Association of nasomaxillary asymmetry in children with unilateral cleft lip and palate and their parents.

OBJECTIVE: It has been suggested previously that increased width of midfacial structures is associated with the development of palatal clefting. The aim of this study was to evaluate the association of transverse craniofacial asymmetry between children with unilateral cleft lip and palate (UCLP) and their parents. Specifically, we hypothesized that parental transverse craniofacial asymmetry is a risk factor associated with the development of asymmetry in children with UCLP. DESIGN: Retrospective cross-sectional investigation including affected children and their noncleft parents. PATIENTS, PARTICIPANTS: A total of 64 children-parent sets of data (32 child-biological mother + 32 child-biological father) were included. Subject records included posteroanterior cephalometric radiographs obtained from 29 Costa Rican families with UCLP. MAIN OUTCOME MEASURES: The side of parental nasal asymmetry was significantly associated with the side of cleft in their children. For the majority of parents with children suffering from a left cleft, nasal width was larger on the left, compared with the right side. Similarly, in the majority of parents with children suffering from a right cleft, nasal width was larger on the right, compared with the left side. CONCLUSION: The results suggest that unilaterally increased nasomaxillary width in parents may play a key role in the development of ipsilateral palatal clefting in their offspring, therefore underscoring the importance of craniofacial form as a genetic etiologic factor in the genesis of clefting. Better understanding of the role of craniofacial form in cleft development will ultimately allow for the assessment of risk for cleft lip and palate.     

Velopharyngeal insufficiency after maxillary advancement in patients with cleft palate − a survey of risk assessment in the United Kingdom and Ireland

Patients with cleft lip and palate may require orthognathic surgery to correct severe impairments in midfacial growth. Maxillary advancement in this group, however, is linked to deterioration in velopharyngeal function (VPF), and it is not clear how cleft teams assess this risk. We therefore surveyed surgeons from 15 cleft units who provide orthognathic treatment, to gain an understanding of current practice in the UK and Ireland. A total of 16/21 surgeons from 14/15 units responded. While 14/16 surgeons agreed that these patients are at risk of a deterioration in VPF after maxillary advancement, two disagreed. Preoperative assessment of perceptual speech is required in all cases, but only 9/14 routinely did an instrumental assessment of VPF. One third of respondents thought that they could not identify “borderline” cases. There were differences in how surgeons obtained preoperative consent regarding deterioration in VPF, and whether surgical plans should be modified accordingly. There was considerable variation in current practice regarding risk, assessment, and management of potential changes in VPF after orthognathic surgery. A national forum for multidisciplinary discussion would allow for the standardisation of care across the UK and Ireland. Further study is needed to establish the effects of orthognathic surgery on VPF in this group, as well as the clinical benefits of instrumental assessments.     

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.     

Biologic basis for a risk assessment model for cleft palate.

A biologic model for palatogenesis is presented, intended as a basis for risk assessment. It comprises a sequence of developmental stages: growth and migration of neural crest cells, downward growth of palatal buds, elevation of palatal shelves, and differentiation of the epithelium followed by shelf fusion. Several events representing these stages and amenable to mathematical translation may be measurable in the form of biomarkers such as DNA and protein synthesis, phospholipid metabolism, and signal transducing systems. Interrupting components of the model will result in cleft palate. Teratogens with known mechanisms of action are compared with the model. The quantitative risk of cleft palate is conceived as a sequence of mathematical probabilities that any stage of the model runs an abnormal course. Stage-specific probabilities are determined by a chemical's potency and dose, and by duration of exposure and gestational age. Species or strain sensitivity may be expressed as quantitative differences in model parameters. Although the model is designed for cleft palate, the risk model may also estimate a multiple response risk to the same exposures.     

Association of the GABRB3 gene with nonsyndromic oral clefts.

OBJECTIVE: Nonsyndromic oral clefts are common craniofacial anomalies classified into two subgroups: cleft lip with or without cleft palate and isolated cleft palate. Nonsyndromic oral clefts are multifactorial diseases, with both genetic and environmental factors involved in their pathogenesis. The inhibitory neurotransmitter, gamma-aminobutyric acid plays a role in normal embryonic, and particularly facial, development and gamma-aminobutyric acid receptor type A beta-3 subunit (GABRB3) knockout mice have been shown to have cleft palate. The GABRB3 gene is therefore a strong candidate gene for nonsyndromic oral clefts. We investigated here whether genetic variations of the GABRB3 gene affect the risk for nonsyndromic oral clefts. METHOD: In this case-control study, a total of 178 Japanese patients with cleft lip with or without cleft palate and 374 unrelated controls were recruited and were genotyped for six single nucleotide polymorphisms and a dinucleotide repeat marker of the GABRB3 gene. RESULTS: None of the single nucleotide polymorphisms showed complete linkage disequilibrium with other single nucleotide polymorphisms. In a case-control association study with the six-locus haplotype of the gene, TGTGCT haplotype frequency in patients with cleft lip with or without cleft palate was significantly higher than in the controls (corrected p value = .029). None of the alleles of the dinucleotide repeat marker showed significant association with cleft lip with or without cleft palate. CONCLUSIONS: Our data suggest that the GABRB3 gene is involved in the pathogenesis of cleft lip with or without cleft palate in the Japanese population.     

