Schutte BC, Murray JC The many faces and factors of orofacial clefts. Hum Mol Genet. 1999; 8:1853-1859
Little J, Cardy A, Munger RG Tobacco smoking and oral clefts: a meta-analysis. Bull World Health Organ. 2004; 82:213-218
Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J. 2007; 44:366-373
Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts. Epidemiology. 2005; 16:(5)698-701
Little J, Cardy A, Arslan MT, Gilmour M, Mossey PA Smoking and orofacial clefts: a United Kingdom based case control study. Cleft Palate Craniofac J. 2004; 41:381-386
Honein MA, Rosmussen SA, Reefhuis J Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts. Epidemiology. 2007; 18:226-233
Billie C, Oslen J, Vach W Oral clefts and life style factors: a case cohort study based on prospective Danish data. Eur J Epidemiol. 2007; 22:173-181
Romitti PA, Sun L, Honein MA Maternal periconceptional alcohol consumption and risk of orofacial clefts. Am J Epidemiol. 2007; 166:775-785
Shaw DM, Lammer EJ Maternal periconceptional alcohol consumption and risks for oro-facial clefts. J Paediatr. 1999; 134:298-303
Puhó EH, Szunyogh M, Métneki J, Czeizel AE Drug treatment during pregnancy and isolated orofacial clefts in Hungary. Cleft Palate Craniofac J. 2007; 44:(2)194-202
Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC Cleft lip and palate. The Lancet. 2009; 374:1773-1785
Asling CW, Nelson MM, Dougherty HD, Wright HV, Evans HM The development of cleft palate resulting from maternal pteroglutamic (folic) acid deficiency during the later half of gestation in rats. Surg Gynecol Obstet. 1960; 111:19-28
Krapels IPC, van Rooij IALM, Wevers RA Myo-inositol glucose and zinc status as risk factors for non-syndromic cleft lip with or without cleft palate in offspring: a case control study. BJOG (an international journal of obstetrics and gynaecology). 2004; 111:661-668
Cordier S, Bergeret A, Goujard J Congenital malformations and maternal occupational exposure to glycol ethers. Epidemiology. 1997; 8:355-363
Holmberg PC, Hernberg S, Kurppa K Oral clefts and organic solvent exposure during pregnancy. 1982; 50:371-376
Proetzel G, Pawlowski SA, Wiles MV Transforming growth factor-β3 is required for secondary palate fusion. Nat Genet. 1995; 11:409-414
Akcam MO, Evirgen S, Uslu O, Memikoglu UT Dental anomalies in individuals with cleft lip and/or palate. Eur J Orthod. 2010; 32:207-213
Nyström M, Ranta R Sizes of dental arches and interdental spaces in 3-year old children with and without cleft lip/palate. Eur J Orthod. 1989; 11:82-88
Trotman CA, Collett AR, McNamara J, Cohen SR Analyses of craniofacial and dental morphology in monozygotic twins discordant for cleft lip and unilateral cleft lip and palate. Angle Orthod. 1993; 63:135-140
Derijcke A, Eerens A, Carels C The incidence of oral clefts: a review. Br J Oral Maxillofac Surg. 1996; 34:488-494
Ranta R A review of tooth formation in children with cleft lip and palate. Am J Orthod Dentofacial Orthop. 1986; 90:11-17
Riberio LL, Das Neves LT, Costa B, Gomide MR Dental development of permanent lateral incisor in complete unilateral cleft lip and palate. Cleft Palate Craniofac J. 2002; 39:193-196
Riberio LL, Das Neves LT, Costa B, Gomide MR Dental development of permanent lateral incisors and prevalence of hypodontia outside the cleft area in complete unilateral cleft lip and palate. Cleft Palate Craniofac J. 2003; 40:172-175
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Baccetti T A controlled study of associated dental anomalies. Angle Orthod. 1998; 68:267-274
Vichi M, Franchi L Abnormalities of the maxillary incisors in children with cleft lip and palate. ASDC J Dent Children. 1995; 62:412-441
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Bjerklin K, Kurol J, Paulin G Ectopic eruption of the maxillary first permanent molars in children with cleft lip and/or palate. Eur J Orthod. 1993; 15:535-540
Clefts of the lip and palate are the most common congenital craniofacial anomaly. They are generally divided into two broad categories, which include cleft lip with or without cleft palate and isolated cleft palate. The incidence of these anomalies varies according to cleft type, geographical location and ethnicity. This article aims to give an overview of the genetic links and the known environmental influences that may contribute to the development of a cleft. In addition, the embryological development of the lip and palate and the patient care pathway from birth to adulthood are highlighted.
