Chapter 9. Development of the craniofacial complex
Development of the face 101
Development of the palate 102
Development of the jaws 102
Development of the tongue 104
Craniofacial development is here defined as the development of the face, palate, jaws and tongue. Much of this development is related to derivatives of the pharyngeal (branchial) arches. However, many different mechanisms are involved, from the merging of mesenchymal facial processes to the intramembranous calcification around the cartilage of the 1st pharyngeal arch to form the body of the mandible to the hydration of palatal shelves to produce shelf elevation necessary for the formation of the definitive palate. Craniofacial development is clinically important since craniofacial anomalies are amongst the most common congenital anomalies found in humans.
• be able to describe the mesenchymal facial processes around the developing mouth (stomodeum) and understand how these contribute to the formation of the upper and lower lip regions
• be able to describe the ectodermal placodes on the developing face and know their derivatives
• be able to give an account of the development of the primary and secondary palates and understand the processes and mechanisms responsible for the elevation and fusion of the lateral palatal shelves
• be able to describe the prenatal and postnatal development of the mandible and the maxillae
• be able to give an account of the development of the tongue and relate this to the innervation of the tongue once fully formed
• know the origin of development of the thyroid gland
• be able to understand, for all aspects of craniofacial development, how disturbances in normal development can result in common congenital abnormalities (e.g. clefts of the lip and palate).
Development of the face
During early development (4 weeks in utero), the primitive oral cavity (stomodeum) is bounded by five facial swellings, produced by proliferating zones of mesenchyme lying beneath the surface ectoderm — the frontonasal, mandibular and maxillary processes. The frontonasal process lies above, the two mandibular processes lie below, and the two maxillary processes are located at the sides. The maxillary and mandibular processes are derived from the 1st pharyngeal (branchial) arches. At this early stage, a membrane (the oropharyngeal membrane) separates the primitive oral cavity from the developing pharynx. The oropharyngeal membrane is composed of an outer ectodermal layer and an inner endodermal layer. This membrane soon breaks down to establish continuity between the ectodermally lined oral cavity and the endodermally lined pharynx.
In a 5-week-old embryo, localized thickenings of ectoderm give rise to the nasal and lens placodes. These placodes will form the olfactory epithelium and the lenses of the eyes respectively. The nasal placodes sink into the underlying mesenchyme, forming two blind-ended nasal pits (the primitive nasal cavities). Proliferation of mesenchyme from the frontonasal process around the openings of the nasal pits produces the medial and lateral nasal processes. The nasal pits continue to deepen until eventually they approach the roof of the primitive oral cavity, being partitioned from it by oronasal membranes. By the end of the fifth week, these membranes rupture to produce communications between the developing nasal and oral cavities.
In the 6-week-old embryo, the two mandibular processes fuse in the midline to form the tissues of the lower jaw. The mandibular processes and maxillary processes meet at the angle of the mouth, thus defining its outline. From the corners of the mouth, the maxillary processes grow inwards beneath the lateral nasal processes and towards the medial nasal processes of the upper lip. Between the merging maxillary and the lateral nasal processes lie the naso-optic furrows. From each furrow a solid ectodermal rod of cells sinks below the surface and canalizes to form the nasolacrimal duct. The maxillary processes subsequently “replace” the medial nasal processes to meet in the midline and thus contribute all the tissue for the upper lip. Fusion of the facial processes ultimately produces the region known as the ‘intermaxillary segment’. It is from this area that the primary palate will develop (see page 102).
Development of the palate
The definitive palate (or secondary palate) appears in the human fetus between the sixth and eighth weeks of intrauterine life. Palatogenesis is a complex event and, while the events and mechanisms responsible for the development of the palate have been much studied, some controversy remains.
