Neural crest cell migration as the neural fold develops into the neural tube. (a) Primitive groove formation. (b) Neural crest cells arise at the margin of the neural folds. (c) Neural fold fusion and neural tube formation. (d) Neural crest cells lose affinity to surface ectoderm
Midbrain flexure and neural crest cell migration. The neural crest cells in the forebrain area do not have to migrate far because they are transported forward by the forward flexion of the embryo. The vertical numbers r1–r8 indicate rhombomeres 1–8 (From: Scott F. Gilbert: Developmental Biology, Ninth Edition. 2010:384. © Sinauer Associates, Inc. Reprinted with permission)
Neural crest cell migration depends on multiple intricate developmental events. Alteration of any step in this developmental sequence can produce fundamentally different but often superficially similar malformations . Typically, cells with longer pathways are more prone to malformations. For example, as the embryo undergoes three-dimensional development, and midbrain flexure occurs, neural crest cells only need to migrate a short path to reach their final destination (Fig. 2.2). This may explain why structures derived from the frontonasal neural crest tissue have a lower incidence of deformities than structures derived from neural crest cells with longer pathways.
Pharyngeal or branchial arches begin to form distal to the frontonasal prominence early in the fourth week. Humans have five pairs of arches, numbered 1, 2, 3, 4, and 6 in a cranial to caudal sequence (Fig. 2.3). Arch 5 does not develop in humans or even if initially present regresses rapidly. They consist of visible layers of tissue outgrowth arising from underneath the early brain and frontonasal prominence. These primitive embryonic structures contribute greatly to the formation of the head and neck . Congenital anomalies in these regions may occur during the transformation of these structures into their adult derivatives. For example, the first arch contributes to the development of the face. The second arch forms the muscles of facial expression. The fourth and sixth arches contribute to the tongue and larynx. Pharyngeal arches are derived from all three germ cell layers: endoderm, mesoderm, and ectoderm. The neural crest cells also contribute to the formation of the pharyngeal arches (Fig. 2.2).
Pharyngeal arches . Pharyngeal arches 1 through 4 are visible prominences in the embryo; pharyngeal arch 6 is detectable histologically but does not manifest as a prominent or exophytic structure
Pharyngeal arch 1 is the main contributor to lower facial prominences and structures and the main one of relevance to this chapter. Early during the fourth week, the paired segments of arch 1 begin to grow, and each divides into a maxillary process and a mandibular process (Fig. 2.4a, b). The cranial limb produces the maxillary prominence, and the caudal limb produces the mandibular prominence. Facial prominences are swellings that appear in the fourth week of embryologic development. Five main facial prominences contribute to facial development (Fig. 2.4a).
Five main facial prominences (a) Frontal view: one frontonasal, two maxillary, two mandibular. (b) Fronto-lateral view
Facial formation involves the union of prominences by either one of two distinct processes: merging and fusion. Merging is the process by which two adjacent prominences are united by an upheaval of the separating valley (Fig. 2.5a). Fusion on the other hand is the process by which two adjacent prominences contact each other while trapping a double layer sheet of epithelial cells (Fig. 2.5b).
(a) Merging vs. (b) fusion in facial development
A single frontonasal prominence develops ventral to the forebrain around the same time as the paired maxillary and mandibular prominences. It is derived from neural crest cells that migrate from the ectodermal folds to invade the space that will form the frontonasal prominence. The five facial prominences constitute the major building blocks of the face and all five appear by the end of the fourth week. Facial development will then be a process of proliferation of cells within prominences, division, merging, and fusion of these prominences .
During the fifth week, the nasal placodes form. These are paired areas of thickened surface ectoderm on the ventrolateral aspect of the frontonasal prominence (Figs. 2.6a and 2.7a). In the sixth week, each nasal placode divides into medial and lateral components (Figs. 2.6b and 2.7b).
