{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:57:32Z","timestamp":1790632652620,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["\u00a0"],"award-info":[{"award-number":["\u00a0"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838\u20130.999] (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648\u20130.920] (<jats:italic>p<\/jats:italic>\u2009=\u20090.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544\u20130.960] (<jats:italic>p<\/jats:italic>\u2009=\u20090.003) in a second multiclass design (MFDM vs. differential diagnoses).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2023.1171277","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T05:19:27Z","timestamp":1692335967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes"],"prefix":"10.3389","volume":"11","author":[{"given":"Quentin","family":"Hennocq","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bongibault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Marlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Amiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Attie-Bitach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Baujat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Boutaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Carpentier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Corre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Denoyelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Djate Delbrah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Douillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Galliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuttichart","family":"Kamolvisit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Lyonnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Milea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Pingault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thantrira","family":"Porntaveetus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Touzet-Roumazeille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolaine","family":"Willems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Picard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marl\u00e8ne","family":"Rio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Garcelon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman H.","family":"Khonsari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1097\/01.mcd.0000220603.09661.7e","article-title":"A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate","volume":"15","author":"Guion-Almeida","year":"2006","journal-title":"Clin Dysmorphol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.1002\/ajmg.a.32816","article-title":"Mandibulofacial syndrome with growth and mental retardation, microcephaly, ear anomalies with skin tags, and cleft palate in a mother and her son: autosomal dominant or X-linked syndrome?","author":"Guion-Almeida","year":"2009","journal-title":"Am J Med Genet A"},{"key":"B3","article-title":"Mandibulofacial dysostosis with microcephaly","volume-title":"Genereviews\u00ae","author":"Lines","year":"1993"},{"key":"B4","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1002\/humu.22924","article-title":"Mandibulofacial dysostosis with microcephaly: mutation and database update","volume":"37","author":"Huang","year":"2016","journal-title":"Hum Mutat"},{"key":"B5","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/cge.12123","article-title":"Human facial dysostoses","volume":"83","author":"Wieczorek","year":"2013","journal-title":"Clin Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/1750-1172-8-110","article-title":"Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies\u2014expanding the phenotypes associated with EFTUD2 mutations","volume":"8","author":"Voigt","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"580477","DOI":"10.3389\/fgene.2020.580477","article-title":"Targeted next-generation sequencing in the diagnosis of facial dysostoses","volume":"11","author":"Bukowska-Olech","year":"2020","journal-title":"Front Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.ajhg.2011.12.023","article-title":"Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly","volume":"90","author":"Lines","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B9","year":""},{"key":"B10","doi-asserted-by":"publisher","first-page":"104478","DOI":"10.1016\/j.ejmg.2022.104478","article-title":"Clinical and molecular delineation of mandibulofacial dysostosis with microcephaly in six Korean patients: when to consider EFTUD2 analysis?","volume":"65","author":"Ryu","year":"2022","journal-title":"Eur J Med Genet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"296","DOI":"10.3390\/diagnostics10050296","article-title":"Novel splice site pathogenic variant of EFTUD2 is associated with mandibulofacial dysostosis with microcephaly and extracranial symptoms in Korea","volume":"10","author":"Kim","year":"2020","journal-title":"Diagnostics (Basel)"},{"key":"B12","article-title":"Mandibulofacial dysostosis with microcephaly","volume-title":"Genereviews\u00ae","author":"Lines","year":"1993"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e229831","DOI":"10.1136\/bcr-2019-229831","article-title":"Mandibulofacial dysostosis with microcephaly: a syndrome to remember","volume":"12","author":"Silva","year":"2019","journal-title":"BMJ Case Rep"},{"key":"B14","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/ajmg.a.35696","article-title":"\u201cMandibulofacial dysostosis with microcephaly\u201d caused by EFTUD2 mutations: expanding the