SKELETAL ELEMENTS OF THE PHARYNGEAL ARCHES

The skeletal elements of each arch are formed by condensation of neural crest-derived mesenchyme, which subsequently chondrifies in part or all of its length. Where chondrogenesis is complete (first and second arch cartilages), the element extends dorsally until it comes into contact with the cranial base lateral to the hindbrain (Fig. 35.5). An arch cartilage may remain as cartilage, undergo endochondral ossification, or become ligamentous, or a combination of these (Fig. 35.6).

The first arch cartilage, Meckel’s cartilage, forms the embryonic jaw skeleton. After the mandible forms by intramembranous ossification of the neural crest-derived mesenchyme lateral to it, Meckel’s cartilage degenerates but its sheath persists as the anterior malleolar and sphenomandibular ligaments. Its proximal end undergoes endochondral ossification to form two of the middle ear bones, the incus and malleus. These are homologous with the quadrate and articular bones of reptiles, and the joint between them is evolutionarily derived from the reptilian jaw articulation. In reptiles, the quadrate forms from the caudal end of the palatopterygoquadrate cartilage; the mammalian evolutionary derivatives of the palatopterygoquadrate are thought to include part of the greater wing of the sphenoid bone and the roots of its pterygoid plates, in addition to the incus. The portion of Meckel’s cartilage that extends from the mental foramen almost to the site of the future mandibular symphysis probably becomes ossified and incorporated into the intramembranous mandibular bone, and the remainder of the cartilage is ultimately absorbed.

The second arch cartilage, Reichert’s cartilage, extends from the proximity of the otic capsule dorsally to the median plane ventrally. It ossifies to form the upper part of the body and lesser cornua of the hyoid bone distally, and the styloid process proximally; between these two bones it becomes ligamentous to form the stylohyoid ligament. It also gives rise to the most ancient of the three auditory ossicles, the stapes (homologous with the rod-shaped columella auris of reptiles and birds). The cartilages of arches 3 and 4 form only anterior neck skeletal structures: the lower part of the body and greater cornua of the hyoid bone (arch 3) and the thyroid cartilage of the larynx (arch 4). Neural crest cells also give rise to ligaments, tendons and connective tissue in the arches. The cricoid and arytenoid cartilages are mesodermal.

MUSCLES OF THE PHARYNGEAL ARCHES

The striated muscle of each arch (sometimes termed branchiomeric) is derived from the rostral continuation of the paraxial mesoderm. The paraxial mesoderm of the head rostral to the occipital region is unsegmented, and the suggestion that a segmental pattern of seven cranial somitomeres exists is not generally accepted today. In the occipital region of the head, epithelialization takes place to form four pairs of somites; these are similar to those of the trunk. Myoblasts migrate from the paraxial mesoderm to sites of future muscle differentiation and form premuscle condensations prior to the development of any skeletal elements. The pattern of primary myotube alignment for any one muscle is specified by the surrounding neural crest-derived mesenchyme and is not related to the source of the myoblasts. The rate and pattern of muscle maturation are closely associated with the development of the skeletal elements but remain unattached until an appropriate time. Figs 35.3 and 35.7 show the muscle masses of each arch, their innervation and their derivatives in the adult.

The muscle mass of the mandibular part of the first arch forms tensor tympani, tensor veli palatini, mylohyoid, anterior belly of digastric, and the masticatory muscles (Fig. 35.7). Tensor tympani retains its connection with the skeletal element of the arch through its attachments to the malleus, and tensor veli palatini remains attached to the base of the medial pterygoid process – which may be derived from the dorsal cartilage of the first arch. However, the masticatory muscles become attached to the mandible, which is mainly a dermal bone. All of these muscles are supplied by the mandibular nerve, the mixed nerve of the first arch.

The muscles of the second arch migrate widely, but retain their original nerve supply from the facial nerve: migration is facilitated by the early obliteration of some of the first groove (cleft) and pouch. Stapedius, stylohyoid and posterior belly of digastric remain attached to the hyoid skeleton, but the facial musculature, platysma, auricular muscles and epicranius all lose connection with it (Fig. 35.7).

The muscle masses from arches 3 and 4 are adapted to form the musculature of the pharynx, larynx and soft palate. Stylopharyngeus is a third arch muscle, cricothyroid develops in the fourth arch (Fig. 35.7), and the rest of the laryngeal muscles are derived from the sixth arch. The precise origin of the remaining palatal muscles and the pharyngeal constrictors is uncertain. Palatoglossus, a muscle of the palate, is innervated by the cranial part of the accessory nerve and may derive from the lower arches.

NERVES OF THE PHARYNGEAL ARCHES

The nerves associated with each arch arise from the adjacent hindbrain (Fig. 35.7; see also Figs 12.4, 24.18). They are cranial nerves V (trigeminal), VII (facial), IX (glossopharyngeal), X (vagal) and XI (accessory). The motor nerves extend from the basal plate of the hindbrain to innervate the striated muscle of the arches: they are termed special branchial (visceral) efferent nerves because they innervate pharyngeal (branchiomeric) musculature. Sensory nerves extend peripherally and centrally from cranial ganglia that are formed partly from neural crest and partly from cells that delaminate from epipharyngeal placodes; they convey general and special somatic afferent axons. Each arch is innervated by a mixed nerve, but the nerves of arches 1–3 also have a purely sensory branch that innervates the arch rostral to its ‘own’ arch; this sensory nerve is called the pretrematic branch, because it extends rostral to the cleft or trema between the two arches (Figs 35.3, 35.7). Hence, the nerves to the mandibular arch include the mandibular division of the trigeminal nerve, which is mixed, and the chorda tympani and greater petrosal nerves, purely sensory pretrematic branches of the facial nerve. The maxillary branch of the trigeminal and the tympanic branch of the glossopharyngeal are also considered to be pretrematic nerves. The ophthalmic branch of the trigeminal nerve, which supplies the frontonasal area, is not an arch nerve; in fishes its ganglion is separate from the first arch nerve ganglion.

The vagus nerve, together with some fibres from the cranial part of the accessory nerve, supplies arches 3 (pharyngeal muscles), 4 and 6 (Fig. 35.7). The recurrent laryngeal branch initially loops under the sixth arch artery on both sides, but the asymmetric changes to the vascular system affect the symmetry of this nerve. On the right, where the sixth aortic arch disappears beyond the right pulmonary artery, the recurrent laryngeal nerve loops under the fourth arch-derived subclavian artery; on the left it loops round the ductus arteriosus (ligamentum arteriosum in the adult). Hence, the right and left branches of this nerve have asymmetric courses in the adult. Further details of cranial nerve development and composition are provided in Chapter 24.

BLOOD VESSELS OF THE PHARYNGEAL ARCHES

The aortic arches initially develop by vasculogenesis, soon after neural crest cells have invaded the early pharyngeal arches. Angiogenic mesenchyme forms the endothelial lining of the vessels and neural crest contributes to the outer layers of the walls (Jiang et al, 2000). The first aortic arch artery is part of the original vascular circuit that links the truncus arteriosus of the heart to the paired dorsal aortae, blood returning to the heart via the allantoic, vitelline and common cardinal veins (see Figs 13.1, 59.8). As the heart descends relative to the forebrain and other rostral structures, the aortic sac gives rise to paired aortic arches at successively more caudal levels, each of which passes laterally on each side of the pharynx to join the dorsal aortae. The dorsal aortae are not invested by neural crest cells, and nor are the more distal (cranial) parts of the carotid arteries, which form by angiogenesis. The whole complement of aortic arches never coexists – the first aortic arch degenerates through remodelling of the cranial arteries before the sixth is formed.

