Etiopathogenesis/Causative Factors

Normal palatogenesis starts during the 5th week of gestation when the nasal placodes invaginate to form nasal pits. Ridges of tissue form on the lateral portion of the nasal pits, which become tissue processes that begin to migrate. During a period of 2 weeks (approximately 5 to 7 weeks gestation), these tissues migrate to form the structures anterior to the incisive foramen. This includes the prolabium (the middle portion of the upper lip), the premaxilla, as well as portions of the nose. The primary palate is formed by the end of the 6th week of gestation. The secondary palate then begins to form at approximately 6 weeks. This is when the medial nasal process, the lateral nasal process, and the maxillary process migrate and fuse. The fusion of the palatine shelves occurs at the 7th week, with the shelves first meeting just behind the incisive foramen. Fusion continues in an anterior-posterior direction, ending at the uvula. Fusion also occurs in a superior direction, with the hard palate fusing to the vomer of the nasal septum at approximately the 9th week. This complete process continues until about the 12th week of gestation.

Palatal clefting may occur when the processes that form the palatal shelves are disrupted either in their migration or fusion medially. Clefting of the secondary palate results from failure of the maxillary process to fuse with the secondary palatal shelves. Although the exact mechanism is unknown, there appears to be a complex interaction between molecular pathway defects, genetic causes, and environmental exposure to drugs and teratogens occurring together as in utero insults. The complexity of these interactions leads to a variety of clefts on physical examination.

A multitude of molecular studies and signaling pathways in animal models help us to understand the etiopathogenesis of facial clefting. A comprehensive review of these pathways will not be addressed in this chapter; however, some pathways merit discussion. Fibroblast growth factor-R1 (FGF-R1) and fibroblast growth factor-R2 (FGF-R2) are expressed specifically in the epithelium of the developing palatal shelves from the time of the outgrowth from the maxillary process through completion of fusion. In murine models, it has been demonstrated that by truncating FGF receptor subtypes, there is a change in epithelial–mesenchymal interactions, and the receptor signaling pathways alone are sufficient for cleft formation.

Other signaling molecules include the transforming growth factors, which have biologic cellular activities that control adhesion, proliferation, differentiation, and epithelial–mesenchymal transformation. Mutated transforming growth factor (TGF-β3) in mice has shown a consistent cleft palate phenotype.

Aside from molecules that signal epithelial migration, there are also signals that induce apoptosis, an element of palatogenesis that has also been extensively studied. In palate formation, apoptosis is thought to facilitate adherence, or touching, of the opposing epithelium to form a midpalatal seam. Studies have shown that intershelf distance increases in an inverse relationship between the number of epithelial cells undergoing apoptosis as the palatal edges migrate and the number of cells transforming into mesenchymal cells during palate fusion. Currently, it is unknown whether the balance between cell death and cell transformation is caused by the inadequate migration of the palatal shelves or if, in fact, it is the cause of the delay. Nonetheless, both apoptosis and epithelial–mesenchymal transformation appear to be necessary for normal palate formation, because clefting occurs in the absence of either one.

Another proposed theory is that deforming forces guide morphogenesis. There are various tissues in the embryo growing at different rates, which may induce stress and strain forces. These mechanical forces may in turn translate into the molecular cues for cell differentiation, migration, death, and transformation. This rationale is used to explain the cause of Pierre Robin sequence, where there is a decrease in the amniotic fluid index causing more external pressure on the fetal chin; this in turn prevents the tongue from relaxing to the floor of the mouth. The presence of the tongue between the palatal shelves prevents fusion.

There are an estimated 300 syndromes that include some form of cleft palate in their presentation; thus, genetic consultation should always be obtained. Some of the more common syndromes that are associated with clefts are velocardiofacial syndrome, Stickler syndrome, Van der Woude syndrome, and Pierre Robin sequence. Nonsyndromic causes include drugs, such as dilantin and corticosteroids, retinoids in high doses (vitamin A), hypoxia, and alcohol. The nonsyndromic causes are far more common, but isolated cleft palate is more frequently associated with syndromic involvement.

Pathologic Anatomy

A developmentally intact palate serves two purposes. First, the hard palate serves as a structural component of the face, dividing the oropharynx from the nasopharynx. Second, the soft palate has a functional component where the musculature, including the tensor veli palatini, levator veli palatini, superior pharyngeal constrictor, muscularis uvulae, palatopharyngeus, and palatoglossus, forms a dynamic valve called the velopharyngeal sphincter, which is raised during speech and swallowing to divide the nose from the mouth. The levator veli palatini fuses to form a “sling” that is primarily responsible for elevation of the palate. The palatoglossus and palatopharyngeus originate from the midline of the palate and insert into the tongue and pharyngeal walls, respectively.

