Craniofacial clefts

Median craniofacial hypoplasia (tissue deficiency and/or agenesis)

Median craniofacial dysraphia

Median craniofacial dysraphia describes a midline anomaly that has normal tissue volume but clefting or an abnormal separation of midline structures is present. Within the spectrum of median craniofacial dysplasia there is a group of malformations which have normal tissue volume but have abnormally split (true median cleft lip) or displaced (encephalocele). This group is better placed as median tissue defects midway between hypoplasia and hyperplasia.

Median craniofacial hyperplasia (tissue excess or duplication)

This spectrum of anomalies includes all forms of excess tissue starting from just thickened or duplicated nasal septum towards the more severe forms of frontonasal dysplasia. “Frontonasal dysplasia” was the most widely known of these types of hyperplasias. Objections are raised about the terminology of this condition. Typically, the term “dysplasia” refers to the whole spectrum of abnormal tissue development starting from tissue agenesis and hypoplasia all the way to the other extreme of hyperplasia and excess tissue.

The basic defect of median craniofacial hyperplasia is not known. Embryologically, if the nasal capsule fails to develop properly, the primitive brain vesicle fills the space normally occupied by the capsule, thus producing anterior cranium bifidum occultum and leading to morphokinetic arrest in the positioning of the eyes and nostrils, which tend to maintain their relative fetal positions. Experiments have shown that a reduction in the number of migrating neural crest cells results in these multiple defects.

Other nasal findings may range from a notched broad nasal tip to completely divided nostrils with hypoplasia and even absence of the prolabium and maxilla with a median cleft lip. In addition, variable notching of the ala is described. Occasionally associated abnormalities include accessory nasal tags, low-set ears, conductive hearing loss, mild to severe retardation, basal encephalocele, and agenesis of the corpus callosum. Importantly, a high incidence of ocular abnormalities is described. More distant anomalies include tetralogy of Fallot, absence of the tibia, and others. When hypertelorism is severe or when extracephalic anomalies occur, mental deficiency appears to be more likely and more severe.

Embryologic craniofacial development

The understanding of normal morphogenesis occurring in the embryo and fetus allows the clinician to describe and classify craniofacial clefts of infants and adults. Likewise, the study of rare craniofacial clefts lends clues to facial and neuroembryology.

A traditional summary of normal facial development and newer understanding of genetically determined development zones of the face based on neuroembryology can be found in the bonus online content .

Failure of fusion

Two theories exist that describe how embryologic failure or errors result in craniofacial cleft malformations. First, the “fusion failure” theory suggests that clefts are created when fusion of facial processes fail. Second, the “failure of mesodermal penetration” theory implicates the lack of mesoderm and neuroectoderm migration and penetration into the bilaminar ectodermal sheets as the cause of craniofacial clefts. Although most of the current knowledge is based on animal cleft lip and palate studies, rare craniofacial clefts may be produced by similar mechanisms.

The “failure of fusion” theory, proposed by Dursy in 1869 and His in 1892, purported that the free edges of the facial processes unite in the central region of the face. As various processes fuse, the face gradually forms. When epithelial contact is established between opposing facial processes, mesodermal penetration completes the fusion. Dursy suggested that the upper lip is created when finger-like advancing ends of the maxillary process and the paired global process unite. He asserted that disruption of this sequence results in craniofacial cleft anomalies.

Proponents of the mesodermal penetration theory believed that the finger-like ends of the facial processes do not exist. Warbrick and Stark and Ehrmann suggest that the central facial processes are composed of bilamellar sheets of ectoderm. This bilamellar membrane is bordered by epithelial seams, which delineate the principal processes. During development, the mesenchymal tissue migrates and penetrates this double-layered ectoderm, called the “epithelial wall”. Caudal to the stomodeum, the lower face is formed by the branchial arches. The arches consist of a thin sheet of mesoderm, which lie between the ectodermal and endodermal layers. The neural crest cells of neuroectodermal origin, which arise from the dorsolateral surface of the neural tube, migrate under the ectoderm and supplement the mesoderm of the frontonasal process and branchial arches. Most of the craniofacial skeleton is believed to be formed by these neural crest cells. If neuroectoderm migration and penetration do not occur, the epithelium breaks down to form a facial cleft. The severity of the cleft is proportional to the failure of penetration by the neuroectoderm. Unfortunately, the precise nature of the proposed mechanisms in the formation of rare craniofacial clefts is not known. Nevertheless, the concepts of fusion and mesodermal penetration provide an understanding of the problems of the rare craniofacial cleft.

Neuromeric theory

Newer understanding of neuroembryology suggests that a direct relationship exists between the development of the nervous system and those structures to which its contents are dedicated. The neural tube is conceived as a series of developmental zones within the central nervous system. Six prosomeres provide a Cartesian system to organize the tracts and nuclei of the prosencephalon (forebrain). The mesencephalon (midbrain) and rhomboencephalon (hindbrain) are subdivided into two mesomeres and 12 rhombomeres, respectively. Each of these neuromeres is defined by a unique overlap of several genetic coding zones along the axis of the embryo. In the hindbrain and caudally to the coccyx these neuromeric units are defined by the Homeobox series of genes (Hox genes). In the forebrain, a more complex series of genes is used, such as Sonic hedgehog (Shh), Wingless (Wnt), and Engrailed (En).

