Fetal markers for the detection of infants with craniofacial malformation

Published:September 17, 2021DOI:https://doi.org/10.1016/j.siny.2021.101291


      Facial clefts and Robin sequence (RS) share the timing of the diagnosis during the course of pregnancy, their association with genetic diseases and the subsequent management following the initial diagnosis. If a suspicion of a facial cleft or RS is made, a detailed anatomical examination of the fetus should be carried out to identify further anomalies. This may also involve genetic testing including a microarray or an exome analysis. Interdisciplinary counseling, including pre- and postnatal experts with sufficient experience in the management of such neonates, should be involved in this counseling. Parents should be informed about disease-specific therapeutic options and postnatal outcome. Delivery should take place in a center with experience in craniofacial malformations where clinicians are prepared for potentially life-threatening airway obstruction immediately after birth.


      To read this article in full you will need to make a payment


      Subscribe to Seminars in Fetal and Neonatal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • James J.N.
        • Schlieder D.W.
        Prenatal counseling, ultrasound diagnosis, and the role of maternal-fetal medicine of the cleft lip and palate patient.
        Oral Maxillofac Surg Clin. 2016; 28: 145-151
        • Nyberg D.A.
        • Sickler G.K.
        • Hegge F.N.
        • Kramer D.J.
        • Kropp R.J.
        Fetal cleft lip with and without cleft palate: US classification and correlation with outcome.
        Radiology. 1995; 195: 677-684
        • Allori A.C.
        • Mulliken J.B.
        • Meara J.G.
        • Shusterman S.
        • Marcus J.R.
        Classification of cleft lip/palate: then and now.
        Cleft Palate Craniofac J. 2017; 54: 175-188
        • McBride W.A.
        • McIntyre G.T.
        • Carroll K.
        • Mossey P.A.
        Subphenotyping and classification of orofacial clefts: need for orofacial cleft subphenotyping calls for revised classification.
        Cleft Palate Craniofac J. 2016; 53: 539-549
        • Maarse W.
        • Boonacker C.W.
        • Breugem C.C.
        • Kon M.
        • Manten G.T.
        • Mink van der Molen A.B.
        A practical prenatal ultrasound classification system for common oral clefts.
        Prenat Diagn. 2015; 35: 894-900
        • Wilhelm L.
        • Borgers H.
        The 'equals sign': a novel marker in the diagnosis of fetal isolated cleft palate.
        Ultrasound Obstet Gynecol. 2010; 36: 439-444
        • Faure J.M.
        • Mousty E.
        • Bigorre M.
        • Wells C.
        • Boulot P.
        • Captier G.
        • et al.
        Prenatal ultrasound diagnosis of cleft palate without cleft lip, the new ultrasound semiology.
        Prenat Diagn. 2020; 40: 1447-1458
        • Steinberg J.P.
        • Gosain A.K.
        Thirty years of prenatal cleft diagnosis: what have we learned?.
        Plast Reconstr Surg. 2015; 136: 550-557
        • Maarse W.
        • Berge S.J.
        • Pistorius L.
        • van Barneveld T.
        • Kon M.
        • Breugem C.
        • et al.
        Diagnostic accuracy of transabdominal ultrasound in detecting prenatal cleft lip and palate: a systematic review.
        Ultrasound Obstet Gynecol. 2010; 35: 495-502
        • Berggren H.
        • Hansson E.
        • Uvemark A.
        • Svensson H.
        • Becker M.
        Prenatal compared with postnatal cleft diagnosis: what do the parents think?.
        J Plast Surg Hand Surg. 2012; 46: 235-241
        • Tonni G.
        • Grisolia G.
        • Sepulveda W.
        Early prenatal diagnosis of orofacial clefts: evaluation of the retronasal triangle using a new three-dimensional reslicing technique.
        Fetal Diagn Ther. 2013; 34: 31-37
        • Sepulveda W.
        • Wong A.E.
        • Martinez-Ten P.
        • Perez-Pedregosa J.
        Retronasal triangle: a sonographic landmark for the screening of cleft palate in the first trimester.
        Ultrasound Obstet Gynecol. 2010; 35: 7-13
        • Chaoui R.
        • Orosz G.
        • Heling K.S.
        • Sarut-Lopez A.
        • Nicolaides K.H.
        Maxillary gap at 11-13 weeks' gestation: marker of cleft lip and palate.
        Ultrasound Obstet Gynecol. 2015; 46: 665-669
        • Hoopmann M.
        • Sonek J.
        • Esser T.
        • Bilardo C.M.
        • Wagner P.
        • Abele H.
        • et al.
        Frontal space distance in facial clefts and retrognathia at 11-13 weeks' gestation.
        Ultrasound Obstet Gynecol. 2016; 48: 171-176
        • Baumler M.
        • Faure J.M.
        • Bigorre M.
        • Baumler-Patris C.
        • Boulot P.
        • Demattei C.
        • et al.
        Accuracy of prenatal three-dimensional ultrasound in the diagnosis of cleft hard palate when cleft lip is present.
        Ultrasound Obstet Gynecol. 2011; 38: 440-444
        • Schlund M.
        • Levaillant J.M.
        • Nicot R.
        Three-Dimensional printing of prenatal ultrasonographic diagnosis of cleft lip and palate: presenting the needed "Know-How" and discussing its use in parental education.
        Cleft Palate Craniofac J. 2020; 57: 1041-1044
        • Maarse W.
        • Rozendaal A.M.
        • Pajkrt E.
        • Vermeij-Keers C.
        • Mink van der Molen A.B.
        • van den Boogaard M.J.
        A systematic review of associated structural and chromosomal defects in oral clefts: when is prenatal genetic analysis indicated?.
        J Med Genet. 2012; 49: 490-498
        • Breugem C.C.
        • Evans K.N.
        • Poets C.F.
        • Suri S.
        • Picard A.
        • Filip C.
        • et al.
        Best practices for the diagnosis and evaluation of infants with Robin sequence: a clinical consensus report.
        JAMA Pediatr. 2016; 170: 894-902
        • Evans K.N.
        • Sie K.C.
        • Hopper R.A.
        • Glass R.P.
        • Hing A.V.
        • Cunningham M.L.
        Robin sequence: from diagnosis to development of an effective management plan.
        Pediatrics. 2011; 127: 936-948
        • Vatlach S.
        • Maas C.
        • Poets C.F.
        Birth prevalence and initial treatment of Robin sequence in Germany: a prospective epidemiologic study.
        Orphanet J Rare Dis. 2014; 9: 9
        • Printzlau A.
        • Andersen M.
        Pierre Robin sequence in Denmark: a retrospective population-based epidemiological study.
        Cleft Palate Craniofac J. 2004; 41: 47-52
        • Holder-Espinasse M.
        • Abadie V.
        • Cormier-Daire V.
        • Beyler C.
        • Manach Y.
        • Munnich A.
        • et al.
        Pierre Robin sequence: a series of 117 consecutive cases.
        J Pediatr. 2001; 139: 588-590
        • Lind K.
        • Aubry M.C.
        • Belarbi N.
        • Chalouhi C.
        • Couly G.
        • Benachi A.
        • et al.
        Prenatal diagnosis of Pierre Robin Sequence: accuracy and ability to predict phenotype and functional severity.
        Prenat Diagn. 2015; 35: 853-858
      1. Wiechers C PC, Hoopman M, Kagan KO. Fetal profile markers for the detection of Robin sequence in fetuses with retrognathia. [Under revision].

