cleft lip

A Review of Orofacial Clefts: Cleft Lip, Cleft Palate, and Both Together

Germaine L. Defendi, MD, MS

ABSTRACT: Cleft lip, cleft palate, or cleft lip plus cleft palate are among the most common birth defects. The epidemiology of each of the 3 orofacial cleft types is described, and parental, genetic, and environmental contributing factors are briefly reviewed. Management of children with cleft lip and/or cleft palate includes surgical repair, supportive care offered by a multidisciplinary health care team, and treatment of orofacial cleft complications such as respiratory and feeding difficulties, hearing loss, speech delays, and dental anomalies.


 

A 2-month-old girl who had been born with bilateral cleft lip was referred to the pediatric outpatient clinic for craniofacial evaluation. This full-term infant had been born via vaginal delivery to a 16-year-old mother. There was no reported history of maternal illness, misuse or abuse of prescribed or over-the-counter medications, cigarette smoking, or alcohol intake during pregnancy. Family history was negative for orofacial clefts.

Prenatal care had been limited and had been initiated at 6 months of gestation. During the pregnancy, the mother’s nutritional status had been a concern, and she had taken no prenatal vitamin supplements. An orofacial cleft had been documented in the fetus via prenatal ultrasonography at 8 months of gestation; complete bilateral cleft of the upper lip was confirmed at birth. No other congenital anomalies were present.

Epidemiology

A cleft is a split or separation resulting from a failure of developmental fusion. Orofacial clefts, splits, or separations affecting the mouth and face are common craniofacial malformations in newborns. The worldwide prevalence rate of orofacial clefts is hard to pinpoint, since data vary by country, method of ascertainment, and reporters’ use of classification groups (isolated, nonsyndromic, or syndromic). In the United States, the estimated prevalence rate of all orofacial clefts is 1.69 per 1,000 live births.1 Outside the United States, the rate is as high 1 in 500 live births.20

Generally, orofacial clefts are categorized into 3 main types: isolated cleft lip (CL), isolated cleft palate (CP), and cleft lip with cleft palate (CLP). Isolated or nonsyndromic clefts are orofacial clefts without other congenital anomalies.3 Overall, the population percentages of orofacial clefts, independent of race or ethnicity, are estimated to be 20% to 21% for CL, 30% to 33% for CP, and 46% to 50% for CLP.4,5 In the United States, CL with or without CP occurs in about 1 per 1,000 live births among the white population. Racial variation exists, with this craniofacial malformation occurring more often in the Asian population and less often in the African American population.5 However, racial difference is not observed in cases of isolated CP, which occurs in 0.5 to 0.64 per 1,000 live births.1,5

Isolated Cleft Lip

Isolated CL, also called cheiloschisis, typically affects the upper lip and accounts for approximately 20% of all orofacial clefts.4 The worldwide incidence of CL with or without CP varies with race or ethnicity, affecting 1 in 500 live births among the Asian population, 1 in 750 among the white population, and 1 in 2,000 among the black population.1,5,6

CL of the upper lip can occur unilaterally (on the left or right side of the anterior nares), bilaterally, or on the median. Unilateral CL is more common than bilateral CL and most often occurs on the left side.5,7 The frequency ratio of left cleft to right cleft to bilateral cleft is 6 to 3 to 1.7 Bilateral CL is reported in 15% of nonsyndromic cases.8 Approximately 86% of bilateral CL cases are associated with CP; this percentage decreases to 68% to 70% with unilateral CL.5,9 A median or midline CL is very rare and is seen in cases of holoprosencephaly sequence.10

The degree of facial involvement varies greatly within the diagnosis of CL.10 The etiology is related to the failed migration of neural crest tissue to the midface during embryonic development. Both genetic and environmental factors (polygenic and multifactorial causes) are involved.

