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 © Springer‐Verlag. (b,d,e) Reproduced with permission from Dr. V.M. Diewert. (f,g) Reproduced with permission from Danescu et al. © '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 Figure e. 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.


Abramyan J, Leung KJ and Richman JM (2014) Divergent palate morphology in turtles and birds correlates with differences in proliferation and BMP2 expression during embryonic development. Journal of Experimental Zoololgy Part B: Molecular and Developmental Evolution 322: 73–85.

Abramyan J and Richman JM (2015) Recent insights into the morphological diversity in the amniote primary and secondary palates. Developmental Dynamics 244: 1457–1468.

Ashique AM, Fu K and Richman JM (2002) Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development 129: 4647–4660.

Beaty TH, Marazita ML and Leslie EJ (2016) Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow's opportunities. Faculty of 1000 Research 5: 2800.

Bush JO and Jiang R (2012) Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development 139: 231–243.

Butali A, Adeyemo WL, Mossey PA, et al. (2014) Prevalence of orofacial clefts in Nigeria. Cleft Palate‐Craniofacial Journal 51: 320–325.

Cox TC (2004) Taking it to the max: the genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology. Clinical Genetics 65: 163–176.

Danescu A, Mattson M, Dool C, et al. (2015) Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion. Journal of Anatomy 227: 474–486.

Diewert VM (1983) A morphometric analysis of craniofacial growth and changes in spatial relations during secondary palatal development in human embryos and fetuses. American Journal of Anatomy 167: 495–522.

Dixon MJ, Marazita ML, Beaty TH, et al. (2011a) Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews. Genetics 12: 167–178.

Dixon MJ, Marazita ML, Beaty TH, et al. (2011b) Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews Genetics 12: 167–178.

da Fontoura CS, Miller SF, Wehby GL, et al. (2015) Candidate gene analyses of skeletal variation in malocclusion. Journal of Dental Research 94: 913–920.

Godbout A, Leclerc JE, Arteau‐Gauthier I, et al. (2014) Isolated versus pierre robin sequence cleft palates: are they different? Cleft Palate‐Craniofacial Journal 51: 406–411.

Gowans LJ, Adeyemo WL, Eshete M, et al. (2016) Association studies and direct DNA sequencing implicate genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in Sub‐Saharan African populations. Journal of Dental Research 95 (11): 1245–1256.

Gross JB and Hanken J (2008) Review of fate‐mapping studies of osteogenic cranial neural crest in vertebrates. Developmental Biology 317: 389–400.

He F, Xiong W, Yu X, et al. (2008) Wnt5a regulates directional cell migration and cell proliferation via Ror2‐mediated noncanonical pathway in mammalian palate development. Development 135: 3871–3879.

Hilliard SA, Yu L, Gu S, et al. (2005) Regional regulation of palatal growth and patterning along the anterior‐posterior axis in mice. Journal of Anatomy 207: 655–667.

Hinrichsen K (1985) The early development of morphology and patterns of the face in the human embryo. Advances in Anatomy, Embryology, and Cell Biology 97: 1–79. DOI: 10.1007/978-3-642-70754-4.

James JN, Costello BJ and Ruiz RL (2014) Management of cleft lip and palate and cleft orthognathic considerations. Oral & Maxillofacial Surgery Clinics of North America 26: 565–572.

Jin YR, Han XH, Taketo MM, et al. (2012) Wnt9b‐dependent FGF signaling is crucial for outgrowth of the nasal and maxillary processes during upper jaw and lip development. Development 139: 1821–1830.

Kaartinen V, Cui XM, Heisterkamp N, et al. (1997) Transforming growth factor‐beta3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane. Developmental Dynamics 209: 255–260.

Khandelwal KD, Ishorst N, Zhou H, et al. (2016) Novel IRF6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing. Journal of Dental Research 96 (2): 179–185.

Kondo S, Schutte BC, Richardson RJ, et al. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics 32: 285–289.

Kummet CM, Moreno LM, Wilcox AJ, et al. (2016) Passive smoke exposure as a risk factor for oral clefts – a large International Population‐Based Study. American Journal of Epidemiology 183: 834–841.

Lan Y, Xu J and Jiang R (2015) Cellular and molecular mechanisms of palatogenesis. Current Topics in Developmental Biology 115: 59–84.

Le Douarin NM and Dupin E (2016) The pluripotency of neural crest cells and their role in brain development. Current Topics in Developmental Biology 116: 659–678.

Leslie EJ and Marazita ML (2013) Genetics of cleft lip and cleft palate. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 163: 246–258.

Leslie EJ, Taub MA, Liu H, et al. (2015) Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. American Journal of Human Genetics 96: 397–411.

Leslie EJ, Carlson JC, Cooper ME, et al. (2016a) Exploring subclinical phenotypic features in twin pairs discordant for cleft lip and palate. Cleft Palate‐Craniofacial Journal 54 (1): 90–93.

Leslie EJ, Carlson JC, Shaffer JR, et al. (2016b) A multi‐ethnic genome‐wide association study identifies novel loci for non‐syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13. Human Molecular Genetics 25 (13): 2862–2872.

Leslie EJ, Koboldt DC, Kang CJ, et al. (2016c) IRF6 mutation screening in non‐syndromic orofacial clefting: analysis of 1521 families. Clinical Genetics 90: 28–34.

Liu W, Sun X, Braut A, et al. (2005) Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 132: 1453–1461.