When the first and second aortic arch arteries begin to regress, the supply to the corresponding pharyngeal arches is derived from a transient ventral pharyngeal artery which terminates by dividing into mandibular and maxillary branches. The second aortic arch artery also degenerates, remaining only as the stem of the stapedial artery. The early vessel anastomoses with the ventral pharyngeal artery passing as it does through the mesenchyme of the stapedial cartilage, which condenses around it, forming the foramen of the stapes. The fully developed stapedial artery possesses three branches, mandibular, maxillary and supraorbital, which follow the divisions of the trigeminal nerve (Fig. 35.8). The mandibular and maxillary branches diverge from a common stem.

Further development of the third, fourth and sixth aortic arches (Fig. 35.9) produces the main arteries to the head and the great vessels arising from the heart. The external carotid artery first appears as a sprout, which extends cranially from the aortic sac close to the ventral end of the third arch artery. The common carotid arises from an elongation of the adjacent part of the aortic sac, and the third arch artery becomes the proximal part of the internal carotid artery. The fourth aortic arch on the right forms the proximal part of the right subclavian artery, whereas the corresponding vessel on the left constitutes the arch of the definitive aorta between the origins of the left common carotid and left subclavian arteries.

Fig. 35.9 Aortic arch arteries and their derivatives.

When the external carotid artery emerges from the base of the third arch, it incorporates the stem of the ventral pharyngeal artery, and its maxillary branch communicates with the common trunk of origin of the maxillary and mandibular branches of the stapedial artery and annexes these vessels. The proximal part of the common trunk persists as the root of the middle meningeal artery. More distally, the meningeal artery is derived from the proximal part of the supraorbital artery. The maxillary branch becomes the infraorbital artery and the mandibular branch forms the inferior alveolar artery.

When the definitive ophthalmic artery differentiates as a branch from the terminal part of the internal carotid artery, it communicates with the supraorbital branch of the stapedial artery which distally becomes the lacrimal artery. The latter retains an anastomotic connection with the middle meningeal artery. The dorsal stem of the original second arch artery remains as one or more caroticotympanic branches of the internal carotid artery.

From its inception, the sixth aortic arch is associated with the developing lung buds. Initially, each bud is supplied by a capillary plexus from the aortic sac; as the sixth aortic arch develops, it becomes the channel for blood from the aortic sac to the developing lung buds as well as to the corresponding dorsal aorta, the latter being the main channel. Soon after formation of the sixth aortic arch, the outflow tract of the heart is divided by an influx of neural crest cells which form the spiral aorticopulmonary septum (Jiang et al 2000) which separates the aortic sac into the pulmonary trunk and ascending aorta; the pulmonary trunk attains alignment with the left sixth aortic arch (see p. 1025). The part of the sixth aortic arch between the pulmonary trunk and the dorsal aorta becomes the main vascular channel on the left, and is defined as the ductus arteriosus when the equivalent vessel on the right side is lost. Loss of the right sixth aortic arch may be related to the changes in blood flow dynamics consequent on division of the outflow tract. The caudal part of the right dorsal aorta (close to its conjunction with the left) also degenerates, separating the definitive aorta from the developing subclavian artery (Fig. 35.9B). The ductus arteriosus remains the main channel for blood to pass from the right ventricle to the descending aorta until the lungs and their associated blood vessels expand at birth. After birth, the ductus arteriosus is functionally closed by contraction of the circular muscle of the tunica media (see Ch. 59) (Fig. 35.9C).

PHARYNGEAL ECTODERM AND CLEFTS

Surface ectoderm lines the roof of the embryonic pharynx up to and including the adenohypophysial pouch (for the early development of the pituitary gland, see page 367 of Chapter 24). It also completely clothes the first arch covering the lateral walls and floor of the pharynx, unlike the more caudal arches which are dependent on the proximity of pharyngeal endoderm for their development. The external surface ectoderm of the first arch ultimately produces the keratinized stratified squamous epithelium of the epidermis including hair follicles, sweat and sebaceous glands, and the specialized epithelium of the vermilion of the lip. The first pharyngeal cleft is obliterated ventrally; its dorsal end deepens to form the external acoustic meatus and the external surface of the tympanic membrane (Fig. 35.4B,C); the ectoderm giving rise to the lining epidermis and ceruminous glands. The ectodermal covering of the oral aspect of the first arch forms the mucous membranes of the palate, oral cavity and anterior part of the tongue and the ectodermal components of the teeth, salivary and mucous glands. Three auricular hillocks form on arches 1 and 2, each side of the first pharyngeal groove beginning at stage 15; they form the auricle of the external ear (see Ch. 38).

Fig. 35.4 Pharyngeal pouch development. A. The arrangement of the early pharyngeal pouches: on the left, the internal aspect of the pharyngeal floor viewed from above; on the right, the external aspect of the pharyngeal floor viewed from below. B. Coronal section of the left side of the pharynx at stage 18, showing changes to the pharyngeal pouches internally and pharyngeal clefts externally. C. Coronal section of the left side of the pharynx at stage 19. See also Fig 35.18 for further development.

The external contours of the arches and clefts are modified as the skeletal and muscular elements develop. During the fifth week, pharyngeal clefts 2 and 3+4 form the rostral and caudal parts of a retrohyoid depression, the cervical sinus (Fig. 35.4C). Cranially, the sinus is bounded by the hyoid arch; dorsally, by a ridge produced by ventral extensions from the occipital myotomes and by mesenchyme that develops into the sternocleidomastoid and trapezius muscles. Caudally, the smaller epipericardial ridge separates the sinus from the pericardium. Fusion of the hyoid arch with the cardiac elevation covers the cervical sinus, excluding the arches 3–6 from contributing to the skin of the neck; it also results in platysma muscle, bounded both superficially and deep with superficial fascia, passing along the neck to the anterior thoracic wall.

Thickened patches of ectoderm, the epibranchial placodes, appear at the dorsal ends of the pharyngeal grooves. They are closely related to the developing ganglia of the facial, glossopharyngeal and vagus nerves, to which they contribute. Together with dorsolateral and suprabranchial placodal cells, the epibranchial placodes also contribute to the trigeminal and vestibulocochlear ganglia (see Figs 12.4, 24.18).

PHARYNGEAL ENDODERM AND POUCHES

The first four pharyngeal pouches appear in sequence craniocaudally during stages 10–13. The rostral pharynx is broad and dorsoventrally compressed (see Fig. 35.18). Laterally, the endoderm of the pouches approaches the ectoderm of the pharyngeal clefts to form thin closing membranes (Fig. 35.4). The approximating ectoderm and endoderm between the first cleft and pouch form the outer and inner surfaces of the tympanic membrane. The ventral end of the first pouch is obliterated, but its dorsal end persists and expands as the head enlarges. This, together with the adjoining lateral part of the pharynx and possibly with a contribution from the dorsal part of the second pharyngeal pouch, constitutes the tubotympanic recess. The recess forms the middle ear cavity, the pharyngotympanic tube and their extensions. Expansion of the middle ear cavity around the ear ossicles occurs late during fetal life, by breakdown of the mesenchyme around the ossicles so that the cavity comes to surround them except at their attachments to the tympanic membrane and fenestra ovalis (fenestra vestibuli, oval window).