Isolated Cleft Palate

Isolated CP, also called palatoschisis, can involve the hard palate, the soft palate, or both. It affects approximately 1 in 2,000 live births and accounts for 30% to 33% of all orofacial clefts.4 Isolated CP occurs more often in girls than in boys.9 Unlike that of isolated CL and CLP, the incidence of isolated CP shows no racial or ethnic predilection, affecting all populations equally.4,9

Isolated CP is caused by failure of fusion of the palatal shelves on either side of the midline of the roof of the mouth. The etiology of isolated CP differs from isolated CL in that CP has a different etiopathogenic path with separate inheritance risks.10

Cleft Lip With Cleft Palate

CLP accounts for approximately 45% to 50% of all orofacial cleft cases.4 Approximately 85% of cases of bilateral CL and 70% of cases of unilateral CL are associated with CP.9 Worldwide, approximately 1 in 1,000 infants are born with CLP.9 A variance in incidence is observed with race and ethnicity, with the condition occurring more often in the Asian (1 in 400 births) and certain American Indian (1 in 300) populations and less often in the white (1 in 800) and black (1 in 1,500) populations.9 As many as 15% of infants with CLP will have additional congenital anomalies and a malformation syndrome.4,5

Embryology

Orofacial clefts occur when the medial, lateral, and maxillary nasal processes on the left, right, or both sides of the craniofacial complex do not fuse properly.10

Human lip formation begins in the first trimester of pregnancy, between the fourth and seventh week of gestation. Great variation exists on the spectrum of CL, with the appearance ranging from a small slit to a large opening with the potential to extend from the upper lip to the nasal base. The terms microform, incomplete, and complete describe the cleft lip’s extent toward the nasal base.5 The infant in the case study described above had a complete bilateral CL, given the cleft’s extension to the nasal base.

The human palate develops later in the first trimester, between the sixth and ninth week of gestation. CP occurs when the palatal shelves of the mouth do not fuse during development. In some patients, both the anterior and posterior aspects of the palate remain open, while in others, a partial palatal opening is present.4 By the end of the first trimester (12 weeks of gestation), the lip and palate have completed their embryologic development.

Etiology and Genetic Counseling

No distinct etiology of orofacial clefts is known. Abnormal facial development is a result of one or more of the following factors: genetic predisposition from one or both biological parents; environment (eg, teenage pregnancy, poor maternal health during early pregnancy; fetal exposure to toxins such as medications, alcohol, or cocaine); or genetic syndromes.4

The multifactorial effect of genetics plus environmental factors increases the risk of nonsyndromic orofacial clefts.11 Maternal environmental factors that increase this risk include disease (eg, diabetes prior to pregnancy), chemotherapy, radiation exposure, smoking, alcohol use, nutritional deficiencies (eg, folate, zinc) and poor nutritional health, excess retinoic acid, and anticonvulsant medications (eg, phenytoin, topiramate, valproic acid).12-14 The risk also is increased in teenage pregnancies15 and with older parental age (> 40 years), with paternal age being more significant than maternal age.16 In the case study above, poor maternal nutrition, prenatal vitamin deficiencies, and young maternal age may have had a role in the development of this infant’s orofacial malformation.

Clustered cases of nonsyndromic orofacial clefts in a family history indicate a genetic component. A defined Mendelian inheritance pattern is not observed, since the cause of orofacial clefts is polygenic and multifactorial. Families with a positive history, or parents with an affected child, should seek genetic counseling to discuss the risks of occurrence and recurrence. The overall risk for nonsyndromic clefts is 1% in the general population. Recurrence risks for subsequent pregnancies depend on whether the child has either CL with or without CP (CL±P) or isolated CP. If the family has one affected parent or one child with CL±P, the risk that a subsequent sibling will have CL±P increases to 4%; 2 prior children with CL±P increase this risk to 9%.5,17 This risk further increases to 17% in subsequent pregnancies if one parent and one child have CL±P.5 In the case described above, the mother’s risk for of having another child with CL±P is 4%, an increase from a risk of 1% in the general population.

