Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 379–389

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Facial cleft detected: Is the palate normal? Wassim A. Hassan, MD, Consultant in Obstetrics and Specialist in Fetal Medicine a, Christoph C. Lees, MD, Consultant in Obstetrics and Subspecialist in Fetal-Maternal Medicine b, * a Fetal Medicine Department, Rosie Hospital, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK b The Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Du Cane Road, London W12 0HS, UK

Keywords: orofacial cleft palate alveolar ridge prenatal ultrasound lip secondary palate detection

Despite advances in ultrasound technology, the sensitivity for detection of facial clefts at the routine mid-trimester details scan remains relatively poor. This can be improved by the use of a three-point ultrasound screening protocol, although this is not routine in many countries. When a facial cleft is suspected at the routine scan, further imaging is usually required to detail the extent of the cleft and presence or absence of any other abnormalities. Involvement of the fetal palate is an important finding that will determine the requirement for surgery, audiology, and orthodontic services well into teenage years. There remains little uniformity in how a facial cleft is described antenatally, with involvement of the alveolar ridge frequently and incorrectly taken to mean involvement of the palate. Further, midline clefts of the hard and soft palates, where the fetal lips and alveolar ridge are intact, are a feature of many genetic conditions, but are almost never diagnosed by prenatal ultrasound. In this chapter, we detail issues surrounding the nomenclature of facial clefts in relation to the palate, and describe some of the more commonly used twodimensional and three-dimensional methodologies for imaging the fetal palate. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Prenatal detection rates for isolated clefts of the lip and alveolus by two-dimensional ultrasound have historically been poor, ranging from 45–68% [1–3], although a more focused approach using highresolution equipment and additional scanning planes (‘face on’; coronal plane through the alveolar * Corresponding author. E-mail address: [email protected] (C.C. Lees). 1521-6934/$ – see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2014.01.010

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ridge and sagittal profile view) has resulted in an improvement from 34–58% in two consecutive time epochs through the introduction of the additional scanning planes detailed [4]. One of the most recent papers on cleft detection, from Southern Sweden reflecting contemporary practice in the period 2006–2010 [5], details a somewhat disappointing detection rate of 31% (43% if isolated midline clefts are excluded). This detection rate compares unfavourably with a study that most closely resembles UK practice, based on birth registry data from 2005–2006. This reported a 64% rate of prenatal detection for cleft lip, palate, or both [6]. It is possible that the detection for facial clefts has fallen in the UK since the recommendation in January 2010 that the ‘face on’ view only should be carried out as part of the anomaly scan [7]. Although there is little doubt that the use of higher resolution ultrasound equipment and incorporation of protocols for examining the fetal face at the time of the detailed anomaly scan can improve sensitivity to as high as 75%, the detection rates for clefts of the secondary (hard) palate using twodimensional ultrasound have remained low, even in those patients in whom a cleft lip has been detected. Secondary palatal involvement, however, can alter the long-term prognosis for the child, being more commonly associated with difficulties in speech, hearing and (after surgery) mid-facial protrusion. Typically, clefts of the secondary palate require more corrective surgery into teenage years, and a greater input of audiology, speech and language therapy, and orthodontic intervention. The accuracy of antenatal diagnosis of facial cleft is, therefore, particularly helpful in preparing parents and cleft teams for the birth of a child with facial cleft, and for advance planning. Recent years have seen improvements in two-dimensional imaging and the advent of three- and four-dimensional ultrasound technology, coupled with different techniques for visualising the fetal face and, in particular, the hard and soft palates. Little uniformity exists in approach between specialists in cleft imaging, however, and the many different ways that facial clefts are described. In this chapter, we consider the confusions in nomenclature associated with facial clefts, and the different techniques and ultrasound modalities described to assess the fetal palate, particularly where a facial cleft is suspected. Embryology Facial clefts result from defective fusion of the facial processes. Clefts of the lip and alveolus occur because of a failure of fusion of the medial nasal process and maxillary swellings [8]. They may be unilateral or bilateral, and associated with a cleft of the alveolus on the side of the lip cleft. Clefting of the secondary (hard) palate has a distinct and different embryological derivation, and is secondary to a failure of fusion of the two palatine shelves [9]. Clefts of the secondary (hard) palate are, therefore, always midline and posterior to the incisive foramen and, if they occur together with cleft of the lip and alveolar ridge, they are termed unilateral or bilateral cleft lip with cleft palate [9,10]. A cleft of the secondary palate where there is also a cleft lip cannot occur in the absence of cleft of the ipsilateral alveolar ridge except for the rare situation of a baby suffering from both embryological variants of facial cleft. Facial clefts have been typically divided into cleft lip with or without palatal involvement. Involvement of the lip and alveolus was said to represent a cleft of the primary palate, that area anterior to the incisive foramen, with clefts of the secondary palate being described distinctly. Confusion in terminology means that a child with ‘cleft lip and palate’ may in fact have a cleft of the primary palate but an intact secondary palate; this represents a cleft alveolus. The embryological origins of isolated clefts of the secondary palate seems to be distinct from those of clefts of the lip and alveolus [8]. The secondary palate comprises the hard palate (immediately posterior to the incisive foramen) and the soft palate (posterior to the hard palate, containing no bone). Isolated cleft palate is rarer than unilateral cleft palate or bilateral cleft palate; ultrasound studies underestimate the incidence of isolated cleft palate, as this condition is rarely diagnosed by prenatal ultrasound and may even not be identified immediately after delivery. In Denmark, isolated cleft palate accounts for 25% of the total number of cases of facial clefts [11,12], but surveys in other countries show that the incidence varies; for example, it is over 50% in Northern Ireland and Scotland [13–16]. Secondary palate clefts are always midline and result from the failure of the palatine processes to elevate or grow, so a cleft of the hard palate must also affect the soft palate; however, it is possible for the soft palate to be cleft with the hard palate.