Fig. 35.18 A, Ventral aspect of the endoderm of the pharynx. showing the pharyngeal pouches. The areas of contact of the pharyngeal endoderm with the surface ectoderm are shown as flattened surfaces. Note the colours of the pharyngeal pouches and the median thyroid diverticulum are retained in B, C and D. B, Ventral and dorsal diverticuli of the third and fourth pharyngeal pouches and midline thyroid gland at 6 weeks. C, Thymus, thyroid and parathyroid glands at 7 weeks. D, Thymus, thyroid and parathyroid glands at 7½ weeks.

(Redrawn by permission from Hamilton WJ, Boyd JD, Mossman HW 1962 Human Embryology: Prenatal Development of Form and Function. Cambridge: W Heffer & Sons.)

The ectoderm of the pharyngeal clefts and the endoderm of the pouches become increasingly separated by mesenchyme. The blind recesses of the second, third and fourth pouches are prolonged dorsally and ventrally as angular, wing-like diverticula (see Fig. 35.18); the pouch endoderm thickens and evaginates into localized neural crest-derived mesenchymal condensations. The ventral part of the second pouch is the focus of lymphoid development as the palatine tonsil. A generalized ring of lymphoid tissue, the lymphatic ring, develops in this region. The third pouch gives rise to the thymus ventrally and the parathyroid III dorsally, whereas the fourth pouch produces the parathyroid IV and an ultimobranchial body. The dorsal and ventral portions of the fourth pouch, together with the lower ultimobranchial body, are collectively termed the caudal pharyngeal complex.

Rarely, failure of normal modification of the pharyngeal clefts and pouches may lead to the formation of fistulae, external or internal sinuses, and cysts. Lateral cervical cysts are now considered to be lymphoepithelial in origin.

FACE

By stage 12, migration of the most rostral neural crest cell population is complete and the sequence of morphogenetic changes that will form the face begins (Fig. 35.10). Neural crest cells have populated the mandibular arch and its dorsal maxillary extension, and formed the frontonasal mesenchyme that covers the telencephalon and caudal diencephalon. They also contribute to the primordium of the trigeminal nerve, whose first fibres develop at stage 13. The three divisions of the trigeminal nerve will provide sensory innervation to the frontonasal, maxillary and mandibular parts of the face. All of the mesenchyme of the facial region is neural crest-derived, except for the angiogenic mesenchyme, which has migrated from the cranial paraxial mesoderm to form the facial blood vessels. There are no muscle cells in this region during the morphogenetic period of facial development.

Fig. 35.10 Development of the face during stages 12–18. A, 4 weeks (3.5 mm); B, 5 weeks (6.5 mm); C, 5½ weeks (9 mm); D, 6 weeks (12 mm); E, 7 weeks (19 mm); F, 8 weeks (28 mm).

Localized mesenchymal proliferation results in the formation of four paired processes: the medial and lateral nasal, maxillary and mandibular processes. The lateral and medial nasal processes surround the nasal placodes, causing them to sink deep to the surface within the nasal pits. Below the developing nasal region, the median tissue forms the premaxillary component of the upper lip and jaw, and the primary palate. Concomitant with formation of the nasal processes, proliferation of the maxillary mesenchyme forms the maxillary processes. These make contact with the medial and lateral nasal processes at stage 16–17. Fusion of the maxillary processes with the medial nasal processes unites the premaxillary and maxillary parts of the upper jaw and lip; failure of this process on one or both sides causes unilateral or bilateral cleft lip (see Fig. 35.17). Superiorly, this fusion closes the cleft at the lower edge of the nasal pits, completing the future nostrils. Fusion of the maxillary with the lateral nasal processes is a much simpler process and rarely gives rise to abnormality. At stage 16, the epithelium of the groove between them thickens to form the lacrimal lamina, the primordium of the lacrimal system. At stage 19, it separates from the surface ectoderm, forming the lacrimal cord beneath the surface. The cord becomes canalized to form the nasolacrimal duct in the tenth week (de la Cuadra-Blanco et al 2006). The original site of the lacrimal lamina marks the lateral division between frontonasal and maxillary contributions to the face, the territories whose sensory nerve supply is respectively from the ophthalmic and maxillary divisions of the trigeminal nerve (Fig. 35.11).

Fig. 35.17 Cleft lip and cleft palate. A, incomplete unilateral cleft lip; B, complete unilateral cleft lip; C, incomplete bilateral cleft lip; D, complete bilateral cleft lip and cleft palate (the nasal septum and both inferior nasal conchae can be seen); E, cleft palate (the nasal septum and left inferior nasal concha can be seen); F, cleft of the soft palate.

(Courtesy of Mr T Goodacre and Oxford Radcliffe Hospitals NHS Trust.)

Fig. 35.11 The parts of the adult face derived from the ophthalmic (frontonasal), maxillary and mandibular divisions of the skin of the face, showing the lines of fusion and definitive innervation.

At the start of facial development, the stomodeal opening extends across the whole width of the embryonic head. A wide mouth is maintained until differential growth brings the eyes and the lateral parts of the maxillary–mandibular structures from the sides to the front of the face (stage 18 to stage 23, 7–8 weeks). Although differential growth makes the mouth opening proportionately smaller, progressive fusion of the lateral regions of the maxillary and mandibular processes also makes an important contribution to decreasing the width of the mouth and to formation of the cheeks. Differences in mouth width within the human population are mainly due to variation in the extent of maxillomandibular fusion. The period from 7 to 8 weeks is the final period of facial development. In addition to formation of the mouth and cheeks, it is marked by further narrowing of the nasal region and philtrum and ascent of the ears. By stage 20, the face is recognizably human, although differential growth will continue to bring about changes in proportion and relative position of the features.

The contribution made by the frontonasal process to surface epithelial derivatives extends from the skin of the forehead, over the supraorbital and glabellar regions including the upper eyelid and conjunctiva, to the external aspect of the nose and philtrum of the upper lip. During later development, the maxillary nerve invades the skin of the philtrum and nasal alae (Fig. 35.11; see Fig. 24.10). Internally, the epithelial contribution to mucous membrane includes the nasal vestibule, the nasal mucosa of the conchae and paranasal sinuses, the olfactory epithelium, the mucosa of the philtrum, gums and primary palate.

NASAL CAVITIES AND PALATE

After formation of the nasal pits, the olfactory placodal cells differentiate into olfactory neuroblasts, supporting (sustentacular) cells and stem cells. Neurites begin to extend from the olfactory neuroblasts, reaching the olfactory region of the telencephalon by stage 16 (sixth week). The earliest pioneer neurites cross a mesenchyme-filled gap between the placode and the brain. The remaining placodal cells differentiate into columnar supporting (sustentacular) cells, rounded basal cells and, by invagination, the flattened duct-lining and polyhedral acinar cells of the glands of Bowman. Basal infiltration by lymphocytes is a relatively late event.