phenotype","author":"Luquetti","year":"2013","journal-title":"Am J Med Genet A"},{"key":"B15","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1177\/1055665618806379","article-title":"Novel de novo EFTUD2 mutations in 2 cases with MFDM, initially suspected to have alternative craniofacial diagnoses","volume":"56","author":"Lacour","year":"2019","journal-title":"Cleft Palate Craniofac J"},{"key":"B16","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.jbi.2018.02.019","article-title":"A clinician friendly data warehouse oriented toward narrative reports: dr. Warehouse","volume":"80","author":"Garcelon","year":"2018","journal-title":"J Biomed Inform"},{"key":"B17","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/humu.22517","article-title":"Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients","volume":"35","author":"Lehalle","year":"2014","journal-title":"Hum Mutat"},{"key":"B18","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.ajhg.2012.04.004","article-title":"Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome","volume":"90","author":"Bernier","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195118612.001.0001","volume-title":"Syndromes of the head and neck","author":"Gorlin","year":"2001"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e23426","DOI":"10.1002\/jcla.23426","article-title":"Broad-spectrum next-generation sequencing-based diagnosis of a case of Nager syndrome","volume":"34","author":"Zhao","year":"2020","journal-title":"J Clin Lab Anal"},{"key":"B21","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1007\/s10792-013-9817-4","article-title":"Two cases of CHARGE syndrome with multiple congenital anomalies","volume":"34","author":"Chang","year":"2014","journal-title":"Int Ophthalmol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1399-0004.2012.01884.x","article-title":"Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome","volume":"83","author":"Husu","year":"2013","journal-title":"Clin Genet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1750-1172-1-34","article-title":"CHARGE Syndrome","volume":"1","author":"Blake","year":"2006","journal-title":"Orphanet J Rare Dis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1086\/500273","article-title":"Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation","volume":"78","author":"Lalani","year":"2006","journal-title":"Am J Hum Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.3390\/genes12091392","article-title":"Treacher collins syndrome: genetics, clinical features and management","volume":"12","author":"Marsza\u0142ek-Kruk","year":"2021","journal-title":"Genes (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"110765","DOI":"10.1016\/j.ijporl.2021.110765","article-title":"De novo TCOF1 mutation in treacher collins syndrome","volume":"147","author":"Liu","year":"2021","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2466\/pr0.1966.19.1.3","article-title":"The intraclass correlation coefficient as a measure of reliability","volume":"19","author":"Bartko","year":"1966","journal-title":"Psychol Rep"},{"key":"B28","first-page":"626","article-title":"Deformable models of ears in-the-wild for alignment and recognition","volume-title":"2017 12th IEEE international conference on automatic face gesture recognition (FG 2017)","author":"Zhou","year":""},{"key":"B29","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1109\/TPAMI.2016.2577031","article-title":"Faster R-CNN: towards real-time object detection with region proposal networks","volume":"39","author":"Ren","year":"2017","journal-title":"IEEE Trans Pattern Anal Mach Intell"},{"key":"B30","first-page":"674","article-title":"An iterative image registration technique with an application to stereo vision (IJCAI)","volume-title":"IJCAI'81: 7th international joint conference on artificial intelligence","author":"Lucas","year":"1981"},{"key":"B31","author":"Paszke","year":""},{"key":"B32","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1145\/2647868.2654890","article-title":"Menpo: a comprehensive platform for parametric image alignment and visual deformable models","volume-title":"Proceedings of the 22nd ACM international conference on multimedia","author":"Alabort-i-Medina","year":"2014"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1002\/ajmg.a.63126","article-title":"An automatic facial landmarking for children with rare diseases","volume":"191","author":"Hennocq","year":"2023","journal-title":"Am J Med Genet A"},{"key":"B34","year":""},{"key":"B35","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1111\/2041-210X.13723","article-title":"Geomorph v4.0 and gmShiny: enhanced analytics and a new graphical interface for a comprehensive morphometric experience","volume":"12","author":"Baken","year":"2021","journal-title":"Methods Ecol Evol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"40","DOI":"10.2307\/2992207","article-title":"Extensions of the procrustes method for the optimal superimposition of landmarks","volume":"39","author":"Rohlf","year":"1990","journal-title":"Syst Zool"},{"key":"B37","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1080\/14786440109462720","article-title":"LIII On lines and planes of closest fit to systems of points in space","volume":"2","author":"Pearson","year":"1901","journal-title":"Lond Edinb,Dublin Philos Mag J Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1056\/NEJMsb025007","article-title":"The importance of race and ethnic background in biomedical research and clinical practice","volume":"348","author":"Burchard","year":"2003","journal-title":"N Engl J