eMedicine Specialties > Pediatrics: Surgery > Otolaryngology

Cleft Lip and Palate

Marie M Tolarova, MD, PhD, DSc, Professor and Executive Director, UOP Craniofacial Team, Cleft Prevention Program, Department of Orthodontics, University of the Pacific School of Dentistry

Updated: Mar 23, 2009

Introduction

Orofacial clefts (ie, cleft lip [CL], cleft lip and palate [CLP], cleft palate [CP] alone, as well as median, lateral [transversal], oblique facial clefts) are among the most common congenital anomalies. Approximately 1 case of orofacial cleft occurs in every 500-550 births. In the United States, 20 infants are born with an orofacial cleft on an average day, or 7500 every year. Children who have an orofacial cleft require several surgical procedures and complex medical treatments; the estimated lifetime medical cost for each child with an orofacial cleft is $100,000, amounting to $750 million for all children with orofacial cleft born each year in the United States.¹ Also, these children and their families often experience serious psychological problems.

With rapidly advancing knowledge in medical genetics and with new DNA diagnostic technologies, more and more orofacial clefts are identified as syndromic. Although the basic rate of clefting (1:500 to 1:550) has not changed since Fogh-Andersen performed his pioneering 1942 genetic study distinguishing 2 basic categories of orofacial clefts (cleft lip with or without cleft palate [CL/P] and cleft palate alone), these clefts can now be more accurately classified. The correct diagnosis of a cleft anomaly is fundamental for treatment, for further genetic and etiopathological studies, and for preventive measures correctly targeting the category of preventable orofacial clefts.

Problem

Classification and diagnostics

The group of orofacial cleft anomalies is heterogeneous. It comprises typical orofacial clefts (eg, cleft lip, cleft lip and palate, cleft palate) and atypical clefts, including median, transversal, oblique, and other Tessier types of facial clefts.^2,3 Typical and atypical clefts can both occur as an isolated anomaly, as part of a sequence of a primary defect, or as a multiple congenital anomaly (MCA). In an MCA, the cleft anomaly could be part of a known monogenic syndrome, part of a chromosomal aberration, part of an association, or part of a complex of MCA of unknown etiology (see Media file 1).

Classification of orofacial clefts.

Examples of cleft lip.

When cleft lip continues from the foramen incisivum further through the sutura palatina in the middle of the palate, a cleft lip and palate (either unilateral or bilateral) is present (see Media file 3).

Examples of cleft lip and palate.

Cleft palate (Media files 4-5) is etiologically and embryologically different from cleft lip with or without cleft palate.

Examples of cleft palate.

Submucous cleft palate.

Examples of cleft palate.

In a significant proportion of patients, the cleft of the hard palate is covered by mucosa and continues through the soft palate, forming a so-called submucous cleft palate. A submucous CP may occur in the hard palate only and continue to the open cleft of the soft palate, or it may occur as a submucous cleft of the soft palate with or without a notch into the hard palate. Careful clinical examination may reveal a blue triangle in continuation of the cleft of the soft palate, which represents a cleft of the bone palate underneath mucosa (see Media file 5).

Submucous cleft palate.

As is described below, the cleft palate posterior to the incisive foramen is defined as the cleft of the secondary palate. Cleft lip and cleft of the palate anterior to the incisive foramen (unilateral or bilateral) is defined as the cleft of primary palate (thus, in bilateral cleft lip, premaxilla is separated from lateral palatal segments). The bifid uvula is a sign that adenoidectomy may result in hypernasal speech if a complete adenoidectomy is done.

Embryology

In facial morphogenesis, neural crest cells migrate into the facial region, where they form the skeletal and connective tissue and all dental tissues except the enamel. Vascular endothelium and muscle are of mesodermal origin.⁴

The upper lip is derived from medial nasal and maxillary processes. Failure of merging between the medial nasal and maxillary processes at 5 weeks' gestation, on one or both sides, results in cleft lip. Cleft lip usually occurs at the junction between the central and lateral parts of the upper lip on either side. The cleft may affect only the upper lip, or it may extend more deeply into the maxilla and the primary palate. (Cleft of the primary palate includes cleft lip and cleft of the alveolus.) If the fusion of palatal shelves is impaired also, the cleft lip is accompanied by cleft palate, forming the cleft lip and palate abnormality.