Once the nasal cavities have formed, the roof of the oral cavity is regarded as the primitive palate (not to be confused with the primary palate). Each nasal cavity has an arcuate shape, extending upwards to the olfactory epithelium and then down again towards the oral cavity, from which it is separated by the thin epithelial choanal membrane. Towards the end of stage 18, the choanal membranes degenerate to form the choanae; the nasal cavites are now a duct from the external environment to the oral cavity. The triangular wedge of tissue between the left and right nasal cavities and the oral cavity comprises the primitive palate below and the nasal septum above. Caudal to the primary palate, the internal aspect of each maxillary process bulges into the oral cavity as a palatal process: the palatal processes (first detectable at stage 17) are the primordia of the secondary palate. The tongue is already well developed, and its domed form fills the space between the nascent palatal shelves laterally, and the primitive palate above. The mandible is at this stage short relative to the maxillary region and does not extend as far as the primary palate. Further growth brings the mandibular region and tongue forwards, to a position below the primary palate. At the same time, the (secondary) palatal processes continue to grow, projecting vertically downwards on either side of the tongue. At stage 23 (56–57 days), the tongue descends and the palatal shelves rotate, bringing the shelves to a horizontal position above the tongue (Fig. 35.12). The rapidity of the process of shelf elevation is caused at least in part by swelling of the palatal mesenchyme due to accumulation and hydration of hyaluronan (Ferguson 1991). This occurs during a period of continuous growth in head height but almost no growth in head width. This latter factor is important, because if palatal shelf elevation is delayed so that it occurs during a period of growth in facial width, the unfused processes may be unable to touch physically, resulting in a cleft palate. Other factors affecting palatal closure are the growth in length of Meckel’s cartilages, which allows the tongue to descend, and the change in position of the maxillae relative to the anterior cranial base, which has the effect of lifting the head and upper jaw away from the mandible during weeks 9 and 10, facilitating withdrawal of the tongue from between the palatal shelves and creating space for their elevation. Mouth opening, tongue protrusion and hiccup movements have also been noted at this time, and it may be that these movements and their associated pressure changes assist palatal shelf elevation. Generally, in female embryos palatal shelf elevation occurs 7 days later than in males, and congenital cleft palate is more common in females.

Fig. 35.12 Development of the palate. A–C show developmental progression over weeks 7–8. Ventral view (top row) and coronal section (bottom row).

Midline fusion of the two palatal shelves involves adherence and breakdown (by apoptosis) of the apposed epithelial surfaces. They also fuse with the posterior border of the primary palate, except over a small median area where a nasopalatine canal maintains connection between the nasal and oral cavities for some time and marks the future position of the incisive fossa. During the period of palatal shelf development, a median downgrowth from the primitive palate forms the definitive nasal septum; it is supported by cartilage. The fusing medial edges of the elevated palatal shelves also fuse with the free edge of the nasal septum, forming separate right and left nasal cavities above the secondary palate. Bone forms by intramembranous ossification within the palatal mesenchyme, and by endochondral ossification of the cartilaginous nasal septum. At this time, the free (caudal) edge of the palatal shelves lies directly below the former position of the attachment of the adenohypophysial pouch to the roof of the oral cavity. Caudal to the hard palate, its free edges grow (especially medially) to form the soft palate and uvula, which extend into the oropharynx. Myogenic mesenchyme from the first (tensor palati only) and third pharyngeal arches migrates into the soft palate and around the caudal margins of the pharyngotympanic tube. Separation of the definitive nasal and oral cavities is now complete. A number of elevations appear on the lateral wall of each nasal cavity: the superior, middle and inferior conchae.

Within the nasal septum, on either side of the septal cartilage, the ectoderm is invaginated to form a pair of small diverticula; these are the vomeronasal organs, auxiliary olfactory organs derived from the olfactory placodes. Their openings are close to the junction between the premaxilla and maxillae on each side. Their function in humans is not clear; but their cells differentiate to form neurones that project to the olfactory area of the brain, and may function in pheromone-related olfactory communication.

Bilateral dorsal expansions of the first, second and possibly third pharyngeal pouches form the tubotympanic recesses, which will become the tympanic cavities and pharyngotympanic tubes. The latter open into the lateral wall of the nasopharynx, above the soft palate. A number of focal proliferations of nasopharyngeal endoderm become invaded by lymphoid tissue. The adenoid or pharyngeal tonsil develops in the posterior midline of the nasopharynx, and the tubal tonsil develops close to the pharyngeal opening of the pharyngotympanic tube.

ORAL CAVITY

In the fifth week (stage 12), the oropharyngeal membrane breaks down so that communication is established between the stomodeum and the cranial end of the foregut (future naso- and oropharynx respectively). Formation of the hard and soft palates separates the cranial foregut into the nasal cavity and nasopharynx above and the definitive oral cavity below. The oral cavity is demarcated from the oropharynx posteriorly by the free edge of the soft palate and uvula above, and the palatoglossal arch laterally, which demarcates the oropharyngeal isthmus.

Tongue

Because the mandibular arch grows more rapidly than the others, this component of the pharyngeal floor is longer craniocaudally than that of the other arches. By stage 14, three swellings are apparent on its surface: a small median elevation, the tuberculum impar or median tongue bud, and paired mandibular (lingual) swellings. The mandibular swellings fuse with each other and with the tuberculum impar to form the anterior two-thirds of the tongue (Fig. 35.13). A sulcus forms along the ventral and lateral margins of this elevation and deepens, internal to the future alveolar process of the mandible, to form the linguogingival groove, while the elevation constitutes the anterior or oral (presulcal) part of the tongue. Caudal to the tuberculum impar, the copula and the hypobranchial (hypopharyngeal) eminence, form in the pharyngeal floor, and the ventral ends of the second, third and fourth pharyngeal arches converge onto them. The third arch component of the hypopharyngeal eminence grows over the second arch and approaches the anterior tongue rudiment; the two parts fuse along a V-shaped line corresponding later to the sulcus terminalis. Another transverse groove separates its caudal (fourth arch) part to delineate the epiglottis.

Fig. 35.13 Development of the pharyngeal floor and tongue. A, Stage 14, showing median and lateral swellings in the floor of the first arch; B, after fusion of the swellings; C, the tongue and oropharynx at birth.

During this sequence of events, the second arch is excluded from the tongue. The sulcus terminalis has its apex at the foramen caecum: this is a small median diverticulum that forms at the time of fusion of the constituent parts of the tongue, and is the site of downgrowth of the median rudiment of the thyroid gland. Failure of downgrowth of all or part of the thyroid gland from this site results in ectopic thyroid tissue within the tongue (lingual thyroid), between the foramen caecum and the epiglottis. The tongue primordia fuse at stage 17 (15 mm), and the sulcus terminalis is formed by the line of fusion. The vallate papillae appear around 10 weeks (52 mm), and increase in number until the end of the second trimester. Serial reconstructions suggest that the territory of the glossopharyngeal nerve extends considerably beyond these papillae. However, in general the composite character of the mucous membrane of the tongue is reflected by its sensory innervation. The anterior, oral part is innervated by the lingual branch of the mandibular nerve, and by the chorda tympani of the facial nerve. The posterior, pharyngeal part of the tongue is innervated by the glossopharyngeal, the nerve of the third arch, and the root of the tongue, near the epiglottis, is innervated by the vagus. During stages 14 and 15, the mesenchyme of the tongue is invaded by cells from the occipital myotomes which migrate from the lateral aspects of the myelencephalon. They pass ventrally round the pharynx to reach its floor accompanied by the hypoglossal nerves. The posterior parts of the tongue and epiglottis, i.e. the embryonic pharyngeal floor derivatives of the third, fourth and sixth arches, lie within the oropharynx. Striations appear on the surface of the tongue early in the fetal period. The tongue is short and broad, and its entire surface lies within the oral cavity (see Fig. 14.5). The posterior third of the tongue descends as the hyoid bone and larynx descend during the first postnatal year, and by the fourth or fifth year it forms part of the anterior wall of the oropharynx.

