Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts

Mostowska A, Hozyasz KK, Biedziak B, Misiak J, Jagodzinski PP. Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts. Eur J Oral Sci 2010; 118: 325–332. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci Nonsyndromic cleft lip with or without cleft palate (NCL/P) is one of the most common craniofacial malformations; however, its aetiology is still unclear. Because the effects of maternal nutrition on fetal development are well known, we decided to pursue the question of whether polymorphic variants of genes encoding enzymes involved in choline metabolism might be associated with the maternal risk of having a baby with NCL/P. Analysis of 18 single nucleotide polymorphisms (SNPs) of betaine‐homocysteine methyltransferase (BHMT), betaine‐homocysteine methyltransferase‐2 (BHMT2), choline dehydrogenase (CHDH), choline kinase (CHKA), dimethylglycine dehydrogenase (DMGDH), choline‐phosphate cytidylyltransferase A (PCYT1A), and phosphatidylethanolamine N‐methyltransferase (PEMT) provided evidence that polymorphisms located in the region containing BHMT and BHMT2 were protective factors against NCL/P affected pregnancies in our population. The strongest signal was found for the SNP located in the intronic sequence of BHMT2. Women carrying two copies of the rs625879 T allele had a significantly decreased risk of having offspring with orofacial clefts. These results were significant, even after correction for multiple comparisons. Moreover, the gene–gene interaction analysis revealed a significant epistatic interaction of BHMT2 (rs673752), PEMT (rs12325817), and PCYT1A (rs712012) with maternal NCL/P susceptibility. Altogether, our study identified a novel gene, the nucleotide variants of which were be associated with a decreased risk of having a baby with NCL/P.     

Common polymorphism in the glycine N-methyltransferase gene as a novel risk factor for cleft lip with or without cleft palate

The objective of this study was to identify new environmental and genetic risk factors for orofacial clefts that arise during early foetal development. In this retrospective, case–control, mother–child pair study, 172 orofacial clefts cases and 199 healthy controls, and their respective mothers, were genotyped for common variants in relevant genes obtained by text and database mining using STRING 10.0. Exposure to environmental risk factors was evaluated using questionnaires. Variant glycine N-methyltransferase (odds ratio (OR) 2.1, 95% confidence interval (95% CI) 1.0–4.4) and dihydrofolate reductase (OR 2.4, 95% CI 1.3–4.5) genotypes were identified as risk factors for cleft lip with or without cleft palate formation. Furthermore, synergy was detected between variant glycine N-methyltransferase and dihydrofolate reductase genotypes in promoting cleft lip with or without cleft palate formation (OR 7, 95% CI 2–23). This study is novel in finding that common glycine N-methyltransferase variant genotypes increase the risk of cleft lip with or without cleft palate.     

The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate: evidence for a protective role

Objective

Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) are among the most common congenital birth defects worldwide. Several lines of evidence point to the involvement of folate, as well as folate metabolizing enzymes in risk reduction of orofacial clefts. Dihydrofolate reductase (DHFR) enzyme participates in the metabolic cycle of folate and has a crucial role in DNA synthesis, a fundamental feature of gestation and development. A functional polymorphic 19-bp deletion within intron-1 of DHFR has been associated with the risk of common congenital malformations. The present study aimed to evaluate the possible association between DHFR 19-bp deletion polymorphism and susceptibility to NS-CL/P in an Iranian population.

Material and Methods

The current study recruited 100 NS-CL/P patients and 100 healthy controls. DHFR 19-bp deletion was determined using an allele specific-PCR method.

Results

We observed the DHFR 19-bp homozygous deletion genotype (D/D) vs. homozygous wild genotype (WW) was more frequent in controls than in NS-CL/P patients (25% vs. 13%), being associated with a reduced risk of NS-CL/P in both codominant (OR=0.33, P=0.027) and recessive (OR=0.45, P=0.046) tested inheritance models. We also stratified the cleft patients and reanalyzed the data. The association trend for CL+CL/P group compared to the controls revealed that the DD genotype in both codominant (OR=0.30, P=0.032) and recessive models (OR=0.35, P=0.031) was associated with a reduced risk of CL+CL/P.

Conclusions

Our results for the first time suggested the DHFR 19-bp D/D genotype may confer a reduced risk of NS-CL/P and might act as a protective factor against NS-CL/P in the Iranian subjects.     

