L66. Embryology - Development of the Pharyngeal Apparatus & Face

• Pharyngeal apparatus forms bulges along the foregut (pharynx) in the neck region of a 4-week embryo.
• Pharyngeal grooves are on the surface between the arches.
• Pharyngeal pouches are outpocketings of the pharyngeal endoderm and are on the inside of the grooves.
• The arches, grooves, and pouches make up the pharyngeal apparatus.
• Bulges reflect brainstem segmentation (rhombomeres) via homeotic gene expression.
• Bulges are transient (~weeks 4-8) but contribute to face and neck development.
• Pharyngeal arch development defects can cause clinical problems in newborns.
• Pharyngeal arches are numbered 1-6, cranially to caudally; arches 4 and 6 tend to fuse, and there is no arch 5 in humans.
• Pharyngeal arches bulge into the pharynx, creating a doughnut/bagel-like structure.
• Each pharyngeal arch has an artery (aortic arch), a muscle component (from paraxial mesoderm), a skeletal component (cartilage mainly from neural crest), and a nerve component.
• Neural crest significantly contributes to the mesenchyme of the arches (especially 1-3) and skeletal component formation.
• Pharyngeal clefts are ectodermal indentations separating each arch, numbered according to the arch rostral to them.
• Pharyngeal pouches are endodermal bulges inside the pharynx, aligned with the clefts, separated by the pharyngeal membrane.
• Structures from pharyngeal arches/clefts/pouches are important for anatomy and neuroscience.

Pharyngeal Arches and Derivatives

• The first pharyngeal arch, also known as the "Mandibular arch", has two subdivisions (prominences), which together form a large part of the skeleton of the lower face.

First Pharyngeal Arch

• The cranial component forms the maxillary prominence and the caudal component forms the mandibular prominence.
• These two prominences partially outline the primitive mouth (stomodeum).

First Arch Derivatives

• Derivatives include Muscles of mastication, tensor tympani, mylohyoid, ant. belly of digastric, tensor palatini.
• Skeletal components contribute to the carilaginous viscerocranium via endochondral ossification (EO) of the incus and malleus of the middle ear ossicles.
• The remainder of the manidibular cartilage is only transiently present to reinforce the mandibular and maxillary primordia.
• Most of rest of the bones (membranous viscerocranium) form by intramembranous ossification (IO).
• Skeletal elements are palatine, maxilla, mandible, zygomatic arch and part of the temporal bone.
• The trigeminal nerve (CN V) provides sensory and motor innervation.

Second Pharyngeal Arch

• It is also known as the "Hyoid Arch".
• Muscles of facial expression, stapedius, posterior belly of digastric, stylohyoid originate here.
• Skeletal elements are part of the cartilagenous viscerocranium (all EO): stapes, styloid process of temporal bone, stylohyoid ligament, lesser horn and upper part of body of the hyoid bone.
• Innervated by the facial nerve (CN VII).

Third Pharyngeal Arch

• Muscles: stylopharyngeus m.
• Skeletal: Lower part of the body and greater horn of the hyoid (EO)
• Nerve: Glossopharyngeal nerve (CN IX)

Fourth (and sixth) pharyngeal arches

• Muscles: Both arches contribute to the pharyngeal constrictors and intrinsic muscles of the larynx.
• Skeletal: Laryngeal cartilages
• Nerve: Vagus nerve (CN X) – pharyngeal and superior laryngeal branches (arch 4); recurrent laryngeal branch to larynx (arch 6).

Pharyngeal Pouches

• First pouch elongates to form the auditory tube, middle ear epithelium, and inner surface of the tympanic membrane.
• Note that the tympanic membrane is a pharyngeal membrane with contributions from both endoderm and ectoderm.
• Second pouch forms epithelium of palatine tonsils.
• Third pouch has dorsal and ventral portions.
• The dorsal portion forms the inferior parathyroid gland and the ventral portion forms the thymus.
• Thymus migrates caudally and guides the inferior parathyroid gland to a location inferior to the superior parathyroid gland.
• Pouch endodermal epithelial cells form the thymic epithelioreticular stroma.
• Fourth pouch has dorsal and ventral portions.
• The dorsal portion forms the superior parathyroid gland.
• The ventral portion forms Parafollicular cells of the thyroid, with origin possibly from the neural crest.

