Background and Objectives:
A healthy periodontium is an important prerequisite for unhindered dentition and long-term oral health. In cleft subjects, especially in those with cleft lip, alveolus and palate (CLAP), maintenance of oral hygiene is a difficult task for the patients because of the patent oro-nasal communication. Crowding of teeth in cleft patients is a common finding, especially in those with CLAP and those with cleft palate (CP). In the case of multiple tooth-malpositions, transverse deficiency, arch length deficiency and primary cross-bite; periodontal trauma increases and is detrimental to periodontal health. According to literature, a critical periodontal situation was found in patients with CLAP. Hence a study was conducted to analyze the periodontal status of patients with cleft lip (CL); those with cleft palate; and those with cleft lip, alveolus and palate.
Materials and Methods:
The present study consisted of 60 cleft subjects divided into 3 groups: those with cleft lip; those with cleft palate; and those with cleft lip, alveolus and palate. Subjects with permanent dentition were selected, and the clinical examination included determination of oral hygiene status using Oral Hygiene Index — Simplified (OHI-S) index and periodontal status using community periodontal index (CPI).
Statistically significant increase in the periodontal disease in the CLAP group as compared with the other 2 groups, and the oral hygiene was seen to be generally poor with the CLAP group.
Interpretation and Conclusion:
Individuals with clefts are more prone to periodontal disease due to the presence of cleft, which causes retention of food in the defect sites and inability to maintain good oral hygiene; but the severity of periodontal disease is more if the defect is large and involving the lip, alveolus and palate.
Alveolus and palate; cleft lip; cleft palate; periodontal disease
Objectives: Orofacial clefts are major human birth defects with complex etiology. Previous studies have proposed Transforming growth factor - beta 3 (TGF-β3) gene as a key player in contributing to non-syndromic cleft lip and palate, however none of the studies have yet included Indian population. Hence this study was designed to detect TGF-β3 gene polymorphism in nonsyndromic cleft lip and palate patients from Indian population which is genetically
distinct from previously studied populations.
Study Design: Peripheral blood samples of forty non-syndromic cleft lip and palate patients and forty unaffected individuals were collected for a case – control study design. Ethical clearance from the institutional review board and informed consent from all subjects was obtained. DNA extracted from the cases and controls was amplified using polymerase chain reaction (PCR) with TGF-β3 specific primers. The obtained fragments were sequenced and TGF-β3 gene polymorphisms were assessed based on the number of CA repeats.
Results: Chi –square test was used to compare the case and control groups. Results showed a significant difference in the number of CA repeats between the case and the control groups (p=0.01).
Conclusion: This study confirms the crucial role of TGF-β3 in the fusion of palatal shelves during development and further, provides novel evidence of TGF-β3 gene polymorphism in the etiology of nonsyndromic cleft lip and palate in Indian subpopulation.
Key words: Orofacial clefts, nonsyndromic cleft lip with/without cleft palate, TGF-β3, Polymerase chain reaction,
Cleft lip and/or palate (CL/P) is a common congenital malformation with a complex etiology which is not fully elucidated yet. Epidemiological studies point to different etiologies in the cleft lip and palate subgroups, isolated cleft lip (CL), isolated cleft palate (CP) and combined cleft lip and palate (CLP). In order to understand the biological basis in these cleft lip and palate subgroups better we studied the expression profiles in human tissue from patients with CL/P. In each of the CL/P subgroups, samples were obtained from three patients and gene expression analysis was performed. Moreover, selected differentially expressed genes were analyzed by quantitative RT-PCR, and by immunohistochemical staining of craniofacial tissue from human embryos. Osteopontin (SPP1) and other immune related genes were significantly higher expressed in palate tissue from patients with CLP compared to CP and immunostaining in palatal shelves against SPP1, chemokine receptor 4 (CXCR4) and serglycin (PRG1) in human embryonic craniofacial tissue were positive, supporting a role for these genes in palatal development. However, gene expression profiles are subject to variations during growth and therefore we recommend that future gene expression in CL/P studies should use tissue from the correct embryonic time and place if possible, to overcome the biases in the presented study.
cleft lip and palate; congenital abnormalities; gene expression profiling; osteopontin; serglycin
Clefts of the lip (CL), the palate (CP), or both (CLP) are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. The frequency and pattern of orofacial clefts in different parts of the world and among different human groups varies widely. Generally, populations of Asian or Native American origin have the highest prevalence, while Caucasian populations show intermediate prevalence and African populations the lowest. To date, little is known regarding the epidemiology and pattern of orofacial clefts in Tanzania.
