Cleft lip and palate are relatively common facial malformations that occur early in gestation. Although they are distinct anomalies, they frequently occur together (Seeds and Cefalo, 1983). In all cases of orofacial clefting, 60% to 75% involve cleft lip, with or without cleft palate, and 25% to 40% are isolated cleft palate (Figure 23-1). Most cases (80%) are unilateral, occurring twice as commonly on the left side as on the right (Gorlin et al., 1971; Seeds and Cefalo, 1983; Bronshtein et al., 1991). Isolated cleft palate is more frequently associated with other anomalies (Jones, 1988a).

Orofacial clefts derive from abnormalities in the migration and proliferation of facial mesenchyme, a neural crest cell derivative. Coalescence of facial mesenchyme results in the formation of the primary palate, which creates the initial separation between oral and nasal cavities, eventually creating part of the upper lip and anterior maxilla (Ross and Johnston, 1972). Cleft lip with or without cleft palate results from failure of the nasal and maxillary facial processes to fuse. Fusion of these processes may be affected by the amount of mesenchyme present, its rate of migration, and the distance over which this migration occurs (Lynch and Kimberling, 1981).

Fifty percent of cleft lip patients also have cleft palate, which is a secondary effect resulting from a defect in facial prominence fusion that precedes palate formation. Isolated cleft palate has a different pathophysiology than either cleft lip or cleft lip associated with cleft palate. It results from interference in any of the following processes that occur during normal closure of the palate:

1. 
   

   The palatal shelves move from bilateral vertical positions lateral to each side of the tongue to horizontal positions overlying the tongue.

   
   
2. 
   

   The tongue exerts resistance to the movement of the palatal shelves.

   
   
3. 
   

   The tongue moves downward to below the palatal shelves.

   
   
4. 
   

   The horizontal palatal shelves become flattened and extend their leading edges toward the midline.

   
   
5. 
   

   The shelves meet in the midline and fuse. Their respective epithelia then dissolve at the point of contact (Lynch and Kimberling, 1981).

From the description above, it is apparent that the tongue plays a role in the etiology of cleft palate. Any factor that interferes with downward displacement of the tongue, tongue movement, or tongue pressure may interfere with palatal fusion.

The worldwide incidence of cleft lip with or without cleft palate is 1 in 700 births (Murray, 2002). Marked variation occurs in different racial and ethnic groups. Black infants have a lower incidence (1 in 2273 births), whereas the incidence among Japanese and Native Americans is higher (1 in 584 and 1 in 276, respectively) (Tretsven, 1963; Lynch and Kimberling, 1981). Isolated cleft palate occurs more rarely and does not vary in different ethnic backgrounds. Cleft lip and palate occur twice as often in males as in females (Bronshtein et al., 1991). In some studies, orofacial clefting has been shown to occur more commonly in fetuses whose mothers are of advanced age (Womersley and Stone, 1987; Shaw et al., 1991); in a large population-based registry, however, no association between maternal age and cleft disorders was seen (Baird et al., 1994). Maternal smoking and alcohol use during pregnancy are thought to increase the incidence of clefts through gene-environment interactions (Eppley et al., 2005). Periconceptual multivitamin use, specifically folate supplementation, decreases the incidence of cleft palate (Werler et al., 1999, Eppley et al., 2005).

Although fusion of the midline structures of the fetal face is complete by 7 weeks of gestation, the mandible and maxilla are not clearly visualized sonographically until week 10 (Cockell and Lees, 2000). Cleft lip and palate cannot be reliably diagnosed until 13 to 14 weeks by transabdominal sonography. The fetal palate is best observed in the axial plane and the fetal lips in the coronal views. Seeds and Cefalo (1983) were the first investigators to advocate a combination of frontal and coronal scanning of the midface (Figure 23-2). In 1984, Benacerraf et al. recommended routinely examining the face as part of a complete antenatal sonographic examination. They described a coronal view through fetal facial structures that encompassed both orbits, the maxilla, and the anterior portion of the mandible in one vertical plane. Sherer et al. (1991) described an oblique coronal facial view that was achieved by aiming the transducer beneath the fetal chin using the nares as a landmark. They sought echogenic evidence of an intact fissure created by the closed lips. The two advantages of this approach are that rarely was this view unobtainable due to position of the fetus and that the appearance of the philtrum was clearly defined. Using a combination of transverse, coronal, and profile views, Turner and Twining (1993) were able to define fetal facial structures in 95% to 97% of fetuses at 16 to 20 weeks of gestation.