Distribution of orofacial clefts and frequent occurrence of an unusual cleft variant in the Rift Valley of Kenya.

OBJECTIVE: To investigate the pattern and distribution of nonsyndromic orofacial clefts among patients in the Rift Valley region of northwestern Kenya. METHODS: Subjects were categorized anatomically for occurrence of an atypical cleft lip variant (ACL), typical cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP), and family history of orofacial clefts. Tribal ethnicity data were obtained from both cleft and noncleft clinic attendees. RESULTS: There were 194 patients with CL (52.7%), 153 with CLP (41.6%), and 21 with CP (5.7%). CL constitutes a greater fraction of orofacial clefts in the Rift Valley region than reported elsewhere in Africa, principally due to frequent occurrence of ACL (52.5% of all CL). Among noncleft clinic attendees there was a lower fraction of Bantu and larger fraction of Nilotic-Paranilotic tribal ethnicity than in Kenya overall. In contrast, among patients with orofacial clefts there was significant underrepresentation of Bantu and overrepresentation of Nilotic-Paranilotic tribes, particularly Kalenjin. Patients of Kalenjin origin had a much higher rate of positive family history of orofacial clefts than Bantu patients. CONCLUSIONS: There is an unusual anatomic distribution of orofacial clefts in the Kenya Rift Valley, with frequent occurrence of an atypical CL variant. Our findings indicate that Bantu tribes have lower risk of orofacial clefts than Nilotic-Paranilotic tribes, possibly due to inherited genetic differences, perhaps accounting for the relatively low prevalence of orofacial clefts through much of Africa.     

Genetic and environmental risk factors for submucous cleft palate

A multifactorial aetiology with genetic and environmental factors is assumed for orofacial clefts. Submucous cleft palate (SMCP), a subgroup of cleft palates with insufficient median fusion of the muscles of the soft palate hidden under the mucosa, has a prevalence of 1:1,250-1:5,000. We described the prevalence of risk factors among 103 German patients with the subtype SMCP and genotyped 24 single nucleotide polymorphisms (SNPs) from 12 candidate genes for orofacial clefts. Analysis of risk factors yielded a positive history for maternal cigarette smoking during pregnancy in 25.2% of the patients, and this was significantly more frequent than in the normal population. The group of patients differed in allele frequencies at SNP rs3917192 of the gene TGFB3 (nominal P = 0.053) and at SNP rs5752638 of the gene MN1 (nominal P = 0.075) compared with 279 control individuals. Our results indicate a potential role of maternal smoking during pregnancy for the formation of SMCP. The analysis of genetic variants hints at the contribution of TGFB3 and MN1 in the aetiology of SMCPs.     

Investigation of MYH14 as a candidate gene in cleft lip with or without cleft palate

Clefts of the orofacial region are among the most common facial defects and are caused by abnormal facial development during gestation. Cleft lip with or without cleft palate (CL/P) is a birth defect with a complex etiology resulting from a mixture of genetic and environmental factors. In the present study we considered myosin 14 ( MYH14 ) as a candidate gene for CL/P. This gene codes for the heavy chain of non-muscle myosin IIC (NMMHC-IIC), maps in the OFC3 region, and shares significant homology with myosin 9, a gene that our group has recently seen to be involved in CL/P. A linkage disequilibrium investigation was conducted with six single nucleotide polymorphisms in MYH14 and a sample of 239 CL/P nonsyndromic patients and their parents. Our family-based investigation provided no evidence of association between MYH14 and CL/P alleles. These data do not support the involvement of MYH14 in CL/P among the Italian population.     

New molecular aspects in the mechanism of oromaxillofacial cleft prevention by B-vitamins

Clinical and experimental studies show a clear positive effect of B-vitamins in the prevention of oromaxillofacial clefts, especially cleft lip and palate (CL/P). Hereby the local effect of thiamin (B1) in the amniotic fluid is very important for the embryonic facial development as seen in palatal organ models stimulated by topical B-vitamin application (Scheller et al., 2013a). Moreover a low B1 concentration in the serum and amniotic fluid was found in pregnant mice with clefts in their offspring (Scheller et al., 2013b). Immunochemical analyses of midface sections (ThTr-1 transporter) and the placenta (ThTr-2 transporter) of cleft fetuses with orofacial clefts showed an atypical cytoplasmatic localization (Scheller et al., 2017). mRNA nalyses of different B-vitamin transporters (B1, B2, B5, B7, B9) were performed and showed ThTr2 transporter in a short splice variant in all cleft fetuses. This splice variant may cause a functional loss of the transport capacity through the placenta barrier and result in a low amniotic fluid concentration of vitamin B1. All other analyzed transport proteins showed no functional change. These findings confirm the hypothesis that cleft prevention by high vitamin B1 substitution fails in genetically determined cleft mice, caused by an insufficient B1 uptake and missing local effect.     

