Cleft Lip Case Study
Most orofacial clefts, like most common congenital anomalies, are caused by the interaction between genetic and environmental factors (see the image below).
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).
View Media Gallery
View Media Gallery
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. 
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). 
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. 
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. 
The first candidate gene was transforming growth factor-α (TGFA), which showed an association with nonsyndromic CLP in a white population.  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  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.  Some have proposed that cleft palate in MSX1 knock-out mice is due to insufficiency of the palatal mesenchyme. 
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.  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). 
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). 
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. 
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.  Kaartinen demonstrated that mice lacking the TGFB3 peptide exhibit cleft palate.  In addition, the exogenous TGFB3 peptide can induce palatal fusion in chicken embryos, although the cleft palate is a normal feature in chickens. 
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.  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.  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;  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.  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. 
In 2004, Marazita performed a meta-analysis of 13 genome scans of 388 extended multiplex families with nonsyndromic CL/P.  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. 
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.  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).  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). 
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.
Cleft lip and palate: series of unusual clinical cases
Lívia Máris Ribeiro ParanaíbaI; Roseli Teixeira de MirandaII; Daniella Reis Barbosa MartelliIII; Paulo Rogério Ferreti BonanIV; Hudson de AlmeidaV; Julian Miranda Orsi JúniorVI; Hercílio Martelli JúniorVII
IMSc in Stomatology - State University of Campinas - Unicamp; PhD student in Stomatology - Unicamp
IIPhD in Oral Diagnosis - University of São Paulo - USP, Professor of Stomatology - University of Alfenas
IIIMSc in Health Sciences - State University of Montes Claros - Unimontes, Professor of Semiology - Unimontes
IVPhD in Stomatology - State University of Campinas - Unicamp, Adjunct Professor - State University of Montes Claros - Unimontes
VResident Physician in Plastic Surgery - Professor at the Medical Sciences School - University of Alfenas
VIMSc in Health - University of Alfenas; Professor at the Dentistry School - University of Alfenas
VIIPhD; Full Professor
Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face, corresponding to approximately 65% of all malformations of the craniofacial region.
AIM: to describe unusual clinical cases of non-syndromic CL/P (CL/PNS), diagnosed in a reference service in Minas Gerais, Brazil, and correlate these alterations with possible risk factors.
MATERIALS AND METHODS: we carried out a retrospective study, between the years of 1992 and the 1st half of 2009, from medical records.
RESULTS: Among the 778 cases of CL/PNS diagnosed in the period of 17 years, 5 (0.64%) were unusual CL/PNS, and all patients were male. It was found that among the 5 patients, 2 had incomplete right cleft lip with incomplete cleft palate, 2 were affected by left incomplete cleft lip and incomplete cleft palate, and 1 had a cleft lip and palate associated with complete right cleft palate. Risk factors such as consanguinity, maternal smoking and alcohol consumption, medication usage during pregnancy, history of abortion and/or stillbirths and maternal diseases were not associated with unusual CL/PNS.
CONCLUSIONS: This study described 5 unusual cases of CL/PNS in a Brazilian population; no associations with the risk factors analyzed were seen. It also confirmed the unusualness of the prevalence of such alterations.
Keywords: congenital abnormalities, cleft lip, cleft palate.
Cleft lip and/or palate (CL/P) (OMIM 119530) represents the most common of the congenital facial anomalies, making up approximately 65% of all craniofacial malformations1. The incidence of CL/P is approximately 1 in every 500-2,000 live births, varying according to geographic location, race and the very social and economic situation of the population studied2,3. In Brazil, there are only a handful of studies as to the incidence of CL/P, and they vary considerably. According to Brazilian epidemiological surveys, the incidence of CL/P varies between 0.19 to 1.54 for every 1,000 births4-6. It is not known whether this epidemiological difference is real or associated with methodological differences6.