A retrospective descriptive study was conducted at Bugando Medical Centre to identify all children with orofacial clefts that attended or were treated during a period of five years. Cleft lip and/or palate records were obtained from patient files in the Hospital's Departments of Surgery, Paediatrics and medical records. Age at presentation, sex, region of origin, type and laterality of the cleft were recorded. In addition, presence of associated congenital anomalies or syndromes was recorded.
A total of 240 orofacial cleft cases were seen during this period. Isolated cleft lip was the most common cleft type followed closely by cleft lip and palate (CLP). This is a departure from the pattern of clefting reported for Caucasian and Asian populations, where CLP or isolated cleft palate is the most common type. The distribution of clefts by side showed a statistically significant preponderance of the left side (43.7%) (χ2 = 92.4, p < 0.001), followed by the right (28.8%) and bilateral sides (18.3%). Patients with isolated cleft palate presented at very early age (mean age 1.00 years, SE 0.56). Associated congenital anomalies were observed in 2.8% of all patients with orofacial clefts, and included neural tube defects, Talipes and persistent ductus arteriosus.
Unilateral orofacial clefts were significantly more common than bilateral clefts; with the left side being the most common affected side. Most of the other findings did not show marked differences with orofacial cleft distributions in other African populations.
Objective: Children with a Cleft Palate (CLP) and with or without cleft lips (non-syndromic) universally present with Secretory Otitis Media (SOM). The purpose of this study was to determine the incidence of secretory otitis media that occurs in patients with cleft palates and to confirm the existence of these manifestations by doing a Basic Audiologic Evaluation (BAE).
Material and Methods: A retrospective study was done on forty four male and female children who were within the 2 to 14 years age range, with non-syndromic cleft palates with or without cleft lips, with the symptoms of SOM. Otoscopy examinations were done in all the cases. X-rays of the mastoids (both sides) were done in all the cases to detect the pneumatization of the mastoid air cell system. The Basic Audiologic Evaluation (BAE) includes an evaluation by tympanometry of the middle ear function and an evaluation by pure tone audiometry to establish the type of hearing loss.
Results: A majority of the patients (47.27%) were in the age group of eight-to-fourteen (8-14) years. The Basic Audiologic Evaluation (BAE) revealed that 77.27% of the children had presented with normal hearing; 13.6% had conductive hearing loss and 2.2% had presented with a mixed hearing loss. We noticed that 68.2% of the children had type A curves; 21.2% of the children had type C tympanometry curves; 7.1% had type B curves and 3.5% had Ad curves. The contralateral acoustic reflex was present in 54.5% of the children and 45.5% did not have this reflex. A majority of the patients (46%) showed sclerotic changes in their mastoid air cell systems in the X-rays of the mastoids.
Conclusion: The significantly higher prevalence of SOM in the children with cleft was confirmed by the study. Also, the hearing loss which was associated with SOM was evident and it demonstrated that there was a high prevalence of a mild conductive hearing loss when SOM was present. The cleft palate contributed to the occurrence of the secretory otitis media and it required proper ENT and audiological follow ups.
Cleft palate; Secretory otitis media; Hearing loss
Objective. Few orofacial cleft (OFC) studies have examined the severity of clefts of the lip or palate. This study examined associations between the severity of cleft of the lip with cleft type, laterality, and sex in four regional British Isles cleft registers whilst also looking for regional variations. Design. Retrospective analysis of cleft classification in the data contained in these four cleft registers. Sample. Three thousand and twelve patients from cleft registers based in Scotland, East England, Merseyside, and Belfast were sourced from the period 2002–2010. Submucous clefts and syndromic clefts were included whilst stillbirths, abortuses, and atypical orofacial clefts were excluded. Results. A cleft of the lip in CLP patients is more likely to be complete in males. A cleft of the lip in isolated CL patients is more likely to be complete in females. Variation in the proportion of cleft types was evident between Scotland and East England. Conclusions. Association between severity of cleft of the lip and sex was found in this study with females having a significantly greater proportion of more severe clefts of the lip (CL) and CLP males being more severe (P < 0.0003). This finding supports a fundamental difference between cleft aetiology between CL and CLP.