Pharyngeal Clefts (Grooves)

• First cleft elongates to form the external auditory meatus and outer lining of the tympanic membrane.
• The external ear forms from auricular hillocks derived from pharyngeal arches 1 and 2.
• Clefts 2-4: Arch 2 grows caudally and covers these spaces, forming the cervical sinus that disappears, smoothing the neck contours.

Clinical Correlations

• Arch 1 syndrome (Treacher Collins syndrome): Small lower jaw, facial defects, malformed ears due to defect in neural crest formation to arch 1. A genetic defect but can be from retinoic acid.
• Di George anomaly: Involves pouches 3 & 4, leading to immune deficiency, hypocalcemia, and heart vessel deformities due to neural crest migration defects.
• Cervical cysts: Cysts and fistulas infrequently remain from the cervical sinus, located laterally, usually anterior to the sternocleidomastoid muscle.

Tongue Development

• At 4 weeks, the tongue has two lateral lingual swellings (arch 1), a median lingual swelling (tuberculum impar, arch 1), a copula (arch 2), and a hypopharyngeal eminence (arch 3 and 4).
• Foramen cecum marks the boundary of the tuberculum impar and the copula/hypobranchial eminence.
• The two lateral swellings increase, fuse, and overgrow the tuberculum impar, forming the anterior 2/3 of the tongue, receiving general sensory innervations via CN V (lingual branch).
• Taste buds are innervated by CN VII (chorda tympani).
• Hypobranchial eminence expands from arch 3 contributions overgrowing arch 2 tissue (copula) to form the posterior 1/3 of tongue.
• It is separated from the anterior 2/3 by the sulcus terminalis.
• Taste buds (circumvallate papillae) are innervated by CN IX; posterior 1/3 of tongue receives general sensory via CN IX.
• The epiglottis forms from arch 4.
• General sensation and taste innervation mediated is by CN X.
• The tongue muscles come from myoblasts migrating from the second to fifth occipital somites innervated by the hypoglossal nerve (CN XII).

Clinical Correlations

• Ankyloglossia: Tongue remains attached to the mouth floor if the frenulum extends to the tongue tip (tongue-tied).
• Bifid tongue: Failure of the lateral tongue swellings to fuse.
• The Thyroid Gland begins as columnar cell proliferation in the floor of the pharynx between Arches 1 and 2 that becomes a diverticulum.
• The thyroid diverticulum elongates inferiorly and anterior to the pharynx along the midline, passing anterior to the hyoid bone and laryngeal cartilages until reaching the trachea.
• During migration, the thyroid maintains contact with the tongue through the thyroglossal duct. The duct later degenerates leaving the foramen cecum as a landmark.

Clinical Correlations

• Thyroglossal cysts: Remnants of the thyroglossal duct that do not degenerate form cysts that can occur anywhere along the midline thyroid migration, but mostly are just inferior to the body of the hyoid bone.
• Aberrant thyroid tissue: Can be found anywhere along the migratory route of the thyroid close to the foramen cecum.
• Congenital (infantile) hypothyroidism (cretinism): Congenital thyroid deficiency that leads to retarded growth and mental retardation. Newborns are tested for thyroid hormone levels.
• The primitive mouth, or stomodeum, is lined with ectoderm.
• It extends inward to the buccopharyngeal membrane.
• The pharynx, part of the foregut, begins at the buccopharyngeal membrane and is lined by endoderm.
• Rathke's Pouch is a diverticulum of the stomodeum roof that extends to a downgrowth of the overlying diencephalon, the infundibulum.
• The diverticulum separates from the oral cavity to form a hollow ball of cells that contacts the anterior part of the infundibulum.
• The ball of cells becomes the adenohypophysis, while the infundibulum becomes the neurohypophysis.
• Salivary glands are submandibular and sublingual glands, which develop from ingrowths of the ventral stomodeum ectoderm.
• The parotid gland develops from an ingrowth of the pharynx endoderm.
• At week 4, the face is composed of 5 prominences surrounding the primitive mouth (stomodeum): a midline frontonasal prominence cranially, two maxillary prominences laterally, and two mandibular prominences cranially.
• The maxillary and mandibular prominences are derived from arch 1.