Clefting alters the normal hard and soft tissue anatomy. This changes the normal physiologic relationship between the upper and lower lip, the tongue with the palate, and the soft palate with the pharyngeal walls. The end result is that there is alteration in speech valves, airway patency, feeding, and, iatrogenically, growth. The velar mechanism that is formed by the aponeurosis, or meeting of the tensor veli and levator veli palatini, is disrupted. This results in inadequate closure of the velopharyngeal orifice during speech and swallowing. Also, both muscles originate from the eustachian tube. The tensor veli palatini muscle acts as the primary dilator of the eustachian tube and may aerate the middle ear to prevent recurrent otitis media and hearing loss. Palatal clefting disrupts muscle insertion and function, resulting in inadequate valve closure. Velopharyngeal insufficiency (VPI) becomes obvious in patients with unrepaired clefts. Even after repair, it must continue to be monitored, because patients with repaired clefts often merit secondary procedures to correct the valve incompetence as speech develops.

Classification schemes for cleft palate are usually anatomically based. This may include complete or incomplete, unilateral or bilateral, as well as the submucous cleft and bifid uvula. The incomplete cleft may involve the soft palate, the hard palate, or both up to the incisive foramen. The terms unilateral or bilateral are used to describe clefting of the secondary palate. A unilateral cleft occurs when one of the palatal shelves has fused with the vomer while the other shelf has failed to migrate and fuse completely. A submucous cleft implies that there is occult clefting of the musculature beneath the oral mucosa. This is the result of separation of the soft palate musculature that has been previously described. It is the most common type of posterior palatal cleft. The natural history of this cleft type often involves its discovery when the child develops velopharyngeal incompetence, manifested as hypernasal speech. It is important to note that not all submucous cleft palates require repair.

Pathologic Anatomy

A developmentally intact palate serves two purposes. First, the hard palate serves as a structural component of the face, dividing the oropharynx from the nasopharynx. Second, the soft palate has a functional component where the musculature, including the tensor veli palatini, levator veli palatini, superior pharyngeal constrictor, muscularis uvulae, palatopharyngeus, and palatoglossus, forms a dynamic valve called the velopharyngeal sphincter, which is raised during speech and swallowing to divide the nose from the mouth. The levator veli palatini fuses to form a “sling” that is primarily responsible for elevation of the palate. The palatoglossus and palatopharyngeus originate from the midline of the palate and insert into the tongue and pharyngeal walls, respectively.

Clefting alters the normal hard and soft tissue anatomy. This changes the normal physiologic relationship between the upper and lower lip, the tongue with the palate, and the soft palate with the pharyngeal walls. The end result is that there is alteration in speech valves, airway patency, feeding, and, iatrogenically, growth. The velar mechanism that is formed by the aponeurosis, or meeting of the tensor veli and levator veli palatini, is disrupted. This results in inadequate closure of the velopharyngeal orifice during speech and swallowing. Also, both muscles originate from the eustachian tube. The tensor veli palatini muscle acts as the primary dilator of the eustachian tube and may aerate the middle ear to prevent recurrent otitis media and hearing loss. Palatal clefting disrupts muscle insertion and function, resulting in inadequate valve closure. Velopharyngeal insufficiency (VPI) becomes obvious in patients with unrepaired clefts. Even after repair, it must continue to be monitored, because patients with repaired clefts often merit secondary procedures to correct the valve incompetence as speech develops.

Classification schemes for cleft palate are usually anatomically based. This may include complete or incomplete, unilateral or bilateral, as well as the submucous cleft and bifid uvula. The incomplete cleft may involve the soft palate, the hard palate, or both up to the incisive foramen. The terms unilateral or bilateral are used to describe clefting of the secondary palate. A unilateral cleft occurs when one of the palatal shelves has fused with the vomer while the other shelf has failed to migrate and fuse completely. A submucous cleft implies that there is occult clefting of the musculature beneath the oral mucosa. This is the result of separation of the soft palate musculature that has been previously described. It is the most common type of posterior palatal cleft. The natural history of this cleft type often involves its discovery when the child develops velopharyngeal incompetence, manifested as hypernasal speech. It is important to note that not all submucous cleft palates require repair.

Diagnostic Studies

When a child is born with a cleft, there are a number of physical findings that require evaluation. Although the diagnosis of cleft lip and palate is primarily one that is solely based on a thorough, routine examination at birth, there are a number of other studies that can be done to supplement the diagnosis as well as determine the timing for repair. The first studies may occur before birth when cleft lip diagnosis by ultrasound examination is commonplace; however, diagnosis of cleft palate using ultrasonography is not as reliable. The author prefers that mothers with a fetus diagnosed with orofacial cleft by ultrasonography see the cleft surgeon prior to delivery.

Diagnosis of VPD can be aided by video fluoroscopy, which demonstrates ineffective pharyngeal wall function as well as oronasal patency. Nasoendoscopic guided–speech assessment also evaluates lateral motion of the pharyngeal walls, soft palate function, and the adenoid pad, and it is preferred.

Treatment/Reconstructive Goals