Cleft lip and palate (CLP) are birth defects that affect the upper lip and the roof of the mouth. CLP has a multifactorial etiology, comprising both genetic and environmental factors. In this review we discuss the recent data on the etiology of cleft lip and palate. We conducted a search of the MEDLINE database (Entrez PubMed) from January 1986 to December 2010 using the key words: ‘cleft lip,’ ‘cleft palate,’ ‘etiology,’ and ‘genetics.’ The etiology of CLP seems complex, with genetics playing a major role. Several genes causing syndromic CLP have been discovered. Three of them—T-box transcription factor-22 (TBX22), poliovirus receptor-like-1 (PVRL1), and interferon regulatory factor-6 (IRF6)—are responsible for causing X-linked cleft palate, cleft lip/palate–ectodermal dysplasia syndrome, and Van der Woude and popliteal pterygium syndromes, respectively; they are also implicated in nonsyndromic CLP. The nature and functions of these genes vary widely, illustrating the high vulnerability within the craniofacial developmental pathways. The etiological complexity of nonsyndromic cleft lip and palate is also exemplified by the large number of candidate genes and loci. To conclude, although the etiology of nonsyndromic CLP is still largely unknown, mutations in candidate genes have been identified in a small proportion of cases. Determining the relative risk of CLP on the basis of genetic background and environmental influence (including smoking, alcohol use, and dietary factors) will be useful for genetic counseling and the development of future preventive measures.
Cleft lip; cleft palate; etiology; genetics
Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed.
Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses.
In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (OR: 0.29, 95% CI: 0.13–0.64 for homozygotes) whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR: 1.36, 95% CI: 1.07–1.74 for heterozygotes and OR: 1.56, 95% CI: 1.09–2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR: 1.45, 95% CI: 1.06–1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (P=0.041).
For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
cleft lip; cleft palate; congenital abnormalities
Orofacial clefts (OFC; MIM 119530) are among the most common major birth defects. Here, we carried out mutation screening of the PVR and PVRL2 genes, which are both located at an OFC linkage region at 19q13 (OFC3) and are closely related to PVRL1, which has been associated with both syndromic and non-syndromic cleft lip and palate (nsCLP). We screened a total of 73 nsCLP patients and 105 non-cleft controls from the USA for variants in PVR and PVRL2, including all exons and encompassing all isoforms. We identified four variants in PVR and five in PVRL2. One non-synonymous PVR variant, A67T, was more frequent among nsCLP patients than among normal controls, but this difference did not achieve statistical significance.
PVR; PVRL2; cleft lip and palate; mutation; SSCP
The results of an epidemiological survey of facial clefting in the province of Manitoba which covered the years 1964 to 1977, inclusive, are reported. The mean annual incidence of total facial clefts was 2 in 1000 births; the incidence of cleft lip +/- cleft palate (CLP), and of cleft palate (CP), unassociated with a syndrome or two or more major malformations, was 1.05 in 1000 and 0.46 in 1000, respectively. Mennonite infants were over-represented in the CLP group and Amerindian infants in both the CLP and CP groups. These ethnic groups also had more familial cases and showed higher average coefficients of inbreeding. Recurrence rates among sibs were found to be influenced by the presence or absence of additional affected relatives and by the presence of malformations in the proband. It is possible that these latter two variables may not be independent.
The transversal measurement on the dento-alveolar fragments of the maxilla, in the unoperated adult patients with unilateral cleft lip and alveolus are rare and have not been well documented and archived in the scientific journals. The effect of the congenital malformation is obvious in the Unilateral Cleft Lip and Alveolus (UCLA) patients and is well documented.