(a) Embryo week 5: Nasal placode formation. The paired nasal placodes arise from a thickened area of surface ectoderm from the ventrolateral aspect of the frontal process. (b) Embryo week 6: The nasal placodes divide to form the medial and lateral nasal prominences
Scanning electron micrograph of a 4- to 5-week-old human embryo in a frontal view: (a) Nasal placodes form on the ventrolateral aspect of the frontonasal prominence. Nasal pits (NP) form as small depressions in the nasal placodes bilaterally. (b) The nasal placodes give rise to the medial and lateral nasal prominences around the nasal pits (From Henrichsen  Reprinted with permission)
Around the same time during the sixth week, the upper jaw begins to form. The medial nasal and maxillary prominences merge to form the upper jaw. The two adjacent medial nasal prominences then merge across the midline to form the philtrum, middle segment of the upper jaw, and the tip of the nose. All five prominences contribute to the formation of the nose. The nasal bridge is formed by the frontonasal prominence. The tip and crest of the nose are formed by the merged medial nasal prominences, as mentioned above. The sides of the nose (alae) are formed by the lateral nasal prominences (Figs. 2.8 and 2.9).
Nasal and midface formation from five prominences. The nose is formed by the merging of the medial nasal prominences (white arrows) joining together across the midline forming the philtrum, the central segment of the upper jaw, and the tip of the nose. The lateral nasal prominences (red arrows) merge with the superior and inferior aspects of the medial nasal prominences. The upper jaw is formed by the merging of the medial nasal prominences and the maxillary prominences (purple arrows)
The child’s face derivation from facial prominences: Frontonasal prominence (F), lateral nasal prominence (LN), medial nasal prominence (MN), maxillary prominence (MX), mandibular prominence (MN)
The cheeks and the maxillae are derived from the maxillary prominences. The maxillary prominences enlarge considerably to develop the majority of the midface area in the mature human face (Fig. 2.9) .
The distal nasolacrimal lacrimal system is formed by the fusion of the lateral nasal prominence and the maxillary prominence and starts as a nasolacrimal furrow (Fig. 2.10). As these two prominences fuse, a double layer of epithelium is trapped between them. At first, this cord of epithelial cells is in a relatively horizontal orientation as depicted in Fig. 2.10, but as the maxillary prominences develop and the midface enlarges, this cord of cells assumes a more mature vertical position (Fig. 2.10). Near birth or soon after, this solid cord of cells canalizes and forms the nasolacrimal duct .
Nasolacrimal duct formation : begins as a furrow between the lateral nasal prominence and the maxillary prominence. Fusion occurs around the groove trapping a double layer of epithelial cells. As the face develops, this cord of cells, which was horizontal in orientation originally, assumes its mature vertical position. This cord of epithelial cells later canalizes to form the lacrimal outflow system
Mandibulofacial dysostosis syndrome , also known as Treacher Collins syndrome , is a good example of how insults at the embryonic stage can result in craniofacial deformities. This condition can be induced when a 9-day-old mouse embryo (approximately equal to a 4-week human embryo) is treated with retinoic acid. This produces a cell deficiency in the proximal aspect of the maxillary and mandibular prominences (Fig. 2.11). This early embryonic cell deficiency is manifested in the mature infant as the hypoplastic midface and jaw area seen in this syndrome [12–14].