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Classification of facial clefts Several classifications for facial cleft exist, most notably those of Kernahan (1958, 1971) [17,18], Elsahy (1973) [19], and Friedman (1991) [20]. These are all based on postnatal examination, and allow the key elements of the facial cleft (lip, alveolar ridge, hard and soft palate) to be delineated and, in addition, the latter two give an indication of the degree of the cleft. The ‘striped Y’ classification described by Kernahan [18], separately identifies a cleft of the lip, alveolus and (secondary) hard and soft palate, and allows as much detail as can reasonably expected from prenatal ultrasound scan (Fig. 1). Confusion may arise in the word isolated: ‘not associated with any other obvious fetal abnormality’ or ‘isolated’ hard/soft palate cleft where this does not affect the fetal lips and alveolar ridge. Therefore, we reserve the use of the word ‘isolated’ to denote a facial cleft where there is no evidence of any other abnormality, and use the term ‘midline cleft palate’ to denote a cleft of the palate not affecting the lips. Epidemiology Orofacial clefting is one of the most common non-lethal congenital abnormalities and is becoming more common. The worldwide incidence ranges between 1 and 2.2 per 1000; in Denmark, the

Fig. 1. Description of modified Kernahan ‘striped Y’ schematic.

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incidence rose from 1.45 per 1000 live births in 1942 to 1.89 per 1000 in 1981. Birth registry data from Denmark and Finland suggest an incidence in livebirths of 1.69 and 1.74 per 1000, respectively [21–24]. Syndromic associations with facial clefts A genetic or chromosomal contribution to facial clefts has been described in many syndromic associations. A number of genes has been identified and known to play a role in the craniofacial development (1p36, 2p21, 3p11.1, 8q21.3, cleft lip and palate transmembrane protein 1, GAD1, AXIN2, FGFR1, FGFR2, IRF6, PDGFC etc) [22–24]. Although many clefts run in families, in a large number of cases there is no corresponding syndromic appearance yet identified. Moreover, our knowledge about the genetic factors that contribute to the more common cases is still incomplete. In Table 1, we detail some of the syndromic associations and their type of inheritance in relation to facial clefts. Two-dimensional techniques for visualising the hard palate Septo-lingual view We have described 11 cases where it was possible to diagnose prenatal cleft palate on twodimensional ultrasound. Cases were considered to have a cleft in the hard palate if the tongue was seen moving next to or abutting the nasal septum in transverse view (Fig. 2a and b). All cases also had three-dimensional reverse rendering technique. In 11 women referred with a possible diagnosis of facial cleft, the technique yielded a positive result. In these cases, there was complete concordance with three-dimensional reverse face views and postnatal follow up. Visualising the tongue abutting the nasal septum in the transverse view indicates strongly the presence of the cleft in the hard palate, as the tongue would not otherwise be visualised in the same plane as the septum. As the tongue may appear indistinct in a frozen image, the technique can only be considered to give a positive result if the tongue is seen moving next to the nasal septum in the transverse view. Two-dimensional ultrasound may be a useful additional modality in the diagnosis of hard palate cleft. We do not yet have sufficient cases where the technique gave a negative result to determine its value in excluding cleft of hard palate.

