Craniofacial Defects and Cleft Lip and Palate


Serious malformations of the face present at birth are due to disturbances of embryonic development. Formation of the face begins during the fifth week post conception, and by 7 weeks, the lip is completely fused and continuous. The secondary palate forms between 7 and 11 weeks and is influenced by the growth of the surrounding head. Early disruption of lip and palate morphogenesis gives rise to severe orofacial clefts, whereas later disturbances cause microforms of clefting. Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is linked to polymorphisms in multiple genes and influences from the environment. In contrast, syndromic facial anomalies are attributed to defined changes in the genome and are accompanied by deficiencies in several organ systems.

Key Concepts

  • The face is susceptible to malformations due to the complex 4D nature of embryonic morphogenesis. Multiple prominences need to come together and fuse at precisely the right time during development in order for lip and palate fusion to occur.
  • The genes that cause syndromes with craniofacial phenotypes overlap with the genes that contribute to nonsyndromic abnormalities such as typical cleft lip with or without cleft palate.
  • Abnormal jaw relationships, especially mandibular prognathism, are partially genetically determined.
  • Novel genes that increase risk of being born with NSCL/P have been identified with Genome Wide Association Studies and targeted sequencing.
  • Midline clefts have a different etiology and appearance than non‐syndromic cleft lip. Midline clefts are part of the midline deficiencies in holoprosencephaly.

Keywords: craniofacial development; orofacial cleft; nonsyndromic cleft lip; cleft palate; mandibular prognathism; medial edge epithelium; facial prominences; medial nasal prominence