A preliminary study of nasal airway patency and its potential effect on speech performance.

The relationship between nasal airway size and articulatory performance was studied in a group of cleft palate patients. Articulation analysis revealed that children with bilateral cleft lip and palate were nearly twice as likely to manifest compensatory articulations as children with unilateral cleft lip and palate or with cleft palate only. When subjects were grouped according to speech performance, aerodynamic assessment indicated that children with compensatory articulations had significantly larger nasal cross-sectional areas than children without compensatory articulations. The findings suggest that children with comparatively large nasal airways may be at increased risk for developing abnormal speech patterns. If these findings are confirmed by further research, such children may be candidates for relatively early palate repair.     

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.     

非综合征性唇腭裂的染色体基因位点研究进展

唇腭裂是常见的先天畸形之一,遗传因素在其发生中发挥着极其重要的作用.随着分子遗传学的发展,越来越多的易感基因被发现.本文就与非综合征性唇腭裂相关的染色体基因位点、与单纯性腭裂相关的染色体基因位点研究进展作一综述.     

Tessier 6号裂伴双牙列1例

面斜裂是一种较罕见的颌面部发育畸形,主要表现为颅面部软组织和骨骼的单发或复合性裂隙畸形,可伴有多生牙等其他畸形。发病机制目前尚不清楚,可能是由于遗传或环境因素引起。本文就临床中发现的1例Tessier 6号裂伴双牙列病例进行报道,具有一定的临床参考价值。     

New evidence for the role of cystathionine beta-synthase in non-syndromic cleft lip with or without cleft palate

Orofacial clefts have a multifactorial aetiology encompassing both genetic and environmental components. While there is wide agreement on the importance of both genetic and nutritional factors, genetic influence in particular has not been well defined. As genetic variants in folate and homocysteine metabolism have been reported to influence the risk of orofacial clefts, an Italian cleft lip with or without cleft palate (CL/P) data set was enrolled for an analysis based on family association to test betaine-homocysteine methyltransferase (BHMT and BHMT2) and cystathionine beta-synthase (CBS) variants. No significant level of association was found between BHMT and BHMT2 variants, while evidence of an allelic association with CL/P was found for the single nucleotide polymorphism rs4920037, mapping at the CBS gene. A log-linear approach indicated that the best genetic model takes into account both mother and child genotypes. This suggests that human orofacial development is influenced by CBS genotypes that possibly operate through intergenerational fetal-maternal interaction.     

Exploration of genetic factors determining cleft side in a pair of monozygotic twins with mirror-image cleft lip and palate using whole-genome sequencing and comparison of craniofacial morphology

ObjectiveThe aim of the present study is to explore genetic factors determining difference of cleft side using whole-genome sequencing and evaluation of craniofacial morphology using cephalometric analysis between Japanese monozygotic (MZ) twins with mirror-image cleft lip and palate (CLP).DesignWe selected a Japanese MZ twin pair (MZ-A and MZ-B) affected with unilateral CLP who are discordant for cleft side (left/right) and conducted whole-genome sequencing to identify genetic factors determining cleft side. Moreover, we compared their craniofacial morphologies using cephalograms.ResultsWhole-genome sequencing results suggested that no discordant DNA variants were found between MZ-A and MZ-B. The comparison of craniofacial morphology between the MZ twins revealed that MZ-B had maxillary deficiency and slightly more mandibular protrusion than MZ-A.ConclusionsIt is indicated that environmental factors might be a critical factor that influences the determination of difference of cleft side in orofacial clefts. In addition, we found some differences in craniofacial morphology between MZ-A and MZ-B. Our findings suggest that various environmental factors, such as epigenetics, might be a critical factor that influences the determination of difference of cleft side in CLP rather than inherited genetic factors.     