Teeth and gums

Demarcation of the lips begins after fusion of the facial primordia at stage 18, during the period of secondary palatal development. Two parallel epithelial thickenings, an outer labiogingival lamina (vestibular band) and an inner dental lamina, form around the interior border of the mouth in both upper and lower jaws (Fig. 35.13; see Fig. 35.15). The linguogingival groove (sulcus) is formed as an indentation between the dental lamina and the tongue. At stage 22, each labiogingival lamina indents the underlying mesenchyme to form a shallow groove that deepens to form the vestibule between the lips and gums. The lining of the oral cavity between the vestibular epithelium of the upper and lower jaws forms the inner aspect of the cheeks. The dental lamina gives rise to the epithelial component of the teeth.

Fig. 35.15 Development of the lip, gums and teeth. A. oral view. B. the right half of the lower jaw viewed from below.

Tooth formation involves a sequence of epithelial–mesenchymal interactions along the dental lamina (Fig. 35.14). These interactions are controlled by a large number of genetic factors, and the extracellular matrix (particularly of the basement membranes) is of major importance (Thesleff 2000, Fukumoto & Yamada 2005). In 25 mm embryos, 10 localized thickenings of the upper and lower dental laminae initiate formation of the dental epithelial components of the tooth primordia (Figs 35.14, 35.15). They expand into dental sacs surrounded by vascular mesenchyme. The epithelium proliferates and indents to form an enamel organ which by 10 weeks forms a cap over a mesenchymal condensation, the dental papilla: collectively this unit constitutes a tooth bud or germ. The enamel organ becomes bell-shaped and differentiates into two layers, the internal and external enamel epithelia; these are separated by a glycosaminoglycan-rich stellate reticulum. The cells of the internal epithelium differentiate into ameloblasts, and the underlying layer of mesenchymal cells differentiates into odontoblasts. The odontoblasts produce and secrete dentine, which influences the ameloblasts to form enamel; this is laid down in successive layers, and after mineralization is the hardest tissue in the body. Enamel and dentine production from the bell-shaped tooth germ both begin at 24 weeks. The dental papilla mesenchyme below the odontoblast layer forms the pulp, which becomes vascularized and innervated. Experimental studies in mice (which have only incisors and molars) have revealed that regional differences in gene expression within the maxillary and mandibular mesenchymes govern the type of tooth produced. Fibronectin is present in the basement membrane of the internal enamel epithelium during the bell phase; it assists attachment of the preodontoblasts and is essential for their differentiation; it becomes progressively more abundant during the later fetal period. Collagen I is the major supportive extracellular scaffold in the maturing dental papilla and stellate reticulum.

Fig. 35.14 A summary of the epithelial–mesenchymal interactions during tooth development.

At birth, each quadrant of the jaws has the five deciduous tooth germs and the germ of the first permanent molar. The timing of eruption of the teeth, beginning with the lower middle incisors, is variable. Permanent teeth develop in accessional positions from the lingual aspects of the deciduous tooth germs, and, for the 12 permanent molar teeth, from posterior extensions of the dental laminae on each side of both jaws. Mineralization begins in both deciduous and permanent teeth before birth. The deciduous teeth have well-developed crowns by full term, and eruption through the gingiva (gum) begins with the lower incisors between 3 and 6 months after birth. After eruption, the gingiva remains attached to the neck of each tooth by the upper part of the periodontal ligament, whose major part attaches the tooth root to the bone of the tooth socket.

ANOMALIES OF FACIAL DEVELOPMENT

Malformations involving the neural crest

Congenital malformations of the face may be initiated early, and related to abnormal migration, proliferation and/or apoptosis of neural crest cells, or later, during the morphogenetic phase of facial development. Craniofrontonasal syndrome is characterized by a broad forehead and hypertelorism, premature fusion of one or both coronal sutures, a central nasal groove, and sometimes cleft lip and palate; there are also extracranial features. It is caused by deletions of the gene EFNB1, which is known to play essential roles in boundary formation between tissues, including those between neural crest and adjacent non-crest cells. Mandibulofacial dysostosis (Treacher Collins syndrome) is characterized by incomplete orbits, reduced jaws and auditory ossicles (hence conductive deafness), abnormal external ears and fistulae or cysts, suggesting involvement of all levels of the cranial neural crest. It is caused by haploinsufficiency of the gene TCOF1. Hemifacial microsomia (Goldenhaar syndrome) affects only one side of the face and comprises a small mandible (sometimes with absence of the temporomandibular joint), malformed or absent ears with accessory ear tags, and facial clefts. Experimental evidence in animals suggests that it is due to haemorrhage of the stapedial artery, which may have a genetic basis. Deficient growth of the mandible (micrognathia) is usually associated with other defects. In Pierre Robin sequence (Fig. 35.16), the small size of the mandible obstructs descent of the tongue, resulting in a U-shaped cleft palate; a conotruncal septum defect is present in one-quarter of cases, suggesting possible involvement of the cardiac neural crest. Further details and references for facial malformations may be found in Gorlin et al (2001), Wilkie and Morriss-Kay (2001), and Morriss-Kay and Wilkie (2005).

Fig. 35.16 Pierre Robin sequence.

(Courtesy of Mr T Goodacre and Oxford Radcliffe Hospitals NHS Trust.)

GLANDS OF THE NECK

The development of the pharyngeal floor and lower pharyngeal pouches gives rise to glands finally disposed in the neck and anterior mediastinum.

PHARYNX, LARYNX, OESOPHAGUS AND TRACHEA

The larynx forms at the cranial end of the laryngotracheal groove, where it is bounded laterally by the ventral ends of the sixth arches and ventrally by the caudal part of the hypobranchial eminence (Figs 35.5, 35.6, 35.13). The thyroid cartilage develops from the ventral ends of the cartilages of the fourth, or fourth and sixth, pharyngeal arches. The cartilage appears as two lateral plates, each chondrified from two centres and united in the midventral line by a fibrous membrane within which an additional centre of chondrification develops. The cricoid cartilage arises from two cartilaginous centres, which soon unite ventrally, gradually extend, and ultimately fuse on the dorsal surface of the tube as the cricoid lamina. Paired arytenoid swellings appear in the ventral ends of the sixth arches from stage 14, one on each side of the cranial end of the groove. As they enlarge, they approximate to each other and to the caudal part of the hypobranchial eminence where the epiglottis develops. The opening into the larynx, at first a vertical slit, is converted into a T-shaped cleft by the enlargement of the arytenoid swellings. The vertical limb of the T lies between the two swellings, and its horizontal limb lies between them and the epiglottis. The arytenoid swellings differentiate into the arytenoid and corniculate cartilages (Fig. 35.6), and the ridges that join them to the epiglottis become the definitive aryepiglottic folds within which the cuneiform cartilages differentiate from the epiglottis. After the caudal part of the hypobranchial eminence has separated from the pharyngeal (posterior) part of the tongue (Fig. 35.13), it is in continuity with two linear ridges which appear in the ventral wall of the pharynx. The ridges are the sixth arches, which are placed very obliquely owing to the shortness of the pharyngeal floor compared with the greater extent of the roof. They are carried downwards on the ventral wall of the foregut and bound the median laryngotracheal groove, from which the lower part of the larynx, the trachea, bronchi and lungs are developed (see Ch. 59).