70% of the affected individuals develop non-syndromic CL/P, in other words, without association with other malformations and without behavioral and/or cognitive changes. The remaining 30% are associated with Mendelian disorders (dominant autosomal, recessive autosomal or x-linked), chromosomal, teratogenic or sporadic conditions which include multiple congenital deffects7,8. Even being a common congenital defect, CL/P etiopathogeny is still uncertain9. This is mostly a reflex of the complexity and diversity of the molecular mechanisms involved in embryogenesis, with the participation of multiple genes and the influence of environmental factors10,11.
It is widely accepted that CL/P has a multifactorial etiology, with genetic and environmental components. Among the environment risk factors for CL/P we stress: maternal diet and vitamin supplements, alcohol ingestion, smoking, the use of anti-seizure medication in the first quarter of gestation and maternal age9,11. As to the genetic contribution for CL/P, so far, there are numerous genes investigated, but very few clearly associated with CL/P, such as the PVRL1 (Poliovirus receptor related-1)12, TGF-b3 (Transforming growth factor beta 3)13, MSX1 (Msh homeobox 1)14, TBX22 (T-box 22)15, FGFs (Fibroblast growth factor)16, PTCH (Patched)17, and the IRF6 (Interferon regulatory factor 6)7.
Clinically speaking, CL/P is classified in four groups based on its location in relation to the incisive foramen, as follows: pre-foramen clefts, or simply: labial fissures (LF), post-foramen fissures (PF), trans-foramen fissures or lip-palate fissures (LPF), and rarely facial fissures18. The limited knowledge on the very etiology of CL/P makes it difficult even to describe and to distinguish between the varied forms of presentation of these malformations.
Thus, because of the scarcity of national studies, the goal of the present study was to describe and analyze the clinical traits of the uncommon and rare cases of CL/P in a reference center for craniofacial deformities.
MATERIALS AND METHODS
We carried out a retrospective study between the first semester of 1992 and the 1st semester of 2009, in a reference Ward for craniofacial deformities in the state of Minas Gerais, Brazil. We assessed the clinical charts from the patients seen during this time interval. The fissure distribution is seen on Table 1. We can notice that of the 778 CL/P cases, only 5 (0.64%) were uncommon, which had an anatomical behavior different from that of usual classifications, in other words, (1) CL: including unilateral or bilateral, complete or incomplete pre-foramen; (2) CLP: including unilateral and bilateral trans-foramen clefts, and pre and post foramen clefts; (3) CP: including all complete or incomplete post foramen clefts and (4) Others: here we find the rare facial clefts18. From this scientific investigation we excluded syndromic patients with CL/P or those who had other uncommon disorders associated with the clefts.
From the clinical charts, besides classifying the CL/P, we also collected the following information: age, gender, a past of consanguinity, maternal smoking and alcohol beverage drinking, the use of medication during pregnancy, use of folic acid in the pre-gestational period and in the first quarter of pregnancy, a past of miscarriages and/or stillbirths, maternal diseases and a Family history of CL/P. all the five patients with unusual CL/P were clinically assessed by two professionals trained in the aforementioned institution. This study was carried out in accordance with the principles established by resolution 196/88 from the National Health Council of the Ministry of Health, besides being approved by the Ethics Committee in Research of our University.
According to Table 1, of the 778 cases of CL/P, seen between the first semester of 1992 and the end of the first semester of 2009, only 5 (0.64%) patients had unusual CL/P. on this same Table we see that all the 5 patients were males and, the mean age at first consultation in visit to our center was 1 year (varying between 2 months and two years and two months). As far as skin color goes, 3 patients were of brown skin and 2 were whites. Considering the type of cleft, 2 patients had incomplete direct cleft lip associated with the incomplete palate cleft (Fig. 1); 2 had incomplete left cleft lip plus incomplete palate cleft (Fig. 2) and 1 had complete left-side palate cleft plus a complete right-side palate cleft.
