Cleft lip and/or palate (CLP) is a relatively common, non-life-threatening abnormality which can have significant effect on maternal bonding. Its aetiology is complex: it can occur in isolation but may be associated with a chromosomal or teratogenic syndrome - an associated syndrome is thought to exist in around 30% of all patients with CLP.
Although not a major cause of mortality in the developed world, it can lead to poor feeding, failure to thrive and impaired survival in places where healthcare resources are poor. CLP is a major cause of morbidity in places where corrective surgery is not available. Children may experience social stigmatisation, in addition to problems with speaking and hearing.
The defects in CLP arise very early in embryonic development, and are thought to have a complex aetiology, with genetic and environmental factors playing a part. Isolated CLP does not follow a simple Mendelian inheritance pattern, although there is a small recurrence risk.
- The most common forms of CLP involve disruption of the tissue planes above the lip extending to nostrils and palate (hard and soft palate may be involved). Most only involve the upper lip and/or palate. Very rarely other parts of the face may be affected.
- 70% occur in isolation, ie without association with any other anomaly or syndrome.
- Incidence seems to have fallen in the last thirty years. An epidemiological study in 2012 looked at 30 countries from 2002 to 2006 and suggested a worldwide incidence of around 0.8/1,000 live births, about half the rates reported in older literature.
- CLP is more common in Asian populations and in Native Americans, the latter having an incidence in older literature of 3.6/1,000.
- CLP is less common in African Americans - about half the European rate.
- Cleft lip (with or without cleft palate) is more frequent in males.
- Cleft palate alone is more common in females and accounts for around a third of cases.
- Cleft lip alone may have stronger genetic associations than cleft palate (with or without cleft lip).
These are thought to be a mixture of genetic and environmental/teratogenic factors in non-syndromic CLP. Pre-pregnancy planning is known to exert a protective effect, although there are several possible sources of bias in this observation.
Simple Mendelian inheritance is not demonstrated and there may be varying levels of genetic predisposition, which environmental factors then influence. Several associated genetic loci have been identified:
- If both parents are unaffected, but have one child with a cleft, the chance of the second child being similarly affected is 2-8%.
- If one or other parent has a cleft, the risk of a cleft in a child is 4-6% with each pregnancy.
- If the cleft is not associated with a syndrome, there is an associated gene; interferon regulatory factor 6 gene variants can confer a risk for isolated CLP. This can be identified in approximately 15% of patients.
- There is a known risk in taking certain types of drugs during pregnancy - eg, phenytoin, isotretinoin, sodium valproate, benzodiazepines and corticosteroids.
- Maternal smoking, both in the first trimester and periconceptually is associated with increased risk.[1, 6]
- Maternal alcohol use in the first trimester, particularly binge drinking, is a risk factor.
- There is debate on the role of folic acid: nutritional factors such as folate deficiency have been suggested as a risk but studies of the effects of vitamin supplementation remain controversial and there is some evidence for the importance of deficiency in other nutrients such as zinc and cholesterol.[8, 9, 10]
- Researchers have also suggested it may be important to evaluate possible associations with maternal obesity, stress, exposure to ionising radiation and infection.
- The lip has usually formed by 5-6 weeks of intrauterine life.
- The palate has formed by 10 weeks.
- The cleft may be picked up by high-resolution ultrasound at 20 weeks of gestation.
- Diagnosis is otherwise made after delivery.
Cleft lip alone
If the cleft affects the lip only and does not affect the palate is is known as cleft lip.
- There may be a small gap in the lip (complete cleft) with the split running from the philtrum to the nostril.
- There may just be an indentation (partial or incomplete cleft).
- Cleft lip may be unilateral or bilateral.
- It is due to a failure of fusion of the maxillary and medial nasal processes in the developing fetus.
- A partial cleft may be so small as to be considered a microform cleft. This may affect the orbicularis oris muscle and require reconstruction, so even if the defect looks minor, babies should be assessed by a craniofacial surgeon.
Cleft palate (with or without cleft lip)
- Cleft palate condition occurs when the two plates in the base of the skull which form the hard palate fail to fuse.
- The cleft is therefore central in the palate, and the soft palate is usually cleft as well.
- Most commonly, cleft lip is also present.
- A complete cleft palate involves both hard and soft palates. However, the condition may involve the soft palate alone, when it appears as a hole in the roof of the mouth.