By the sixth week of development, the primitive nasal cavities are separated by a primary nasal septum and are partitioned from the primitive oral cavity by a primary palate. Both the primary nasal septum and the primary palate are derived from the frontonasal process. The stomodeal chamber is divided at this stage into the small primitive oral cavity beneath the primary palate and the relatively large oronasal cavity behind the primary palate. During the sixth week of development, two lateral palatal shelves develop behind the primary palate from the maxillary processes. A secondary nasal septum grows down from the roof of the stomodeum behind the primary nasal septum, thus dividing the nasal part of the oronasal cavity into two.
During the seventh week of development, the oral part of the oronasal cavity becomes completely filled by the developing tongue. Growth of the palatal shelves continues such that they come to lie vertically. During the eighth week of development, the stomodeum enlarges, the tongue ‘drops’ and the vertically inclined palatal shelves become horizontal. On becoming horizontal, the palatal shelves contact each other (and the secondary nasal septum) in the midline to form the definitive or secondary palate. The shelves contact the primary palate anteriorly so that the oronasal cavity becomes subdivided into its constituent oral and nasal cavities. After contact, the medial edge epithelia of the two shelves fuse to form a midline epithelial seam. Subsequently, this degenerates so that mesenchymal continuity is established across the now intact and horizontal secondary palate. Fusion of the palatal processes is complete by the twelfth week of development. Behind the secondary nasal septum, the palatal shelves fuse to form the soft palate and uvula.
Several mechanisms have been proposed to account for the rapid movement of the palatal shelves from the vertical to the horizontal position. Although it was once thought that extrinsic forces might be responsible (e.g. forces derived from the tongue or jaw movements), research has primarily focused on the search for a force intrinsic to the palatal shelf. It has been proposed that the intrinsic shelf elevation force might develop as a result of hydration of extracellular matrix components (principally hyaluronan) in the shelf mesenchyme, or as a result of mesenchymal cell activity. Present evidence favours the former hypothesis.
Once the palatal shelves have elevated, they contact each other (initially in the middle third of the palate) and adhere by means of a ‘sticky’ glycoprotein, which coats the surface of the medial edge epithelia of the shelves. The epithelial cells develop desmosomes and consequently an epithelial seam is formed. The adherence of the medial edge epithelia is specific, as palatal epithelia will not fuse with epithelia from other sites (e.g. the tongue).
The signals that are responsible for breakdown of the midline epithelial seam are not yet fully understood. Nevertheless, the breakdown of the basal lamina is likely to be a significant event. The seam is also ‘thinned’ by growth of the palate and by epithelial cell migration from the region of the seam on to the oral and nasal aspects of the palate. There is also programmed cell death (apoptosis) in the seam. Recent evidence indicates that extracellular matrix molecules may provide the signal and work has been undertaken to assess the role of type IX collagen. At the earliest stages before shelf elevation, the medial edges of the palatal shelves label poorly for type IX collagen compared with floor of the mouth epithelia. Present-day thinking suggests that the control of the synthesis of type IX collagen is influenced by epidermal growth factors.
Once fusion is complete, the hard palate ossifies intramembranously from four centres of ossification, one in each developing maxilla and one in each developing palatine bone:
• The maxillary ossification centre lies above the developing deciduous canine tooth germ and appears in the eighth week of development.
• The palatine centres of ossification are situated in the region forming the future perpendicular plate and appear in the eighth week of development.
Incomplete ossification of the palate from these centres defines the median and transverse palatine sutures. There does not appear to be a separate centre of ossification for the primary palate in humans (in other species there is a separate ‘premaxilla’).
Development of the jaws
The mandible initially develops intramembranously, but its subsequent growth is related to the appearance of secondary cartilages (the condylar cartilage being the most important). The developing mandible is preceded by the appearance of a rod of cartilage belonging to the first pharyngeal (branchial) arch. This is known as Meckel’s cartilage and it first appears at about the sixth week of intrauterine life. Meckel’s cartilage extends from the cartilaginous otic capsule in the region of the developing ear to a midline symphysis. However, it makes little contribution to the adult mandible, merely providing a framework around which the bone of the mandible forms.