Table 1 Genetic and chromosomal associations with cleft lip and palate. Syndrome

Cleft lip and palate

Inheritance

Genetic or chromosomal basis

Trisomy 13 Trisomy 18

Bilateral cleft lip and palate Unilateral or bilateral cleft lip with or without alveolar ridge or palate Bilateral cleft lip and palate or complete absence of midline facial structures Lip and palate Palate

Sporadic or translocation Sporadic or translocation

47 XX or 47 XY þ13 47 XX or 47 XY þ18

Sporadic

XXX, XXY, XYY

Sporadic Autosomal dominant

1 in 5000 1 in 50 000

Palate and bifid uvula Palate Palate Palate Palate with or without lip Lip, alveolar ridge and palate Lip, alveolar ridge and palate Lip, alveolar ridge and palate

Autosomal dominant Sporadic Autosomal dominant Autosomal recessive Sporadic Autosomal dominant Autosomal recessive X-linked dominant

1 1 1 1 1 1 1 1

Lip, alveolar ridge and palate

Autosomal recessive

Not known

Lip, alveolar ridge and palate

Autosomal dominant

1 in 75 000

Triploidy

Goldenhar Treacher–Collins syndrome Sticklers Pierre–Robin DiGeorge Meckel–Gruber Nager Gorlin Hydrolethalus Oral–facial-digital type I Oral–facial-digital type II Van der Woude

22q deletion

Incidence

in in in in in in in in

7500 10 000 3000 20 000 50 000 100 000 20 000 100 000

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Fig. 2. (a) Transverse ultrasound view of the fetal face at the level of the nasal septum showing a deviated nasal septum with the tip of the tongue abutting the nasal septum; (b) coronal representation of the fetal face and nasal septum showing in the left image the normal relationship between the hard palate, nasal septum and tongue. On the right is shown a gap in the hard palate with tongue protruding into the ethmoid sinus adjacent to the nasal septum Published with permission from Mr Jeffrey Brain, FRCS.

Two-dimensional techniques for visualising the soft palate and uvula Recently Wilhelm and Borgers [25] suggested the use of a novel marker for diagnosing isolated cleft palate with the sonographic appearance of an ‘equals sign’. A total of 667 consecutive women between 20 and 25 weeks gestation were referred for a detailed anomaly scan. The uvula was visualised by frontal section through the neck and pharyngeal space, and the epiglottis served as the landmark for identifying the uvula. A normal uvula resembled an equals sign (two hyperechogenic lines with hypoechoic intermediate space). Also the uvula could be visualised in a transverse section through the head at the level of the thalamus; the transducer was moved parallel to this plane in the caudal direction until the nasopharynx was visualised in the centre; further movements of the transducer enabled the soft palate and uvula to be identified. A typical ‘equals sign’ could be visualised in 90% of cases (605 out of 667) and the soft palate in median sagittal section in 85% of cases (569 out of 667). Detection of either the uvula or

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the soft palate was successful in 98% of cases (656 and 667). Three cases with clefts were diagnosed. In one case, neither the uvula nor the soft palate could be visualised by ultrasound; in another case of unilateral cleft, this method confirmed the involvement of the soft palate and a complete cleft uvula. In a third case of bilateral cleft, this method correctly diagnosed continuous cleft of the soft palate. A significant training effect was observed during the study; the examination time required for making appropriate adjustments significantly decreased over time, and the ability to interpret ultrasound findings made in poor conditions increased significantly. The method could be used as a routine twodimensional ultrasound screening examination of the soft palate. Three-dimensional techniques for visualizing the hard palate In the past decade, three-dimensional ultrasound began to play an important detecting role in the evaluation of craniofacial anomalies. It has proved to be more effective in visualising the palate and palate defects. In this section, we describe some of the more commonly cited three-dimensional techniques used for visualising the hard palate. Whether or not three-dimensional imaging represents a genuine advance in cleft imaging remains open to debate. In a series of craniofacial anomalies, Ghi et al., in 2002, compared the effectiveness of two- and three-dimensional ultrasound in the accuracy of diagnosis [26]. Thirty-seven cases before 24 weeks gestation with clefts (lip and palate) were analysed retrospectively. Two-dimensional evaluation of the fetuses included multiple sections of the fetal face and cranium to demonstrate the eyes, nose, lips and the alveolar ridge of the palate and the mandible. Coronal, axial views, and a profile view of the face were obtained. Three-dimensional acquisitions were captured and rearranged in a computer workstation and then processed for surface rendering to provide a realistic representation of the fetal face and the palate. Two-dimensional ultrasound easily and rapidly recognised and categorised facial clefts in all cases using a combination of coronal and axial views. Cleft lip was always best visualised in an anterior coronal plane; however, when the defect was extended to the palate, an axial view of the maxilla proved better (Fig. 3). Three-dimensional ultrasound confirmed the diagnosis in 11 out of 12 fetuses; however, they reported time-consuming methods (30 mins) with three-dimensional ultrasound was compared with two-dimensional ultrasound when the examination was carried out in a few minutes. Two-dimensional ultrasound in expert hands allows an accurate diagnosis of craniofacial abnormalities from early gestation, and that three-dimensional ultrasound did not add any valuable diagnostic information. Reverse face view Campbell and Lees in 2003 described a novel technique ‘three-dimensional reverse face’ for visualising the palate [27]. Using a four-dimensional slow frame rate (2.7 Hz) image or a three-