From stage 12, the early pharyngeal foregut develops a ventral endodermal outgrowth into the mesenchyme surrounding the sinus venosus and inflow tract of the heart (see Figs 59.1, 73.3). This initiates the separation of the respiratory and alimentary tubes. The point at which the original respiratory diverticulum buds from the foregut, the laryngotracheal groove, remains at a constant level during the embryonic period, and the trachea lengthens distally as the bifurcation point descends. The cells of the splanchnopleuric mesenchyme that surrounds the developing trachea and oesophagus are sufficiently diverged in their inductive ability to promote the characteristics of the two different tubes. The respiratory diverticulum becomes surrounded by angiogenic mesenchyme that connects to the developing sixth aortic arch artery. By stage 17, the mesenchyme around the trachea is beginning to condense to form C-shaped cartilages, whereas that around the oesophagus has a wide submucosal zone and muscular coats can be distinguished.

For details of early development of the trachea see p. 1033, and early development of the oesophagus see p. 1203.

In the neonate the pharynx is one-third of the relative length in the adult. The nasopharynx is a narrow tube which curves gradually to join the oropharynx without any sharp junctional demarcation. An oblique angle is formed at this junction by 5 years of age and in the adult the nasopharynx and oropharynx join at almost a right angle. The oesophagus in the newborn commences and ends one to two vertebrae higher than in the adult, extending from between the fourth and sixth cervical vertebrae to the level of the ninth thoracic vertebra. The narrowest constriction is at its junction with the pharynx, where the inferior pharyngeal constrictor functions to constrict the lumen, and in this region it may be traumatized with instruments or catheters.

In the normal neonate the hyoid bone and larynx are relatively high in the neck; both descend during infancy, and the trachea is relatively small in relation to the larynx (see Fig. 14.4). The walls of the trachea are relatively thick and the tracheal cartilages are relatively closer together than in the adult. The trachea commences at the upper border of the sixth cervical vertebra, a relationship that is conserved with growth, and it bifurcates at the level of the third or fourth thoracic vertebra.

BLOOD VESSELS IN THE NECK

With elongation of the neck and the appearance of the major conducting vessels from the aortic arch arteries, longitudinal anastomoses in the cervical region link intersegmental arteries and their branches and direct blood flow to the developing brain in the vertebral arteries, in parallel with the internal carotid arteries (see Figs 35.8, 35.9).

The primary blood vessels of the head and neck consist of a close-meshed capillary plexus drained on each side by the precardinal vein, which is at first continuous cranially with a transitory primordial hindbrain channel that lies on the neural tube medial to the cranial nerve roots (see Figs 13.1, 13.2). This is soon replaced by the primary head vein which runs caudally from the medial side of the trigeminal ganglion, lateral to the facial and vestibulocochlear nerves and the otocyst, then medial to the vagus nerve, to become continuous with the precardinal vein. A lateral anastomosis subsequently brings it lateral to the vagus nerve.

The ventral pharyngeal vein drains the mandibular and hyoid arches into the common cardinal vein (see Fig. 24.36A). As the neck elongates, its termination is transferred to the cranial part of the precardinal vein which later becomes the internal jugular vein (see Fig. 24.36B). The ventral pharyngeal vein receives tributaries from the face and tongue and becomes the linguofacial vein. As the face develops, the primitive maxillary vein extends its drainage into the territories of supply of the ophthalmic and mandibular divisions of the trigeminal nerve, including the pterygoid and temporal muscles, and it anastomoses with the linguofacial vein over the lower jaw. This anastomosis becomes the facial vein which receives a strong retromandibular vein from the temporal region, and drains through the linguofacial vein into the internal jugular. The stem of the linguofacial vein is now the lower part of the facial vein, whilst the dwindling connection of the facial with the primitive maxillary becomes the deep facial vein. The external jugular vein develops from a tributary of the cephalic vein from the tissues of the neck; it anastomoses secondarily with the anterior facial vein. At this stage the cephalic vein forms a venous ring around the clavicle by which it is connected with the caudal part of the precardinal vein. The deep segment of the venous ring forms the subclavian vein and receives the definitive external jugular vein. The superficial segment of the venous ring dwindles, but may persist in adult life. The deep aspects of the maxillomandibular facial prominences, retrogingival oral cavity, the pharyngeal walls and their lymphoid and endocrine derivatives, and the cervicothoracic oesophagus, thus all have drainage channels that connect with the precardinal complex. Laryngeal and tracheobronchial veins also drain to the precardinal complex, whilst the capillary plexuses, developed in the (splanchnopleuric) walls of the fine terminal respiratory passages and alveoli, converge on pulmonary veins of increasing calibre, finally making secondary connections with the left atrium of the heart, and may be grouped with the vitelline systems.

CHONDROCRANIUM

The first cranial skeletal structures to differentiate are the cartilages of the skull base, sensory capsules, viscerocranium and occiput (Figs 35.5, 35.20B). Development of the pharyngeal arch-related cartilages of the viscerocranium and ear ossicles has been described in the pharynx section above. Before any mesenchyme condenses to initiate the formation of cranial cartilage, the major cranial nerves and blood vessels are already in place – hence, the foramina of the skull are specified before the bones are formed. The adenohypophysial pouch is still connected to the roof of the oral cavity as the skull base cartilage forms, but already lies adjacent to the diencephalon-derived neurohypophysis to form the downwardly projecting pituitary gland (hypophysis) at the base of the caudal diencephalon.

Fig. 35.20 Representative stages in the development of the cranium. In all the diagrams, the chondrocranium and cartilaginous stages of vertebrae are shown in blue, except where ossification is occurring and here the colour is green. The desmocranium, consisting of elements ossifying directly in mesenchyme, is shown in yellow. Cranial nerves are indicated by the appropriate Roman numeral. A, Sagittal section through the cranial end of the developing axial skeleton in an early human embryo of approximately 10 mm, showing the extent of the notochord. B, Superior aspect of cranium of human embryo at 40 mm. C, Lateral aspect of B. D, Lateral aspect of cranium of human embryo at 80 mm.

The rostral tip of the notochord extends to a position just caudal to the hypophysis (Fig. 35.20A). Its sheath is rich in sulphated glycosaminoglycans, which play a role in inducing condensation and chondrification of the occipital sclerotome-derived mesenchyme on either side of it.