Mandibulofacial dysostosis (MFD) : cell deficiency and result. In MFD there is a cellular deficiency in the area of the maxillary and mandibular prominence. (a) A normal maxillary prominence produces normal midface area. (b) Cellular deficient maxillary and mandibular prominences produce hypoplastic midface and mandibular areas
Development of the Skull
The skull consists of two major portions, the cranial base and the calvarium, both of which derive from neural crest mesenchyme. The cranial base derives from the chondrocranium, also known as the cartilaginous neurocranium . The latter arises from the fusion of several cartilaginous centers surrounding the notochord in the cranial portion of the embryo. Its development is quite complex, as the formation of the cranial base should allow for the formation of the numerous foramina for the transit of nerves and vessels in and out of the skull. The bones of the cranial base derive from cartilage and ossify by a process called endochondral ossification. The skull base consists of the sphenoid bones, the sella turcica (saddle shaped depression in the body of the sphenoid bone), the ethmoid bones, the nasal concha bones, and the nasal septum. The membranous neurocranium on the other hand forms the cranial vault or the calvaria. Mesenchyme surrounds the sides and the top of the brain. This subdivides into an inner and outer layer. The inner layer forms the pia and arachnoid coverings of the brain. The outer layer divides into the dura and the cranial bones of the skull. Ossification centers develop in the outer layer of the mesenchyme to form the individual calvarial bones. Sutures are areas of dense connective tissue that separate cranial bones from one another. They allow for the overlapping of neonatal cranial bones for head passage through the birth canal. Areas where sutures meet are called fontanelles in infants. There are six membrane-covered fontanelles including one anterior, one posterior, two sphenoid, and two mastoid fontanelles (Fig. 2.12). Sutures, fontanelles, and growth plates at the edges of the calvarial bones allow for skull growth resulting from expansive forces of the growing brain  (Fig. 2.13).
Lateral (left) and superior (right) view of the skull fontanelles and sutures. Note the larger size of the anterior fontanelle as compared to the posterior
Growth of the skull is a combination of factors: cellular proliferation in the suture areas, surface apposition and resorption, and the expanding forces from the growing brain
The posterior fontanelle usually closes around 3 months of postnatal life, whereas the anterior fontanelle remains open until about 18 months of age. Palpation of the anterior fontanelle is useful for detecting increased intracranial pressure or dehydration and is routinely performed by pediatricians during physical exams to check for premature closure. The fetal and newborn skulls are large in proportion to the rest of the body. Increase in calvarial size is greatest during the first 2 years of life, which coincides with the most rapid period of brain growth. The skull continues to increase in size until the mid-teenage years and then increases slightly in size for 3 or 4 more years due to thickening of the bones. Craniosynostosis results from the premature fusion of the calvarial sutures. The type and severity of skull deformity depend on which and how many sutures have closed prematurely [16, 17]. Craniosynostosis is covered in detail in Chaps. 38 and 40. Growth defects in the cranial base also lead to morphological deformities and mainly exorbitism (shallow orbits), skull deformities, and midface hypoplasia . Since the cranial base involves cartilaginous growth, disturbances in cartilage growth can also produce skull and facial abnormalities, such as in achondroplasia and Down syndrome.
The face is also relatively small when compared to the size of the skull in the newborn period. This is due to the small size of the mandibular and midface areas and the underdevelopment of the paranasal sinuses. There is rapid growth of the face and jaw with the eruption of the primary teeth during early childhood and again at the time of the secondary teeth eruption. In addition, growth and aeration of the sinuses contribute greatly to the maturation of the facial area (Fig. 2.14). The maxillary sinuses are the largest sinuses in the adult human face, and their pneumatization leads to growth of the midface area. The ethmoidal sinuses are located in between the orbits, and their pneumatization leads to an increase in the intercanthal distance.
Sinus development and aeration. Coronal view depicting ethmoidal and maxillary sinus development at 2 months (top left), 1 year (top right), 5 years (bottom left), and 10 years of age (bottom right)
Eyelid and Orbital Development
Eyelid formation is closely related to the development of the eye. The eyes begin their development as swellings called the optic placodes on the sides of the embryo’s forebrain early in the fourth week of gestational age (Fig. 2.15a). Optic placodes later give rise to the optic vesicles, which project from the sides of the forebrain. The optic vesicles’ surface layer then invaginates to form the optic cups. As the optic cup begins its indentation, the overlying ectoderm thickens and forms the lens placode. The surrounding edges of the optic cup continue to migrate forward, and the lens placode is pinched off internally and migrates to become the ocular lens (Fig. 2.15b, c). The ectoderm overlying the optic cup later becomes the cornea. During the sixth week, small folds of surface ectoderm appear cranial and caudal to the developing cornea, with a mesenchymal core (Fig. 2.16). These two folds give rise to the upper and lower eyelids. They continue to grow toward each other, until they meet and fuse together between weeks 8 and 10. They remain fused until the fifth to seventh month, at which time they separate again (Fig. 2.17). During this period, muscle cells originating from the mesenchyme begin to form the circular orbicularis muscle around the palpebral fissure.