Med"},{"key":"B39","first-page":"620","article-title":"Die missblindungen des ohreds","volume":"12","author":"Marx","year":"1926","journal-title":"Handb Spez Pathol Anat Histol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1111\/j.0014-3820.2002.tb00117.x","article-title":"Shape analysis of symmetric structures: quantifying variation among individuals and asymmetry","volume":"56","author":"Klingenberg","year":"2002","journal-title":"Evolution"},{"key":"B41","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/978-94-011-0830-0_26","article-title":"Fluctuating asymmetry analyses: a primer","volume-title":"Developmental instability: its origins and evolutionary implications: proceedings of the international conference on developmental instability: its origins and evolutionary implications, tempe, Arizona, 14\u201315 June 1993","author":"Palmer","year":"1994"},{"key":"B42","author":"McInnes","year":""},{"key":"B43","year":""},{"key":"B44","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1145\/2939672.2939785","article-title":"XGBoost: a scalable tree boosting system","volume-title":"Proceedings of the 22nd ACM SIGKDD international conference on knowledge discovery and data mining","author":"Chen","year":"2016"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2","DOI":"10.18637\/jss.v079.c02","article-title":"plotROC: a tool for plotting ROC curves","volume":"79","author":"Sachs","year":"2017","journal-title":"J Stat Softw"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1056\/NEJMra1814259","article-title":"Machine learning in medicine","volume":"380","author":"Rajkomar","year":"2019","journal-title":"N Engl J Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1148\/radiol.2018171820","article-title":"Current applications and future impact of machine learning in radiology","volume":"288","author":"Choy","year":"2018","journal-title":"Radiol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1001\/jamadermatol.2019.1633","article-title":"Marking the path toward artificial intelligence-based image classification in dermatology","volume":"155","author":"Novoa","year":"2019","journal-title":"JAMA Dermatol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1001\/jamasurg.2019.4917","article-title":"Artificial intelligence and surgical decision-making","volume":"155","author":"Loftus","year":"2020","journal-title":"JAMA Surg"},{"key":"B50","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s41591-018-0279-0","article-title":"Identifying facial phenotypes of genetic disorders using deep learning","volume":"25","author":"Gurovich","year":"2019","journal-title":"Nat Med"},{"key":"B51","doi-asserted-by":"publisher","first-page":"808919","DOI":"10.3389\/fgene.2022.808919","article-title":"Molecular and phenotypic expansion of alstr\u00f6m syndrome in Chinese patients","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Genet"},{"key":"B52","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/s41433-021-01563-5","article-title":"Evaluation of a computer-based facial dysmorphology analysis algorithm (Face2Gene) using standardized textbook photos","volume":"36","author":"Javitt","year":"2022","journal-title":"Eye"},{"key":"B53","doi-asserted-by":"publisher","first-page":"E1042","DOI":"10.3390\/ijms21031042","article-title":"Evaluating Face2Gene as a tool to identify cornelia de lange syndrome by facial phenotypes","volume":"21","author":"Latorre-Pellicer","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/s10038-019-0619-z","article-title":"Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan","volume":"64","author":"Mishima","year":"2019","journal-title":"J Hum Genet"},{"key":"B55","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1097\/00019605-200009040-00004","article-title":"Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases","volume":"9","author":"Guion-Almeida","year":"2000","journal-title":"Clin Dysmorphol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s13353-014-0255-4","article-title":"Phenotype analysis of Polish patients with mandibulofacial dysostosis type guion-almeida associated with esophageal atresia and choanal atresia caused by EFTUD2 gene mutations","volume":"56","author":"Smigiel","year":"2015","journal-title":"J Appl Genet"},{"key":"B57","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1097\/MCD.0000000000000214","article-title":"Mandibulofacial dysostosis guion-almeida type caused by novel EFTUD2 splice site variants in two Asian children","volume":"27","author":"Yu","year":"2018","journal-title":"Clin Dysmorphol"},{"key":"B58","article-title":"Treacher collins syndrome","volume-title":"Genereviews\u00ae.","author":"Katsanis","year":"1993"},{"key":"B59","first-page":"45","article-title":"A case report: nager acrofacial dysostosis","volume":"24","author":"Fakhim S","year":"2012","journal-title":"Iran J Otorhinolaryngol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/S0165-5876(86)80071-4","article-title":"CHARGE Syndrome. Part I. External ear anomalies","volume":"12","author":"Davenport","year":"1986","journal-title":"Int J Pediatr Otorhinolaryngol"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1171277\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T06:59:42Z","timestamp":1702969182000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1171277\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,17]]},"references-count":60,"alternative-id":["10.3389\/fped.2023.1171277"],"URL":"https:\/\/doi.org\/10.3389\/fped.2023.1171277","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,17]]},"article-number":"1171277"}}