The mandible first appears as a band of dense fibrous tissue on the anterolateral aspect of Meckel’s cartilage. During the seventh week of intrauterine life, a centre of ossification appears in this fibrous tissue at a site close to the future mental foramen. From this centre, bone formation spreads rapidly backwards, forwards and upwards, around the inferior alveolar nerve and its terminal branches (the incisive and mental nerves). Further spread of the developing bone in a forwards and backwards direction produces a plate of bone on the lateral side of Meckel’s cartilage that corresponds to the future body of the mandible and which extends towards the midline where it comes to lie in close relationship with the bone forming on the opposite side. However, the two plates of bone remain separated by fibrous tissue to form the mandibular symphysis. At a later stage in the development of the body of the mandible, continued bone formation markedly increases the size of the mandible, with development of the alveolar process occurring to surround the developing tooth germs. At an even later stage, Meckel’s cartilage resorbs. The neurovascular bundle that initially was located with the developing tooth germs now becomes contained within its own bony canal and there is considerable development of the alveolar process. Although Meckel’s cartilage contributes no significant tissue to the developing mandible, nodular remnants of cartilage may be seen in the region of the mandibular symphysis until birth and, in its most dorsal part, Meckel’s cartilage ossifies to form ear ossicles (the malleus and incus). Behind the body of the mandible the perichondrium of Meckel’s cartilage persists as the sphenomandibular and sphenomalleolar ligaments. The sphenomandibular ligament ossifies at its sites of attachment to form the lingula of the mandible and the spine of the sphenoid bone.
As the developing tooth germs reach the bell stages (see page 114), developing bone becomes closely related to it to form the alveolus. The size of the alveolus is dependent upon the size of the growing tooth germ. Resorption occurs on the inner wall of the alveolus (indicated by Howship’s lacunae) while, on the outer wall of the alveolus, bone is deposited (indicated by osteoblasts lining an osteoid seam). The developing teeth therefore come to lie in a trough of bone. Later, the teeth become separated from each other by the development of interdental septa. With the onset of root formation, inter-radicular bone develops in multirooted teeth.
The ramus of the mandible is first mapped out as a condensation of fibrocellular tissue that, although continuous with the developing body of the mandible, is positioned some way laterally from Meckel’s cartilage. Further development of the ramus is associated with a backward spread of ossification from the body and by the appearance of secondary cartilages. Between the tenth and fourteenth weeks in utero, three secondary cartilages develop within the growing mandible. The largest, and most important, of these is the condylar cartilage, which, as its name suggests, appears beneath the fibrous articular layer of the future condyle. By proliferation and subsequent ossification, the cartilage is thought by some to serve as an important centre of growth for the mandible, functioning up to about the twentieth year of life. Less important, transitory, secondary cartilages are seen associated with the coronoid process and in the region of the mandibular symphysis.
Postnatally, the ratio of body to ramus is greater at birth than in the adult, indicating a proportional increase with time in the development of the ramus. At birth, there is no distinct chin and the two halves of the mandible are separated by the mandibular symphysis. Ossification of the symphysis is complete during the second year, the two halves of the mandible uniting to form a single bone. The chin becomes most prominent after puberty (especially in the male). There is some evidence that the angle of the mandible decreases from birth to adulthood. Growth of the mandible occurs by the remodelling of bone. In general terms, increase in the height of the body occurs primarily by formation of alveolar bone, although some bone is also deposited along the lower border of the mandible. Increase in the length of the mandible is accomplished by bone deposition on the posterior surface of the ramus with compensatory resorption on its anterior surface, accompanied by deposition of bone on the posterior surface of the coronoid process and resorption on the anterior surface of the condyle. Increase in width of the mandible is produced by deposition of bone on the outer surface of the mandible and resorption on the inner surface. Present evidence suggests that proliferation of the condylar cartilage is a response to growth and not its cause.