Embryo week 4: optic vesicle formation. (a) As seen through a cutout diagram, the optic vesicle forms from an evagination from the prosencephalon. (b, c) The optic vesicle invaginates to form a bilayered optic cup. The surface ectoderm invaginates into the optic cup and separates from the surface, forming the lens placode
Embryo week 6 – eyelid formation. The upper and lower eyelids form from folds of surface ectoderm with a core of mesenchymal tissue
Embryo weeks 8–10: eyelid fusion. The eyelids meet and fuse together. While the eyelids are fused, a closed conjunctival sac exists. The eyelids separate later during the second trimester
Cryptophthalmos is a rare congenital condition caused by anomalous eyelid development. It usually occurs in association with systemic malformations, in which case the condition is referred to as Fraser syndrome . In this condition, the eyelid folds do not develop or fail to separate; the surface of the globe is covered by epithelial tissue fused to the surface, leading to underdevelopment of the cornea and microphthalmia [19, 20]. Cryptophthalmos can be partial or complete, where no eyelids can be identified.
Normal orbital development is dependent on a complex array of factors that includes normal eye development. The orbital development is influenced by the formation and normal evolution of the optic cup, and the limits of the orbital walls are determined by the optic cup. Neural crest cells migrate to surround the optic cup and ultimately give rise to the bony orbital walls. As mentioned earlier, the skull base development also has an influence on the orbital shape and size, as the sphenoid and ethmoid bones contribute to the orbital walls. The maxillary process contributes to the floor and the lateral wall. During the third month, the orbital bones become differentiated. As the face and cranium of the embryo develop, the angle between the two orbital axes as seen on an axial view begins to decrease. The orbital angle starts at 180°, reduces to 105° at 3 months GA, and is 71° around birth. It will decrease slightly more after birth until reaching the adult angle of about 68° (Fig. 2.18) .
Axial view drawing depicting the change in orbital position and convergence with increasing age
During early childhood, orbital volume increases in a linear fashion, achieving 77% of its final adult volume at around 5 years of age. There is a total increase in the size of orbital volume by a factor of 1.7–1.8 by age 15. However, the total growth of the maxillary and mandibular area overcomes that of the orbital area; hence, the eyes take up more surface area in the infant’s face as compared to that of the adult .
Orbital Bones and Fissures
The human orbit is cone shaped, with its narrow apex situated posteriorly and wider opening formed by the orbital rims situated anteriorly. There are no distinct sharp demarcations between the walls of the orbit because of variations in bony curvatures among individuals. However for practcial purposes, the bony orbit is clinically and anatomically subdivided into four walls: medial, lateral, floor, and roof. The periosteal lining of the orbit is loosely adherent to the bone and can easily be dissected off surgically, except at certain areas where it becomes tightly adherent such as bony sutures, fissures, canals, the trochlear fossa, and the optic nerve canal where it fuses with the dura of the brain. The term periorbital soft tissue refers to any soft tissue adjacent to or surrounding the orbit.