Cleft lip and cleft palate in Santo Domingo

The purpose of this study was to analyze the occurrence of isolated cleft lip (CL), cleft lip with cleft palate (CL + CP) and isolated cleft palate (CP) and their distribution according to sex and laterality in Santo Domingo, Dominican Republic, located in the Caribbean Archipelago. The sample consisted of 439 hospital records (204 males and 235 females) of patients attending a children's public hospital in Santo Domingo over the period of May 1973 to December 1976. Of all facial clefts, the highest percentage (36.4%) was presented by CL, followed by CP (32.1%) and CL + CP (31.4%). Of all facial clefts, males presented the highest percentage (53.5%). For both sexes, there was an equal number of cases with CL (17.54 %) but more males had CL + CP (0.20 > P0.10) and more females presented CP (P < 0.001). The left-sided defects were almost twice as common as the right-sided defects. The ratio of unilateral clefts-to-bilateral clefts was 5.4:1.     

Seasonal variation and regional distribution of cleft lip and palate in zambia

Objective: To assess variations in seasonality and regional distribution of orofacial clefts in babies born in Zambia. Design: A retrospective chart review was done using records of all cleft procedures performed by the only plastic surgeon in Zambia (G.J.). Delivery data from the University Teaching Hospital (UTH) were also examined to estimate the birth prevalence of orofacial clefts (55,108 live births between 2001 and 2005). Patients: All cleft patients operated in Zambia from 2000 to 2006 (413 patients). Results: A low birth prevalence of clefts (1/4239 live births) was found using UTH delivery data. Surgical data showed no difference for the frequency of one gender over another overall (M:F ratio is 1.04; p = .70). More bilateral clefts occurred in cleft lip and palate (CLP) patients than in cleft lip (CL) patients (p < .01), and more unilateral left-sided clefts occurred in CL than in CLP patients (p = .03). The data reflected seasonal variation in month of birth of cleft lip with or without cleft palate (CL+/-P) patients (p < .01), with a peak in April and May and more births in March through August (57.2%) than in September through February (42.8%). There was regional variation in cleft births among the nine Zambian provinces (p < .01). Conclusions: This study shows seasonal variation in clefts that may be explained, at least in part, by environmental factors affecting the development of CL+/-P. Access to treatment is likely the major determinant of regional disparity in clefts. These results provide a basis for further epidemiological studies of orofacial clefts in Zambia.     

MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate

Jagomägi T, Nikopensius T, Krjut?kov K, Tammekivi V, Viltrop T, Saag M, Metspalu A. MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate. Eur J Oral Sci 2010; 118: 213–220. © 2010 The Authors. Journal compilation©2010 Eur J Oral Sci Recent studies suggest that multiple interacting loci, with possible additional environmental factors, influence the risk for nonsyndromic oral clefts, one of the most common birth defects in humans. Advances in high‐throughput genotyping technology allow the testing of multiple markers, simultaneously, in many candidate genes. We tested for associations between 176 haplotype‐tagging single nucleotide polymorphisms (SNPs) in 18 candidate genes/loci and nonsyndromic clefts in a case–control study in an Estonian sample (153 patients, 205 controls). The most significant associations with nonsyndromic cleft lip with or without cleft palate (CL/P) were found for SNPs in MSX1, MTHFR, and PVRL2, including several common haplotypes in the MTHFR and MSX1 genes. The strongest association was observed for rs6446693 in the MSX1 region, which remained statistically significant after Bonferroni correction. The strongest association with nonsyndromic cleft palate (CP) was found for the SNP rs11624283 in the JAG2 gene. Epistatic interactions were observed for SNPs within PVRL2, between BCL3 and EDN1, and between IRF6 and MSX1 genes. This study provides further evidence implicating MSX1 and MTHFR in the etiology of nonsyndromic CL/P across different populations.     