Cleft palate is a partial or total lack of fusion of palatal shelves. It can occur in numerous ways:

• Defective growth of palatal shelves
• Failure of the shelves to attain a horizontal position
• Lack of contact between shelves
• Rupture after fusion of shelves

The secondary palate develops from the right and left palatal processes. Fusion of palatal shelves begins at 8 weeks' gestation and continues usually until 12 weeks' gestation. One hypothesis is that a threshold is noted beyond which delayed movement of palatal shelves does not allow closure to take place, and this results in a cleft palate.

Cleft lip can be easily diagnosed by performing ultrasonography in the second trimester of pregnancy when the position of the fetal face is located correctly (see Media files 6-7).
 

Bilateral cleft lip on ultrasound.

Median cleft lip on ultrasound.

Frequency

Reported data on the frequency of orofacial clefts vary according to the investigator and the country. In general, all typical orofacial cleft types combined occur in white populations with a frequency of 1 per 500-550 live births. Although the total combined frequency of cleft lip, cleft lip and palate, and cleft palate is often used in statistics, combining the 2 etiologically different groups (cleft lip with or without cleft palate and cleft palate) represents a misclassification bias similar to that of combining clefts with other congenital malformations.

The sex ratio in patients with clefts varies. In whites, cleft lip and cleft lip and palate occur significantly more often in males, and cleft palate occurs significantly more often in females. In cleft lip with or without cleft palate, the sex ratio correlates with the severity and laterality of the cleft. A large study of 8,952 orofacial clefts in whites found the male-to-female sex ratio to be 1.5-1.59:1 for cleft lip, 1.98-2.07:1 for cleft lip and palate, and 0.72-0.74:1 for cleft palate.⁵

The prevalence rate of clefts in different racial groups is considerable. The lowest rate is for blacks. A high prevalence of cleft lip with or without cleft palate was found for the Japanese population, and the highest prevalence was found for the North American Indian populations. In contrast, no remarkable variation among races was found in isolated cleft palate. In particular, its prevalence did not significantly vary between black and white infants or between infants of Japanese and European origin in Hawaii. Leck (1984) considered that such findings may reflect a higher etiological heterogeneity of cleft palate than of cleft lip with or without cleft palate. Methods of ascertainment and classification criteria undoubtedly have major influence on the prevalence values.²

In a large population-based study of 4,433 children born with orofacial cleft (ascertained from 2,509,881 California births), the birth prevalence of nonsyndromic cleft lip with or without cleft palate was 0.77 per 1,000 births (cleft lip, 0.29/1,000; cleft palate, 0.48/1,000) and prevalence of nonsyndromic cleft palate was 0.31 per 1,000 births (see Media file 8).⁶

Prevalence of orofacial clefts (Tolarova and Cervenka, 1998).

Risk of recurrence

Genetic factors (ie, genes participating in the etiology of nonsyndromic orofacial clefts) are passed to the next generation, thus creating an increased risk for such anomaly in offspring. The risk of recurrence also differs with respect to proportion of genetic and nongenetic factors. In cleft lip with or without cleft palate, the hypothetical 4-threshold model (see Etiology) closely corresponds with differences in the risk of recurrence.

From a clinical point of view, 2 factors are most important when evaluating the risk of recurrence for cleft lip with or without cleft palate: the sex of the individuals (ie, patient and individual at risk) and the severity of the affect in the patient (eg, unilateral vs bilateral). The lowest recurrence risk for cleft lip with or without cleft palate is for the subcategory of male patients with unilateral cleft (see Media file 9) and, within this category, for sisters of males with a unilateral cleft and for daughters of fathers with a unilateral cleft lip with or without cleft palate (see Media file 10). The highest risk of recurrence of CL/P is for the subcategory of female patients affected with a bilateral CL/P.

Recurrence risk in cleft lip with or without cleft palate.

Highest and lowest risk of recurrence of cleft lip with or without cleft palate.

Recurrence risk in cleft palate.

Etiology

Etiology of cleft lip and palate anomalies.

The proportion of environmental and genetic factors varies with the sex of the individual affected with cleft. In cleft lip and cleft palate, it also varies with the severity and the unilaterality or bilaterality of the cleft anomaly; the highest proportion of genetic factors are in the subgroup of females with a bilateral cleft, and the smallest proportion is in the subgroup of males with a unilateral cleft.