Mean maternal and paternal ages during gestation in these cases of unusual CL/P was of 26 years for both; we excluded the clinical information from 1 patient who had been adopted, thus making it impossible to collect information. There was no past of consanguinity between the couples, maternal ingestions of alcohol and smoking, use of medication during pregnancy, miscarriage and/or stillbirth past and maternal diseases among the five cases of unusual CL/P we analyzed (Table 1). Nonetheless, one case (case 3) was positive for the family history of CL/P. In such case, a paternal uncle had complete bilateral CL/P. All the five patients, as well as family members, were seen at the health care facility and are currently under multiprofessional clinical follow up.
Numerous epidemiological studies have shown that CL/P has a unique distribution and the incidence of these anomalies varies among the different populations assessed19-23. Thus, the Asian population, ancestors of American natives and northern Europeans have a higher incidence of CL/P1,20 and, contrasting that, Africans and their descendants have a higher incidence of CL alone20. In most of the studies, CLP is the most common among NSCL/P19,20,23,24(Non-Syndromic Cleft Lip/Palate) cases. Nonetheless, the prevalence of CL and CP vary according to the population studied19,22,25-27. A reduced share of the patients with NSCL/P (1-3.6%) had uncommon forms of bilateral clefts, thus encompassing numerous combinations of CL with different degrees of severity in both sides, such as associations of incomplete CL on one side and complete CLP on the other side22,27,28. Thus, in the present study, because of the scarcity of national studies, uncommon and rare forms of CL/P were described and analyzed.
Of the 778 cases of NSCL/P diagnosed in a Reference Ward in Minas Gerais, Brazil, in the 17 year period, only 5 (0.64%) patients had uncommon forms of these anomalies. A study assessing 803 Brazilian patients who were not operated for CL/P, with or without additional malformations and without recognizable syndromes, found a prevalence of 1.9% of bilateral clefts with unusual associations22. In two other studies assessing 835 Mexican patients and 1,669 Iranian patients with CL/P, the uncommon clefts were found in 1% and 3.6% of the cases, respectively27,28. Nonetheless, differently from these papers analyzed, the present study included only NSCL/P, in other words, without alterations or associated syndromes. Thus, the reduced prevalence found in the present study compared to literature indexes22,27,28 can reflect the methodological difference employed in these populations analyzed.
All the 5 patients affected by unusual NSCL/P were males. Considering the relationship between cleft type and patient gender, most of the studies show that CLP is more frequent in males29,30. Nonetheless, considering CL and CP alone, the epidemiological investigations showed controversial results6,25,27,28. Partially corroborating the results found in the present study, as far as gender is concerned, González et al. (2008)27 found the occurrence of unusual CL/P in males, with only one exception.
Bilateral clefts have a relevant morphological variation, with different combinations, but most with limited frequency and, rarely, reported in the literature22. The forms of clinical presentation of the unusual NSCL/P found in the present study were, respectively, incomplete left-side CL associated with incomplete CP (2 cases, 40%); direct incomplete CL associated with incomplete CP (2 cases, 40%) and complete left-side CL/P and complete CP (1 case 20%). It is worth noticing that the most severe form of extension of these NSCL/P was associated in only one case.
Comparing the three major types of NSCL/P (CL, CLP and CP), the distribution of unusual CLP by type (unilateral/bilateral), extension (complete/incomplete) and laterality (right/left), is partially in agreement with the literature because of the predominance of incomplete left-side CL, complete left-side CLP and, incomplete CP in the populations investigated22,24,25,27.
Among environmental risk-factors for CL/P we stress, consanguinity, smoking, alcohol ingestion, use of medication during pregnancy, insufficient ingestion of folic acid in the pre-gestational period and in the first quarter of pregnancy, a past of miscarriage and/or stillbirth, maternal diseases and family history of clefts9,31. Nonetheless, in the present scientific investigation we did not find a positive association between these variables and the uncommon NSCL/P. We stress that no mother reported the use of vitamin supplementation or the ingestion of folic acid in the pre-gestational period and/or on the first quarter of pregnancy and only one patient had positive Family history of orofacial clefts. Having in mind the reduced prevalence of unusual NSCL/P in the different populations, the present study confirms the rarity of such malformations in the Brazilian population, besides stressing the importance of describing and assessing these rare cases in an attempt to better understand their etiopathogeny.