Clinical Relevance: A basic understanding of cleft lip and palate is important for clinicians involved in the delivery of regular dental care for a patient born with an oro-facial cleft.
Article
Ourvinder Chawla
Clefts of the lip and palate are the commonest congenital craniofacial abnormalities in humans. Clefts are most often discussed as either those that involve the lip, with or without the palate (CL/P), or those that involve the palate only (CP). The prevalence of clefting varies considerably according to geographical location, racial and ethnic background,1 socioeconomic status and cleft type.2 In general, the Asian and Native American populations have the highest reported prevalence rates of CL/P, which are often as high as 1 in 500.3 In the United Kingdom (UK), non-syndromic CP occurs approximately once in every 1000 live births, whilst CL/P has a higher prevalence of 1 in 700 live births.3 Currently, the CRANE database is used to register birth and demographic data of all children born with an oral cleft in England, Wales and Northern Ireland (Table 1).4 Clefting can occur either unilaterally or bilaterally and may be complete or incomplete (Figure 1). There is also laterality in that CL/P has an increased frequency of left-sided over right-sided unilateral clefts and this is more frequent in males compared to females in a ratio of 2:1. Cleft palate, however, is most typical in females.
Cleft Type
Percentage (%) of Clefts
Isolated cleft lip
23
Isolated cleft palate
45
Unilateral cleft lip and palate
22
Bilateral cleft lip and palate
10
Figure 1. Orofacial clefts. (A) Cleft lip and alveolus. (B) Cleft palate. (C) Incomplete unilateral cleft lip and palate. (D) Complete unilateral cleft lip and palate. (E) Complete bilateral cleft lip and palate. Reprinted from Mossey et al. Cleft lip and palate. The Lancet 2009; 374, with permission from Elsevier.18
Associated syndromes
CL/P and CP commonly occur as isolated birth defects, but are also associated with many genetic conditions. Approximately 70% of CL/P and 50% of CP cases are non-syndromic, occurring with no other physical or developmental anomalies. In the remaining cases, the cleft is an associated feature in over 300 syndromes (Online Mendelian inheritance in man: http://www.ncbi.nlm.gov/omim). Some of the more common syndromes associated with CL/P and CP are listed in Table 2. One of the commonest autosomal dominant disorders associated with CL/P or CP is van der Woude syndrome, with a prevalence of 1 in 70,000. This accounts for approximately 1% of all syndromic CL/P cases.5 This condition is classically characterized by ‘pitting’ of the lower lip.
The aetiology of non-syndromic CL/P and CP is still relatively obscure, although there is general agreement that it is multifactorial with both environmental and genetic factors playing an important role at specific points during the development of the face.6,7,8
Genetic factors
The evidence for a genetic influence comes from a number of observations in particular studies on siblings, where the risk for CL/P is approximately 30 times that for the non-cleft population. Studies on twins have been particularly informative. In monozygotic twins, the concordance rate ranges between 40% and 60%, whereas in dizygotic twins it is much lower at 5%.7 This suggests that genetic factors alone are not responsible for the phenotypic appearance of the clefts and environmental risk factors may also cause, or interact with, genetic factors.
Environmental factors
Environmental factors are known to include:
Maternal smoking during pregnancy;
Maternal alcohol consumption;
Medication;
Nutritional deficiencies;
Occupational exposure.