The aim of this study is to investigate whether there are any influences of the final transversal development of the maxilla based on the location and extent of the defect in patients with UCLA.
168 adult unoperated UCLA patients (study group) and 24 non cleft patients (control group) participated in this study. Plaster of Paris (POP) casts were made of the maxillary dentition and mesurement were taken using coordinate measuring machine (CCM) (Zeiss Numere, Carl Zeiss, Stuttgart, Germany).
The mean values of maxillary transverse measurement of first premolar through the second molar of the UCLA and control group patients showed no statistically significant difference. The inter-canine distance was significantly smaller in the UCLA patients than non-cleft patients
The maxillary inter-canine distance in untreated UCLA patients were significantly different from that of non cleft patients. There is narrow and constricted maxillary growth in UCLA patients causing maxillary morphological changes and cosmetic facial changes.
Cleft palate; Orthodontics growth
The purpose of this study was to investigate the contribution of MSX1 gene to the risk of nonsyndromic cleft lip with or without cleft palate (NS-CL ± P) in the Korean population. The samples consisted of 142 NS-CL ± P families (9 with cleft lip, 26 with cleft lip and alveolus, and 107 with cleft lip and palate; 76 trios and 66 dyads). Three single nucleotide polymorphisms (SNPs: rs3821949, rs12532, and rs4464513) were tested for association with NS-CL ± P case-parent trios using transmission disequilibrium test (TDT) and conditional logistic regression models (CLRMs). Minor allele frequency, heterozygosity, χ2 test for Hardy-Weinberg equilibrium, and pairwise linkage disequilibrium (LD) at each SNP were computed. The family- and haplotype-based association test programs were used to perform allelic and genotypic TDTs for individual SNPs and to fabricate sliding windows of haplotypes. Genotypic odds ratios (GORs) were obtained from CLRMs using R software. Although the family-based TDT indicated a meaningful association for rs3821949 (P = 0.028), the haplotype analysis did not reveal any significant association with rs3821949, rs12532, or rs4464513. The A allele at rs3821949 had a significant increased risk of NS-CL ± P (GOR, 1.64; 95% confidence interval,1.03-2.63; P = 0.038, additive model). A positive association is suggested between MSX1 rs3821949 and NS-CL ± P in the Korean population.
MSX1 SNP; Nonsyndromic Cleft Lip with or without Palate; Korean; Association Analysis
Non-syndromic cleft lip and palate (NS CLP) is a complex birth defect resulting from multiple genetic and environmental factors. We have previously reported the sequencing of the coding region of genes in the fibroblast growth factor (FGF) signaling pathway, in which missense and non-sense mutations contribute to approximately 5%–6% NS CLP cases. In this article we report the sequencing of conserved non-coding elements (CNEs) in and around 11 of the FGF and FGFR genes, which identified 55 novel variants. Seven of variants are highly conserved among ≥8 species and 31 variants alter transcription factor binding sites, 8 of which are important for craniofacial development. Additionally, 15 NS CLP patients had a combination of coding mutations and CNE variants, suggesting that an accumulation of variants in the FGF signaling pathway may contribute to clefting.
cleft lip and palate; fibroblast growth factor; conserved non-coding elements; sequencing
The application of three-dimensional computed tomography (3D CT) to analyse craniofacial morphology in individuals with cleft lip and palate (CLP) enables detailed assessments to be made of asymmetry in the region of the cleft and in regions distant from the cleft. The aim of this study was to compare craniofacial morphology in a sample of Malaysian infants with unoperated CLP with a control sample of unaffected Malaysian infants.
The study sample comprised 29 individuals: 10 with unilateral CLP (UCLP), 5 with bilateral CLP (BCLP), 7 with cleft lip and primary palate (CLPP), and 7 with isolated cleft palate (ICP). The control sample consisted of 12 non-cleft (NC) infants. All subjects were between 0.4 and 12.2 months of age. Nine mid-facial and 4 nasal bone landmarks were located on 3D CT scans and compared to a midline reference plane, which was created using the landmarks basion, sella, and nasion. Unpaired t tests and F tests were used to compare means and variances between sample groups, whereas paired t tests were used for comparisons within the UCLP and NC groups.