VAX1 gene associated non-syndromic cleft lip with or without palate in Western Han Chinese

ObjectiveNon-syndromic cleft lip with or without palate (NSCL/P) is one of the most common human birth defects, it results from multiple genetic and environmental risk factors. Recently, GWA studies identified associations between NSCL/P and two genetic risk loci, rs7078160 and rs4752028, at VAX1.DesignCurrently, we tried to investigate the roles of the two loci among 302 NSCL/P trios (129 non-syndromic cleft lip only (NSCLO) trios and 173 non-syndromic cleft lip and cleft palate (NSCLP) trios) from Western Han Chinese. The two SNPs were genotyped by SNPscan method; Hardy–Weinberg equilibrium test, allelic TDT and parent-of-origin effect were performed by PLINK software, and genotypic TDT and haplotype by FBAT software.ResultsAllelic TDT analysis revealed allele A at rs7078160 was over-transmitted among NSCL/P group (P = 0.0086, OR_transmission = 1.36, 95%CI: 1.08–1.72). Parent-of-origin effect analysis revealed a paternal special over-transmission of allele A at rs708260 in NSCL/P group (P = 0.0079). Haplotype AC of rs7078160-rs4752028 was significant over-transmitted in the NSCL/P group.ConclusionsOur study firstly confirmed that allele A at rs7078160 at VAX1 gene was a risk factor for NSCL/P in Western Han Chinese population.     

Periodontal conditions in adult patients with cleft lip, alveolus, and palate.

The present study assessed the progression rate of periodontal disease over 8 years in a group of 52 adult patients with various forms of cleft lip, alveolus, and palate considered at risk for progression of periodontal disease. Of special interest was the evaluation of periodontal disease progression at sites adjacent to cleft regions compared to changes found at control sites not directly affected by such defects. High incidences of generalized plaque accumulation and bleeding on probing were noted at both examinations in 1979 and 1987. A mean apical shift of the clinical attachment level amounting to 0.2 mm had occurred over the 8-year observation period. A slight apical displacement of the mesial and distal mean crestal alveolar bone was also noted. The rate of progression of periodontal disease over the 8 years was not found to be different at statistically significant levels at cleft sites compared to control sites. However, the results of this study documented that the cumulative periodontal destruction at 26 to 28 years of age was statistically significant and more pronounced at cleft sites as revealed by greater probing pocket depth and loss of clinical attachment. The differences between test and control sites amounted to 0.3 and 0.4 mm respectively for probing depth and 0.6 mm for loss of clinical attachment. In addition, the discrepancy between alveolar bone height and the levels of the clinical attachment at cleft sites demonstrated the presence of a long supracrestal connective tissue attachment adjacent to cleft defects. Therefore, the alveolar bone height as visualized in radiographs at such sites was considered an unreliable diagnostic tool for the assessment of the degree of periodontal destruction.     

No evidence for a role of CRISPLD2 in non-syndromic cleft lip with or without cleft palate in an Italian population

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a malformation with variable phenotypes, resulting from a mixture of genetic and environmental factors. Some studies have supported a role for the 16q24 region and its candidate gene, CRISPLD2, in clefting. A replication study is necessary to confirm these findings. The aim of the present study was to test, by genetic linkage and association analyses, whether the candidate gene, CRISPLD2, represents a risk factor for NSCLP. The analysis of 39 multigenerational families provided formal exclusion of a linkage between NSCLP and the CRISPLD2 locus under different genetic models and non-parametric analyses. The family-based study of 239 unrelated probands and their parents revealed no association between any particular allele or haplotype and NSCLP. Therefore, the present investigation did not support the hypothesis of the involvement of CRISPLD2 in NSCLP malformation, at least with regard to the Italian population.     

Human tooth-size asymmetry in cleft lip with or without cleft palate.

Failure of corresponding teeth on the right and left sides to form as exact mirror images of each other is an expression of imprecise developmental control. Levels of tooth-size asymmetry can therefore be used to quantify developmental instability in different regions of the dentition. Mesiodistal and buccolingual diameters of deciduous and permanent teeth were measured to the nearest 0.1 mm on serial plaster models of 77 patients with cleft lip with or without a cleft of the palate, and 63 control non-cleft orthodontic patients. In the cleft group as a whole, there were abnormally high levels of tooth-size asymmetry but, although most marked in the upper lateral incisor region, these were neither restricted to the vicinity of the cleft nor to the upper jaw. Thus, in addition to major local disturbances related to the malformation itself, it appears that tooth-size asymmetry results from a generally high level of developmental instability throughout cleft lip/palate dentitions. This generalized developmental instability may be to some extent under genetic control, as cases with positive family histories showed some signs of greater asymmetry than those with negative family histories.     

