{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:15:43Z","timestamp":1788282943482,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,14]],"date-time":"2019-12-14T00:00:00Z","timestamp":1576281600000},"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":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain\u2010of\u2010function pathogenic variants in <jats:italic>SMAD4<\/jats:italic>. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic\u2010like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss\u2010of\u2010function pathogenic variants in <jats:italic>SMAD4<\/jats:italic> cause juvenile polyposis syndrome and we hypothesize that the gain\u2010of\u2010function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6\/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3\/34, mean age 40\u2009years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.<\/jats:p>","DOI":"10.1002\/ajmg.a.61430","type":"journal-article","created":{"date-parts":[[2019,12,14]],"date-time":"2019-12-14T10:41:16Z","timestamp":1576320076000},"page":"328-337","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Gain\u2010of\u2010function pathogenic variants in <i>SMAD4<\/i> are associated with neoplasia in Myhre syndrome"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-4572","authenticated-orcid":false,"given":"Angela E.","family":"Lin","sequence":"first","affiliation":[{"name":"Medical Genetics Unit, MassGeneral Hospital for Children  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrazak","family":"Alali","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics, Montefiore Medical Center Albert Einstein College of Medicine  Bronx New York"},{"name":"Division of Genetics, Department of Pediatrics Akron Children's Hospital  Akron Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9212-2499","authenticated-orcid":false,"given":"Lois J.","family":"Starr","sequence":"additional","affiliation":[{"name":"Munroe\u2010Meyer Institute, University of Nebraska Medical Center  Omaha Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi","family":"Shah","sequence":"additional","affiliation":[{"name":"Harvard Medical School Genetics Training Program  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Beavis","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Johns Hopkins University  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine M.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics, Montefiore Medical Center Albert Einstein College of Medicine  Bronx New York"},{"name":"Division of Clinical Genetics, Department of Pediatrics Columbia University Medical Center  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Thoracic Aortic and Cardiovascular Genetics Centers Massachusetts General Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Klugman","sequence":"additional","affiliation":[{"name":"Division of Reproductive and Medical Genetics, Department of Obstetrics &amp; Gynecology and Women's Health, Montefiore Medical Center Albert Einstein College of Medicine  Bronx New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000462977.61229.de"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38560"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000428646.67925.9a"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13977"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0000000000000109"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.12.011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.2690"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2017.10.022"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079737"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0000000000000188"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15732-2"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13053-017-0083-8"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep14051"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022210"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2014.0128"},{"key":"e_1_2_10_17_1","first-page":"531210","article-title":"Variation across 141,456 human exomes and genomes reveals the spectrum of loss\u2010of\u2010function intolerance across human protein\u2010coding genes","author":"Karczewski K. 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