Thus, the classic multifactorial threshold (MFT) model of liability (see Media file 13) can be applied to cleft lip with or without cleft palate as the multifactorial model of liability with 4 different thresholds (see Media file 14).

Multifactorial threshold model for the distribution of liability for cleft lip and palate.

Four-threshold multifactorial threshold model of the liability for cleft lip and palate.

Theoretically, the subgroup of clefts closest to the population average should have the highest population prevalence, the lowest value of heritability, and, thus, the lowest risk of recurrence. This has been confirmed on a large, population-based study of whites with clefts (see Media file 19).⁵

Decreased occurrence of orofacial clefts.

A higher proportion of environmental factors indicates a lower risk of recurrence and also gives a better chance to act in prevention, because the only etiological factors that can be changed are environmental factors. Thus, the subgroup whose average prevalence is closest to the population average represents males affected with a unilateral cleft lip with or without cleft palate. This subgroup is most common among orofacial clefts; the risk of recurrence for siblings and for offspring of an individual with cleft is the lowest, the value of heritability is the lowest, and efficacy of primary prevention is the highest (see details for other subgroups in Future and Controversies).

As mentioned in the previous section, a cleft develops when embryonic parts called processes (which are programmed to grow, move, and join with each other to form an individual part of the embryo) do not reach each other in time and an open space (cleft) between them persists. In the normal situation, the processes grow into an open space by means of cellular migration and multiplication, touch each other, and fuse together.

In general, any factor that could prevent the processes from reaching each other by slowing down migration, multiplication, or both of neural crest cells by stopping tissue growth and development for a time or by killing some cells that are already in that location would cause a persistence of a cleft. Also, the epithelium that covers the mesenchyme may not undergo programmed cell death, so that fusion of processes cannot take place.⁴

DNA studies

Over the past decade, a considerable interest has developed in the identification of genes that contribute to the etiology of orofacial clefting. Advances in modern molecular biology, new methods of genome manipulation, and availability of complete genome sequences led to an understanding of the roles of particular genes that are associated with embryonic development of the orofacial complex.

The first candidate gene was transforming growth factor-a (TGFA), which showed an association with nonsyndromic cleft lip and palate (NCLP) in a white population.⁷ Lidral et al investigated 5 different genes (TGFA, BCL3, DLX2, MSX1, TGFB3) in a largely white population from Iowa.^8,9 They found a significant linkage disequilibrium between cleft lip with or without cleft palate and both MSX1 and TGFB3 and between CP and MSX1. The TGFB3 gene was identified as a strong candidate for clefting in humans based on both the mouse model¹⁰ and the linkage disequilibrium studies.^11,9,12 Other candidate genes that show an association with nonsyndromic cleft lip and palate include D4S192, RARA, MTHFR, RFC1, GABRB3, PVRL1, and IRF6.

MSX1 was found to be a strong candidate gene involved in orofacial clefts and dental anomalies. Recent analysis of the MSX1 sequence in a multiplex Dutch family showed that a nonsense mutation (Ser104stop) in exon 1 segregated with the phenotype of nonsyndromic cleft lip and palate.¹³ Some have proposed that cleft palate in MSX1 knock-out mice is due to insufficiency of the palatal mesenchyme.¹⁴

Zucchero et al reported that variants of IRF6 may be responsible for 12% of nonsyndromic cleft lip and palate, suggesting that this gene would play a substantial role in the causation of orofacial clefts.¹⁵ A meta-analysis of all-genome scans of subjects with nonsyndromic cleft lip and palate, including Filipino, Chinese, Indian, and Colombian families, found a significant evidence of linkage to the region that contains interferon regulatory factor 6 (IRF6).¹⁶

Also, gene-gene interactions have been examined. A complex interplay of several genes, each making a small contribution to the overall risk, may lead to formation of clefts. Jugessur et al reported a strong effect of the TGFA variant among children homozygous for the MSX1 A4 allele (9 CA repeats).¹⁷

Evaluation of gene-environment interactions is still in a preliminary stage. Studies of the role of smoking in TGFA and MSX1 as covariates suggested that these loci might be susceptible to detrimental effects of maternal smoking.^12,18 Folate-metabolizing enzymes such as methylenetetrahydrofolate reductase (MTHFR), which is a key player in etiology of neural tube defects, and RFC1 are considered candidate genes based on data that suggest that folic acid supplementation can reduce incidence of nonsyndromic cleft lip and palate.¹⁹