The central regions of all four occipital sclerotomes contribute to the parachordal cartilage, which surrounds the notochord and extends as a flat plate on either side of it by the end of the seventh week, forming the basioccipital component of the occipital bone. The exoccipital components (derived from sclerotomes 3 and 4) chondrify soon afterwards; they border the rostral half of the foramen magnum, forming the occipital arch, which is developmentally equivalent to the neural arch components of vertebrae. Roots of the hypoglossal nerve run between the parachordal and exoccipital cartilages, so that when the exoccipital and parachordal components fuse, they leave foramina for these nerve roots. The supraoccipital part of the occipital cartilage (tectum posterius, which is not sclerotome-derived) extends from the exoccipital cartilage around the foramen magnum, completing it. After formation of the exoccipital cartilages, differentiation also extends further rostrally in the medial part of the skull base, with formation of the hypophysial cartilages on either side of the stalk of the hypophysial pouch; they unite in the median plane to form the primordium of the postsphenoid, cradling the hypophysis and retaining a perforation for the hypophysial stalk until the third month. This part of the basisphenoid cartilage will form the sella turcica with its hypophysial fossa. The presphenoid cartilages, rostral to it, form the jugum of the sphenoid body. This is the last part of the medial part of the cranial base to differentiate as cartilage, bridging the gap between the postsphenoid and the cartilaginous nasal capsule.

At stage 17, mesenchyme begins to condense and later to chondrify around the nasal pits at the same time as the polar cartilages, forming the outer part of the nasal capsule and the nasal septum; the roof of each nasal capsule is completed slightly later, when cartilage differentiates around the olfactory nerve bundles to form the cribriform plates of the ethmoid bone. During the third month, cartilaginous conchae form. The whole nasal capsule is well developed by the end of the third month, and consists of a common median septal part – sometimes initially termed the interorbitonasal septum or mesethmoid – and the outer ectethmoid. The conchae ossify during the fifth month; the superior and middle conchae form part of the ethmoid bone, and the inferior pair become separate elements. Each lateral part of the nasal capsule becomes ossified as the orbital plate and ethmoidal labyrinth, whose spaces (‘cells’) communicate with the nasal cavity and become filled with air after birth. Part of the capsule remains cartilaginous as the septal and alar cartilages of the nose, and part is replaced by the intramembranous vomer and nasal bones.

Orbital cartilages surround the eye, but do not undergo ossification in their entirety. The most rostral of them becomes continuous with the presphenoid cartilage by differentiation of a cartilaginous bridge that forms the caudal boundary of the optic foramen, enclosing the optic nerve: this later ossifies to form the lesser wing of the sphenoid bone (orbitosphenoid). The greater wing of the sphenoid (alisphenoid) has both intramembranous and endochondral components; the endochondral part initially differentiates as a cartilage surrounding the mandibular branch of the trigeminal nerve, forming the foramen ovale. This condensation extends medially to join the rostral edge of the polar cartilage on each side. It also expands rostrally, coming to surround the maxillary branch of the trigeminal nerve to form the foramen rotundum. Lastly it extends laterally to join the intramembranous part of the bone, which replaces the caudal part of the orbital cartilage. The greater and lesser wings of the sphenoid are separated by the oculomotor, trochlear and abducent nerves and by the first (ophthalmic) division of the trigeminal nerve.

The otic capsule differentiates from a mesenchymal condensation around the otocyst, after its morphogenesis to form the cochlea and semicircular canals. Differentiation of cartilage begins laterally, at the same time as the polar cartilages are first detectable; it is complete by stage 20. Chondrogenesis around the point of exit of the vestibulocochlear nerve creates the internal acoustic meatus. Chondrogenesis of mesenchyme around the carotid arteries joins each polar cartilage to the otic capsule, forming the carotid canals. A gap occupied by the jugular vein remains between each otic capsule and the parachordal cartilage: this is the jugular foramen. Chondrogenesis of the mesenchyme between the separate cartilages completes formation of the cartilaginous skull base and sensory capsules, which together form a continuous framework around the pre-existing blood vessels and cranial nerves by 9 weeks (40 mm) (Fig. 35.20B).

The process of endochondral ossification in the skull is essentially the same as that of the long bones except that each ossification centre is equivalent to a primary centre, and follows a specific programme of growth and patterning. Growth takes place in the unossified cartilage between adjacent ossification centres; these joints are termed synchondroses. The first ossification centres to appear are those of the lesser and greater wings of the sphenoid, at 8 and 9 weeks respectively. A single basisphenoid ossification centre appears at 11 weeks; three presphenoid and four postsphenoid ossification centres appear at 16 weeks. Bone replaces most of the cartilage until only the major synchondroses remain; these enable the endochondral skull base and sense capsules to continue growing until they reach their final size at puberty or earlier. At birth, unossified chondrocranium persists in the alae, lateral nasal cartilage and septum of the nose, the sphenoethmoidal junction, the spheno-occipital and sphenopetrous junctions, the apex of the petrous temporal bone (foramen lacerum), and between ossification centres of the sphenoid and occipital bones. As indicated above, parts of the chondrocranium do not ossify, but are replaced by adjacent intramembranous bone. In general, endochondral ossification centres form later than intramembranous ossification sites, which first appear during the seventh and eighth weeks.

SKULL VAULT

The bones of the skull vault or calvaria (roof and lateral walls of the neurocranium) are formed entirely by intramembranous ossification. They are also described as dermal bones, since they are considered to be the evolutionary descendants of dermal plates formed as a protective cover for the brain in fishes. In humans, as in all mammals, the major part of the skull vault is formed by paired frontal and parietal bones and the unpaired interparietal (membranous part of the occipital bone). The squamous part of the temporal bones and the membranous part of the alisphenoid contribute to the lateral walls. Lineage data from mouse studies indicates that the frontal and squamous temporal bones are of neural crest origin and the parietals are of mesodermal origin; the interparietal is mixed (Jiang et al 2002). The coronal suture thus forms at the neural crest–mesoderm interface, as does the sagittal suture, due to a small tongue of neural crest tissue lying between the two developing bones. These tissue interfaces may be significant for initiating the molecular signalling system that governs growth of the skull vault. Growth at the borders of adjacent bone, i.e. in the sutures, is the major mechanism of skull vault growth. A sequence of events that maintains a balance between cell proliferation and osteogenic differentiation is mediated by an intercellular signalling system that includes the transcription factor TWIST and ligand–receptor interactions between fibroblast growth factors (FGFs) and their receptors (FGFRs). Mutations in the genes encoding these proteins cause premature fusion of the cranial sutures (craniosynostosis) (for further details and references for this and related descriptions in this section, see Morriss-Kay & Wilkie 2005). In addition to the expansion-related growth that takes place in the sutures, appositional growth, in which bone is laid down on, and resorbed from, the bone surfaces, plays an important role in remodelling the calvarial bones to maintain a degree of curvature that matches the curved surface of the growing brain.

The frontal and parietal bones are initiated as basolateral mesenchymal primordia which extend upwards between the dermal connective tissue and the mesenchymal dura mater. They do not, as previously thought, differentiate within the mesenchyme of an ‘ectomeninx’ that surrounds the brain. As the frontal and then the parietal primordia extend upwards, the differentiating osteoblasts secrete osteoid which then undergoes mineralization. Only the mineralized parts of the bones are detected in Alizarin-stained specimens and X-rays. Clear frontal bone primordia are detectable in the superciliary arch region of Alizarin-stained human embryos by the eighth week. As they become mineralized above this level, the parietal bone primordia can also be seen. The two bones appear to be separated by a wide gap at the coronal suture; in fact, this gap only shows the separation of the mineralized parts of the bone – the unmineralized edge of the parietal bone actually overlaps the caudal edge of the frontal bone. After the upgrowth phase, mineralization takes place centrifugally from the central points of the frontal and parietal bones, which by this time form convex plates over the curvature of the underlying brain.

