{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:19:48Z","timestamp":1790194788904,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T00:00:00Z","timestamp":1386201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label\/><jats:p>In 2005, we reported on a family as having Fr\u00edas syndrome (OMIM: 609640), with four affected members displaying a pattern of congenital defects nearly identical to those observed in a mother and son described by Frias [Fr\u00edas et al. (1975). <jats:italic>Birth Defects Orig Artic Ser<\/jats:italic> 11:30\u201333]. These defects included growth deficiency, facial anomalies, and hand and foot alterations. We had the opportunity to study this family again due to the birth of another affected girl, who presented with similar facial characteristics to those of her elder half\u2010sister and the rest of affected relatives, which consisted of mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral fissures, and hypertelorism. We performed array\u2010CGH, which identified an identical interstitial deletion of chromosome 14q22.1\u2013q22.3 in the mother and two daughters. The deletion is 4.06\u2009Mb in length and includes the <jats:italic>BMP4<\/jats:italic> gene, a member of the bone morphogenetic protein (BMP) family of secreted proteins. A review of the literature showed that deletions or mutations of this gene underlie congenital defects affecting brain, eye, teeth, and digit development. Although the clinical manifestations of the current family correlate with the defects observed in patients having either 14q22\u2013q23 deletions or mutations of <jats:italic>BMP4<\/jats:italic>, they show a milder phenotype. In order to understand the clinical variability, we evaluated the already known functional characteristics of the <jats:italic>BMP<\/jats:italic> gene members. This gene family plays an important role during early embryogenesis, and the complex synergistic functions and redundancies of the BMPs led us to conclude that haploinsufficiency of <jats:italic>BMP4<\/jats:italic> is likely to be responsible for the clinical expression of Fr\u00edas syndrome. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36224","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T18:45:09Z","timestamp":1386269109000},"page":"338-345","source":"Crossref","is-referenced-by-count":11,"title":["Haploinsufficiency of <i>BMP<\/i><i>4<\/i> gene may be the underlying cause of Fr\u00edas syndrome"],"prefix":"10.1002","volume":"164","author":[{"given":"Mar\u00eda Luisa","family":"Mart\u00ednez\u2010Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"CIBER de Enfermedades Raras (CIBERER) (U724) Instituto de Salud Carlos III, Ministerio de Econom\u00eda y Competitividad Madrid Spain"},{"name":"Spanish Collaborative Study of Congenital Malformations (ECEMC) CIAC (Research Center on Congenital Anomalies), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Bermejo\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"CIBER de Enfermedades Raras (CIBERER) (U724) Instituto de Salud Carlos III, Ministerio de Econom\u00eda y Competitividad Madrid Spain"},{"name":"Spanish Collaborative Study of Congenital Malformations (ECEMC) CIAC (Research Center on Congenital Anomalies), Instituto de Salud Carlos III Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n de Enfermedades Raras (IIER) Instituto de Salud Carlos III, Ministerio de Econom\u00eda y Competitividad Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Servicio de Neonatolog\u00eda Hospital Universitario Central de Asturias Oviedo (Asturias) Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Spanish Collaborative Study of Congenital Malformations (ECEMC) CIAC (Research Center on Congenital Anomalies), Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Fern\u00e1ndez\u2010Toral","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Central de Asturias, Facultad de Medicina Universidad de Oviedo Oviedo (Asturias) Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Mart\u00ednez\u2010Fr\u00edas","sequence":"additional","affiliation":[{"name":"CIBER de Enfermedades Raras (CIBERER) (U724) Instituto de Salud Carlos III, Ministerio de Econom\u00eda y Competitividad Madrid Spain"},{"name":"Spanish Collaborative Study of Congenital Malformations (ECEMC) CIAC (Research Center on Congenital Anomalies), Instituto de Salud Carlos III Madrid Spain"},{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina Universidad Complutense de Madrid Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,12,5]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.04-0641"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2007.09.023"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1168755"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.28.4.280"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.10.011"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30181"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.22.2795"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199703)208:3<349::AID-AJA6>3.0.CO;2-I"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1997.8664"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.30.3.251"},{"key":"e_1_2_6_12_1","first-page":"30","article-title":"Growth deficiency, facial dysmorphogenesis and brachydactyly. 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