Maternal smoking during pregnancy
This has been linked consistently with increased risk of both CL/P and CP. A recent meta-analysis strongly suggests that mothers who smoke have an approximately 30% increased risk of having a child with a CL/P.9 In addition, evidence is emerging which suggests that certain foetal metabolizing enzymes may play a crucial role in inactivating teratogens in tobacco smoke.10 A foetus whose DNA lacks both copies of the gene called glutathione S-transferase theta 1 (GSTT1) may be at an increased risk for oro-facial clefts. GSTT1 has been found to be relevant to detoxification of chemicals in cigarette smoke.11
Few previous studies have explored the effect of passive smoking on CL/P. A weak effect of passive smoking in non-smokers was found in a small case control study.12 However, a larger case control study failed to find an association between exposure to any passive smoke at home or work and the risk of CL/P.13
Maternal alcohol consumption
The role of alcohol in the development of orofacial clefts has also been suggested as a risk factor. However, the evidence appears to be less consistent and the relationship would therefore appear to be inconclusive.14,15 Certainly, those women that consume high levels of alcohol during pregnancy are at a significant risk of having a child with foetal alcohol syndrome (FAS). Affected individuals have mental and physical defects of varying degrees. Characteristic facial features include, short palpebral fissures (separation between the upper and lower eyelid), sunken nasal bridge, short nose, flattening of the cheekbones and midface smoothing and elongation of the philtrum and thin upper lip. In addition, the heavier the consumption of alcohol, the more likely that a CL/P phenotype will form a component of the craniofacial defect.16
Medication
Certain anticonvulsant drugs have been linked to increased risk of orofacial clefts. In one study, a total of 16 (2.3%) of 684 infants exposed to lamotrigine (Lamictal) had major malformations that were identified at birth. Of these, five infants had oral clefts. An increased risk for non-syndromic CL/P has also been found in babies born to mothers treated with phenytoin during the first trimester.17 Positive associations with maternal corticosteroid use in pregnancy have also been reported.18
Nutritional deficiencies
Folate deficiencies are known to cause cleft palate in animals,19 however, its role in human clefts still remains uncertain. Food fortification programmes using folic acid have shown decreases in the rates of clefting but this is not entirely reproducible.3 Zinc deficiency causes isolated cleft palate and other malformations in animals. Mothers in the Netherlands bearing children with cleft lip with or without palate and palate alone had lower concentrations of zinc in erythrocytes than did mothers of children without clefts.20 Other nutrients that may play a part in the development of orofacial clefts include riboflavin and vitamin A.18
Occupational exposure
Maternal occupational exposure to glycol ethers, a chemical found in a variety of domestic and industrial products, has been reported to increase the rate of cleft lip.21 Exposure to organic solvents such as xylene, toluene and acetone has also been reported to increase the rate of this defect.22
Embryology of cleft lip and palate
Development of the face occurs between the fifth and ninth weeks in utero from individual elements called facial processes (Figure 2). Facial processes consist of a mesenchymal core derived mainly from cranial neural crest cells and an ectodermally derived epithelial surface. These facial processes must grow correctly, make contact and fuse (Table 3).
Figure 2. Development of the face.
Process
Development of Structures Resulting from Fusion of Processes
Mandibular process
Lower lip
Lower portion of the cheeks
Mandible
Mandibular dentition
Medial nasal process
Philtrum
Primary palate
Four upper incisors and the surrounding alveolar bone
Maxillary process
Fusion with the medial nasal process forms the remainder of the upper lip
Secondary palate
Upper portion of the cheeks
Rest of the upper teeth and maxilla
Lateral nasal processes
Fusion with the maxillary process and medial nasal process to form the ala of the nose
Development of the lip and primary palate
Begins during the fifth week in utero in humans;
The medial and lateral nasal processes develop from the frontonasal process;
The medial nasal processes merge with each other and with the maxillary processes.
Development of the secondary palate
This begins during the sixth week in utero in humans;
The palatal shelves form from bilateral outgrowths of the maxillary processes.
The palatal shelves grow vertically down on either side of the developing tongue and the mandible. The palatal shelves then elevate (very rapidly over about 24 hours) into a horizontal position above the tongue around the seventh to eighth week in utero (Figure 3).
The palatal shelves then approximate and fuse with the primary palate anteriorly and with each other posteriorly.
Figure 3. Normal development of the palate. Palatal shelves have elevated into the horizontal position and in contact. PS, palatal shelves; T, Tongue.
Molecular control of palatal shelf growth
The palatal shelf formation is regulated by epithelial-mesenchymal interactions. These interactions are managed by signalling molecules and growth factors, which are important for the initial budding of the palatal shelves and their subsequent growth. The signalling network includes:
Sonic Hedgehog (Shh);
Fibroblast growth factors (FGFs);
Bone morphogenetic proteins (BMPs);
Members of the transforming growth factor β superfamily (TGFβ).