For families with a history of CP, if the parents are unaffected and have one child with CP, the risk increases to 2% with a subsequent pregnancy. If one parent has CP, this risk increases to 6%. If one parent and one child have CP, the risk increases to 15% for a future sibling.5,17

A population-based cohort study in Denmark showed that persons affected with more severe orofacial clefts have a higher recurrence risk among both offspring and their siblings; the recurrence risk for siblings of a proband with isolated bilateral CLP was 4.6% versus 2.5% for siblings of a proband with a unilateral orofacial cleft.18

Most orofacial cleft cases are nonsyndromic and have no clearly defined cause.10 An estimated 70% of patients with CL±P and 50% of patients with CP are nonsyndromic.19 Approximately 30% of orofacial clefts are syndromic and are associated with a genetic syndrome. Nearly 33% of cases of CL±P are syndromic, whereas up to 50% of cases of isolated CP are syndromic.19 

Among the genetic syndromes associated with orofacial clefts are Waardenburg syndrome, Pierre Robin sequence, Crouzon syndrome, and trisomy 13 syndrome.4,20 Van der Woude syndrome is the most common genetic syndrome due to an autosomal dominant gene and associated with CLP plus lower lip pits or mucous cysts.10

Diagnosis and Management

Orofacial clefts can be detected with prenatal ultrasonography. CL can be diagnosed using 2-dimensional ultrasonography in the second trimester of pregnancy with the correct positioning of the fetal face.2,21 However, many craniofacial malformations more commonly are diagnosed postnatally. Minor palatal clefts (eg, submucous cleft palate, bifid uvula) may not be diagnosed until years later in life. Submucous cleft palate, in which the palate has a muscle discontinuity but with intact overlying mucosa, has an approximate prevalence of 0.8 cases per 1,000 births.10

Newer techniques for prenatal diagnosis of orofacial clefts use 3- and 4-dimensional prenatal ultrasonography. These imaging modalities allow for easier and more precise evaluation of different facial components and cleft definition.2,22

Treatment and continuing care of children with orofacial clefts depend on the severity and location of the cleft(s), the patient’s age and overall health, and the presence of additional congenital defects and/or other clinical findings suggestive of a genetic syndrome. 

Newborns with orofacial clefts require care from a multidisciplinary medical and surgical team for assessment, treatment, and continued coordinated care. The team’s objective is to maximize the patient’s final functional and aesthetic outcome. This coordinated team at minimum should include a pediatrician, a geneticist, an oral-maxillofacial surgeon, a plastic surgeon, an otolaryngologist, an audiologist, a speech pathologist, a pediatric dentist, an orthodontist, a dietitian, and a psychologist or social worker.

Infant and early childhood complications associated with orofacial clefts vary with the degree and location of the cleft(s).4 These complications can include the following:

Nutritional problems. Oral feeding difficulties occur because infants cannot create adequate suction to draw milk through a standard nipple. Difficulty with breastfeeding also arises. Special feeding techniques and orofacial cleft nipples help milk flow to support adequate nutritional needs for an infant’s proper growth. Nutritionists and occupational therapists can assist parents and caregivers in the infant’s care.

Respiratory problems. In newborns, malformations of the palate and jaw can make breathing difficult, such as in infants diagnosed with Pierre Robin sequence. Surgery and the use of oral appliances may be indicated.

Otitis media with effusion (OME) and hearing loss. Malformations of the upper airway can affect Eustachian tube function and drainage, leading to an increased risk of fluid persisting in the middle ear chamber. Persistent OME is reported in 80% to 95% of children with CP. Conductive hearing loss is a significant concern. Insertion of tympanostomy tubes can alleviate persistent middle-ear effusion and help restore impaired hearing.4

Speech and language delay. Normal development of the lips and palate are essential to a child’s ability to form sounds, enunciate, and speak clearly. Craniofacial surgery may be indicated to repair facial structures. Audiologic evaluation is critical. Speech therapy can assist with language development and speech impediments.

Dental anomalies. Orofacial clefts involving the gums and jaw can impact dental development and jaw alignment. Referral to a pediatric dentist and/or orthodontist is indicated.4

Surgical nostril and CL repair is recommended at 10 to 12 weeks of age, given that the infant is thriving and demonstrating adequate weight gain and has stable health without signs of infection.4 At 2.5 to 3 months of age, the infant’s lip has grown in size to allow for better overall alignment of lip elements and of the vermillion border.23 To clear patients for surgical repair, craniofacial surgery teams have used the rule of 10s23,24: age of at least 10 weeks, weight of at least 10 pounds, hemoglobin level of at least 10 g/dL, and a white blood cell count of less than 10,000/µL.