Figure 1. Classification of clefts. (a) Normal anatomy of the lip and palate; (b) microform of the cleft lip which consists of a notch in the upper lip. The nose is normal, there is no deviation of the columella and the nares is not flattened on the cleft side. An ultrasound might reveal a discontinuity in the orbicularis oris muscle. The palate and alveolar ridge are normal. (c) The complete unilateral cleft lip extends into the left nostril, leading to a flattened ala. The cleft also penetrates the lip and alveolar ridge but does not extend into the palate. This is one of the subtypes embodied in the CL/P classification. (d) Typical unilateral cleft lip with cleft palate, passing through the nose, premaxilla and into the palate. The columella is deviated. (e) Bilateral cleft lip with cleft palate, the most severe type of CL/P. The nasal septum is visible in the midline. (f) Isolated, bilateral cleft palate. The cleft is bilateral so the nasal septum is visible.
Figure 2. Sequence of lip fusion in the human embryo. (a) Stage 16 (days 37–42) human embryo with facial prominences present around the nasal slits. (b) A stage 17, (44–48 days) embryo with deep grooves or furrows between the facial prominences. Internally fusion has already taken place between the maxillary and medial nasal prominences. (c) A stage 19 (48–51 days) embryo where fusion is complete; however, merging of the remaining grooves is incomplete. (d) A histological section through an embryo at approximately stage 16. The bilateral epithelial seam is visible. (e) A section of an embryo approximately stage 17. The medial nasal prominences are merging closer to the midline, no seam is present; however, a furrow remains between the medial nasal and maxillary prominences. (f) The lip fusion zone passes through three stages on the way to the formation of the lip (i–iii). (g) In the nasolacrimal groove, between the medial nasal prominences and in the midline of the mandible, merging is taking place. The deep furrows fill in by proliferation and migration of neural crest‐derived mesenchyme (i–iii). Key: e, eye; lnp, lateral nasal prominence; md, mandibular prominence; mnp, medial nasal prominence; mxp, maxillary prominence; nlg, naso lacrimal grooove and ns, nasal slit. (a,c) Reproduced with permission from Hinrichsen 1985 © Springer‐Verlag. (b,d,e) Reproduced with permission from Dr. V.M. Diewert. (f,g) Reproduced with permission from Danescu et al. 2015 © 'John Wiley and Sons Ltd.
Figure 3. Formation of the secondary palate. (a) In the 7th week or stage 19, the palatal shelves are vertically positioned on either side of the tongue. The nasal septum has not fully extended caudally. The mandibular bone is stained blue and cartilage is pink. (b) A schematic with arrows showing the directional movement of palatal shelves as they reorient horizontally. The tongue is repositioned inferiorly due to mandibular growth and changes in head posture. (c) An older embryo in which the soft palatal shelves are horizontal in position. The section is posterior to the hard palate so that palatal shelves do not contain bone. The aponeurosis is condensing in the shelves before contact. (d) A schematic with arrows showing growth directions of the nasal septum and palatal shelves. (e) An early 8‐week specimen with a fully formed hard palate containing a midline seam. Cartilage is blue and bone is red in this section. (f) A schematic illustrating the seams that are formed between the medial edges of the palatal shelves and the nasal septum. (g) Histological section of a 57d specimen illustrating the seam under the nasal septum (arrowhead). (h) Islands of epithelium are retained in the midline of this 57d hard palate (arrowheads). (i) A different 57d specimen stained with antibodies to cytokeratin in which epithelium is highlighted. The midline cells are still epithelial in character (arrowhead). Scale bars in (a), (c), (e) = 1 mm and bars in (g–i) = 100 µm. Key: an, aponeurosis; mc, Meckel's cartilage; md, mandible; mxb, maxillary bone; ns, nasal septum; pb, palatine bone; ps, palatal shelf and tb, tooth bud. Human embryo sections from the collection of Dr. Richman and Diewert, UBC Human ethics approval number H08‐02576.
Figure 4. Three‐dimensional imaging of a 64d human foetus stained with phosphotungstic acid. Three orthogonal planes are shown with red being transaxial or horizontal and blue frontal or coronal and green sagittal. The PTA staining provides contrast for all the soft tissues of the head. (a) A frontal slice through the hard palate similar to Figuree. The green line represents the plane of section for (b). The red line is the plane of section for (c). (a′) The close‐up view of the palate shows the midline seam which is present in the oral side of the palate. (b) A sagittal slice showing the 70° angle of the soft palate relative to the hard palate. The red dashed line shows the plane of section for (c) as it passes through the bend in the soft palate. Two positions in the palate are shown by the dark blue (a′) and lighter blue lines (d). (c) The horizontal slice through the hard palate illustrates that the midline seam extends throughout most of the hard palate, close to the oral surface. (d) A posterior frontal slice through the soft palate and pharynx. The complex bending of the soft palate leads to the pharynx being visible on both sides of the soft palate. The aponeurosis is stained with PTA. Key: an, aponeurosis; ph, pharynx; s, seam and sp, soft palate. Human foetus from the collection of Dr. Richman and Diewert, UBC Human ethics approval number H08‐02576.
Figure 5. A unilateral cleft palate in a 9‐week, 45‐mm CRL human foetus. The foetal specimen is sectioned midway through the hard palate in the frontal or coronal plane. (a) Bone is stained blue and cartilage is lighter blue. The foetus is well past the age at which the palate should have fused and yet there is a unilateral cleft on the right side. (b) A schematic showing the lack of fusion on the right side. (c) A higher power view of the cleft showing full formation of a mesenchymal bridge on the left side with an open cleft on the right, separating the palatine bone from fusing with the contralateral side. The vomer is unaffected by the cleft. Scale bar = 2 mm. Key: c, cleft; mc, Meckel's cartilage; md, mandibular bone; mxb, maxillary bone; palatine process; ns, nasal septum; pb, palatine bone; vertical plate and v, vomer. Human foetal sections from the collection of Dr. Richman and Diewert, UBC Human ethics approval number H08‐02576.


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Further Reading

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Richman, Joy M, and Vora, Siddharth R(Apr 2017) Craniofacial Defects and Cleft Lip and Palate. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020915.pub2]