- The uvula is usually also split, due to failure of the palatine processes which form the soft palate in utero.
- Submucous cleft palate can occur and involves only a split uvula, a furrow along the soft palate and a notch at the back of the hard palate.
- The hole in the roof of the mouth connects the oral cavity to the nasal cavity. As a result of this, if the defect is not corrected the resonance of the voice is altered. There will also be disorders of articulation, as the palate is involved in production of speech sounds.
- Cleft lip presents with an obvious gap in the newborn lip - usually the upper lip is affected.
- Further inspection and palpation (essential, as the mucosa may be intact over the palatal gap) of the roof of the mouth may reveal clefting of the hard and/or soft palate also. The newborn may have difficulty bottle-feeding as a consequence of being unable to create a sufficient vacuum. However, most babies are able to be breast-fed.
- Special teats and bottles are available to deliver the milk to the back of the throat. A further option is to use a dental plate to seal the roof of the mouth.
- There may be associated poor weight gain but where the defect is corrected, children usually catch up by age 6 months.
Mainly the diagnostic decision involves looking for syndromal cases (around one third) versus isolated cases, and determining the extent of any associated palatal defect.
Associated syndromes include:
- Apert's syndrome.
- Goldenhar's syndrome.
- DiGeorge's syndrome: this is underdevelopment of the third and fourth pharyngeal pouches. The syndrome is often associated with congenital heart defects, abnormalities of the large blood vessels around the heart, failure of the oesophageal tube to develop, abnormalities of facial structures, and hypoparathyroidism. In most cases, there is a defect on chromosome 22.
- Coloboma, Heart defect, Atresia choanae, Restricted growth and development, Genital hypoplasia, Ear anomalies/deafness (CHARGE) syndrome.
- 3q29 microdeletion syndrome.
- Pierre Robin sequence.
- Trisomy 18 (Edwards' syndrome), trisomy 13 (Patau's syndrome) and trisomy 15.
- Van der Woude syndrome.
- Thorough physical examination of the neonate by a paediatrician is needed to exclude presence of any associated syndrome.
- Chromosome analysis may be required.
- Females may have increased risk of breast cancer and primary brain malignancy.
- Males have increased risk of primary lung cancer.
- Psychosocial problems may also be associated with clefting, particularly if uncorrected. These include behavioural problems, anxiety and depression. This is particularly true by adolescence, when older studies (1989) observed that young people with uncorrected defects showed high levels of social anxiety and alienation.[19, 20]
Ideally, patients should be managed by a multidisciplinary team which includes:
plastic surgeons, maxillofacial surgeons, ENT, speech and language therapists, dentists, orthodontists, psychologists and specialist nurses. They will provide support and treatment until growing is complete at around the age of 18 years.
This comprises the bulk of the treatment. A number of operations will be required as the child grows.The absence of a sound evidence base for selection of treatment protocols is shown by a striking diversity of practices across Europe for surgical care.
The approach is a team one, involving cosmetic and craniofacial surgeons, speech therapists, dentists, ENT specialists and paediatricians. Psychologists, social workers and counsellors are usually involved, for parents as well as children.
- Primary lip closure is performed at three months after birth, as long as weight and haemoglobin levels are adequate.
- Palate closure is performed at 6-12 months.
- Further operations are performed to improve appearance.
- If there is a gap in the gums, a bone graft may be required.
Recent advances in fetal (intrauterine) surgery using a fetal endoscopic technique, offer the prospect of scarless wound healing, and bone healing without callus formation. This allows for better or even normal maxillary growth. As the technique improves, the outcome for mother and fetus is improving.
- Chronic glue ear.
- Hearing loss; the muscles of the palate affect the ear.
- Dental cavities.
- Displaced teeth.
- Poor speech; the degree of problem is not related to the size of the defect. Speech is normally fine after repair, but may sound nasal.
- Lip deformity.
- Nasal deformity.
- Poor feeding, failure to thrive.
- Social exclusion.
- Psychological distress.
Treatment takes place over several years as the child grows and the palate and dentition develop. However, it is possible to achieve a normal appearance, and normal speech and eating habits, early in the process.
Identification of modifiable risk factors is the first step towards primary prevention:
- Pre-pregnancy planning seems to reduce risk.