Palatal shelf elevation
Palatal shelf elevation is thought to be driven by accumulation and hydration of glycoaminoglycans (GAGs), which are long chains of repeating disaccharides. These provide an intrinsic force for palatal shelf elevation. The developmental changes in the surrounding craniofacial region are also thought to be a contributing factor. As the mandible enlarges, the tongue adopts a lower position and this may allow elevation of the shelves to relocate above the tongue.
Palatal fusion
Once the palatal shelves have elevated and come into contact, the medial edge epithelia must adhere to each other. This is followed by removal of the epithelial seam through a process of cell apoptosis, transformation of the epithelium into mesenchyme or migration of the epithelium, thus allowing the underlying mesenchymal tissue to unite. Members of the transforming growth factor β superfamily (TGFβ), in particular TGFβ3, have been found to be essential in the process of palatal fusion.3 This is supported by demonstration that removal of the gene in mice prevented palatal fusion and that the cleft palate could be rescued by administration of exogenous TGFβ3.23
A cleft palate can result from:
Failure of palatal shelf growth;
Failure of palatal shelf elevation;
Failure of palatal shelf fusion due to an abnormality in the breakdown or adhesion at the midline;
Obstruction from the tongue preventing the palatal shelves from meeting at the midline.
Dental anomalies in cleft lip and palate
When compared to the general population, dental anomalies tend to be a common finding in individuals with CL/P. These may be primary, as a result of the cleft itself, or secondary, due to surgery. In a study of 122 subjects with cleft lip and palate, it was found that 96.7% of patients had a least one dental anomaly on the cleft side.24
They are most often seen in the incisor region and more so in the maxilla than in the mandible.25 Dental anomalies vary depending on the cleft type25,26 and racial/ethnic group.27
Agenesis of teeth is the most common dental anomaly in individuals with cleft lip and palate.28 Ribeiro et al29,30 found a prevalence of hypodontia of the permanent cleft side lateral incisor in 49.8% of the patients. Following hypodontia, the presence of a supernumerary tooth is the second most common dental anomaly. In the normal population, supernumerary teeth have been reported to be present at rates ranging from 0.1% to 3.8%.31,32 However, in patients with a unilateral cleft lip or palate (UCLP), a higher rate of 22.2% of supernumerary teeth has been found.33
Teeth in the region of an alveolar cleft have also commonly been found to be microformed. A recent study in Caucasians found a higher prevalence of microdontia (1.9–4.2%) on the cleft side when compared with the general population (1.5–2%).24 Ectopic eruption of the first maxillary molar is reported to be 2–6% for the non-cleft population.34 However, in a radiographic study of 225 children,35 a higher prevalence of ectopic eruption of the first permanent molar (15.4%) was found in children with a cleft lip or cleft lip and alveolus.
Care of a patient born with cleft lip and palate
Clefts are repairable structural defects. The type of treatment depends on the classification and severity of the cleft. Adverse effects on speech, hearing and appearance are some of the problems that require management from a multidisciplinary team comprising a range of specialists, including specialist nurses, surgeons (Plastic, Ear Nose and Throat and Maxillofacial), Orthodontists, Dieticians, Psychologists, Geneticists, Speech and Language therapists, Audiologists, Paediatric dentists and many other supporting staff. The care provided is often complex and protracted with lifelong implications for those affected (Table 4).
Timing
Management
Prenatal
Counselling and information for parents on feeding
Advice on the post birth and long-term management
At Birth
Counselling and information for parents on feeding
Advice on the immediate and long-term management
Records
3-6 months
Lip repair
Continued advice on feeding
6-9 months
Palate repair
Continued advice and support on communication skills and speech development
Oral heath advice
Hearing assessment
2-10 years
Records for audit at 5 and 10 years of age
Speech and language assessments and speech therapy as required
Pharyngoplasty
ENT input
Secondary alveolar bone grafting around 8-10 years of age
Pre-secondary alveolar bone graft orthodontics, if necessary
Oral health advice and input from paediatric dentists
12-15 years
Orthodontic treatment
Screening by clinical psychologist
Restorative input regarding any missing teeth
15 years
Records for audit
18 + years
Records for audit at age 20 years
Orthognathic surgery if necessary to correct jaw relationships
Rhinoplasty if necessary
Further surgery as necessary - lip revision
Dental implants, crown and bridge work, as necessary
Additional surgeries may be performed to improve the appearance of the lip and nose. Final repairs of the scars left by the initial surgery will probably not be performed until adolescence, when the facial structure is more fully developed.
