G.O. Oboli1, D.I. Chukwuma2, O.F. Fagbule2, E.O. Abe3 and A.O. Adisa1,3

  1. College of Medicine, University of Ibadan, Ibadan
  2. Department of Periodontology and Community Dentistry, University College Hospital, Ibadan
  3. Department of Oral Pathology and Oral Medicine, University College Hospital, Ibadan

Dr. E.O. Abe
Department of Oral Pathology and Oral Medicine,
University College Hospital,
Ibadan, Nigeria.


Cleft lip with or without cleft palate (CLP) is a common congenital disability. They exist either in combination with one or more other anomalies (syndromic cleft) or in isolation (non-syndromic cleft). Non-syndromic CL/P is more common as it is present in about 70% of cases, out of which 80% are sporadic, and 20% are familial.1 CLP which is commoner in males, occurs in 1 out of 300 to 2500 births, while isolated cleft palate (CP) which occurs more frequently in females, occurs in 1 out of 1500 births2.3. People with cleft lip and palate often require multidisciplinary care involving several surgical repairs commencing in the first year of life, orthodontic interventions for malocclusion, speech therapy, treatment of recurrent
middle ear infections, and psychological interventions. These have been noted to contribute a significant burden to the patient, family, and society at large. Thus, an intense effort has been made to unravel its aetiology, which would be important in genetic counselling, risk prediction, and overall prevention of cleft lip and palate4.

Aetiology of Cleft Lip and Palate
Generally, cleft lip and palate is thought to result from interactions between genetic and environmental factors. Substantial pieces of evidence for the former have arisen from family, and twin studies which revealed high rates of familial aggregation and increased concordance rates in monozygous twins, compared with dizygous twins5. For instance, studies by Sivertsen et al.6 and Grosen et al.7 showed that cleft palate has a relative risk of occurrence which is 15 to 56 times higher among first degree relatives. Although environmental factors such as maternal use of alcohol, cigarette and antiepileptic drugs have been identified as risk factors for CLP, recent studies have now revealed important genes either acting alone or within
gene networks. Such cases are found as parts of Mendelian monogenic syndromes, chromosomal abnormalities, or otherwise unknown genetic syndromes8. These identified genetic risk factors have shed more light on normal craniofacial development with some also implicated in non-syndromic CL/P. As an example of gene-environment interaction, Shaw et al.9 demonstrated a 3 to 8 fold increase in CLP in babies with lack of multivitamins in the first trimester of pregnancy and the TaqI C2 mutation in the Tgfa gene. The same mutation was shown to raise the risk of CLP by 6 to 8 times when co-existent with maternal smoking10, while Jugessur et al.11 found that combined mutations of the Tgfa and Msx1 genes cause an almost ten-fold increase in cleft lip and palate risk as an evidence of gene-gene interaction.

Genetic Regulation of Craniofacial Development Craniofacial development is a complex event involving several transcription factors and molecular signals. Disruptions in the network of these proteins lead to the development of facial clefts. The diversity in the functions of these genes and their products shows the susceptibility of the craniofacial developmental pathways to form clefts4. Facial development in humans begins in the fourth week of intrauterine life with the migration of cranial neural crest cells (CNC) from the rostral part of the neural tube to form the facial primordia and secondary palate8. Genes such as Tgfb2, Hoxa2, Gli2, and Gli3 have been identified to play a role in CNC migration, mutations of which have been shown to contribute to cleft lip and palate in mice12-14. Palatal shelves are subsequently derived from the secondary palate and undergo elevation to become horizontally apposed in the midline. Failure of apposition has been linked with mutations in the genes Msx1, Pax9and Lhx8 leading to CP15-17. Furthermore, epithelial-mesenchymal interactions mediated by interrelated gene networks – sonic hedgehog (Shh), bone morphogenetic proteins (Bmp), and fibroblast growth factors (Fgf) – are essential in normal palatal development18.