Development of the Face & Palate Flashcards
When do the pharyngeal arches begin to form?
How do they develop over the coming weeks to have a characteristic appearance?
- pharyngeal arches appear in the 4th and 5th weeks of development
- they initially consist of bars of mesenchymal tissue separated by deep clefts (pharyngeal clefts)
- with development of numerous arches and clefts, a number of outpocketings called pharyngeal pouches begin to appear along the lateral walls of the pharynx
What is significant about the contents of each pharyngeal arch?
- each pharyngeal arch is characterised by its own muscular components
- the muscular components of each arch have their own cranial nerve, and they carry this nerve component wherever they migrate
- each arch also has its own arterial component
How do the pharyngeal arches contribute to formation of the face at the end of the 4th week?
What 5 mesenchymal prominences can be recognised by day 42?
End of week 4:
- the centre of the face is formed by the stomodeum surrounded by the first pair of pharyngeal arches
By day 42:
- there are 5 mesenchymal prominences now visible:
- mandibular prominences (1st pharyngeal arch) caudal to the stomodeum
- maxillary prominences (dorsal portion of 1st pharyngeal arch) lateral to the stomodeum
- frontonasal prominence that is a rounded elevation cranial to the stomodeum
What is the composition of each pharyngeal arch?
- each pharyngeal arch consists of a core of mesenchyme
- this core consists of mesenchyme derived from paraxial and lateral plate mesoderm, as well as substantial numbers of neural crest cells (NCCs)
- NCCs migrate into the arches to contribute to skeletal components of the face
- each arch is covered on the outside by surface ectoderm** and on the inside by **epithelium of endodermal origin
What is formed by the mesenchymal core and NCCs of each pharyngeal arch?
- the original mesoderm of the arches gives rise to the musculature of the face and neck
- the NCCs give rise to viscerocranium (facial skeleton) of the face
How many pharyngeal arches are present?
- the pharyngeal arches are 1, 2, 3, 4 and 6
- the 5th pharyngeal arch is rudimental and transient and quickly regresses so it can no longer be seen
What muscles arise from the first pharyngeal arch?
What is their nerve supply?
- muscles of mastication (temporalis, masseter, pterygoids)
- anterior belly of digastric
- mylohyoid
- tensor tympani
- tensor palatini
- all of these muscles are supplied by the mandibular branch of the trigeminal nerve
What group of muscles form from the second pharyngeal arch?
What is their nerve supply?
- muscles of facial expression
- the facial nerve supplies all the muscles derived from the second arch
How many pharyngeal clefts are present in the 5-week embryo?
Which structures are formed from these clefts and how do they develop?
- there are 4 pharyngeal clefts in the 5-week embryo
- only the first pharyngeal cleft goes on to form any adult structures - the external acoustic meatus
- the second pharyngeal cleft ectoderm grows caudally to cover the rest of the clefts
What are pharyngeal pouches and how many are present?
When does formation of these pouches occur?
- there are 4 pairs of pharyngeal pouches that form prior to NCC migration
- they are epithelial endodermal structures that form on the inside of the pharynx, between the arches
- they are formed by migration of endodermal cells laterally**, which is stimulated by **FGFs
What is signalling from pouch endoderm important for?
- signalling from pouch endoderm is important in the regulation of skeletal patterning
- it was previously thought that NCCs within the core of the arches were responsible for this as they form the skeletal components
- Formation of pharyngeal pouches occurs prior to NCC migration and even takes place in the absence of crest cells
Where do the NCCs that migrate into the core of the pharyngeal arches originate from?
What transition must they undergo and what factors are important in ensuring this happens?
- NCCs originate from neuroepithelial cells adjacent to the surface ectoderm all along the edges of the neural folds
- BMP signalling is important in establishing this edge region
- BMP signalling then regulates WNT expression** to cause NCCs to undergo an **epithelial-to-mesenchymal transition
- this allows them to begin their migration into the surrounding mesenchyme
How are pharyngeal pouches formed?
What factor is important in this process?
- pharyngeal pouches are formed by migration of endoderm cells laterally
- this migration is stimulated by fibroblast growth factors (FGFs)
What expression of genes is exhibited by pharyngeal pouches as they form?
