Face, Lip & Palate Development and Orofacial Clefts – Comprehensive Study Notes

Page 1 – Objectives

• Identify:
  • Facial prominences (bulges of epithelium-covered mesenchyme)
  • Morphogenetic processes leading to the formation of the face, lip and palate.
• Describe different types of clefts in face, lip and palate.

Page 2 – Lecture Scope

• Two broad themes:
  1. Development of the Face, Lip & Palate (normal embryology).
  2. (Oro)facial clefts (pathology & birth-defect spectrum).

Page 3 – Facial Prominences: Names & Origins

• Definition: Transient mesenchymal bulges covered by ectoderm, visible in presumptive facial region of embryo.
• Components
  • Frontonasal mass (FNM) – midline craniofacial tissue.
    • Sub-divides into Lateral Nasal Prominence (LNP) & Medial Nasal Prominence (MNP).
  • First Pharyngeal Arch (PA1, aka BA1) – paired structure.
    • Maxillary Arch (mxPA1, future upper jaw).
    • Mandibular Arch (mdPA1, future lower jaw).
• Developmental timing: Human wk 4–5.
• Visual mnemonic: 5 "petals" around primitive mouth (stomodeum).

Page 4 – Arrangement at End of 4ᵗʰ Week

• Five prominences encircle the stomodeum:
  1. Frontonasal Prominence (FNP).
  2. Pair of Maxillary Prominences (MXP).
  3. Pair of Mandibular Prominences (MDP).
• Nasal placodes emerge on FNP (ectodermal thickenings that will invaginate).
• Weeks & morphology snapshots: 4.0 wk → 4.5 wk.

Page 5 – Prominence Contributions (Final Adult Structures)

Page 6 – Growth, Morphogenesis & Differentiation

• Week 5 → birth: continuous expansion, migration & fusion of prominences.
• Underlying mechanisms: proliferation, ECM remodeling, neural-crest cell differentiation.
• Animated embryology resources (Hill 2016) illustrate cell-lineage movements.

Page 7 – Early Mid-face Dynamics

• Nasal placodes invaginate forming nasal pits.
• Emergent prominences: Lateral Nasal & Medial Nasal flank each pit.
• Maxillary prominences grow medially, compressing MNPs toward midline.

Page 8 – Lip Formation & Nasolacrimal Groove

• Weeks 7–10 sequence:
  1. Two MNPs fuse in the midline.
  2. MNP complex fuses with each MXP → definitive upper lip.
  3. LNPs do NOT contribute to lip tissue.
  4. Lower lip formed by fusion of paired MDPs.
• Nasolacrimal groove (between LNP & MXP) → lacrimal sac & nasolacrimal duct (eye–nose tear drainage).

Page 9 – Mid-face Anatomy Snapshots (5 → 6 wk)

• Labels: frontal prominence, MNP, LNP, nasal pit, MXP, MDP.
• Demonstrates progressive medial migration and enlargement of MXP relative to nasal structures.

Page 10 – Mid-face Anatomy Snapshots (7 wk)

• Clear depiction of positional relationships: eye, external ear, fused mandibular prominence, etc.

Page 11 – Fusion Mechanism (Upper Lip)

• Fusion of MNP & MXP creates epithelial seam.
• Seam removal via:
  1. Programmed cell death (apoptosis).
  2. Epithelial-to-mesenchyme transition (EMT) → cells integrate with mesenchyme.
• Timing: ~5–7 wk human.

Page 12 – Development of the Nose

• Middle nose (bridge → tip) derives from MNP (outer portions).
• Alae derive from LNP.
• Nasolacrimal duct path becomes distinct.

Page 13 – Primary Palate (aka Intermaxillary Segment)

• Source: fusion of inner parts of paired MNPs (distinct from outer parts forming nose).
• Gives rise to:
  • Philtrum.
  • Median upper lip.
  • Primary (premaxillary) palate – anterior to incisive foramen.
  • Segment of maxilla bearing upper incisors.

Page 14 – Secondary Palate

• Origin: palatal shelves – medial outgrowths from maxillary arches.
• Eventually forms majority of hard palate + entire soft palate.
• Posterior growth relative to primary palate.

Page 15 – Secondary Palate Stages (Mouse ⇒ parallels human)

1. Shelf formation (P).
2. Vertical elongation (downward beside tongue).
3. Elevation (flip to horizontal).
4. Horizontal outgrowth toward midline.
5. Fusion & seam disappearance.

• Human timing: ≈ 6 wk (formation) → 10 wk (fusion).

Page 16 – Vertical Growth Phase (6.5 wk)

• Palatal shelves grow downward on both sides of developing tongue; tongue occupies nasal/oral cavity preventing premature fusion.