Although the mandible is a single bone, it may be thought of as a number of skeletal units, each associated with one or more soft tissue ‘functional matrices’. The behaviour of these matrices primarily determines the growth of each skeletal unit. For example, the coronoid process forms a skeletal unit acted upon by the temporalis muscle. Sectioning of the temporalis muscle during early mandibular development may result in atrophy or complete absence of a coronoid process in the adult mandible. Similarly, the alveolar process is influenced by the teeth, the condyle by the lateral pterygoid muscle, the ramus by the medial pterygoid and masseter muscles, and the body by the neurovascular bundle.
As with the mandible, the maxilla develops intramembranously. The centre of ossification appears during the eighth week of intrauterine life, close to the site of the developing deciduous canine tooth. Unlike the mandible, maxillary growth and development is not related to the appearance of secondary cartilages. Because of the maxilla’s position in the developing skull, this jaw’s growth is influenced by the development of the orbital, nasal and oral cavities. From the region of the developing deciduous canine, ossification spreads throughout the developing maxilla into its growing processes (palatine, zygomatic, frontal and alveolar processes). The ossification of the palatine processes is described on page 102. At one time it was thought that the incisor-bearing part of the maxilla, which develops from the frontonasal process (see page 101), had a separate centre of ossification. It was consequently called the premaxilla. However, it is now clear that ossification spreads from the body of the maxilla into its incisor-bearing component.
Growth of the maxilla occurs by bone remodelling (i.e. surface deposition of bone with associated resorption) and by sutural growth. Among the agents that provide the forces separating the maxilla from the adjacent bones (thus permitting growth at the sutures) are the growing eyeballs, cartilaginous nasal septum and orbital pad of fat. Thus, growth of the maxilla is not an isolated phenomenon but occurs in association with the development of the orbital, nasal and oral cavities. It has been suggested that the growing nasal septum pulls the maxilla forward by means of a septopremaxillary ligament that runs from the anterior border of the nasal septum posteroinferiorly towards the anterior nasal spine and intermaxillary suture. As in the lower jaw, growth in height of the maxilla is related to the development of the alveolar process. The maxillary sinus appears as an out-pocketing of the mucosa of the middle meatus of the nose at the beginning of the fourth month of intrauterine life. Although small at birth, the maxillary sinus is identifiable radiologically. After birth, the maxillary sinus enlarges with the growing maxilla, although it is only fully developed following the eruption of the permanent dentition.
Forward growth of the whole face (including the maxillae) is dependent upon growth of the spheno-occipital synchondrosis at the base of the skull.
The mandible and maxillae develop intramembranously. Thus, in a fibrocellular condensation, a centre of ossification appears in which osteoblasts lay down first-formed or woven bone. As the teeth develop, bone extends from the developing mandible and maxillae to surround and protect the teeth, forming the alveolus. The alveolus is separated from the developing enamel organ by the dental follicle. To accommodate the growing tooth germs, the lamellae of the developing alveolar bone undergo resorption, which occurs on the inner wall of the alveolus (indicated by Howship’s lacunae) while, on the outer wall of the alveolus, bone is deposited (indicated by osteoblasts lining an osteoid seam). The developing teeth therefore come to lie in a trough of bone. Later, the teeth become separated from each other by the development of interdental septa. With the onset of root formation, inter-radicular bone develops in multirooted teeth. As in other sites, the collagen fibres in the newly formed alveolar bone have a more variable diameter and lack a preferential orientation, giving the bone a matted (basket weave) appearance when viewed in polarized light. This immature bone, termed woven bone, has larger and more numerous osteocytes compared with adult bone. It is formed more rapidly and has a higher turnover rate. Woven bone is subsequently converted to fine-fibred adult lamellar bone. The source of the cells forming alveolar bone is uncertain, although some have suggested that it may be from neural crest cells of the investing layer of the dental follicle (see page 116).