Clinical and genetic study on 356 Brazilian patients with a distinct phenotype of cleft lip and palate without alveolar ridge involvement

Oral clefts include cleft lip (CL), cleft lip with cleft palate (CLP) and cleft palate (CP), with wide variations in clinical presentation and degree of severity. We described a sample of individuals with CL and CP without alveolar arch involvement (CL + CP) to verify if the characteristics of this group are distinct from those with CL with or without CP (CL/P) described in literature. The sample was composed of 356 patients with CL + CP, registered at HRCA-USP, Bauru-SP-Brazil. The following characteristics were investigated: sex ratio, parental age at the time of conception, parental consanguinity, familial recurrence, laterality of the cleft and associated anomalies. A subgroup of 30 individuals with microforms of CL and CP were taken from the sample and compared with the remaining cases. Statistical differences were found between this CL + CP sample and the literature data for groups with CL/P regarding laterality, sex ratio, consanguinity, familial recurrence, and the presence of associated anomalies. The microform sample showed a statistical difference in paternal age. In most evaluated aspects, this sample presents similar characteristics to the consulted literature data for CL/P; as do the group of microform cleft cases when compared with the remaining CL + CP sample in this study. Microforms of cleft can represent a target group for investigation into the embryogenetic mechanisms of oral clefts and their phenotypic variability.     

Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts.

OBJECTIVE: To examine the interactions between four fetal xenobiotic metabolizing gene polymorphisms, maternal cigarette smoking, and risk for oral cleft defects. DESIGN AND PARTICIPANTS: California population-based case-control study of 431 infants born with isolated orofacial clefts and 299 nonmalformed controls. MAIN OUTCOME MEASURES: Infants were genotyped for functional polymorphisms of the detoxification enzymes microsomal epoxide hydrolase-1 (EPHX1 T-->C [Tyr113His], and A-->G [His139Arg]), and glutathione-S transferase Pi-1 (GSTP1 A-->G [Ile105Val] and C-->T [Ala114Val]), and risks for cleft outcomes were measured for gene only and gene-maternal smoking effects. RESULTS: Although smoking was associated with an increased risk for isolated cleft lip+/-palate, we found no independent associations of genotypes of EPHX1-codon 113 or GSTP1-codon 105 polymorphisms for either isolated cleft lip+/-palate or isolated cleft palate. The heterozygote genotype for the EPHX1-codon 139 polymorphism was associated with an increased risk of isolated cleft palate (odds ratio=1.6 [95% confidence interval, 1.0 to 2.6]). Infant EPHX1 and GTSP1 polymorphic variants did not appreciably alter the risks for clefts associated with maternal smoking, nor were any EPHX1 combined genotype-specific risks found. Infant genotypes of the GSTP1-codon 105 polymorphism, combined with glutathione-S-transferase-mu-1 null genotypes, did not appreciably alter the risk of orofacial clefts. CONCLUSIONS: Our results suggest that genetic variation of the detoxification enzymes EPHX1 and GSTP1 did not increase the risks of orofacial clefting, nor do they influence the risks associated with maternal smoking.     

Incidence of cleft lip and palate in Sri Lanka

In a prospective study that surveyed 51,542 live births and 5,263 still births in central Sri Lanka, cleft lip with or without cleft palate (CL +/- P) was found to have an incidence of 0.83 per 1,000 births, and isolated cleft palate (CP) an incidence of 0.19 per 1,000 births. Distribution by sex, type of cleft, and site was similar to that in whites. Family history was positive in 19.6% of CL +/- P and in 9.1% of CP subjects. Furthermore, the frequency of CL +/- P in relatives of subjects with CL +/- P was significantly greater than that of CP. Of the three major ethnic groups that inhabit Sri Lanka, the incidence was significantly greater in the Moors than in the Sinhalese and the Tamils. Social status was found to have no association with the occurrence of clefts.     

