{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:43:09Z","timestamp":1790516589537,"version":"4.1.0"},"reference-count":11,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T00:00:00Z","timestamp":1570579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Fund for Scientific Research Flanders","award":["Grant G028415N to BC"],"award-info":[{"award-number":["Grant G028415N to BC"]}]},{"name":"Fund for Cardiac Surgery","award":["Grant 2015 to BC"],"award-info":[{"award-number":["Grant 2015 to BC"]}]},{"name":"Special Research foundation of Ghent University","award":["Starting grant BOFSTA2016002401 to BC"],"award-info":[{"award-number":["Starting grant BOFSTA2016002401 to BC"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain\u2010of\u2010function mutation in <jats:italic>SMAD4<\/jats:italic>, encoding the SMAD4 transducer protein required for both transforming growth factor\u2010beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C&gt;T (p.Arg496Cys) mutation in <jats:italic>SMAD4<\/jats:italic>. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age\u2010related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.<\/jats:p>","DOI":"10.1002\/ajmg.a.61377","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T07:40:13Z","timestamp":1570606813000},"page":"2494-2499","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5502-0568","authenticated-orcid":false,"given":"Ilse","family":"Meerschaut","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"},{"name":"Department of Pediatrics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aude","family":"Beyens","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"},{"name":"Department of Dermatology Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Steyaert","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riet","family":"De Rycke","sequence":"additional","affiliation":[{"name":"Department of Biomedical Molecular Biology Ghent University  Ghent Belgium"},{"name":"VIB Center for Inflammation Research  Ghent Belgium"},{"name":"Ghent University Expertise Centre for Transmission Electron Microscopy and VIB Bioimaging Core  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Bonte","sequence":"additional","affiliation":[{"name":"Department of Head, Neck and Maxillofacial Surgery Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine","family":"De Backer","sequence":"additional","affiliation":[{"name":"Department of Cardiology Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Janssens","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Panzer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Plasschaert","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00ebl","family":"De Wolf","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-4205","authenticated-orcid":false,"given":"Bert","family":"Callewaert","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,10,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38560"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36544"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.12.011"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-016-2761-3"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1016"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37739"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.288"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1981.tb01798.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2015.04.005"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.283"},{"key":"e_1_2_7_12_1","volume-title":"GeneReviews","author":"Starr L. 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