The Millard rotation-advancement procedure (cheiloplasty), pioneered by plastic surgeon Ralph Millard, is the most common surgical procedure used for unilateral CL repair. When the CL is bilateral and extensive, separate surgeries may be required to close the cleft first on one side with subsequent repair of the other side weeks later. Achieving facial symmetry is very important in this surgical repair. If CL repair is not possible at 10 weeks of age, it is strongly recommended to occur within the first year of life.25 CP repair, also called palatoplasty, is recommended between 9 and 18 months of age.4,25

As a child gets older, additional craniofacial surgeries may be needed for cosmetic improvement. The objectives of orofacial cleft surgery are to obtain good clinical outcomes in philtrum size and definition, lip shape, nasal cartilage positioning, and orofacial muscular continuity. Older children with cleft repairs may have concerns about their facial appearance and how it differs from unaffected children. Nasal speech quality and word enunciation difficulties can be concerns in older peer groups. Poor self-esteem and social isolation indicate a need for referral for psychological support or psychiatric care. An adolescent male may grow a mustache to hide visible upper-lip surgical scars.

Orofacial clefts are correctable anomalies that should not handicap those affected with them. With appropriate multidisciplinary health care, mental health support, and continuity of care, patients born with orofacial clefts can succeed and lead healthy, productive lives.

Germaine L. Defendi, MD, MS, is an associate clinical professor of pediatrics at Olive View–UCLA Medical Center in Sylmar, California.

References

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3. Parker SE, Mai CT, Canfield MA, et al; National Birth Defects Prevention Network. Updated national birth prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res A Clin Mol Teratol. 2010;88(12):1008-1016.

4. Cleft lip and cleft palate. American Academy of Otolaryngology-–Head and Neck Surgery. http://www.entnet.org/content/cleft-lip-and-cleft-palate. Updated October 13, 2011. Accessed December 18, 2014.

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10. Sperber GH, Sperber SM. Embryogenetics of cleft lip and palate. In: Berkowitz S, ed. Cleft Lip and Palate: Diagnosis and Management. 3rd ed. New York, NY: Springer; 2013:3-34.

11. Fraser FC. The genetics of cleft lip and palate. Am J Hum Genet. 1970(3);22:336-352.

12. Correa A, Gilboa SM, Besser LM, et al; National Birth Defects Prevention Study. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;199(3):237.e1-237.e9.

13. Margulis AV, Mitchell AA, Gilboa SM, et al; National Birth Defects Prevention Study. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol. 2012;207(5):405.e1-405.e7.

14. Werler MM, Ahrens KA, Bosco JLF, et al; National Birth Defects Prevention Study. Use of antiepileptic medications in pregnancy in relation to risks of birth defects. Ann Epidemiol. 2011;21(11):842-850.

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16. Herkrath AP, Herkrath FJ, Rebelo MA, Vettore MV. Parental age as a risk factor for non-syndromic oral clefts: a meta-analysis. J Dent. 2012;40(1):3-14.

17. Slavkin HC. Incidence of cleft lips, palates rising. J Am Dent Assoc. 1992;123(11):61-65.

18. Grosen D, Chevrier C, Skytthe A, et al. A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance. J Med Genet. 2010;47(3):162-168.

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20. Jones KL. Genetics, genetic counseling, and prevention. In: Jones KL. Smith’s Recognizable Patterns of Human Malformation. 4th ed. Philadelphia, PA: WB Saunders; 1988:706-727.

21. Centers for Disease Control and Prevention. Facts about cleft lip and cleft palate. http://www.cdc.gov/ncbddd/birthdefects/cleftlip.html. Updated October 20, 2014. Accessed November 18, 2014.

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23. Wilhelmsen HR, Musgrave RH. Complications of cleft lip surgery. Cleft Palate J. 1966;3(3):223-231.

24. Lydiatt DD, Yonkers AJ, Schall DG. The management of the cleft lip and palate patient. Nebr Med J. 1989;74 (11):325-328.

25. American Cleft Palate-Craniofacial Association. Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. Cleft Palate Craniofac J. 1993;30(suppl 1):S1-S16.