        • Sepulveda W.
        • Cafici D.
        • Bartholomew J.
        • Wong A.E.
        • Martinez-Ten P.
        First-trimester assessment of the fetal palate: a novel application of the Volume NT algorithm.
        J Ultrasound Med. 2012; 31: 1443-1448
        • Paladini D.
        • Morra T.
        • Teodoro A.
        • Lamberti A.
        • Tremolaterra F.
        • Martinelli P.
        Objective diagnosis of micrognathia in the fetus: the jaw index.
        Obstet Gynecol. 1999; 93: 382-386
        • Kruse T.
        • Neuschulz J.
        • Wilhelm L.
        • Ritgen J.
        • Braumann B.
        Prenatal diagnosis of Robin sequence: sensitivity, specificity, and clinical relevance of an index for micrognathia.
        Cleft Palate Craniofac J. 2020; (1055665620972297)
        • Bronshtein M.
        • Blazer S.
        • Zalel Y.
        • Zimmer E.Z.
        Ultrasonographic diagnosis of glossoptosis in fetuses with Pierre Robin sequence in early and mid pregnancy.
        Am J Obstet Gynecol. 2005; 193: 1561-1564
        • Nicholls W.
        • Jennings R.
        • Yeung Y.
        • Walters M.
        • Hewitt B.
        Antenatal ultrasound detection of cleft in western Australia from 2003 to 2012: a follow-up study.
        Cleft Palate Craniofac J. 2017; 54: 321-326
        • Sreejith V.P.
        • Arun V.
        • Devarajan A.P.
        • Gopinath A.
        • Sunil M.
        Psychological effect of prenatal diagnosis of cleft lip and palate: a systematic review.
        Contemp Clin Dent. 2018; 9: 304-308
        • Duek I.
        • Gil Z.
        • Solt I.
        Modified ex utero intrapartum treatment procedure in a bicornuate uterus breech presentation Pierre Robin fetus with severe micrognathia and cleft palate.
        Clin Case Rep. 2018; 6: 2040-2044
        • Luedders D.W.
        • Bohlmann M.K.
        • Germer U.
        • Axt-Fliedner R.
        • Gembruch U.
        • Weichert J.
        Fetal micrognathia: objective assessment and associated anomalies on prenatal sonogram.
        Prenat Diagn. 2011; 31: 146-151
        • Di Pasquo E.
        • Amiel J.
        • Roth P.
        • Malan V.
        • Lind K.
        • Chalouhi C.
        • et al.
        Efficiency of prenatal diagnosis in Pierre Robin sequence.
        Prenat Diagn. 2017; 37: 1169-1175
        • Rotten D.
        • Levaillant J.M.
        • Martinez H.
        • Ducou le Pointe H.
        • Vicaut E.
        The fetal mandible: a 2D and 3D sonographic approach to the diagnosis of retrognathia and micrognathia.
        Ultrasound Obstet Gynecol. 2002; 19: 122-130
        • de Jong-Pleij E.A.
        • Ribbert L.S.
        • Pistorius L.R.
        • Tromp E.
        • Bilardo C.M.
        The fetal profile line: a proposal for a sonographic reference line to classify forehead and mandible anomalies in the second and third trimester.
        Prenat Diagn. 2012; 32: 797-802
        • de Jong-Pleij E.A.
        • Ribbert L.S.
        • Manten G.T.
        • Tromp E.
        • Bilardo C.M.
        Maxilla-nasion-mandible angle: a new method to assess profile anomalies in pregnancy.
        Ultrasound Obstet Gynecol. 2011; 37: 562-569
        • Palit G.
        • Jacquemyn Y.
        • Kerremans M.
        An objective measurement to diagnose micrognathia on prenatal ultrasound.
        Clin Exp Obstet Gynecol. 2008; 35: 121-123


      Fetal profil line
      Inferior facial angle
      Maxillary nasion mandible angle
      Magnetic resonance imaging
      Prefrontal space ratio
      Robin sequence