Pediatric Cleft Lip and Palate

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Updated: Nov 30, 2015
  • Author: Marie M Tolarova, MD, PhD, DSc; Chief Editor: Ravindhra G Elluru, MD, PhD  more...
Overview

Background

Orofacial clefts—including cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) alone, as well as median, lateral (transversal), and oblique facial clefts—are among the most common congenital anomalies. [1] Approximately 1 case of orofacial cleft occurs in every 500-550 births. The prevalence varies by ethnicity, country, and socioeconomic status. Nonsyndromic CLP, which forms the largest subgroup of craniofacial anomalies, occurs in the range of 1.5-2.5 cases per 1000 live 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 multidisciplinary treatment and care; the conservative 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. [2] In addition, these children and their families often experience serious psychological problems.

With rapidly advancing knowledge in medical genetics and with new DNA diagnostic technologies, more cleft lip and palate anomalies are diagnosed prenatally and more orofacial clefts 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 two basic categories of orofacial clefts—namely, CL with or without CP (CL/P) and CP alone [3] —these clefts can now be more accurately classified.

The correct diagnosis of a cleft anomaly is fundamental for treatment, for further genetic and etiopathologic studies, and for preventive measures correctly targeting the category of preventable orofacial clefts.

For patient education resources, see the Children's Health Center.

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Pathophysiology

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. CL 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 CL and cleft of the alveolus.) If the fusion of palatal shelves is impaired also, the CL is accompanied by CP, forming the CLP abnormality.

CP 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 CP.

Classification

The group of orofacial cleft anomalies is heterogeneous. It comprises typical orofacial clefts (eg, CL, CLP, and CP) and atypical clefts (eg, median, transversal, oblique, and other Tessier types of facial clefts). [5, 6] 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 the image below).

Classification of orofacial clefts. Classification of orofacial clefts.

The varying physical characteristics of CL, CP, and CLP, as well as further issues in classification, are discussed in greater detail in Presentation.

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Etiology

Most orofacial clefts, like most common congenital anomalies, are caused by the interaction between genetic and environmental factors (see the image below).

Etiology of cleft lip and palate anomalies. Etiology of cleft lip and palate anomalies.

In those instances, genetic factors create a susceptibility for clefts. When environmental factors (ie, triggers) interact with a genetically susceptible genotype, a cleft develops during an early stage of development.

The proportion of environmental and genetic factors varies with the sex of the individual affected with cleft. In CL and CP, 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 the first image below) can be applied to CL/P as the multifactorial model of liability with four different thresholds (see the second image below).

Multifactorial threshold model for the distributio Multifactorial threshold model for the distribution of liability for cleft lip and palate.
Four-threshold multifactorial threshold model of t Four-threshold multifactorial threshold model of the liability for cleft lip and palate.

This model can facilitate understanding of differences in values of risk of recurrence as well as differences in prevention approaches between different subgroups of clefts. [7]

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 was confirmed in a large, population-based study of whites with clefts (see the image below). [7]

Decreased occurrence of orofacial clefts. Decreased occurrence of orofacial clefts.

The value of heritability expresses a ratio of genetic and nongenetic factors. Heritability is equal to 1 for conditions completely controlled by genetic factors and equal to 0 for conditions completely controlled by environmental factors.

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 etiologic 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 CL/P. 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 Treatment, Prevention).

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—for instance, by slowing down migration or multiplication 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

Considerable interest has developed in the identification of genes that contribute to the etiology of orofacial clefting. Advances in modern molecular biology, newer 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. [8]

The first candidate gene was transforming growth factor-α (TGFA), which showed an association with nonsyndromic CLP in a white population. [9] Lidral et al investigated five different genes (TGFA, BCL3, DLX2, MSX1, TGFB3) in a largely white population from Iowa. [10, 11] They found a significant linkage disequilibrium between CL/P 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 model [12] and the linkage disequilibrium studies. [13, 11, 14]

Other candidate genes that show an association with nonsyndromic CLP 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. 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. [15] Some have proposed that cleft palate in MSX1 knock-out mice is due to insufficiency of the palatal mesenchyme. [16]

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. [17] 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). [18]

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). [19]

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. [14, 20] 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 on the basis of data that suggest that folic acid supplementation can reduce incidence of nonsyndromic cleft lip and palate. [21]

More than 30 potential candidate loci and candidate genes throughout the human genome have been 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. [18, 22, 23]  

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. [24] Kaartinen demonstrated that mice lacking the TGFB3 peptide exhibit cleft palate. [12] In addition, the exogenous TGFB3 peptide can induce palatal fusion in chicken embryos, although the cleft palate is a normal feature in chickens. [25]

In humans, association studies between the TGFB3 gene and nonsyndromic CL/P showed conflicting results. Lidral reported failure to observe an association of a new allelic variant of TGFB3 with nonsyndromic CL/P in a case-control study of the Philippines’ population. [10] Another study by Tanabe analyzed DNA samples from 43 Japanese patients and compared results with those from 73 control subjects with respect to four candidate genes, including TGFB3. [26] No significant differences in variants of TGFB3 between case and control populations were observed.