Recently, more than 30 potential candidate loci and candidate genes throughout the human genome were identified as strong susceptibility genes for orofacial clefts. The MSX1 (4p16.1), TGFA (2p13), TGFB1 (19q13.1), TGFB2 (1q41), TGFB3 (14q24), RARA (17q12), and MTHFR (1p36.3) genes are among the strongest candidates.^16,20,21

The TGFB3 gene was identified as a strong candidate for clefting in humans based on a mouse model. Generally, palatogenesis in mice parallels that of humans and shows that comparable genes are involved.²² Kaartinen demonstrated that mice lacking the TGFB3 peptide exhibit cleft palate.¹⁰ In addition, the exogenous TGFB3 peptide can induce palatal fusion in chicken embryos, although the cleft palate is a normal feature in chickens.²³

In humans, association studies between the TGFB3 gene and nonsyndromic cleft lip with or without cleft palate have shown conflicting results. Lidral reported failure to observe an association of a new allelic variant of TGFB3 with nonsyndromic cleft lip with or without cleft palate in a case-control study of the Philippines' population.⁸ Another study by Tanabe analyzed DNA samples from 43 Japanese patients and compared results with those from 73 control subjects with respect to 4 candidate genes, including TGFB3.²⁴ No significant differences in variants of TGFB3 between case and control populations were observed.

On the other hand, more recent case-control association studies, family based studies, and genome scans have supported a role of TGFB3 in cleft development. Beaty examined markers in 5 candidate genes in 269 case-parent trios ascertained through a child with nonsyndromic orofacial clefts;¹²  85% of the probands in the study were white. Markers at 2 of the 5 candidate genes (TGFB3 and MSX1) showed consistent evidence of linkage and disequilibrium due to linkage. Similarly, Vieira attempted to detect transmission distortion of MSX1 and TGFB3 in 217 South American children from their respective mothers.²⁵ A joint analysis of MSX1 and TGFB3 suggested a possible interaction between these 2 genes, increasing cleft susceptibility. These results suggest that MSX1 and TGFB3 mutations make a contribution to clefts in South American populations.

In a study of the Korean population, Kim reported that the G allele at the SfaN1 polymorphism of TGFB3 is associated with an increased risk of nonsyndromic cleft lip with or without cleft palate. The population study consisted of 28 patients with nonsyndromic cleft lip with or without cleft palate and 41 healthy controls.²⁶

In 2004, Marazita performed a meta-analysis of 13 genome scans of 388 extended multiplex families with nonsyndromic cleft lip with or without cleft palate.¹⁶ The families came from 7 diverse populations including 2,551 genotyped individuals. The meta-analysis revealed multiple genes in 6 chromosomal regions including the region containing TGFB3 (14q24).

In the Japanese population, blood samples from 20 families with nonsyndromic cleft lip with or without cleft palate have been analyzed using TGFB3 CA repeat polymorphic marker. Based on the results of the study, the investigators concluded that either the TGFB3 gene itself or an adjacent DNA sequence may contribute to the development of cleft lip and palate.²⁷  

Another study by Ichikawa and colleagues, investigated the relationship between nonsyndromic cleft lip with or without cleft palate and 7 candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) in a Japanese population.²⁸ The sample consisted of 112 patients with their parents and 192 controls. Both population based case-control analysis and family based transmission disequilibrium test (TDT) were used. The results showed significant associations of single nucleotide polymorphisms (SNPs) in TGFB3 and nonsyndromic cleft lip with or without cleft palate, especially IVS+5321(rs2300607), with a P value of 0.0016. Although IVS-1572 (rs2268625) alone did not show a significant difference between cases and controls, the haplotype "A/A" for rs2300607- rs2268625 showed significant association. The author concluded that the results demonstrated positive association of TGFB3 with nonsyndromic cleft lip with or without cleft palate in Japanese patients.

Several micromanifestations of orofacial clefts have been studied,^29,30 and additional candidate genes associated with these minimal, clinically less significant anomalies have been suggested.^29,31

Associations of specific candidate genes with nonsyndromic cleft lip and palate have not been found consistent across different populations. This may suggest that multiplicative effects of several candidate genes or gene-environmental interactions are noted in different populations.