Lowry RB, Sibbald B and Bedard T (2014) Stability of orofacial clefting rate in alberta, 1980–2011. Cleft Palate‐Craniofacial Journal 51: e113–e121.

Ludwig KU, Mangold E, Herms S, et al. (2012) Genome‐wide meta‐analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nature Genetics 44: 968–971.

Mangold E, Bohmer AC, Ishorst N, et al. (2016) Sequencing the GRHL3 coding region reveals rare truncating mutations and a common susceptibility variant for nonsyndromic cleft palate. American Journal of Human Genetics 98: 755–762.

Marcucio RS, Cordero DR, Hu D, et al. (2005) Molecular interactions coordinating the development of the forebrain and face. Developmental Biology 284: 48–61.

McBratney‐Owen B, Iseki S, Bamforth SD, et al. (2008) Development and tissue origins of the mammalian cranial base. Developmental Biology 322: 121–132.

McBride WA, McIntyre GT, Carroll K, et al. (2016) Subphenotyping and classification of orofacial clefts: need for orofacial cleft subphenotyping calls for revised classification. Cleft Palate‐Craniofacial Journal 53: 539–549.

Minoux M and Rijli FM (2010) Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137: 2605–2621.

Moreno Uribe LM and Miller SF (2015) Genetics of the dentofacial variation in human malocclusion. Orthodontics and Craniofacial Research 18 (Suppl 1): 91–99.

Mossey PA, Little J, Munger RG, et al. (2009) Cleft lip and palate. Lancet 374: 1773–1785.

Person AD, Beiraghi S, Sieben CM, et al. (2010) WNT5A mutations in patients with autosomal dominant Robinow syndrome. Developmental Dynamics 239: 327–337.

Richieri‐Costa A and Ribeiro LA (2010) Holoprosencephaly and holoprosencephaly‐like phenotypes: review of facial and molecular findings in patients from a craniofacial hospital in Brazil. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154C: 149–157.

Richman JM and Lee SH (2003) About face: signals and genes controlling jaw patterning and identity in vertebrates. Bioessays 25: 554–568.

Roessler E and Muenke M (2010) The molecular genetics of holoprosencephaly. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154C: 52–61.

Schneider RA and Helms JA (2003) The cellular and molecular origins of beak morphology. Science 299: 565–568.

Song L, Li Y, Wang K, et al. (2009) Lrp6‐mediated canonical Wnt signaling is required for lip formation and fusion. Development 136: 3161–3171.

Sun D, Baur S and Hay ED (2000) Epithelial‐mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Developmental Biology 228: 337–349.

Suzuki A, Sangani DR, Ansari A, et al. (2016) Molecular mechanisms of midfacial developmental defects. Developmental Dynamics 245: 276–293.

Szabo‐Rogers HL, Geetha‐Loganathan P, Nimmagadda S, et al. (2008) FGF signals from the nasal pit are necessary for normal facial morphogenesis. Developmental Biology 318: 289–302.

Watkins SE, Meyer RE, Strauss RP, et al. (2014) Classification, epidemiology, and genetics of orofacial clefts. Clinics in Plastic Surgery 41: 149–163.

Wehby GL, Felix TM, Goco N, et al. (2013) High dosage folic acid supplementation, oral cleft recurrence and fetal growth. International Journal of Environmental Research and Public Health 10: 590–605.

Yoshida T, Vivatbutsiri P, Morriss‐Kay G, et al. (2008) Cell lineage in mammalian craniofacial mesenchyme. Mechanisms of Development 125: 797–808.

Yu K and Ornitz DM (2011) Histomorphological study of palatal shelf elevation during murine secondary palate formation. Developmental Dynamics 240: 1737–1744.

Further Reading

De‐Regil LM, Fernandez‐Gaxiola AC, Dowswell T, et al. (2010) Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews 10: CD007950.

Kousa YA and Schutte BC (2016) Toward an orofacial gene regulatory network. Developmental Dynamics 245: 220–232.

Prasad MK, Geoffroy V, Vicaire S, et al. (2016) A targeted next‐generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement. Journal of Medical Genetics 53: 98–110.

Price KE, Haddad Y and Fakhouri WD (2016) Analysis of the relationship between micrognathia and cleft palate: a systematic review. Cleft Palate‐Craniofacial Journal 53: e34–e44.

Saal HM (2016) Genetic evaluation for craniofacial conditions. Facial Plastic Surgery Clinics of North America 24: 405–425.

Seto‐Salvia N and Stanier P (2014) Genetics of cleft lip and/or cleft palate: association with other common anomalies. European Journal of Medical Genetics 57: 381–393.

Suzuki A, Sangani DR, Ansari A, et al. (2016) Molecular mechanisms of midfacial developmental defects. Developmental Dynamics 245: 276–293.

Van Otterloo E, Williams T and Artinger KB (2016) The old and new face of craniofacial research: how animal models inform human craniofacial genetic and clinical data. Developmental Biology 415: 171–187.

Velazquez‐Aragon JA, Alcantara‐Ortigoza MA, Estandia‐Ortega B, et al. (2016) gene interactions provide evidence for signaling pathways involved in cleft lip/palate in humans. Journal of Dental Research 95: 1257–1264.

Webber DM, MacLeod SL, Bamshad MJ, et al. (2015) Developments in our understanding of the genetic basis of birth defects. Birth Defects Research. Part A, Clinical and Molecular Teratology 103: 680–691.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]