The unique “barcode” for each neuromeric zone is shared with all cells exiting from a particular level to form the mesoderm and endoderm of the embryo. For example, the Hox gene which codes for the rhombomeres 2 and 3 (which make up the first pharyngeal arch [PA1]) is shared with the mesoderm that makes up those arches. This same Hox gene is also shared with the neural crest cells which subsequently move into the mesodermal “zones” of PA1. The migrating neural crest cells then provide the instructions for differentiation into the appropriate facial tissues. Thus, all the bones and soft tissues of the face can be thought of as genetically determined “fields” with defined cellular content and a fixed position in space. With the folding of the embryo, these fields are placed into their correct topologic positions and a three-dimensional form results.

The three primary germ layers, ectoderm, mesoderm, and endoderm, are the basis for tissue and organ formation. In the third week of gestation, the primitive tissues of the trilaminar embryo give rise to notochordal and prechordal mesoderm. Simultaneously, the rostral ectoderm differentiates to form highly specialized neural crest cells, which are responsible for the ultimate development of the brain and midline facial structures. The ectoderm forms a neural plate with bilateral folds which conjoin into a neural tube. During closure of the neural tube, neural crest cells (mesenchyme) migrate into underlying tissue, forming pluripotential stem cells. The embryonic prominences of the face are formed by the migration of these neural crest cells. A segmental pattern of ventral migration of neural crest, termed rhombomeres, provides the precursors of cartilage, bone, muscle, and connective tissue of the face and head.

Any defect in the quantity and quality of this migrating ectomesenchyme is manifest as a craniofacial malformation from severe holoprosencephaly to minor clinical stigmata of craniofacial clefts like dimples or skin tags. Another cause for arrested development causing dysplasias and dystopias (the abnormal formation and location of structures) is abnormal development or involution of embryologic arteries.

Starting at the fourth week of gestation, the face assumes a recognizable form. Between 4 and 8 weeks of gestation the crown–rump length increases from approximately 3.5 mm to 28 mm. The double-layer stomodeal membrane creates the opening for the primitive mouth. An overhanging frontonasal prominence represents the superior border of the stomodeum. Five prominences (the frontonasal and paired maxillary and mandibular) formed by neural crest migration surround the stomodeum ( Fig. 24.2 ). The frontonasal prominence is formed by neural crest cells migrating ventrally from the mesencephalic region and contributes to the frontal and nasal bones. The maxillary and mandibular prominences are formed by more caudally located migrating neural crest cells that encounter pharyngeal endoderm in their ventral migration around the aortic arches.

Optic vesicles appear from lateral evaginations of the diencephalons and induce lens placodes in ectoderm and neural crest migration to form the sclera. Defective optic vesicle formation results in microphthalmos, or anophthalmos. The movement of this optic tissue from lateral to medial results from the narrowing frontonasal prominence and expansion of the lateral face. Inadequate transition of the eyes produces hypertelorism and overmigration produces hypotelorism or even median cyclopia.

During the sixth week, the medial nasal processes enlarge and coalesce in the midline. The nasal placodes arise from ectodermal tissue inferolateral to the frontonasal prominence and cephalad to the stomodeum. Nasal placodes invaginate into the face to form nasal pits and elevations at the margins produce a horseshoe-shaped median and lateral nasal prominences. The caudal extensions of the medial nasal processes, the globular processes, are united with the developing maxillary processes to form the upper lip. The medial nasal process gives rise to the nasal tip, the columella, the philtrum, and the premaxilla. The nasal alae are derived from the lateral nasal processes. The frontonasal process contributes the bridge and the root of the nose.

The posterior aspect of each nasal pit is separated from the oral cavity by an oronasal membrane. Failure of this membrane to disintegrate normally leads to choanal atresia. The paired median nasal processes merge with the frontonasal prominence to form most of the frontal process. These structures gradually enlarge and superiorly displace the frontonasal prominence. During the sixth week, the two median nasal processes coalesce in the midline and their most caudal limbs, the premaxillary prominence, expand above the stomodeum. The nasal tip, philtrum, columella, cartilaginous septum, and primary palate are derived from these paired median elements. Cephalad to the medial nasal process, the frontonasal process persists to form the nasal dorsum and root. Elevation of the lateral nasal prominence creates the nasal alae. Defects during this development may be midline and produce arrhinia or a bifid nose.

The maxillary processes are paired mesodermal masses that lie cephalad to the mandibular arch and ventral to the optic neuroectoderm. These triangular masses enlarge, separate from the mandibular arch, and then migrate ventrally. The maxillary process ultimately coalesces with the mesoderm of the globular processes to form the upper lip. The cheek, maxilla, zygoma, and secondary palate are also derived from the maxillary processes. Between the maxillary prominence and lateral nasal prominence a depression exists with a solid rod of epithelial cells. The ends of this rod form a connection from the nasal pit to the conjunctival sac (nasolacrimal duct). With inadequate neural crest cell migration, a fissure within the line of this duct may persist as an oblique facial cleft.