The identification of factors that contribute to the etiology of nonsyndromic cleft lip and palate is important for prevention, treatment planning, and education. With an increasing number of couples who seek genetic counseling as a part of their family planning, the knowledge of how specific genes contribute to formation of nonsyndromic cleft lip and palate has gained an increased importance.

Indications

Children who have an orofacial cleft require several surgical procedures and complex medical treatments.

Treatment

Medical Therapy

Neonatal care

When a neonate with a cleft is born, a pediatrician has 3 major concerns:

• Risk of aspiration because of communication between oral and nasal cavities
• Airway obstruction (in addition to sequelae of aspiration, especially in Robin sequence in which the cleft palate [CP] is combined with micrognathia and the tongue has a normal size)
• Difficulties with feeding of a child with a cleft and nasal regurgitation

These 3 factors are influenced by the presence of other major or minor anomalies that may, in association with a cleft, represent 1 of 300 known cleft syndromes.⁴ Therefore, a neonate with an orofacial cleft should be seen by a medical geneticist as soon as possible.

As with any other medical condition, each case is different. A child with a severe cleft may do very well, whereas a child with a much less severe condition may experience many problems. An individual approach is necessary; however, several major rules apply to every neonate born with a cleft.

A pediatrician/neonatologist is usually the first person to take care of a neonate born with a cleft and the first to talk to the parents. As soon as possible, refer each baby born with orofacial cleft to the cleft palate or craniofacial center, where each specialist evaluates the baby, delineates the best management options and treatment plan, and continuously revises individual procedures and treatment during follow-up visits.

Feeding an infant with a cleft

The vast majority of children with cleft lip and palate (CLP) anomalies are born with a normal birth weight. However, because of feeding and other difficulties mentioned above, the most common problem the pediatrician has to deal with is insufficient weight gain. One of the pediatrician's main responsibilities is to closely monitor the infant's weight. Pediatricians may supervise mothers themselves or may refer them to a nutritionist, feeding specialist, experienced nurse practitioner, or other specialist.

Most children born with cleft lip and palate are unable to be breastfed. Those with cleft palate cannot produce the negative pressure necessary for suction. Mothers of children with a unilateral cleft lip may succeed with breastfeeding when the child is positioned so that the cleft in the lip is obstructed by the mother's breast.

No single right or correct method of feeding has been identified. Parents working together with the health care provider should choose the method that is best for their infant. Most infants can complete a feeding in 18-30 minutes. If more than 45 minutes is required, the infant may be working too hard and may be burning calories that should be used for weight gain. An infant who nurses or bottle feeds every 3-4 hours tends to gain weight better than an infant who feeds frequently (<2 h apart) for short periods.

Helpful hints for a parent are as follows:

• Breastfeeding an infant with a cleft
  • In a case of an isolated cleft lip, the infant typically does not experience feeding problems beyond learning how to "latch on" to the nipple at the beginning of the feeding. Infants with cleft palate must squeeze the milk out of the nipple by compressing the nipple between the tongue and whatever portion of the palate that remains.
  • Massaging the breast and applying hot packs on the breast 20 minutes before nursing usually helps.
  • The mother should apply pressure to the areola with her fingers to help the engorged nipple protrude. She should hold the infant in a semi-upright, straddle, or football position. She should support the breast by holding it between her thumb and middle finger, making sure that the infant's lower lip is turned out and the tongue is under the nipple.
  • If the infant cannot hold onto the nipple any more, the mother can collect the remaining milk using an electrical or manual breast pump or by squeezing the breast with both hands and can finish the feeding with collected milk in a bottle.
  • The mother should increase her fluid intake (drink lots of water).
• Feeding breast milk with a bottle
  • Particularly for infants with bilateral cleft lip and palate, breastfeeding is not possible.
  • The mother can use a breast pump (an electric pump ensures the highest level of success). Then, she can feed the baby with a bottle (see below).
• Feeding milk formula with a bottle
  • The most appropriate milk formula should be selected by a pediatrician or feeding specialist.
  • Various nipples and bottles are made specifically for infants with clefts. The goal is to find a nipple and bottle that make feeding easy for the infant and still allow ample opportunity to suck.
  • A soft nipple is generally better than a hard nipple (some can be softened by boiling).
  • Use a crosscut nipple to prevent choking. Any nipple can be crosscut manually using a single-edged razor blade. The crosscut is on the tongue side.
  • The bottle should be squeezed and released, not continually squeezed.
  • The nipple is angled to a side of the mouth, away from the cleft.
• Other recommendations
  • More upright or seated positions prevent the milk from leaking to the nose and causing the infant to choke.
  • Advise the mother to stop feeding and allow the infant to cough or sneeze for a few seconds when nasal regurgitation occurs. A palatal obturator may be used.