During birth, the overlap of the frontal and parietal bones enables them to slide over each other; during the neonatal period, when the baby cries and intracranial pressure rises, the overlapping bones slide apart, increasing the fronto-occipital diameter of the skull. Growth at the coronal suture provides the major increase of the fronto-occipital plane of the skull vault. Premature synostosis of the coronal sutures restricts growth in this plane, causing brachycephaly; unilateral coronal synostosis leads to plagiocephaly, in which one side of the skull fails to grow in the fronto-occipital plane. Uni- and bilateral coronal synostosis comprises 20–25% of all forms of craniosynostosis.

The metopic and sagittal sutures are formed when the upwardly extending frontal and parietal bones (respectively) reach the vertex of the skull and abut in the median plane. Growth in these sutures increases the breadth of the skull. The metopic suture fuses at around 18 months after birth, by which time most of the increase in breadth of the forehead is complete; further growth of the frontal bones is mediated by appositional growth. The sagittal suture continues as an active growth centre until puberty, when growth of the brain is complete. Premature fusion results in the formation of a narrow, elongated skull. Sagittal synostosis is the most common form of craniosynostosis (40–55%).

The interparietal bone (supranuchal squamous portion of the occipital bone) forms from two ossification centres that appear in the eighth week. These are considered to be homologous with the paired postparietal bones of reptiles. The fact that they unite to form a single bone in mammals may be due to the interpolation of a small area of neural crest that migrates from the hindbrain after neural tube closure (Jiang et al 2002). Two further ossification centres develop laterally at 12 weeks. There is at first a wide gap occupied by cartilage between the interparietal and parietal bones, which disappears as the membrane bones grow towards each other, forming the lambdoid suture when they abut. The cartilage is in a deeper tissue layer than the intramembranous bone, reflecting the dermal origins of the latter. The lambdoid suture contributes growth to the caudal border of the parietal bones and to the upper part of the occipital bone. Synostosis of this suture is relatively rare (0–5% of craniosynostosis cases) and has a less severe effect on overall skull growth than coronal and median fusions. Posteriorly, between the interparietal bone and the foramen magnum, the skull vault is not formed by membrane bones but by endochondral ossification of the supraoccipital component of the occipital bone.

In addition to the sutures that are formed where two membrane bones abut, fontanelles are formed where three or four bones meet. In the median plane these are the anterior fontanelle, at the junction of the metopic and sagittal sutures, and the posterior fontanelle, at the junction of the sagittal and lambdoid sutures. Laterally, the anterolateral fontanelle lies between the frontal, parietal, greater wing of the sphenoid and squamous temporal bones; its site after closure is called the pterion. The posterolateral fontanelle lies between the parietal, petrous temporal, exoccipital and basioccipital bones; after closure its site is called the asterion. The size of the fontanelles at birth, and the timing of their closure, are highly variable. Delayed growth of the skull bones causes ossification defects including cranium bifidum and parietal foramina, for which several genetic defects have been identified. Cleidocranial dysplasia is a defect of ossification affecting the intramembranous part of the clavicle as well as the skull vault; it is caused by haploinsufficiency of the bone master gene RUNX2.

MEMBRANE BONES OF THE FACE AND VISCEROCRANIUM

The face and viscerocranium are formed from neural crest-derived membrane bones. The facial skeleton includes, from forehead to chin, the frontal bones, the orbital bones (frontal, lacrimal and zygomatic), the nasal bones and vomer, the maxilla and mandible. The maxilla and mandible are also classed as part of the membranous viscerocranium since they form from first arch mesenchyme; this category also includes the medial pterygoid plates of the sphenoid bone, the palatine and the tympanic bones. These components are considered together in this section.

During migration, the trigeminal neural crest cells divide into a frontonasal population that migrates superior to the eye, a mandibular population that migrates into the first pharyngeal arch, and a maxillary population closely associated with the proximal end of the first arch (Fig. 35.2). The frontal, lacrimal, nasal bones, the vomer and the premaxillary (incisor tooth-bearing) part of the maxilla are derived from the frontonasal mesenchyme; the maxilla and zygoma are derived from the maxillary mesenchyme; the mandible and tympanic bone are derived from the mandibular mesenchyme. The mandible is the first membrane bone to begin ossification: its single ossification centre appears in the seventh week. The maxilla and premaxilla have primary ossification centres by 7 weeks, and three further ossification centres form in the maxillary mesenchyme at 8 weeks; all of these components fuse to form a single bone, in contrast to some mammals in which the premaxilla remains separate. In the neonatal skull, the suture between the primary and secondary parts of the palate is still patent, indicating the premaxillary contribution here. By 8 embryonic weeks, ossification centres for most of the facial and viscerocranial bones are present, except for the tympanic ring, for which four ossification centres appear at 12 weeks. They fuse to form the sickle-shaped bone that supports the tympanic membrane.

The mandible is a developmentally complex bone. Although the body of the bone is formed by intramembranous ossification, the coronoid region and condyle are formed by endochondral ossification in cartilage that develops after formation of the membrane bone. These secondary ossification centres form at 10–14 weeks. Distal cartilage forms secondary ossification centres, the mental ossicles, at 7 months. This complex system enables the mandible to grow at both proximal and distal ends, analogous to a long bone.

Growth of the face occurs in the sutures between the membrane bones in a similar manner to that of the skull vault sutures, but the amount of growth is proportionately less than in the skull vault, reflecting the dominant influence of brain growth in the latter.

POSTNATAL GROWTH OF THE SKULL

Postnatal growth of the skull is characterized by changing proportions of its components. Growth of the brain continues to be extremely rapid in the first 2 years; in addition to continuing growth of the frontal and parietal bones, the squamous temporal bone increases in size so that it contributes a greater proportion of the skull vault in the adult than in the neonate (Fig. 35.21). The inner ear and the petrous temporal bone around it grow very little after birth, so the increasing breadth of the skull draws the petrous temporal bone out laterally, creating the bony external acoustic meatus. The tympanic ring (with the tympanic membrane) lies at the surface of the meatus in the neonatal skull; it remains at the proximal end of the deepening canal. Use of the sternocleidomastoid muscle to lift the head results in formation of the mastoid process of the temporal bone, which develops air-filled spaces that are continuous with the middle ear cavity. The paranasal sinuses begin to form in late fetal life as diverticula from the nasal cavity which gradually invade the maxilla, frontal, ethmoid and sphenoid bones. At birth they fill with air when the amniotic fluid drains from them. Thickening of the skull bones is accompanied by increasing size of the sinuses, and by a change in form of the sutures, from straight to wavy lines and finally to the complex interdigitations seen in the adult. After growth ceases, the skull sutures contain inert connective tissue and some cartilage; in old age some of them are completely replaced by bone (natural synostosis).

Fig. 35.21 Much of the postnatal growth of the skull is concerned with development of the viscerocranium. This diagram shows that with the height of the cranial vault expressed as similar in newborn and adult skulls (lines a↔b), the facial skeleton increases particularly during childhood and puberty.