Lecture 11: Development of the face, lip, palate and related birth defects

What are facial prominences?

Bulges of epithelium-covered mesenchyme that form in the presumptive facial region of an embryo

What two structures make up the facial prominences overall?

Frontonasal mass (FNM) + 1st pharyngeal arch (PA1)

What is PA1 also known as, and what does it consist of?

Also called BA1 (first branchial arch); consists of the maxillary arch (mxPA1) + mandibular arch (mdPA1)

What two prominences make up the frontonasal mass (FNM)?

Lateral nasal prominence (LNP) + medial nasal prominence (MNP)

By the end of which week do 5 facial prominences surround the stomodeum?

4th week

What are the 5 facial prominences surrounding the stomodeum?

Frontonasal prominence (FNP), a pair of maxillary prominences (MXP), a pair of mandibular prominences (MDP)

What forms on the frontonasal prominence?

A pair of nasal placodes

What does the medial nasal prominence give rise to?

Philtrum, bridge and tip of the nose, medial portion of the upper lip, upper incisors, primary palate

What does the lateral nasal prominence give rise to?

Alae of the nose

What does the maxillary prominence give rise to?

Upper jaw including cheeks, lateral portion of the upper lip, upper canines, upper premolars, upper molars, secondary palate

What does the mandibular prominence give rise to?

Lower lip, chin, lower jaw, all the lower teeth, tongue

What happens to the nasal placode during midface development?

It invaginates to become the nasal pit

What happens as the maxillary prominence grows medially?

It compresses the medial nasal prominence

What two prominences fuse to form the upper lip?

Medial nasal prominence and maxillary prominence

Does the lateral nasal prominence participate in lip formation?

No, the lateral nasal prominence does NOT participate in lip development

How does the lower lip form?

From fusion of the two mandibular prominences

What is the nasolacrimal groove and where is it located?

A groove between the lateral nasal and maxillary prominences; gives rise to the lacrimal sac and nasolacrimal duct (eye-to-nose connection)

What structure forms from fusion of the two medial nasal prominences (outer part)?

The middle part of the nose (bridge/tip) and part of the nostrils

How is the epithelial seam removed during fusion of the MNP and MXP to form the upper lip?

By apoptosis and epithelium-to-mesenchyme transition

What is the intermaxillary segment and how does it form?

It forms from the fusion of the two medial nasal prominences (inner part)

What does the intermaxillary segment give rise to?

The philtrum, middle part of the upper lip, primary palate (with the premaxilla - middle part of the maxilla), and upper incisors

How does the secondary palate form?

From fusion of the palatal shelves - outgrowths on the medial side of the maxillary arches

What are the 6 stages of secondary palate development, in order?

1) Formation of palatal shelves, 2) Vertical growth, 3) Elevation, 4) Horizontal growth, 5) Adhesion, 6) Fusion

Where do palatal shelves initially grow, and in what direction?

From the maxillary arches, initially growing downward on either side of the tongue

What signaling molecules are essential in palatal shelf formation/growth?

FGF (fibroblast growth factor), BMP (bone morphogenetic protein), SHH (sonic hedgehog)

What happens during "elevation" of the secondary palate?

The palatal shelves elevate above the tongue to a horizontal position and continue to grow

What is the medial epithelial seam (MES)?

The seam formed when the palatal shelves meet at the midline and adhere to each other

What growth factor is required for adhesion (removal of the periderm) during secondary palate fusion?

TGFβ3 (transforming growth factor beta 3)

What happens if TGFβ3 is knocked out (Tgfβ3-/-)?

The palatal shelves fail to fuse, resulting in a cleft palate

What 4 mechanisms remove the medial epithelial seam (MES) during fusion?

Apoptosis, extrusion, epithelium-to-mesenchyme transition, intra-epithelial migration

What does the fused secondary palate connect to anteriorly and dorsally?

Fuses with the primary palate anteriorly, and with the nasal septum dorsally

When does ossification of the palate begin, and by what process?

Around 8 weeks, by intramembranous ossification

What does the primary palate ossify into?

Hard palate (premaxilla part of the maxilla)

What does the secondary palate ossify into?

Hard palate (maxilla, palatine) + soft palate

What causes (oro)facial clefts (cleft lip and cleft palate)?

Partial or complete lack of fusion between the facial prominences

What is the incidence of orofacial clefts, and how does it vary?

1 in ~700 births; frequency varies by race/ethnicity/gender - Native Americans and Asians > Caucasians > Africans

What are the major ways to categorize orofacial clefts?

CL/P (cleft lip with or without cleft palate) vs. CPO (cleft palate only); isolated (nonsyndromic) vs. syndromic; unilateral vs. bilateral; complete vs. incomplete; overt vs. submucous

What causes CL/P (cleft lip with or without cleft palate)?

Lack of fusion between the medial nasal and maxillary prominences

What causes CPO (cleft palate only, secondary palate)?

Lack of fusion between the palatal shelves

What causes a midline cleft of the mandible?

Lack of fusion between the two mandibular prominences

What causes a median cleft of the upper lip/nose (Frontonasal Dysplasia)?

Lack of fusion between the medial nasal prominences

What causes an oblique facial cleft?

Lack of fusion between the maxillary and lateral nasal prominences

What are the general developmental mechanisms behind orofacial clefting?

Prominences/palatal shelves deficient in shape or size and fail to make contact; prominences make contact but fail to adhere; prominences adhere but the epithelial seam is not removed; tongue interferes with elevation of the palatal shelves (as in Pierre Robin sequence)

Name several genes associated with CL/P in humans.

TBX22, IRF6, MSX1, PVRL1, P63, CDH1, EFNB1, TGFB3, among many others

What is the general genetic model for orofacial clefting risk?

Interaction of many genes of small effect can produce significant phenotypic deficiencies (multifactorial/polygenic)

What environmental factors contribute to orofacial clefting?

Nutrition and teratogens (alcohol, smoking, certain medications)