The present study assessed 5 rare or unusual cases of NSCL/P in a Brazilian population and confirmed the limited prevalence of such alterations. The clinical types of these fissures were incomplete unilateral lip fissure associated to incomplete palate fissure and complete unilateral cleft lip and palate and complete cleft palate, and they were all seen in male individuals. Moreover, the unusual NSCL/P cases were not associated to the risk factors evaluated. Investigations concerning the rare forms of NSCL/P may enable a better understanding of the etiopathogeny of orofacial clefts.
Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Fapemig) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (HMJ).
1. Gorlin R, Cohen M, Hennekam R. Syndromes of the head and neck. 4th ed. New York: Oxford University Press; 2001. [ Links ]
2. Mitchell LE, Beaty TH, Lidral AC, Munger RG, Murray JC, Saal HM et al. Guidelines for the design and analysis of studies on nonsyndromic cleft lip and cleft palate in humans: summary report from a Workshop of the International Consortium for Oral Clefts Genetics. Cleft Palate Craniofac J. 2002; 39(1):93-100. [ Links ]
3. Slayton RL, Williams L, Murray JC, Wheeler JJ, Lidral AC, Nishimura CJ. Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J. 2003; 40:274-9. [ Links ]
4. Nagem Filho H, Moraes N, Rocha RGF. Contribuição para o estudo da prevalência das más formações congênitas lábio-palatais na população escolar de Bauru. Rev Fac Odontol São Paulo. 1968; 6:111-28. [ Links ]
5. Loffredo L, Freitas J, Grigolli A. Prevalência de fissuras orais de 1975 a 1994. Rev Saúde Pública. 2001; 35(6):571-5. [ Links ]
6. Martelli-Júnior H, Orsi Júnior J, Chaves MR, Barros LM, Bonan PRF, Freitas JA. Estudo epidemiológico das fissuras labiais e palatais em Alfenas - Minas Gerais - de 1986 a 1998. RPG. 2006; 13(1):31-5. [ Links ]
7. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004; 351:769-80. [ Links ]
8. Paranaíba LMR, Martelli-Júnior H, Swerts MSO, Line SRP, Coletta RD. Novel mutations in the IRF6 gene in Brazilian families with Van der Woude syndrome. Int J Mol Med. 2008; 22(4):507-11. [ Links ]
9. Vieira AR. Unraveling human cleft lip and palate research. J Dent Res. 2008; 87: 119-25. [ Links ]
10. Carinci F, Scapoli L, Palmieri A, Zollino I, Pezzetti F. Human genetic factors in nonsyndromic cleft lip and palate: An update. Int J Pediatr Otorhinolar. 2007; 71(10): 1509-19. [ Links ]
11. Martelli DRB, Cruz KW, Barros LM, Silveira MF, Swerts MSO, Martelli-Júnior H. Maternal and paternal age, birth order and interpregnancy interval evaluation for cleft lip-palate. RBOt. 2009 (in press). [ Links ]
12. Sozen MA, Suzuki K, Tolarova MM, Bustos T, Fernandez Iglesias JE, Spritz RA. Mutation of PVRL1 is associated with sporadic, nonsyndromic cleft lip/palate in northern Venezuela. Nat Genet. 2001; 29:141-2. [ Links ]
13. Vieira AR, Orioli IM, Castilla EE, Cooper ME, Marazita ML, Murray JC. MSX1 and TGFB3 contribute to clefting in South America. J Dent Res. 2003; 82:289-92. [ Links ]
14. van den Boogaard MJ, Dorland M, Beemer FA, van Amstel HK. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet. 2000; 24: 342-3. [ Links ]
15. Braybrook C, Doudney K, Marcano AC, Arnason A, Bjornsson A, Patton MA et al. The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. Nat Genet. 2001; 29:179-83. [ Links ]
16. Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM et al. Impaired FGF signaling contributes to cleft lip and palate. Proc Natl Acad Sci U S A. 2007; 104(11):4512-7. [ Links ]
17. Mansilla MA, Cooper ME, Goldstein T, Castilla EE, Lopez Camelo JS et al. Contributions of PTCH gene variants to isolated cleft lip and palate. Cleft Palate Craniofac J. 2006; 43:21-9. [ Links ]
18. Spina V. A proposed modification for the classification of cleft lip and cleft palate. Cleft Palate J. 1973; 10: 251-2. [ Links ]
19. Vanderas AP. Birth prevalence of cleft lip, cleft palate and cleft lip and palate among races: a review. Cleft Palate J. 1987; 24(5):147-53. [ Links ]
20. Moosey PA, Little J. Epidemiology of oral clefts: An international perspective In: Wyszynski DF, editor Cleft lip and palate: From origin to treatment. Oxford: Oxford University Press; 2002. p 127-58. [ Links ]
21. Wantia N, Rettinger G. The current understanding of cleft lip malformations. Facial Plast Surg. 2002; 18(4):147-53. [ Links ]
22. Freitas JA, Dalben GS, Santamaria M Jr, Freitas PZ. Current data on the characterization of oral clefts in Brazil. Braz Oral Res. 2004;18:128-33. [ Links ]
23. Jaruratanasirikul S, Chichareon V, Pattanapreechawong N, Sangsupavanich P.Cleft lip and/or palate: 10 years experience at a pediatric cleft center in Southern Thailand. Cleft Palate Craniofac J. 2008; 45(6):597-602. [ Links ]
24. Martelli-Junior H, Porto LCVP, Barbosa DRB, Bonan PRF, Freitas AB, Coletta RD. Prevalence of nonsyndromic oral clefts in a reference hospital in Minas Gerais State, between 2000-2005. Braz Oral Res. 2007; 21(4):314-7. [ Links ]
25. Shapira Y, Lubit E, Kuftinec MM, Borell G. The distribution of clefts of the primary and secondary palates by sex, type, and location. Angle Orthod. 1999; 69(6):523-8. [ Links ]
26. McLeod NMH, Urioeste MLA, Saeed NR. Birth prevalence of cleft lip and palate in Sucre, Bolivia. Cleft Palate Craniofac J. 2004; 41:195-8. [ Links ]
27. González BS, López ML, Rico MA, Garduño F. Oral clefts: a retrospective study of prevalence and predisposal factors in the State of Mexico. J Oral Sci. 2008; 50(2):123-9. [ Links ]
28. Rajabian MH, Sherkat M. An Epidemiologic Study of Oral Clefts in Iran: Analysis of 1669 Cases. Cleft Palate Craniofac J. 2000, 37(2):191-6. [ Links ]
29. Menegotto BG, Salzano FM. Epidemiology of oral clefts in a large South American sample. Cleft Palate Craniofac J. 1991; 28(4):373-6. [ Links ]
30. Puhó EH, Szunyogh M, Métneki J, Czeizel AE. Drug Treatment During Pregnancy and Isolated Orofacial Clefts in Hungary. Cleft Palate Craniofac J. 2007; 44(2):194-202. [ Links ]
31. Zeiger JS, Beaty TH. Is there a relationship between risk factors for oral clefts? Teratology. 2002; 66(3):205-8. [ Links ]
Paper submitted to the BJORL-SGP (Publishing Management System - Brazilian Journal of Otorhinolaryngology) on January 11, 2009; and accepted on February 1, 2010. cod. 6758
Centro de Ciências Biológicas e da Saúde (CCBS) - Universidade Estadual de Montes Claros, Unimontes, Minas Gerais, Brasil. Campus Universitário Darcy Ribeiro, s/n Vila Mauricéia Montes Claros MG 39400-000.
Fundação de Amparo à Pesquisa do Estado de Minas Gerais - Fapemig