Differences in variances of some mid-facial breadths and nasal bone dimensions were found in both male and female cleft groups when compared to the NC sample. In the UCLP group, some nasal bone and facial breadth dimensions were larger than in the NC sample and the nasal bone tended to deviate to the contralateral side of the cleft.
CLP affects the size and orientation of the nasal bones and is associated with an altered morphology of some facial bones at positions distant from the region of the cleft.
cleft lip; cleft palate; facial asymmetry; infant; radiology; three-dimensional imaging; tomography
Labial and nasal deformities have always been a fundamental problem in the treatment of cleft lip, alveolus and palate patients. The primary surgical treatment of nasolabial area is of paramount importance in order to obtain both an esthetical correction of the deformity and a progressive and a balanced development of mid-face. In this study the nasal deformities in patients with cleft lip, alveolus and palate (CLAP) were analyzed and the relevant role of the perinasal, perioral muscular balance and the inborn dislocation of the alar cartilages are presented.
Patients and Methods
50 CLAP patients were analyzed, 40 UCLP and 10BCLP. The lip repair was done by modification of Millard’s technique. The severity of the cleft appearance was evaluated pre and post operatively, according to a pre-agreed visual rating scale. There are 4° of severity of the deformity pre operatively (mild, moderate, severe and very severe) and post operatively 5 categories of outcome (excellent,very good, good, satisfactory and poor), depending on the scores obtained by summing up the points corresponding to different types of deformity. This scale is closely related to the American Cleft Palate classification of clefts.
In the 40 UCLP patients, 8 excellent, 10 very good, 16 good and 6 satisfactory results were obtained following primary cheiloplasty. In 10 BCLP patients 1 very good, 7 good, 1 satisfactory and 1 poor result were obtained.
During the primary repair, it is important to correct the abnormal position of ala nasi, the nasal floor and the base of the columella. Abnormalities in the insertion of the nasolabial muscles with their abnormal function contribute to the cleft nose deformities. Therefore the reconstruction not only the orbicularis muscle but also of the paranasal muscles is therefore important for a symmetrical growth of the nose. Separate suture of intrinsic orbicularis oris provide a better shape to the vermillion. The position of the alar cartilage plays an important role for the symmetry of the nose. It is necessary to place the alar base symmetrically in three dimensions.
Cleft lip; Palate; Rating scale; Secondary deformities; Cheiloplasty
Secondary bone grafting of maxilla and residual alveolar clefts at the stage of transitional dentition was first introduced by Boyne and Sands. The aim of this prospective case control study was to clinically and radiologically evaluate the success rate of anterior iliac crest graft in primary alveolar cleft.
Methods and Material:
In this study we evaluated 10 patients who underwent secondary alveolar bone grafting for various types of cleft palate with autologous iliac crest graft. Type of septum measured radiologically was taken as the outcome measure.
Postoperative radiographic evaluation revealed Type I inter alveolar septum in 7 cases (87.5%), with complete unilateral cleft lip, palate and alveolus. Non-eruption of canine occurred in 5 patients (50%). Periodontal Examination revealed presence of pocket formation (less than 4 mm) and Grade II mobility in 2 cases (20%).
In conclusion, secondary alveolar bone grafting done during the time of transitional dentition, before the eruption of permanent canine is an excellent treatment modality.
Alveolar bone grafting; autogenous graft; maxilla; palate
The receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene has been recently shown to play important roles in palatal development in animal models and resides in the chromosomal region linked to non syndromic cleft lip with or without cleft palate in humans. The aim of this study was to investigate the possible association between ROR2 gene and non-syndromic oral clefts.
Here we tested 38 eligible single-nucleotide polymorphisms (SNPs) in ROR2 gene in 297 non-syndromic cleft lip with or without cleft palate and in 82 non-syndromic cleft palate case parent trios recruited from Asia and Maryland. Family Based Association Test was used to test for deviation from Mendelian inheritance. Plink software was used to test potential parent of origin effect. Possible maternally mediated in utero effects were assessed using the TRIad Multi-Marker approach under an assumption of mating symmetry in the population.