Four bones contribute to the medial orbital wall (Fig. 2.19): the frontal process of the maxilla, the lacrimal bone, the ethmoidal bone, and the lesser wing of the sphenoidal bone, listed from anterior to posterior. The lacrimal sac is situated in a deep groove in the lacrimal bone delineated anteriorly by the anterior lacrimal crest (an extension of the maxillary process) and posteriorly by the posterior lacrimal crest (part of the lacrimal bone). Posterior to the lacrimal bone is the ethmoid bone, a paper-thin bony layer overlying the ethmoidal air cells, also referred to as the lamina papyracea . The anterior and posterior ethmoidal foramina are important anatomic landmarks. The anterior and posterior ethmoidal arteries, which are branches of the ophthalmic artery, and the nasociliary nerve, enter the orbit through these foramina. They are located at the frontoethmoidal suture approximately 20 and 35 mm respectively, posterior from the anterior lacrimal crest. These foramina are believed to be the culprit in orbital cellulitis in children via hematogenous spread. The cribriform plate (horizontal plate) is located just above the frontoethmoidal suture. A fracture of the cribriform plate can result in cerebrospinal fluid leak into the nose and anosmia, or loss of the sense of smell.
Medial orbital wall
The ethmoidal-maxillary suture delineates the inferior border of the medial orbital wall and beginning of the orbital floor medially (Fig. 2.20). The orbital plate of the maxilla contributes to the majority of the orbital floor. Two other bones that contribute to the floor are the zygomatic bone and the minute orbital process of the palatine bone. The thinnest portion of the orbital floor is the posteromedial portion, which is also the roof of the maxillary sinus, where blowout fractures can result in inferior rectus muscle entrapment. The infraorbital fissure delineates the orbital floor laterally. The infraorbital groove is located medial to the infraorbital fissure and near the middle posterior surface of the orbital floor. The infraorbital canal is a continuation of the infraorbital groove as it dives into the middle of the orbital floor and serves as a conduit to the infraorbital neurovascular bundle. The infraorbital neurovascular bundle exits the canal at the infraorbital foramen along the medial side of the inferior orbital rim. Injury to the infraorbital nerve is often associated with orbital floor fractures or repairs, leading to hypoesthesia of the ipsilateral superior cheek area.
The lateral wall consists of the zygoma anteriorly and the greater wing of the sphenoid posteriorly. The superior and inferior orbital fissures demarcate the superior and inferior borders of the lateral orbital wall. They serve as a conduit for major neurovascular structures in and out of the orbit. The major nerves and vessels enter the orbit through three openings: the superior orbital fissure (SOF), the inferior orbital fissure (IOF), and the optic canal (Table 2.1). The lateral orbital wall is the thickest, making it the most resilient, which is relevant since it is the most exposed and at risk for injury. The lateral orbital tubercle is a small prominence on the orbital side of the zygoma about 3–4 mm posterior from the lateral orbital rim. It serves as an anchor for the attachments of the lateral canthal tendon, levator aponeurosis fascia, superior transverse ligament, and inferior suspensory ligament (Fig. 2.21).
Major neurovascular structures that enter/exit the orbital apex through the optic canal, the superior orbital fissure (SOF), and the inferior orbital fissure (IOF)
Cranial nerves CN III, IV, and VI
Parasympathetics to lacrimal gland
Orbital branch of middle meningeal artery
Recurrent branch of lacrimal artery
Inferior ophthalmic vein branch to pterygoid plexus
Superior orbital vein
Superior ophthalmic vein
Lateral orbital wall
The frontal bone is the main contributor to the orbital roof, with a small posterior contribution from the lesser wing of the sphenoid near the apex. Superior to the roof is the frontal sinus anteriorly and the anterior cranial fossa posteriorly. In the medial aspect of the orbital roof lies the supratrochlear notch anteriorly (a small groove) 5 mm inside of the orbital rim. The supratrochlear notch houses the trochlea, a cartilaginous ring that serves as a pulley for the superior oblique muscle as it passes through it. The trochlea is the only cartilaginous structure found within the orbit. Lateral to the supratrochlear notch is the supraorbital notch. It is closed in 25% of individuals to form the supraorbital foramen, which transmits the supraorbital nerve and vessels. Laterally in the orbital roof lies the lacrimal gland fossa, a small depression in the frontal bone that houses the orbital portion of the lacrimal gland (Fig. 2.22).