Changes in cleft care in the UK
During the early 1990s, health professionals expressed concerns over the standard of cleft care, both within the NHS and between the UK and Europe. This led to the Department of Health commissioning the Clinical Standards Advisory Group (CSAG) to carry out an investigation into the quality of care provided for children born with a cleft lip and palate. The study commenced in 1996 over a 15-month period and aimed to include all non–syndromic children born with a complete UCLP aged 5 and 12 years of age. Outcomes assessed included the quality of speech, hearing, naso-labial appearance, dental arch relationships, including the oral health, success of alveolar bone grafts (in the 12-year-old cohort only) and patient/parent satisfaction.
In 1998, the group produced the main report, indicating that the outcomes of cleft care at units in the UK were disappointing when compared with three centres in Europe (Norway, Denmark and the Netherlands).36 Fifty-seven centres were identified as providing a cleft service, with the number of cases being treated per year varying considerably between high and low volume operators. One of the key findings was the poor outcome with respect to dental arch relationships. It was reported that 36% of 5-year-olds and 39% of 12-year-olds had poor dental arch relationships. Also of particular concern was the number of children who failed to receive alveolar bone grafts at an appropriate time, with an overall low quality of outcome achieved. In those that had been grafted, only 58% of the grafts were successful. In comparison, the success from one of the European centres was 97%. In addition, by the age of 12 years, 20% of patients had a poor lip appearance and 42% had a poor nasal appearance.
Subsequently, the group made nine recommendations, all of which were accepted and led to a period of change and reorganization of cleft services across the UK, including the concentration of resources and expertise into eight regional cleft centres and two Managed Clinical Networks (MCN) (Table 5).4
Regional Centre/MCN
Administrative Unit
Northern and Yorkshire
Royal Victoria Hospital, NewcastleLeeds General Infirmary, Leeds
North West and North Wales and Isle of Man
Alder Hey Children's Hospital, LiverpoolRoyal Manchester Children's Hospital, Manchester
Trent
Nottingham City Hospital, Nottingham
West Midlands
Birmingham Children's Hospital
East
Addenbrooke's Hospital, Cambridge
North Thames
Great Ormond Street Hospital, LondonBroomfield Hospital, Chelmsford
The Spires
John Radcliffe Hospital, OxfordSalisbury District Hospital, Salisbury
South Wales and South
Morriston Hospital, Swansea
West
Frenchay Hospital, Bristol
South Thames
Guy's Hospital, London
Northern Ireland
Royal Belfast Hospital for Sick Children, Belfast
CSAG recommendations to the UK health departments included:
Expertise should be limited to 8–15 centres in the UK;
Each centre should provide a full range of cleft care;
Documentation must be improved, including a nationwide database;
Results should be regularly audited allowing comparisons between centres;
Training should be provided for specialists in cleft care in high volume centres only.
Currently, a repeat study is being carried out to evaluate the impact of this re-organization of services on the standard of care provided in the UK, 14 years since the CSAG recommendations in 1998. The results of this study are eagerly awaited.
Summary
Over the past two decades there have been significant changes in the UK cleft service. The currently accepted model for delivery of care is a centralized, multidisciplinary team approach, which comprises carers from different specialist backgrounds working closely together, and co-ordinating expertise to the patient to achieve an optimum outcome.
In relation to prevention, there is strong evidence to suggest that maternal cigarette smoking is associated with an increased incidence of non-syndromic CL/P and CP. Some attention has also been given to the nutritional status of pregnant mothers, in particular the role of folic acid supplementation as a method of reducing CL/P and CP incidence. However, the evidence is still inconclusive. Continued research will help to dissect further the genetic and environmental aetiological factors in non-syndromic CL/P and CP and will allow more accurate identification of high-risk individuals or families.