Face Development

• Laterally, nasal placodes, aggregates of placodal ectoderm cells, are on the frontonasal prominence.
• The changing shape is largely due to neural crest/mesenchyme underlying migration and proliferation.
• The lateral nasal prominence meets the maxillary prominence and forms the nasolacrimal groove, from the eye to the stomodeum. The nasolacrimal duct then widens dorsally as the lacrimal sac.
• The medial nasal prominences enlarge and fuse medially (~7 weeks) to form the intermaxillary segment.

Intermaxillary Segment

• The labial component is the philtrum of the lip.
• The part included is the upper jaw and gum containing the 4 incisor teeth.
• The palatal component produces the triangular primary palate
• At the meeting point of the medial nasal prominence and maxillary prominence, the temporary cleft normally obliterates by their fusion
• The upper lip forms laterally by the two maxillary prominences and medially by the merged medial nasal prominences (philtrum).
• The lower lip is formed by the merged mandibular prominences.
• The cheek is formed from the maxillary prominence.
• The chin and mandible are formed by the merging of the mandibular prominences
• The primary palate also makes a small but important contribution to the entire palate.
• The remaining palate derives from an outgrowth of the maxillary prominence, the palatine shelves.
• These shelves initially grow downward alongside the tongue during the 6th week.
• The shelves reorient their growth horizontally, above the tongue, and fuse with the primary palate during the 7th week. As they continue to grow medially they fuse to form the secondary palate (7th to 8th wks). The junction of the primary and secondary palate remains as the incisive foramen
• As the palatal shelves fuse, the downward-growing nasal septum also fuses with them along the midline.
• The uvula is formed on the posterior midline.

Clinical Correlations

• Lateral cleft lip (and jaw) - failure of fusion between medial nasal prominence and maxillary prominence (1/1,000), located anterior to the incisive foramen.
• These result from insufficient neural crest cells migrating, and this class of defects is multifactorial.
• Median cleft lip: Failure of the two medial nasal prominences merging (rare).
• Oblique facial cleft: Failure of merging of maxillary prominence with the lateral nasal prominence (rare).
• The cleft secondary palate (or cleft uvula) is the failure of the fusion of the palatine shelves (1/2,500). This is posterior to incisive foramen
• Clefts of the secondary palate can occur with or without cleft lip or clefts between the maxilla and primary palate. Anticonvulsant drugs increase the occurrence of cleft secondary palate.
• Nasal Cavities form as the nasal pits sink deeper into the face toward the pharynx
• Connective tissue forms the nasal septum, and a thin layer of connective tissue is temporarily found between the pits and the oral cavity that form the oronasal membrane
• The oronasal membrane quickly breaks down to form the primitive choana.
• The nasal cavity walls expand to form the nasal conchae
• As the palatal shelves fuse and the overlying nasal septum continues, the choanae are displaced posteriorly to form the definitive choanae
• Paranasal air sinuses develop as outpouchings of the lateral wall of the nasal cavities and take place after birth until puberty, producing the mature facial appearance.

Pharyngeal arches develop as bulges along the foregut in a 4-week embryo, contributing to face and neck formation. These arches, grooves, and pouches consist of arteries, muscles, skeletal components, and nerves. Defects in pharyngeal arch development can lead to clinical issues in newborns.