The stomodeal aperture is reduced by migrating mesenchyme fusing the maxillary and mandibular prominences to form the oral commissures. Inadequate neural crest cells result in macrostomia while excessive tissue produces microstomia or macrostomia. The mandibular prominence lies between the stomodeum and the first branchial groove, which delineates the caudal limits of the face. The paired free ends of the mandibular arch enlarge and converge ventrally during the sixth week. The lower lip and mandible are developed from this arch. Paired lateral pharyngeal elevations of the arch unite to form the anterior portion of the tongue.

The external and middle ear are also formed during the sixth week of gestation. The tragus and the crus of the helix are derived from three hillocks at the caudal border of the first branchial arch. The malleus and incus of the middle ear are also formed by the first branchial arch. The remainder of the external ear is formed from three hillocks on the cephalic border of the second branchial arch. The stapes of the middle ear is also formed by the second branchial arch.

During a short 4-week period, there is a coordination of cell migration, cellular interaction, and apoptosis. Failure of this intricate program will result in clefts that will usually fall along predictable embryonic lines.

This system permits the “mapping” of the face into developmental zones with distinct spatial origins in their precursor tissue units. The midline mesoderm of the nasal and ocular fields is of different origin, innervation, and blood supply from all surrounding mesodermal elements. When all the developmental zones are accounted for, the occurrence of craniofacial clefts is nothing more than an orderly progression of deficiency states in the precursor fields, resulting in varying degrees of absence of soft-tissue functional matrix or underlying bone. The anatomic and clinical observations of Tessier and his classification system are compatible with this map. Variations include: (1) clefts number 2 and 3 fall within the same zone (cleft number 3 being more posterior) and (2) clefts number 4 and 5 represent varying degrees of involvement in the same zone of the maxilla. Tessier’s classification system has been widely adopted by surgeons and other clinicians and has stood the test of time. However, geneticists and embryologists have been slow to embrace his numeric organization of craniofacial clefts because it could not previously be understood by existing theories of embryologic developmental. The consistency of these newer neuroembryologic theories with Tessier’s classification of craniofacial clefts reinforces the importance of Tessier’s descriptions. With progression of the neuromeric theory, the value of Tessier’s organization of rare craniofacial clefts should become apparent to embryologists and geneticists.

Number 0 cleft

The number 0 cleft has been called median craniofacial dysraphia, centrofacial microsomia, frontonasal dysplasia, median cleft face syndrome, or holoprosencephaly; but, for accuracy, it is the facial manifestation or lower half of “median craniofacial dysplasia,” as described above. Patients with this midline facial cleft may have a cranial extension or a number 14 cleft. As mentioned above, the number 0 Tessier craniofacial clefts are unique in that there may be: (1) deficiency (hypoplasia); (2) normal (dysraphia); or (3) excess (hyperplasia) tissue. With tissue agenesis and holoprosencephaly at one end (the hypoplasias), and frontonasal hyperplasia and excessive tissue (the hyperplasias) at the other end, median anomalies with normal tissue volume occupy the middle portion of the spectrum. Tessier number 0 clefts are therefore best subdivided by the classification described above for median craniofacial dysplasia.

Median craniofacial hypoplasia (deficiency of midline structures)

A deficiency may manifest as hypoplasia or agenesis, in which portions of midline facial structures are missing ( Fig. 24.3A ). This developmental arrest may range from the mildest form of hypoplasia of the nasomaxillary region and hypotelorism to a severe form of cyclopia, ethmocephaly, or cebocephaly. The subcategories ( Table 24.1 ) demonstrate that the severity of facial anomalies correlate well with the severity of brain abnormality and mental retardation. A CT scan of the brain can differentiate between alobar and lobar brain anomalies and clarify the spectrum of holoprosencephalic patients. Clinically it may be important to distinguish among patients with poor brain differentiation who may die in infancy from those with a better prognosis.

Soft-tissue hypoplasia

Soft-tissue deficiencies with Tessier 0 clefts include the upper lip and nose. Agenesis or hypoplasia may result in a false median cleft lip and absence of philtral columns. When a wide central cleft exists, it typically extends the length of the upper lip and up into the nasal floor ( Fig. 24.3B,C ). With nasal anomalies, the columella may be narrowed or totally absent. The nasal tip may be depressed from lack of a nasal spine and poor septal support. The septum may often be vestigial with no caudal attachment to the palate. Dental abnormalities may include absent central maxillary incisors, single maxillary central incisor, and/or hypoplastic central maxillary incisors.

Skeletal hypoplasia

Skeletal deficiencies range from separation between the upper central canines to absence of the premaxilla and a cleft of the secondary palate ( Fig. 24.3D ). Nasal deficiency may include partial or total absence of the septal cartilage and even nasal bones. Nasomaxillary deficiencies like these may be seen in Binder syndrome. The bone defect may extend cephalad (number 14 cleft) into the area of the ethmoid sinuses and result in hypotelorism or cyclopia.