- BMP7** is expressed in the **posterior endoderm of each pouch
- FGF8 is expressed in the anterior endoderm of each pouch
- PAX1 is restricted to the dorsalmost endoderm of each pouch
- SHH is expressed in the posterior endoderm of the 2nd and 3rd pouches
What is the significance of the characterisitc pattern of gene expression of the pharyngeal arches?
What is this process dependent upon?
- the highly specific expression of genes within each pharyngeal pouch regulates differentiation and patterning of pharyngeal arch mesenchyme into specific skeletal structures
- this process is dependent on the mesenchyme, so is an example of an epithelial-mesenchymal interaction
What transcription factors are present in the mesenchymal core?
How is this different between the arches?
- transcription factors within the arches include HOX genes and others that are carried there by the NCCs
- NCCs acquire their specific gene expression from the primitive brain regions that they originate from
- Different arches have different patterns of HOX gene expression within the mesenchyme
- NCCs travelling to the arches have originated from different primitive brain regions
What is the epithelial-mesenchymal interaction involved in skeletal patterning?
- the pouch endoderm signals to the mesenchymal core to begin to express transcription factors (incl. HOX genes)
- as HOX gene expression is different in each arch, the interaction between the mesenchyme and the endoderm is different in each arch
- different expression patterns of transcription factors allow each arch to respond differently to the signals emanating from pouch endoderm
- this ultimately gives rise to different structures from each arch
What is formed by the neural crest and mesenchyme within the frontonasal prominence?
What factors are important in this process?
- the upper facial skeleton is derived from NCCs that migrate into the frontonasal prominence
- signals emanating from the surface ectoderm and underlying areas of neuroepithelium dictate the fate of the mesenchyme
- SHH & FGF8 have major roles in patterning this area, but specific genetic interactions are not known
Which of the 3 facial prominences are formed by the 1st pharyngeal arch?
- both the maxillary and mandibular prominences are formed by the 1st pharyngeal arch
- the frontonasal prominence is formed by proliferation of mesenchyme located ventral to the developing brain vesicles
How can the 3 facial prominences appearing in the 4th week be distinguished from each other?
- the maxillary prominences are located lateral to the stomodeum
- the mandibular prominences are located caudal to the stomodeum
- the frontonasal prominence constitutes the upper border of the stomodeum
What are the 5 facial prominences mainly derived from?
- the mesenchyme of the facial prominences is primarily derived from NCCs
- this will go on to form bone, facial cartilage and ligaments
- the mesenchymal core proliferates and rapidly increases in size
- as the maxillary and mandibular processes increase in size, they begin to push other structures together
What do local thickenings near the frontonasal prominence go on to form?
- on both sides of the frontonasal prominence, local thickenings of surface ectoderm form the nasal placodes
- during week 5, the nasal placodes invaginate to form nasal pits
- this creates a ridge of tissue that surrounds each pit and forms the nasal prominences
- the prominences on the outer edge of the pits are the lateral nasal prominences
- the prominences on the inner edge of the pits are the medial nasal prominences
Following the formation of the medial and lateral nasal prominences, what happens to the maxillary prominences?
- over the next 2 weeks, the maxillary prominences continue to increase in size
- they simultaneously grow medially to push the medial nasal prominences toward the midline
- the cleft between the medial nasal prominence and the maxillary prominence on each side is lost and they fuse together
- the upper lip is formed from the 2 medial nasal prominences and the 2 maxillary prominences
- the lateral nasal prominences do not participate in formation of the upper lip
How is the nasolacrimal duct formed?
- initially, the maxillary prominences and the lateral nasal prominences are separated by a deep furrow - the nasolacrimal groove
- ectoderm in the floor of the nasolacrimal groove forms a solid epithelial cord that detaches from the overlying ectoderm
- the cord canalises to form the nasolacrimal duct
- its upper end widens to form the lacrimal sac
What happens following detachment of the nasolacrimal duct?
Where does this duct run to and from?
- the maxillary and lateral nasal prominences merge with each other after detachment of the nasolacrimal duct
- the duct then runs from the medial corner of the eye to the inferior meatus of the nasal cavity
- the maxillary prominences enlarge to form the cheeks** and **maxillae
What forms the intermaxillary segment?
What is it continuous with?