Fig. 3. Unilateral cleft lip and palate; (a) the coronal view shows the cleft lip with distortion of the nasal tip and asymmetry of the nostrils; (b) the axial scan through the fetal maxilla (b); (c and d) the cleft extending to the alveolar ridge. Three-dimensional sonogram with surface rendering in the same case. Published with permission UOG.

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Fig. 4. Three-dimensional ultrasound image (frontal view) of the affected fetus showing the bilateral cleft lip. Published with permission UOG.

Fig. 5. Face view to allow visualisation of the lips, and then the viewbar is scrolled through the lips until the alveolar ridge is identified. Published with permission UOG.

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Fig. 6. The alveolar ridge and palate using the reverse face view. Clear visualisation of the orbits, nasal cavity with septum and palate are identified at all levels from the alveolus (a) to the posterior aspect of (b–d) the hard palate. Published with permission UOG.

dimensional sweep, the viewbar was adjusted to provide an optimised surface-rendered image of the face (Fig. 4). The face was adjusted in a frontal view to allow visualisation of the lips, and then the viewbar is scrolled through the lips until the alveolar ridge is identified (Fig. 5). A return to the frontal view of the face was made, and the face rotated through 180 . This provides an unobstructed

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view of the palatal area, nasal cavity, and orbits. The viewbar is then scrolled through the length of the palate (Fig. 6a–d). The same group in 2005 evaluated this technique in eight cases, and found that the visualisation of the palate is feasible and rapid, taking only 2–3 mins [28]. Optimal visualisation of the hard palate was obtained by surface-rendered mode; the appearance of a limb in front the face may cause significant shadowing; however, the views were not affected by the umbilical cord or the placenta. A larger study, including over 100 patients using three-dimensional imaging as an adjunct to two-dimensional imaging, showed that the accuracy of diagnosis of most types of cleft was over 90% [29]. In this study, only one baby was subsequently found to have an undiagnosed genetic condition. Flipped face view Subsequently, Platt et al. [30] suggested the ‘flipped face’ technique for assessing the hard and soft palates. Using three-dimensional static volume of the fetal face with the fetus in supine position, 90 rotation of the acquisition is carried out so that the cut plane was directed in a plan from the chin to the nose. The viewbar is then scrolled from chin to nose to examine the lower lip, mandible and alveolar ridge, then the tongue, upper lip, maxilla, alveolar ridge and hard and soft palates. The authors of this study suggested this technique could provide full description of the fetal palates and face; however, they reported a major limitation. The technique requires the acquisition of an adequate facial volume that does not have shadowing of the palate, which could be misinterpreted as a defect. In addition, if the fetal face is directed posterior, this technique cannot be used because of shadowing from the occipital bones of the skull. Angled insonation Pilu et al. [31], in 2007, described a new technique for the visualisation of the secondary palate using three-dimensional ultrasound. Fifteen normal fetuses between 19 and 28 weeks gestation, and one fetus with cleft lip and palate at 33 weeks gestation, were studied. This method suggested obtaining an image of the face, aligning the probe with the profile of the fetus. To avoid shadowing from the alveolar ridge, Pilu et al. [31] used an angled approach by insonating the secondary palate at an angle of about 45 (Fig. 1). Static ultrasound volumes were obtained and analysed offline using multiplanar, surface mode, static volume contrast imaging, and tomographic ultrasound imaging. Good-quality volumes were possible in 10 of the 15 normal fetuses, and in the fetus with cleft lip and palate. Unfavourable position of the fetus and fluid in the oral cavity were the main disadvantages of the technique, whereas better results were obtained when the fetus was facing the transducer and the head was slightly extended. Three-dimensional techniques for visualising the soft palate and uvula A first-trimester method for evaluating the anatomy of the palate and the ‘retronasal triangle’ has been described by Sepulveda et al. [32] One hundred consecutive normal fetuses at the time of routine two-dimensional first-trimester screening (11–13 þ 6 weeks) had the retronasal triangle identified as the three echogenic lines formed by two frontal processes of the maxilla and the palate visualised in a coronal view of the fetal face posterior to the nose. In a separate study of five fetuses confirmed postnatally with cleft of the palate, three-dimensional ultrasound images, including multiplanar views, were analysed. Abnormal appearance of the retronasal triangle was identified in all five cases with cleft of the palate. The group suggested incorporating the ‘retronasal triangle’ in first-trimester screening in view of the feasibility of obtaining clear anatomy of the palate by twodimensional ultrasound. Conclusion With the use of modern ultrasound techniques and the ability to define facial clefts according to a systematic classification, it should be possible both to image and describe facial clefts prenatally with a