Gaining weight and preventing aspiration and ear infections are the most important parts of caring for neonates with a cleft during their first days and weeks of life.

Multidisciplinary team

Most individuals with cleft lip, cleft palate, or both (and many individuals with other craniofacial anomalies) require the coordinated care of providers in many fields of medicine and dentistry, as well as those in speech pathology, otolaryngology, audiology, genetics, nursing, mental health, and social medicine.

Treatment of cleft lip and palate anomalies requires years of specialized care and is costly. The average lifetime medical cost for treatment of one individual affected with a cleft lip and palate is $100,000.¹ Although successful treatment of the cosmetic and functional aspects of orofacial cleft anomalies is now possible, it is still challenging, lengthy, costly, and dependent on the skills and experience of a medical team. This especially applies to surgical, dental, and speech therapies. 

Because otitis media with effusion is very common among children with cleft palates, involvement of an otolaryngologist in the multidisciplinary treatment plan is very important. The otolaryngologist performs placement of ventilation tubes in conjunction with the cleft palate repair.³² If a concurrent cleft lip is present, the ventilation tubes are placed during that repair. Many of these children see otolaryngologists well beyond the time they see many of the other specialists because some children continue to have eustachian tube dysfunction after their palates are closed.

A team for the multidisciplinary treatment of a child with an orofacial cleft includes the following specialists:

• Pediatrician
• Nurse practitioner
• Plastic surgeon
• Pediatric dentist
• Otolaryngologist
• Geneticist
• Genetic counselor
• Speech pathologist
• Orthodontist
• Maxillofacial surgeon
• Social worker
• Psychologist

No single treatment concept has been identified, especially for a cleft lip and palate. The timing of the individual procedures varies in different centers and with different specialists.

Below is the most common treatment protocol presently used in most cleft treatment centers:

• Newborn - Diagnostic examination, general counseling of parents, feeding instructions, palatal obturator (if necessary); genetic evaluation and specification of diagnosis; empiric risk of recurrence of cleft calculated; recommendation of a protocol for the prevention of a cleft recurrence in the family
• Age 3 months - Repair of cleft lip (and placement of ventilation tubes)
• Age 6 months - Presurgical orthodontics, if necessary; first speech evaluation
• Age 9 months - Speech therapy begins
• Age 9-12 months - Repair of cleft palate (placement of ventilation tubes if not done at the time of cleft lip repair)
• Age 1-7 years - Orthodontic treatment
• Age 7-8 years - Alveolar bone graft
• Older than 8 years - Orthodontic treatment continues

Other surgical procedures can be performed in patients with severe clefts as necessary (see Surgical Therapy).

Surgical Therapy

Anatomical differences predispose children with cleft lip and palate and with isolated cleft palate to ear infections. Therefore, ventilation tubes are placed to ventilate the middle ear and prevent hearing loss secondary to otitis media with effusion. In multidisciplinary teams with significant participation of an otolaryngologist, the tubes are placed at the initial surgery and at the second surgery routinely. The hearing is tested after the first placement when ears are clear with tubes. If no cleft surgery is planned early, placing the tubes by age 6 months and monitoring hearing with repeated testing is recommended. Complications include eardrum perforation and otorrhea, particularly in patients with open secondary palates in which closure is planned for later.

For preventive reasons, ear tubes are usually placed when the child is still under general anesthesia for cleft repair.

The most common surgical procedures for a child with a cleft lip and palate anomaly are as follows:

• Repair of the cleft lip
• Repair of the cleft palate
• Revision of the cleft lip
• Closure and bone grafting of the alveolar cleft
• Closure of palatal fistulae
• Palatal lengthening
• Pharyngeal flap
• Pharyngoplasty
• Columellar lengthening
• Cleft lip rhinoplasty and septoplasty
• Lip scar revision
• LeFort I maxillary osteotomy

In addition, orthodontic treatment is very specialized and varies case by case. The 2 stages of orthodontic treatment of a child with cleft lip and palate are as follows:

• Surgery-related orthodontics
  • Early management (since birth until the time of surgical closure of the palate)
  • Orthodontics related to alveolar bone graft
  • Permanent dentition management
• Cleft-related orthodontics (not related to surgical treatments)

Patient Education

For excellent patient education resources, visit eMedicine's Children's Health Center.