阜新市阜蒙县非综合征性唇腭裂的多因素分析

目的:研究阜蒙县近8年先天性非综合征性唇腭裂的发病因素,为唇腭裂的预防与治疗提供依据。方法:采用1∶4配对的方法,对32例唇腭裂患儿的母亲与128例非唇腭裂小儿的母亲进行了对照研究,调查范围包括母亲自身及环境中的危险因素和遗传因素两大方面。资料用条件Logistic回归方法进行单因素和多因素分析。结果:病例对照单因素分析显示与唇腭裂发病有显著性意义的因素共13种,最终进入多因素Logistic回归模型的变量有7种。结论:本研究发现家庭人均收入,母亲孕早期食用水果、呕吐反应、患风疹、接触农药、精神刺激以及家族史这7种因素是唇腭裂的主要影响因素。     

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.

OBJECTIVE: The members of the International Consortium for Oral Clefts Genetics recognize the need for collaboration between researchers involved in etiologic studies of nonsyndromic cleft lip and palate and cleft palate. To address this need, the consortium established four working subcommittees: diagnostic and phenotypic assessment, molecular genetic studies, epidemiologic data collection and analysis, and genetic data collection and analysis. These subcommittees were charged with the development of guidelines for data collection and analysis that would facilitate both a priori and a posteriori comparisons and pooling of data from multiple centers. This report presents summary statements of the four subcommittees.     

Analysis of interactions between genetic variants of BMP4 and environmental factors with nonsyndromic cleft lip with or without cleft palate susceptibility

A hospital-based case-control study was conducted to identify interactions between the 538(T→C) polymorphic site of bone morphogenetic protein 4 gene (BMP4T538C) and exposures in pregnancy with nonsyndromic cleft lip, with or without cleft palate (nsCL/P). Associations between offspring polymorphism of BMP4T538C, paternal smoking, paternal high-risk drinking, maternal passive smoking, and maternal multivitamin supplement with nsCL/P were analyzed by logistic regression analysis. BMP4T538C polymorphism, maternal passive smoking exposures and maternal multivitamin use were associated with the risk of nsCL/P but paternal smoking and paternal high-risk drinking were not. Gene–environment interactions were analyzed using the multifactor dimensionality reduction (MDR) method. The two-factor model including maternal passive smoking and BMP4T538C, was the best for predicting nsCL/P risk with a maximum cross-validation consistency (10/10) and a maximum average testing accuracy(0.605; P < 0.0001). The findings suggested that: BMP4T538C could be used as a genetic susceptibility marker for nsCL/P; maternal passive smoking exposure is a risk factor for nsCL/P; maternal multivitamin supplements are a protective factor; the synergistic effect of BMP4T538C and maternal passive smoking could provide a new tool for identifying individuals at high risk of nsCL/P, and provides additional evidence that nsCL/P is determined by genetic and environmental factors.     

Population and family studies of HLA in Japanese with cleft lip and cleft palate

Population and family studies of HLA were performed in Japanese patients with cleft lip and/or cleft palate (CL/P). Frequency of HLA-Cw 7 was significantly increased in cleft lip (CL) patients (37.5%) and cleft palate (CP) patients (37.8%) but was not increased in cleft lip and palate (CLP) patients (17.5%), compared with control subjects (13.3%). However, the intensities of the associations were not great (relative risk = 4.0). The affected sib pairs method was studied in 13 families with CL- or CLP-affected sib pairs and 10 families with CP-affected sib pairs. However, in both groups of families the distributions of HLA haplotypes in affected sib pairs did not significantly differ from random Mendelian expectation. Thus, HLA-linked major genes (loci) which determine the development of CL/P were not found. These results seem indirectly to support the multifactorial theory of CL/P, but does not exclude other possible genetic mechanisms.     

Use of rotation flap in repair of cleft palate and velopharyngeal insufficiency

Although cleft palate anomaly is frequent, the criterion standards in surgical treatment have not been determined yet. There are a few techniques described for cleft palate repair owing to the limited tissue in the palatal mucosa, the rigid structure of the palatal mucosa, and the limited vascularity of the hard palate. In this study, a novel cleft palate repair technique based on separating the soft palate from the hard palate as a musculomucosal flap and using it as a rotation flap has been described. The operation is evaluated individually for each anomaly because variations occur in the surgical technique according to the extension of the cleft toward the teeth in the palate. This operation was performed on a total of 28 patients (17 girls and 11 boys) aged between 1.5 and 16 years and presented to our clinic. Patients were assessed for speech analysis outcomes, tympanogram values, hearing functions, magnitude of palatal lengthening during the operation, and rate of fistulae. Statistically significant differences in values of the speech analysis and the audiometric assessment were determined between before and 6 months after surgery. Complete recovery of otitis was observed 1 month after surgery without another treatment in 9 (42.8%) of 21 patients who were detected to have serous otitis media preoperatively. Tension-free closure, lower risk of fistula, good restoration of velopharyngeal functions, ability to be performed on all types of cleft palate, ability to provide a good intraoperative exposure, and being a single stage seem to be the most important advantages of this technique.