- as a result of medial growth of the maxillary prominences, the 2 medial nasal prominences merge not only at the surface but at a deeper level
- the structure formed by the 2 merged medial nasal prominences is the intermaxillary segment
- the intermaxillary segment is continuous with the rostral portion of the nasal septum (formed by the frontal prominence)
What are the 3 parts of the intermaxillary segment?
Labial part:
- forms the philtrum of the upper lip
Upper jaw:
- gives rise to the 4 incisor teeth
Palatal part:
- gives rise to the triangular primary palate
How is the secondary palate formed and what is it formed from?
When does this formation occur?
- the definitive palate is formed from 2 shelf-like outgrowths from the maxillary prominences - the palatine shelves
- the palatine shelves appear in the 6th week and are directed obliquely downwards on either side of the tongue
- in week 7, the palatine shelves ascend to attain a horizontal position above the tongue
- the 2 palatine shelves fuse to form the secondary palate
How is the definitive palate formed?
What delineates the primary and secondary palates?
- the definitive palate is formed when the secondary palate (from palatine shelves) fuses with the primary palate (from intermaxillary segment)
- the incisive foramen delineates where the primary palate fuses with the secondary palate
- at the same time as this fusion, the nasal septum grows down to join with the cephalic aspect of the newly formed palate
Why does abnormal facial development usually occur?
What usually occurs alongside this?
- it occurs as a result of disruption of neural crest cells
- NCCs are essential for formation of much of the craniofacial region, so their disruption results in craniofacial abnormalities
- NCCs also contribute to the conotruncal endocardial cushions, which septate the outflow tract of the heart into pulmonary and aortic channels
- this means infants with craniofacial abnormalities often also have cardiac abnormalities
- e.g. tetralogy of Fallot, persistent truncus arteriosus, transposition of the great vessels
What is the triad associated with Robin sequence?
What type of syndrome is this?
- micrognathia (small oral opening)
- cleft palate
- glossoptosis (posteriorly placed tongue)
- it is a form of “first arch syndrome” that most severely affects the mandible
- poor growth of the mandible results in a posteriorly placed tongue that fails to drop from between the palatal shelves, preventing their fusion
What can cause Robin sequence?
- it can occur independently or in association with other syndromes
- it can be due to genetic or environmental factors
- it can also be caused by a deformation, such as oligohydramnios, in which the chin may be compressed against the chest
What causes Treacher-Collins syndrome (mandibulofacial dystosis)?
- it is a rare autosomal dominant condition
- 60% of cases arise as new mutations
- it is caused by a mutation in the TCOF1 gene
- the product of the TCOF1 gene is a protein called treacle, which prevents apoptosis and maintains proliferation in NCCs
- treacle is not responsible for regulating migration of NCCs as this still happens normally
Why do the roles of the treacle protein reflect the presentation of mandibulofacial dystosis?
- treacle is needed to prevent apoptosis and maintain proliferation of NCCs
- the NCCs still migrate to the relevant areas, but they do not differentiate properly and undergo apoptosis before they can develop
- this results in insufficient tissue being present to develop all of the relevant facial structures
What possible environmental factor could be associated with Treacher-Collins syndrome?
- the majority of cases are genetic
- teratogenic doses of retinoic acid may also be responsible
What are the main characteristic features of Treacher-Collins syndrome?
- it is characterised by hypoplasia of the maxilla, mandible and zygomatic arches (which may be absent)
- the TMJ is badly affected and is positioned in the wrong location
What are other presentations that are commonly seen in Treacher-Collins syndrome?
- cleft palate is common (as well as other features of Robin sequence)
-
external ear defects accompanied by atresia of the auditory canals and abnormalities of the middle ear ossicles
- bilateral conductive hearing loss is often present as a result
- eyes are usually involved in down-slanting palpebral fissures and lower eyelid colobomas
What causes DiGeorge syndrome?
- it is a common deletion syndrome caused by a microdeletion in the q11.2 region of chromosome 22 (22q11.2 deletion syndrome)
- it occurs due to a genetic malformation of the NCCs, which contribute to the mesenchyme
- the mesenchyme forms the connective tissue of glands and interacts with endodermal cells
- these endodermal cells form the cells of the thymus and parathyroid glands
What is the triad of symptoms associated with DiGeorge syndrome?
- shortened philtrum
- low set ears
- nasal clefts
What are some other associations of DiGeorge syndrome?