RFC1 and non-syndromic cleft lip with or without cleft palate: An association based study in Italy

The molecular basis of orofacial development is largely unknown and needs to be unravelled. Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial malformation, with an incidence of about 1/700 live births, although variable according to ethnicity. Being a multifactorial disease, it arises as a result of an interplay between genetic and environmental factors. Several approaches have been developed to identify susceptibility genes. Genes belonging to the folate/homocysteine pathway are attracting increasing interest because folate supplementation before and during early pregnancy can reduce the risk of NSCL/P. We performed a family based association study in order to assess if a genetic variant of RFC1 could be involved in NSCL/P onset.We genotyped 404 unrelated probands and their relatives for three biallelic polymorphic variants (rs1051266, rs4818789 and rs3788205), that were selected because they produced conflicting results on previous investigations.Evidence of association was found between the investigated polymorphisms and NSCL/P in our sample of the Italian population, albeit with weak significance levels.Results from this investigation provided a support of previous studies suggesting a role of RFC1 in NSCL/P aetiology, reinforcing the concept that genetic predisposition to NSCL/P varies enormously within different ethnic groups.     

Significant association of MTHFD1 1958G>A single nucleotide polymorphism with nonsyndromic cleft lip and palate in Indian population

Objectives: Nonsyndromic cleft lip and palate (NSCLP) is genetically distinct from those with syndromic clefts, and accounts for ~70% of cases with Oral clefts. Folate, or vitamin B9, is an essential nutrient in our diet. Allelic variants in genes involved in the folate pathway might be expected to have an impact on risk of oral clefts. Given the key role of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) in folate metabolism, it would be of significant interest to assess its role in NSCLP etiology. Study Design: The present study aims at examining the association between MTHFD1 1958G>A polymorphism and NSCLP risk by conducting a case-control study in south Indian population. Our sample comprised of 142 cases with nonsyndromic clefts and 141 controls without clefts or family history of clefting. The MTHFD1 1958G>A polymorphism was genotyped using PCR-RFLP. Results: An increased risk was found for the heterozygous 1958GA (OR=2.44; P=0.020) and homozygous 1958AA (OR=2.45; P=0.012) genotypes in the children. When the dominant model (AG+AA vs GG) was applied the risk remained the same as co-dominant model, but the level of significance increased (OR=2.44; P=0.002). Conclusions: The results indicated the MTHFD1 1958G>A polymorphism to be one of the important genetic determinants of NSCLP risk in South Indian subjects. Key words:MTHFD1, orofacial cleft, SNP, genetics.     

非综合征型唇腭裂与MTHFR基因多态性的相关性研究

目的：研究亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）基因位点C677T和A1298C与中国江苏地区汉族人群非综合征型唇腭裂（（nonsyndromic cleft lip with or without cleft palate,NSCL/P）发生的相关性。方法：采用聚合酶链反应-限制性片段长度多态性检测法对200例NSCL/P患者和213例健康人进行基因型检测。结果：MTHFR C677T对照组与病例组在基因型分布无统计学差异（P〉0.05）,TT基因型和携带T等位基因儿童罹患NSCL/P的风险分别是CC基因型儿童的1.84倍及1.57倍。进一步分层分析发现TT基因型和CT基因型能分别显著增加儿童唇裂伴或不伴腭裂和单纯性唇裂的发病风险。MTHFR A1298C病例组和对照组在基因型频率和等位基因频率有统计学差异（P〈0.05）,AC基因型和携带C等位基因的儿童罹患NSCL/P的风险分别比AA基因型儿童降低49%及43%。分层分析中,AC基因型和携带C等位基因可降低罹患唇裂伴腭裂及唇裂伴或不伴腭裂的风险。结论：MTHFR C677T可能为中国江苏地区汉族儿童NSCL/P的危险因素,而MTHFR A1298C有可能是NSCL/P发生的保护因素。     

Nonsyndromic cleft lip with or without cleft palate in China: assessment of candidate regions.