Bronshtein et al. (1994) described the use of transvaginal sonography to detect facial clefts in the early second trimester. In 14,988 examinations performed, 11 cases of orofacial clefts were detected. Of these, 10 were cases of cleft lip and palate and 1 was isolated cleft lip. All diagnoses were confirmed after termination of the pregnancy or at birth.

Despite these studies, sonographic diagnosis of facial clefts remains challenging. The overall detection rate is currently on the order of 65% (Cash et al., 2001) to 73% (Robinson et al., 2001). In general, cleft lip is easier to demonstrate than cleft palate. Bronshtein et al. (1991) advocated the use of the sagittal paramedian view to detect pseudoprognathism, a protrusion of the mandible relative to the maxilla. In bilateral cleft lip and palate, a paranasal echogenic mass may be present due to premaxillary protrusion of the prolabial structure that exists in this condition (Nyberg et al., 1992, 1993). Sherer et al. (1993) have advocated for the use of color Doppler imaging to demonstrate abnormal amniotic fluid flow across the fetal pharyngeal bone defect, although this technique has not gained widespread acceptance and is of uncertain value.

Because of the challenges associated with the 2D sonographic diagnosis of orofacial clefts, several authors advocate for a 3D approach (Figures 23-3A and 23-3B). One study examined the use of 3D sonographic visualization of fetal tooth buds as a means of improving antenatal characterization of fetal facial clefts (Ulm et al., 1999). In all 17 fetuses studied, it was possible to classify the clefts as either cleft lip alone or unilateral or bilateral cleft lip and palate. Lee et al. (2000) described a standardized 3D protocol that included multiplanar imaging of the upper lips and sequential axial views to evaluate the alveolar ridge contour and anterior tooth socket alignment.

More recently, 3D ultrasound has been used to evaluate the anatomy of the fetal palate from within the fetal head. Using this technique, a 3D volume of the fetal head is obtained and then a cut volume of tissue is removed from the back of the head. By rotating the remaining volume containing the anterior part of the face and head, the fetal palate can then be inspected from behind the face, revealing the interior of the mouth (Platt et al., 2006). Alveolar ridge disruption, or premaxillary protrusion (by multiplanar imaging or surface rendering) suggests the presence of bilateral cleft lip and palate. Additional advantages of 3D sonography include the fact that it allows assessment of the secondary (posterior) palate, it saves time, and that it is easier for prospective parents to visualize the defect (Rotten and Levaillant, 2004).

Fetal MRI is being increasingly used to evaluate structures that are difficult to identify by sonography alone. With MRI, the fetal nose and lips are best seen with coronal images. The secondary palate is best seen when amniotic fluid fills the mouth and outlines the tongue and palate (Smith et al., 2004). A major advantage of MRI appears to be that it allows a more accurate assessment of the secondary palate, which cannot be seen by 2D sonography (Ghi et al., 2003; Kazan-Tannus et al., 2005).

The most important consideration in the differential diagnosis of cleft lip is to distinguish between the normal vertical midline appearance of the philtrum and a pathologic median cleft lip. Although most cleft lips are left-sided and unilateral, a median cleft lip can be associated with syndromes such as orofacialdigital, type I, or frontonasal dysplasia. Consideration should also be given to detection of premaxillary agenesis, which is almost always associated with alobar holoprosencephaly (see Chapter 14).

When a paranasal echogenic mass is detected in cases of bilateral cleft lip and palate, the differential diagnosis includes hemangioma, anterior meningocele, teratoma, and enlarged tongue and proboscis (Nyberg et al., 1992). Of these conditions, only premaxillary protrusion associated with cleft lip and palate contains bone within the mass, resulting from anterior migration of maxillary and alveolar bones (Nyberg et al., 1992).

Once a cleft is identified, a diligent search should be made to detect associated anomalies. The finding of additional anomalies will significantly affect the differential diagnosis. More than 400 syndromes are associated with facial clefts (Shprintzen et al., 1985; Lidral and Murray, 2004). Common syndromes include Goldenhar (facioauriculovertebral dysplasia), Treacher–Collins (mandibulofacial dysostosis), Pierre–Robin, Stickler, DiGeorge, and Shprintzen (velocardiofacial) (Table 23-1). Additional anomalies seen in cases of Pierre–Robin sequence include micrognathia and polyhydramnios (Hsieh et al., 1999). Neurologic and myopathic conditions such as Stickler syndrome, can be associated with cleft palate. Syndromes that involve relatively broad faces, such as Crouzon and Waardenburg, are associated with an increased incidence of facial clefts.