On the other hand, subsequent case-control association studies, family-based studies, and genome scans supported a role of TGFB3 in cleft development. Beaty examined markers in five candidate genes in 269 case-parent trios ascertained through a child with nonsyndromic orofacial clefts; [14] 85% of the probands in the study were white. Markers at two of the five 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. [27] A joint analysis of MSX1 and TGFB3 suggested a possible interaction between these two 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 CL/P. The population study consisted of 28 patients with nonsyndromic CL with or without CP and 41 healthy controls. [28]

In 2004, Marazita performed a meta-analysis of 13 genome scans of 388 extended multiplex families with nonsyndromic CL/P. [18] The families came from seven diverse populations including 2551 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 CL/P were analyzed by using TGFB3 CA repeat polymorphic marker. On the basis of 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. [29]

A study by Ichikawa et al investigated the relationship between nonsyndromic CL/P and seven candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) in a Japanese population. [30] 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 CL/P, especially IVS+5321(rs2300607). [30] 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 CL/P in Japanese patients.

A study by Bu et al found evidence of an association between nonsyndromic CLP and SNPs in FOXF2 (6p25.3). [31]

Several micromanifestations of orofacial clefts have been studied, [32, 33] and additional candidate genes associated with these minimal, clinically less significant anomalies have been suggested. [32, 34]

Associations of specific candidate genes with nonsyndromic CL/P 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 CL/P 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 CL/P has gained an increased importance.

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Epidemiology

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 CL, CLP, and CP is often used in statistics, combining the two etiologically different groups (ie, CL/P and CP alone) 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 CL/P, the sex ratio correlates with the severity and laterality of the cleft. A large study of 8952 orofacial clefts in whites found the male-to-female sex ratio to be 1.5-1.59:1 for CL, 1.98-2.07:1 for CLP, and 0.72-0.74:1 for CP. [7]

The prevalence of clefts varies considerably in different racial groups. The lowest rate is for blacks. A high prevalence of CL/P 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 CP. In particular, its prevalence did not significantly vary between black and white infants or between infants of Japanese and European origin in Hawaii. Leck considered that such findings may reflect a higher etiologic heterogeneity of CP than of CL/P. Methods of ascertainment and classification criteria undoubtedly influence prevalence figures. [5]

In a large population-based study of 4433 children born with orofacial cleft (ascertained from 2,509,881 California births), the birth prevalence of nonsyndromic CL/P was 0.77 per 1000 births (CL, 0.29/1000; CP, 0.48/1000), and the prevalence of nonsyndromic CP was 0.31 per 1000 births (see the image below). [35]

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

In that study, the risk of CL/P was slightly lower among the offspring of non–US-born Chinese women compared to US-born Chinese women and slightly higher among non–US-born Filipinos relative to their US-born counterparts. For CP, lower prevalences were observed among blacks and Hispanics than among whites. The risk of CP was higher among non–US-born Filipinos compared to US-born Filipinos. These prevalence variations may reflect differences in both environmental and genetic factors affecting risk for development of orofacial cleft.

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 CL/P, the hypothetical four-threshold model (see Etiology) closely corresponds with differences in the risk of recurrence.

From a clinical point of view, the following two factors are most important in evaluating the risk of recurrence for CL/P:

  • Sex of the individuals (ie, patient and individual at risk)
  • Severity of the effect in the patient (eg, unilateral vs bilateral)

The lowest recurrence risk for CL/P is for the subcategory of male patients with unilateral cleft (see the first image below) and, within this category, for sisters of males with a unilateral cleft and for daughters of fathers with a unilateral CL/P (see the second image below). 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 Recurrence risk in cleft lip with or without cleft palate.
Highest and lowest risk of recurrence of cleft lip Highest and lowest risk of recurrence of cleft lip with or without cleft palate.

The risk of recurrence for CP seems to be influenced only by sex. The risk is highest for daughters of fathers affected with a CP and lowest for sons of mothers affected with a CP (see the image below).

Recurrence risk in cleft palate. Recurrence risk in cleft palate.
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