OBJECTIVE: Although Asians have the highest birth prevalence of oral-facial clefts, the majority of gene mapping studies of cleft lip with or without cleft palate (CL/P) have been in European or American Caucasians. Therefore, the objective of this study of Chinese families was to evaluate linkage and association between CL/P and 10 genetic markers in five chromosomal regions that have shown positive results in Caucasians. SETTING: Families were ascertained through nonsyndromic CL/P surgical probands from hospitals throughout Shanghai, China. PARTICIPANTS: Study participants included 671 individuals from 60 families with two or more members affected with oral-facial clefts. Of the 671 total individuals, 145 were affected. RESULTS: Ten markers from chromosomes 2, 4, 6, 17, and 19 were assessed (TGFA, MSX1, D4S194, D4S175, F13A1, GATA185H, D17S250, D17S579, D19S49, APOC2). LOD scores were calculated between each of the 10 markers and CL/P as well as model-free statistics of linkage (SimIBD) and association (TDT). None of the markers showed significantly positive LOD scores with CL/P. A significantly positive result (p =.01) was seen using SimIBD for APOC2 on chromosome 19, and a positive TDT result (p =.004) was obtained for D19S49, near APOC2. CONCLUSIONS: This is the first gene mapping study of CL/P in China. These results indicate that most of the genetic regions with positive results in Caucasian families may not be involved in CL/P found in China, although there is some positive evidence for the candidate region on chromosome 19.     

Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate

The wingless-type MMTV integration site family (Wnt) signalling pathway plays a crucial role in craniofacial development. Recently, nucleotide variants in WNT genes have been shown to be associated with oral congenital anomalies, including facial clefts. Therefore, in the current study we decided to assay the association of nucleotide variants in selected WNT genes with the risk of non-syndromic cleft lip with or without cleft palate (NCL/P) in the Polish population. Fourteen polymorphisms in WNT3, WNT3A, WNT5A, WNT8A, WNT9B, and WNT11 were tested in a group of 210 patients with NCL/P and in a properly matched control group. The most significant results were found for the WNT3 rs3809857 variant, which, under the assumption of a recessive model, was associated with a two-fold decrease in the risk of NCL/P (OR(TT vs. GT + GG) = 0.492, 95% CI: 0.276-0.879, P = 0.015). Moreover, haplotype analysis revealed that WNT3 is significantly correlated with NCL/P. The global P-values for haplotypes of rs12452064_rs7207916 and rs3809857_rs12452064_rs7207916 were 0.0034 and 0.0014, respectively, and these results were statistically significant, even after the permutation test correction. In conclusion, our study confirmed the involvement of polymorphisms in the WNT3 gene in NCL/P aetiology in the tested population.     

Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft

The aim of this study was to determine the rate of undetected additional anomalies following a prenatal diagnosis of isolated oral cleft. Data of all infants with a prenatal diagnosis of isolated oral cleft born between 2000 and 2015 were studied retrospectively. Additional anomalies detected after birth were categorized as minor or major and included structural and chromosomal anomalies. Isolated clefts of the lip (CL), lip and alveolus (CLA) and lip, alveolus, and palate (CLAP) were diagnosed prenatally in 176 live-born infants. The type of cleft was more extensive after birth in 34/176 (19.3%) and less extensive in 16/176 (9.1%) newborns. Additional anomalies were diagnosed in 24 infants (13.6%), of which 12 (6.8%) were categorized as major. The latter included two submicroscopic chromosome anomalies and two gene mutations. Postnatal additional anomalies occurred more frequently in CLA and CLAP than in CL, and more in bilateral than in unilateral clefts. Major anomalies are still found in infants with a prenatal diagnosis of an isolated oral cleft. The prevalence of additional anomalies seems to be related to the type and bilaterality of the cleft, and this should be considered during prenatal counselling.     

Is alveolar cleft reconstruction still controversial? (Review of literature)

Cleft lip and palate (CL/P) is a frequent congenital malformation that manifests in several varieties including unilateral or bilateral and complete or incomplete. Alveolar cleft reconstruction remains controversial with regard to timing, graft materials, surgical techniques, and methods of evaluation. Many studies have been conducted addressing these points to develop an acceptable universal protocol for managing CL/P. The primary goal of alveolar cleft reconstruction in CL/P patients is to provide a bony bridge at the cleft site that allows maxillary arch continuity, oronasal fistula repair, eruption of the permanent dentition into the newly formed bone, enhances nasal symmetry through providing alar base support, orthodontic movement and placement of osseointegrated implants when indicated. Other goals include improving speech, improvement of periodontal conditions, establishing better oral hygiene, and limiting growth disturbances. In order to rehabilitate oral function in CL/P patients alveolar bone grafting is necessary. Secondary bone grafting is the most widely accepted method for treating alveolar clefts. Autogenous bone graft is the primary source for reconstructing alveolar cleft defects and is currently the preferred grafting material.