- Preventative efforts might involve manipulation of maternal lifestyle, improved diet, use of multivitamin and mineral supplements, avoidance of certain drugs and medicines and general awareness of social, occupational, and residential risk factors.
- Genetic counselling can identify high-risk families. Research continues into likely environmental triggers including influenza, high gravidity, varicella infection, drugs and diet.
- Hippocrates and Galen both describe cleft lip in their works. Cleft palate was then thought to be secondary to syphilis , and it has in fact been associated with congenital syphilis.
- CLP was not recognised as a congenital abnormality until 1556, nearly 2,000 years after Hippocrates.
- The first closure of a soft palate was in 1764 by a French dentist, Le Monier.
- The first hard palate closure was in 1834 by Dieffenbach.
Further reading and references
Orofacial Cleft 1, OFC1; Online Mendelian Inheritance in Man (OMIM)
Dixon MJ, Marazita ML, Beaty TH, et al; Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011 Mar12(3):167-78. doi: 10.1038/nrg2933.
Shkoukani MA et al; Cleft Lip - A Comprehensive Review, Front Pediatr. 2013 1: 53.
Tanaka SA, Mahabir RC, Jupiter DC, et al; Updating the epidemiology of cleft lip with or without cleft palate. Plast Reconstr Surg. 2012 Mar129(3):511e-518e. doi: 10.1097/PRS.0b013e3182402dd1.
Carinci F, Scapoli L, Palmieri A, et al; Human genetic factors in nonsyndromic cleft lip and palate: An update. Int J Pediatr Otorhinolaryngol. 2007 Jun 30.
Zucchero TM, Cooper ME, Maher BS, et al; Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004 Aug 19351(8):769-80.
Lammer EJ, Shaw GM, Iovannisci DM, et al; Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts. Epidemiology. 2005 Sep16(5):698-701.
DeRoo LA, Wilcox AJ, Drevon CA, et al; First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based case-control study. Am J Epidemiol. 2008 Sep 15168(6):638-46. doi: 10.1093/aje/kwn186. Epub 2008 Jul 30.
Bille C, Knudsen LB, Christensen K; Changing lifestyles and oral clefts occurrence in Denmark. Cleft Palate Craniofac J. 2005 May42(3):255-9.
Shaw GM, Carmichael SL, Laurent C, et al; Maternal nutrient intakes and risk of orofacial clefts. Epidemiology. 2006 May17(3):285-91.
Czeizel AE, Timar L, Sarkozi A; Dose-dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics. 1999 Dec104(6):e66.
Merritt L; Part 1. Understanding the embryology and genetics of cleft lip and palate. Adv Neonatal Care. 2005 Apr5(2):64-71.
Apert Syndrome; Online Mendelian Inheritance in Man (OMIM)
Hemifacial Microsomia, HFM; Online Mendelian Inheritance in Man (OMIM)
CHARGE Syndrome; Online Mendelian Inheritance in Man (OMIM)
Willatt L, Cox J, Barber J, et al; 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet. 2005 Jul77(1):154-60. Epub 2005 May 25.
Van Der Woude Syndrome 1, VWS1; Online Mendelian Inheritance in Man (OMIM)
Merritt L; Part 2. Physical assessment of the infant with cleft lip and/or palate. Adv Neonatal Care. 2005 Jun5(3):125-34.
Bille C, Winther JF, Bautz A, et al; Cancer risk in persons with oral cleft--a population-based study of 8,093 cases. Am J Epidemiol. 2005 Jun 1161(11):1047-55.
Hunt O, Burden D, Hepper P, et al; The psychosocial effects of cleft lip and palate: a systematic review. Eur J Orthod. 2005 Jun27(3):274-85.
Tobiasen JM; Psychosocial correlates of congenital facial clefts: a conceptualization and model. Cleft Palate J. 1984 Jul21(3):131-9.
Papadopulos NA, Papadopoulos MA, Kovacs L, et al; Foetal surgery and cleft lip and palate: current status and new perspectives. Br J Plast Surg. 2005 Jul58(5):593-607.
Mossey PA, Little J, Munger RG, et al; Cleft lip and palate. Lancet. 2009 Nov 21374(9703):1773-85. Epub 2009 Sep 9.
Gupta R, Chotaliya K, Marfatia YS; Cleft lip as a presentation of congenital syphilis. Indian J Sex Transm Dis. 2012 Jan33(1):58-9. doi: 10.4103/0253-7184.93831.
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