- absent thymus & parathyroid glands
- defective T-cell function
- cardiac abnormalities
- facial dysmorphology (tends to be mild - smaller mouth)
- learning disabilities
Why are an absent thymus & parathyroid glands seen in DiGeorge syndrome?
What are the consequences?
- these fail to develop from the 3rd and 4th pharyngeal pouches
- this leads to congenital hypoparathyroidism, which presents as seizures
- it is caused by disruptive signalling between the pharyngeal endoderm and the NCCs
Why does defective T-cell function occur in DiGeorge syndrome?
What is this associated with?
- thymic hypoplasia / aplasia disrupts the immune system’s T-cell mediated response
- the thymus gland is important for the immune response in children
- this presents with frequent infections
Why might there be abnormal midline craniofacial development?
What signalling factor may be implicated?
- this occurs when there is insufficient midline tissue early on in development (during gastrulation)
- this results in underdevelopment of the forebrain and frontonasal prominence
- SHH is important for development of midline structures
What are the 3 most common causes of midline disorders?
- SHH mutations
- maternal diabetes
- alcohol
- there is not enough tissue present in the midline to form all of the structures that should be present
What are the characteristics of the most severe midline disorder (holoprosencephaly)?
- medial nasal prominences do not form due to insufficient tissue
- the lateral nasal prominences fuse to form a proboscis with a single midline opening
- narrow head
- fusion of the eyes (synophthalmia)
- the upper lip is formed by the fusion of the maxillary prominences
- there is a single midline brain ventricle formed by the fusion of the lateral ventricles
What are the 3 types of orofacial clefts?
- lip only (CLO)
- lip + palate (CLP)
- palate only
- all of these can be unilateral or bilateral
- midline and oblique clefts can occur, but these are much less common
How can orofacial clefts be divided into anterior and posterior deformities?
- the incisive foramen is the dividing landmark between anterior and posterior deformities
- the incisive foramen is the midline landmark between the primary and secondary palates
What are examples of an anterior cleft deformity?
What is the underlying cause of this?
- anterior deformities are those occurring anterior to the incisive foramen, such as:
- cleft lip (unilateral or bilateral)
- cleft jaw
- cleft between primary and secondary palates
- these defects occur due to partial or complete lack of fusion of the maxillary prominence with the medial nasal prominence on one or both sides
What are examples of posterior cleft deformities?
What is the underlying cause?
- posterior clefts are those that lie posterior to the incisive foramen, such as
- cleft uvula
- cleft secondary palate
- these result from failed fusion of the palatine shelves, which may be due to:
- shelves are too small
- shelves fail to elevate
- inhibition of the fusion process itself
- failure of the tongue to drop between the shelves due to micrognathia
What is the third type of cleft that can occur?
- it is possible to have a combination of both anterior and posterior clefts
What is the underlying process that results in unilateral and bilateral cleft lips?
How is it treated?
Unilateral cleft lip:
- occurs when the maxillary prominence fails to fuse with the merged medial nasal prominences
Bilateral cleft lip:
- occurs when there is failure of the BOTH maxillary prominences to fuse with the merged medial nasal prominences
- treatment for cleft lip is performed by 3 months and tends to have positive results
What are the 4 main causes of cleft lip +/- palate?
What are the ethnic differences in the presentation of this condition?
- syndromic (e.g. Van der Woude syndrome)
- related to genetics but not syndromic
- non-syndromic
- teratogen exposure - smoking, anti-epileptics, benzos & rubella
- has a male predominance and incidence is higher in Asians & Native Americans
What is Van der Woude syndrome and why does it occur?
- it is the most common syndrome that is associated with cleft lip +/- palate
- it is an autosomal dominant disorder that occurs due to mutations in INTERFERON REGULATORY FACTOR 6 (IRF6)
- IRF6 is expressed in the medial (fusing) edge of the palatal shelves
Why do oblique facial clefts occur?
- due to failure of the maxillary prominence to merge with its corresponding lateral nasal prominence along the line of the nasolacrimal duct
- the nasolacrimal duct is usually exposed to the surface
What are the problems associated with cleft lip and palate?
- difficulty feeding can lead to poor weight gain / failure to thrive
- aspiration pneumonia
- hearing problems
- speech problems
- dental problems (incisor teeth cannot form if intermaxillary segment is affected)
- cosmesis