Page 17 – Elevation Phase (7–8 wk)

• Rapid "flip" above tongue into horizontal plane.
• Requires:
  • Intrinsic shelf forces (ECM hydration, actin-myosin).
  • Space created by tongue descent & mandibular growth.

Page 18 – Fusion Phase (≈10 wk)

• Palatal shelves contact → medial epithelial seam (MES).
• MES breakdown by apoptosis & EMT → complete mesenchymal continuity.
• Anterior fusion with primary palate; dorsal fusion with nasal septum.

Page 19 – Fate of MES Cells

• Two fates demonstrated by lineage tracing:
  1. Displacement/extrusion to oral & nasal surfaces.
  2. Apoptosis (programmed cell death) within seam.

Page 20 – Palatal Ossification

• Primary palate ossifies into hard palate exclusively.
• Secondary palate ossifies anteriorly (hard palate) but remains muscular posteriorly (soft palate, uvula).

Page 21 – Transition to Pathology Segment

• Re-states dual focus: development vs. orofacial clefts.

Page 22 – Orofacial Cleft Epidemiology & Classification

• Cause: partial/complete failure of fusion between facial prominences.
• Incidence: 1 in \sim 700 live births (variable).
• Ethnic/Gender trends: Native Americans & Asians > Caucasians > Africans.
• Classification axes:
  • CL/P (cleft lip ± palate) vs. CPO (cleft palate only).
  • Isolated (nonsyndromic) > Syndromic.
  • Unilateral vs. Bilateral.
  • Complete vs. Incomplete.
  • Overt vs. Submucous (intact mucosa, muscular defect).

Page 23 – Developmental Anatomy of Cleft Types

• CL/P: failure of fusion between MNP & MXP.
• CPO: failure of palatal shelf fusion (secondary palate).
• Clinical phenotypes illustrated: normal, unilateral CL, unilateral CLP, bilateral CLP, isolated CPO, combined CP + unilateral CL.

Page 24 – Additional Clinical Photographs

• Unilateral incomplete CL (partial) vs. complete bilateral CL (including primary palate involvement).

Page 25 – Complete Bilateral & Secondary Clefts

• Example: complete bilateral cleft lip + primary palate + complete secondary palate cleft (U-shaped gap through entire palate).
• Isolated complete cleft of secondary palate (CPO) also shown.

Page 26 – Rare Cleft Variants (Midline)

• Midline mandibular cleft: failure of the two MDPs to fuse → split lower lip/chin.
• Median cleft of upper lip: failure of two MNPs to fuse (frontonasal dysplasia spectrum).

Page 27 – Rare Cleft Variants (Oblique)

• Oblique facial cleft: failure of fusion between MXP & LNP → cleft from lip toward eye, often following nasolacrimal groove path.

Page 28 – Developmental Mechanisms Leading to Clefts

• Tongue interposition preventing shelf elevation (Pierre Robin sequence – micrognathia → glossoptosis → U-shaped cleft).
• Structural deficiency: shelves/prominences too small or mis-shaped to contact.
• Epithelial seam persistence: contact occurs but MES fails to be removed.
• Other hypothesized mechanisms: abnormal ECM, ciliary defects, vascular disruption.

Page 29 – Multifactorial Etiology

Genetic Factors

• Key genes linked to CL/P: TBX22, IRF6, MSX1, PVRL1, P63, CDH1, EFNB1, TGFB3, among others.
• Polygenic model: many variants of small effect combine to create clinically significant defect.
  Environmental Factors
• Maternal nutrition (folate, vitamin A balance).
• Teratogens: alcohol, tobacco smoke, certain anticonvulsants & corticosteroids.
• Possible gene–environment interactions amplify risk.

Ethical & Practical Implications (Cross-cutting)

• Early detection by prenatal ultrasound enables parental counseling.
• Surgical repair protocols (e.g., “rule of 10”: 10 weeks, 10 lbs, 10 g Hb for lip repair).
• Multidisciplinary long-term care: feeding, speech therapy, orthodontics, psychosocial support.
• Global health disparity: access to surgical correction remains limited in low-resource settings (ethical imperative).

Foundational Principles & Connections

• Neural crest cell migration & pharyngeal arch patterning (from earlier embryology lectures) underpin facial prominence formation.
• EMT, apoptosis, and extracellular matrix dynamics are recurring morphogenetic mechanisms across organogenesis (e.g., heart septation, limb interdigital regression).
• Example parallel: palatal shelf elevation resembles epithelial fold movements in gut villus formation (forces, ECM).