a.62915","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T12:23:50Z","timestamp":1658579030000},"page":"3084-3088","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["An additional patient with <scp><i>SMAD4\u2010<\/i>Juvenile Polyposis\u2010Hereditary<\/scp> hemorrhagic telangiectasia and connective tissue abnormalities: <scp><i>SMAD4<\/i><\/scp> loss\u2010of\u2010function and gain\u2010of\u2010function pathogenic variants result in contrasting phenotypes"],"prefix":"10.1002","volume":"188","author":[{"given":"Gregory M.","family":"Gheewalla","sequence":"first","affiliation":[{"name":"Tufts University School of Medicine  Boston Massachusetts USA"},{"name":"Cardiovascular Genetics Program, Cardiology Division, Department of Medicine Mass General Brigham  Boston Massachusetts USA"},{"name":"Pediatric Cardiology Division, Department of Pediatrics Mass General Brigham  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Luther","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, MGB Alcohol Liver Center Mass General Brigham  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4521-4606","authenticated-orcid":false,"given":"Saumya","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Center Mass General Brigham  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey B.","family":"Kreher","sequence":"additional","affiliation":[{"name":"Division of Pediatric Orthopaedics, Department of Orthopaedics Mass General Brigham  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor R.","family":"Scimone","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Unit, Mass General Brigham for Children  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley W.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Unit, Mass General Brigham for Children  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-7938","authenticated-orcid":false,"given":"Mark E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program, Cardiology Division, Department of Medicine Mass General Brigham  Boston Massachusetts USA"},{"name":"Pediatric Cardiology Division, Department of Pediatrics Mass General Brigham  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-4572","authenticated-orcid":false,"given":"Angela E.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Unit, Mass General Brigham for Children  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33968"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1609060"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36544"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.12.011"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31771"},{"key":"e_1_2_10_7_1","first-page":"1993","volume-title":"GeneReviews\u00ae","author":"Dietz H.","year":"2001"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.7326\/M20-1443"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33206"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124287"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37093"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.1287-18"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2009.129932"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12693"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1404731"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1016"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61430"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37739"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.072785"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32518-8"},{"volume-title":"GeneReviews\u00ae","year":"2017","author":"Starr L. J.","key":"e_1_2_10_21_1"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35659"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2017.06.059"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.5"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.09.024"}],"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.62915","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62915","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62915","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T06:43:12Z","timestamp":1708497792000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,23]]},"references-count":24,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1002\/ajmg.a.62915"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62915","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2022,7,23]]},"assertion":[{"value":"2022-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}