Future and Controversies

Available research on the association between orofacial clefts and folic acid consumption highly suggests that a certain proportion of these serious anomalies can be prevented by periconceptional supplementation of folic acid and multivitamins. The preventive approach is assumed to be especially successful in those situations in which environmental factors represent a substantial part of the etiological background.

Primary prevention (ie, prevention of a birth defect before it develops in the embryo or fetus) is attempted for prevention of recurrences in at-risk families in which a previous baby with the anomaly has been born; it is also applicable in the general population for prevention of occurrences.

More than 20 years after the first studies in experimental animals indicated that vitamin deficiency in a mother could cause congenital malformations in the offspring,^33,34,35 formiminoglutamic acid excretion testing for defective folate metabolism was found to be positive more often in women pregnant with a child with a neural tube defect (NTD) or other congenital abnormality than in control subjects.³⁶ Furthermore, periconceptional supplementation with multivitamins³⁷ or folic acid (Laurence, 1981)³⁸ was found to have a role in the prevention of NTDs.

Nonetheless, prevention of congenital anomalies seemed impossible to realize as the ultimate goal of teratology,³⁹ until a randomized, controlled, double-blind, multicenter trial sponsored by the British Medical Research Council (MRC) showed a 72% decrease in the recurrence of NTDs when women ingested 4 mg/d of folic acid from the day of randomization before conception and during 12 weeks thereafter.^40,41

However, prophylactic multivitamin therapy, including folic acid, was first used to prevent cleft lip (CL) and palate (CLP) anomaly in future offspring of women whose first child had cleft lip with or without cleft palate (CL/P).^42,43,44

Based on the results of those studies, Burian (of the Czechoslovak Academy of Sciences in Prague) initiated a study in which women who had given birth to a child with an orofacial cleft began taking the multivitamin supplement preparation Spofavit (vitamins A, B-1, B-2, B-6, C, D-3, and E; nicotinamide; and calcium pathothenicum) either immediately after a subsequent pregnancy was confirmed or periconceptionally when pregnancy had been planned.⁴⁵ Although Burian's observations were mainly empirical, a prospective trial of periconceptional multivitamin and high folic acid supplementation was conducted in women at risk of giving birth to a child with a cleft lip with or without cleft palate.

In a nonrandomized interventional study completed in the Czech Republic, a dramatic reduction of cleft recurrences was found after periconceptional supplementation with multivitamins and a high dose of folic acid.^46,19 In this study, 221 pregnancies in women at risk for a child with a cleft lip and palate were prospectively evaluated. The 10-step protocol included multivitamin supplementation with Spofavit and folic acid (10 mg/d), beginning at least 2 months before planned conception and continuing for at least 3 months thereafter. A comparison group comprised 1901 women at risk of giving birth to a child with a cleft lip with or without cleft palate; this group received no supplementation and gave birth within the same period as the study group.

In the supplemented group, 3 of 214 informative pregnancies resulted in neonates with cleft lip with or without cleft palate, a 65.4% decrease from the expected value (see Media file 15).

Subset analysis by proband sex, severity of cleft lip with or without cleft palate, and both variables showed the highest supplementation efficacy in probands with unilateral cleft (82.6% decrease from the expected value).
 

Recurrence of clefts in supplemented and nonsupplemented groups.

Prevention of cleft lip and palate by periconceptional vitamin (with particularly high folic acid) supplementation.

Similarly, a large population-based case control study of fetuses and live-born infants in the 1987-1989 cohort of births in California reported that periconceptional use of multivitamins, which usually contain 0.4 mg or more of folic acid, reduced the occurrence of cleft lip with or without cleft palate by approximately 27-50% (see Media file 18).⁴⁷ In this study, 734 mothers with an infant with an orofacial cleft and 734 control mothers with an infant without a birth defect were evaluated.

Recurrence of clefts in supplemented and nonsupplemented groups, severity of cleft.