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high degree of accuracy. This includes defining hard palate involvement by targeted systematic two-, three-dimensional ultrasound examination, or both, in over 90% of cases where there is a cleft in the fetal lips, alveolar ridge, or both. A greater challenge is in identifying isolated clefts of the hard and soft palate, where there is no cleft of the fetal lips to alert the ultra-sonographer to look in more detail at the fetal face. Screening for isolated hard and soft palate cleft is unlikely to be realistic in routine practice. Targeted assessment, however, of the fetal palate in the context of either a family history of hard and soft palate clefts (e.g. in Stickler Syndrome), or where there is another fetal abnormality, is realistic, although the sensitivity for diagnosis of midline facial cleft in the absence of any other ultrasound markers may be low.

Practice points  In routine ultrasound screening using a three-point multiplanar technique, 65% or more of facial clefts can be identified at the mid-trimester scan.  Where cleft lip, alveolar ridge, or both, is detected, careful two-dimensional ultrasound, supplemented with three-dimensional ultrasound can in over 90% of cases detect a cleft of the hard palate.  Midline cleft palate, where the fetal lips are normal, is almost never diagnosed prenatally unless there is suspicion from family history, and expert ultrasound is carried out specifically looking for a defect in the hard and soft palates.  Where facial cleft is identified in the presence of low-risk trisomy screening, and detailed ultrasound discloses no other abnormality, the risk of an underlying genetic or chromosomal condition is less than 2%.

Conflict of interest None declared. Acknowledgements Christoph Lees is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. References [1] Hanikeri M. Antenatal transabdominal ultrasound detection of cleft lip and palate in Western Australia from 1996 to 2003. Cleft Palate Craniofac J 2006;43:61–6. *[2] Wayne C. Sensitivity and accuracy of routine antenatal ultrasound screening for isolated facial clefts. Br J Radiol 2002;75: 584–9. *[3] Clementi M, Tenconi R, Bianchi F, et al. Evaluation of prenatal diagnosis of cleft lip with or without cleft palate and cleft palate by ultrasound: experience from 20 European registries. Prenat Diagn 2000;20:870–5. *[4] Offerdal K, Blaas HG, Eik-Nes SH. Prenatal ultrasound detection of facial clefts: a prospective study of 49,314 deliveries in a non- selected population in Norway. Ultrasound Obstet Gynecol 2008;31:639–46. [5] Berggren H, Hansson E, Uvemark A, et al. Prenatal ultrasound detection of cleft lip, or cleft palate, or both, in southern Sweden, 2006–2010. J Plast Surg Hand Surg 2012;46:69–74. [6] Boyd PA, Tonks AM, Rankin J, et al. Monitoring the prenatal detection of structural fetal congenital anomalies in England and Wales: register-based study. J Med Screen 2011;18:2–7. *[7] NHS Fetal Anomaly Screening Programme. Standards and policies; http://fetalanomaly.screening.nhs.uk/ standardsandpolicies [last accessed 22.01.14]. [8] Diewert VM, Lozanoff S. A morphometric analysis of human embryonic craniofacial growth in the median plane during primary palate formation. J Craniofac Genet Dev Biol 1993;13:147–61. *[9] Tolerova M, Cervenka J. Classification and birth prevalence of orofacial clefts. Am J Med Genet 1998;75:126–37.

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[10] Chung CS, Bixler D, Watanabe T, et al. Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data. Am J Hum Genet 1986;39:603–11. [11] Fog-Andersen P. Incidence and aetiology. In: Edwards M, Watson ACH, editors. Advances in the management of cleft palate. Edinburgh: Churchill Livingstone; 1980. pp. 43–8. [12] Melnick M, Bixler D, Fogh-Andersen P, et al. Cleft lip þ/– cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968. Am J Med Genet 1980;6:83–97. [13] Derijcke A, Eerens A, Carels C. The incidence of oral clefts: a review. Br J Oral Maxillofac Surg 1996;34:488–94. [14] Fitzpatrick DR, Raine PAM, Boorman JG. Facial clefts in the West of Scotland in the period 1980–1984: epidemiology and genetic diagnosis. J Med Genet 1994;31:126–9. [15] Gregg T, Boyd D, Richardson A. The incidence of cleft lip and palate in Northern Ireland from 1980–1990. Br J Orthod 1994;21:387–92. [16] Hagberg C, Larson O, Milerad J. Incidence of cleft lip and palate and risks of additional malformations. Cleft Palate Craniofac J 1998;35:40–5. [17] Kernahan DA, Stark RB. A new classification for cleft lip and palate. Plast Reconstr Surg 1958;22:435. [18] Kernohan DA. The striped Y – a symbolic classification for cleft lips and palates. Plast Reconstr Surg 1971;47:469. [19] Elsahy NE. The modified striped Y-a systematic classification for the cleft lip and palate. Cleft Palate J 1973;10: 247–50. *[20] Friedman HI, Sayetta RB, Coston GN, et al. Symbolic representation of cleft lip and palate. Cleft Palate Craniofac J 1991;28: 252–9. [21] Jensen BL, Kreilborg S, Dahl E, et al. Cleft lip and palate in Denmark 1976–1981: epidemiology, variability and early somatic development. Cleft Palate J 1988;25:258–69. [22] Ludwig KU, Mangold E, Herms S, et al. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet 2012;44:968–71. [23] Shi M, Murray JC, Marazita ML, et al. Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts. Am J Med Genet A 2012;158A:784–94. [24] Beaty TH, Taub MA, Scott AF, et al. Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. Hum Genet 2013;132:771–81. [25] Wilhelm L, Borgers H. The ‘equals sign’: a novel marker in the diagnosis of fetal isolated cleft palate. Ultrasound Obstet Gynecol 2010;36:439–44. [26] Ghi T, Perolo A, Banzi C, et al. Two-dimensional ultrasound is accurate in the diagnosis of fetal craniofacial malformation. Ultrasound Obstet Gynecol 2002;19:543–51. *[27] Campbell S, Lees CC. The three-dimensional reverse face (3D view for the diagnosis of cleft palate). Ultrasound Obstet Gynecol 2003;22:552–4. *[28] Campbell S, Lees C, Moscoso G, et al. Ultrasound antenatal diagnosis of cleft palate by a new technique: the 3D ‘reverse face’ view. Ultrasound Obstet Gynecol 2005;25:12–8. [29] Sommerlad M, Patel N, Vijayalakshmi B, et al. Detection of lip, alveolar ridge and hard palate abnormalities using twodimensional ultrasound enhanced with the three-dimensional reverse-face view. Ultrasound Obstet Gynecol 2010;36: 596–600. [30] Platt LD, Devore GR, Pretorius DH. Improving cleft palate/cleft lip antenatal diagnosis by 3-dimensional sonography: the ‘flipped face’ view. J Ultrasound Med 2006;25:1423–30. *[31] Pilu G, Segata M. A novel technique for visualization of the normal and cleft fetal secondary palate: angled insonation and three-dimensional ultrasound. Ultrasound Obstet Gynecol 2007;29:166–9. *[32] Sepulveda W, Wong AE, Martinez-Ten P, et al. Retronasal triangle: a sonographic landmark for the screening of cleft palate in the first trimester. Ultrasound Obstet Gynecol 2010;35:7–13.

Facial cleft detected: is the palate normal?

Despite advances in ultrasound technology, the sensitivity for detection of facial clefts at the routine mid-trimester details scan remains relatively...
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