In contrast, the study completed by Hayes did not support a protective association between the periconceptional folic acid supplementation and the risk of oral cleft.⁴⁸

However, the most interesting results that strongly support using a high dose of folic acid in the prevention of nonsyndromic clefts are those of Czeizel and his colleagues in the Hungarian Case-Control Surveillance of Congenital Anomalies.^49,50 The Hungarian randomized double-blind, controlled trial of periconceptional supplementation with a multivitamin including a low "physiologic" (as the authors call it) dose of folic acid (0.8 mg/d) did not show any preventive effect on the first occurrence of isolated cleft lip with or without cleft palate and cleft palate alone.^49,50 However, the general evaluation of congenital anomalies in this study indicated a reduction of nonsyndromic clefts after the use of high doses of folic acid (3-9 mg/d) in the early postconception period.⁵⁰

Czeizel's latest article discusses these 2 controversial findings and suggests a "dose-dependent effect" of folic acid in the prevention of orofacial clefts.⁴⁹

Multimedia

Media file 1: Classification of orofacial clefts.

Media file 2: Examples of cleft lip.

Media file 3: Examples of cleft lip and palate.

Media file 4: Examples of cleft palate.

Media file 5: Submucous cleft palate.

Media file 6: Bilateral cleft lip on ultrasound.

Media file 7: Median cleft lip on ultrasound.

Media file 8: Prevalence of orofacial clefts (Tolarova and Cervenka, 1998).

Media file 9: Recurrence risk in cleft lip with or without cleft palate.

Media file 10: Highest and lowest risk of recurrence of cleft lip with or without cleft palate.

Media file 11: Recurrence risk in cleft palate.

Media file 12: Etiology of cleft lip and palate anomalies.

Media file 13: Multifactorial threshold model for the distribution of liability for cleft lip and palate.

Media file 14: Four-threshold multifactorial threshold model of the liability for cleft lip and palate.

Media file 15: Four categories of 4-threshold model of liability for cleft lip with or without cleft palate (Tolarova, 1990).

Presentation available at http://img.medscape.com/pi/emed/ckb/pediatrics_surgery/1331340-1331352-995535-995656.ppt.

Media file 16: Recurrence of clefts in supplemented and nonsupplemented groups.

Media file 17: Prevention of cleft lip and palate by periconceptional vitamin (with particularly high folic acid) supplementation.

Media file 18: Recurrence of clefts in supplemented and nonsupplemented groups, severity of cleft.

Media file 19: Decreased occurrence of orofacial clefts.

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Keywords

cleft lip and palate, orofacial cleft, orofacial clefts, facial cleft, facial clefts, cleft lip, CL, cleft lip and palate, CLP, cleft lip with or without cleft palate, CL/P, cleft palate, CP, oral cleft, infant with a cleft, neural tube defect, NTD, folic acid supplementation, CLP anomaly, orofacial anomaly, congenital anomaly, unilateral anomaly, bilateral anomaly, unilateral cleft, bilateral cleft, neural crest cells, palate cleft, Robin sequence, multiple congenital anomaly, Pierre Robin malformation

Contributor Information and Disclosures

Author

Marie M Tolarova, MD, PhD, DSc, Professor and Executive Director, UOP Craniofacial Team, Cleft Prevention Program, Department of Orthodontics, University of the Pacific School of Dentistry
Marie M Tolarova, MD, PhD, DSc is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American Society of Human Genetics, and International Association for Dental Research
Disclosure: Nothing to disclose.

Medical Editor

Orval Brown, MD, Director of Otolaryngology Clinic, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center at Dallas
Orval Brown, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, American Bronchoesophagological Association, American College of Surgeons, American Medical Association, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, and Society of University Otolaryngologists-Head and Neck Surgeons
Disclosure: Nothing to disclose.

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Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Alan D Murray, MD, Pediatric Otolaryngologist, ENT for Children; Full-Time Staff, Medical City Dallas Children's Hospital; Consulting Staff, Department of Otolaryngology, Medical Center of Lewisville, Children's Medical Center at Dallas, Cook Children's Medical Center; Full-Time Staff, Texas Pediatric Surgery Center, The Pediatric Surgery Center
Alan D Murray, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, American College of Surgeons, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, and Texas Medical Association
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center
Maureen Strafford, MD is a member of the following medical societies: American Medical Women's Association, American Pain Society, American Society of Anesthesiologists, International Anesthesia Research Society, Society for Education in Anesthesia, Society for Pediatric Anesthesia, and Society of Cardiovascular Anesthesiologists
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor HeeSoo Oh, DDS, PhD, to the original writing and development of this article.

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