Significant evidence of linkage and association was shown for 3 SNPs (rs7858435, rs10820914 and rs3905385) among 57 Asian non-syndromic cleft palate trios in Family Based Association Tests. P values for these 3 SNPs equaled to 0.000068, 0.000115 and 0.000464 respectively which were all less than the significance level (0.05/38=0.0013) adjusted by strict Bonferroni correction. Relevant odds ratios for the risk allele were 3.42 (1.80–6.50), 3.45 (1.75–6.67) and 2.94 (1.56–5.56), respectively. Statistical evidence of linkage and association was not shown for study groups other than non-syndromic cleft palate. Neither evidence for parent-of-origin nor maternal genotypic effect was shown for any of the ROR2 markers in our analysis for all study groups.
Our results provided evidence of linkage and association between the ROR2 gene and a gene controlling risk to non-syndromic cleft palate.
receptor tyrosine kinase-like orphan receptor 2; cleft lip; cleft palate; association; transmission disequilibrium test
This study aimed to investigate the mutation of T-box transcription factor TBX22 exon 5 in children with non-syndromic cleft palate. Four mutations in TBX22 exon 5 in X-linked cleft palate with ankyloglossia (CPX) patients had been identified in the previous studies. The study used the syndromic cleft palate susceptibility gene as a candidate gene for more common non-syndromic cleft palate.
Material and methods
A family-based study with parents and their children composing parent-child trios was performed in this research. Twenty children with non-syndromic cleft palate and 38 healthy parents were enrolled. TBX22 exon 5 was examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing. The peaks of the sequence diagrams were analyzed using chromas221 and the results of sequencing were proofread using dnastar6.13. The index of the transmission disequilibrium test (TDT) was calculated through McNemar testing.
We have not found the presence of any mutation of TBX22 exon 5 reported in syndromic cleft palate patients in references. The index of TDT was 0.56 and showed no statistically significant difference (p<0.05). No TBX22 exon 5 mutation was found in the 20 children.
Mutation of TBX22 exon 5 is not associated with non-syndromic cleft palate in the population of Jiangzhe areas in China.
non-syndromic cleft palate; TBX22; transmission disequilibrium test
This study was done to determine the prevalence of dental anomalies and facial profile abnormality and its association with the non-syndromic cleft lip and palate (CLP) as compared to the non-cleft children. A comparative cross sectional study was conducted where the case group consist of 98 non-syndromic CLP children-unilateral (UCLP) and bilateral (BCLP) who attended the Combined Clinic at Kota Bharu Dental Clinic (KBDC) while the comparison group comprised of 109 non-cleft children who attended the outpatient clinic at KBDC. Their ages were between 3 to 12 years old. Clinical oral and facial profile examinations were carried out to look for dental anomalies (morphology, number and alignment of teeth) and facial profile abnormality. The prevalence of anomalies in morphology of teeth in CLP (24.5%) and non-cleft (10.1%), number of teeth in CLP (44.9%) and non-cleft (7.3%), mal-alignment in CLP (79.6%) and non-cleft (27.5%) and facial profile abnormality in CLP (26.5%) and non-cleft (9.1 %). There was a significant association between CLP and anomalies in morphology, number, mal-alignment and abnormality in facial profile; (p < 0.05). Therefore, there was a high prevalence and risk of dental anomalies and facial profile abnormality in the CLP children compared to the non-cleft children.
cleft lip and palate; dental anomalies; hypodontia; supernumerary; facial profile
Objective. To evaluate characteristics of smile related to visibility in individuals with cleft lip, alveolus, and palate. Design. Cross-sectional. Setting. HRAC/USP, Brazil. Patients. Individuals with repaired complete unilateral cleft lip and palate (n = 45), aged 15–30 years. Interventions. Frontal facial photographs were obtained in natural and forced smiles (n = 135). Six specialists in periodontics evaluated the photographs as to the smile line, thickness, and curve of the upper lip. Main Outcome Measures. The cleft area was compared with the contralateral region. Results were expressed as percentages and means. The findings were compared between groups of periodontists. Results. Statistically significant relationship was observed in the smile line between examiners and between natural and forced smiles, regardless of the association with the cleft side. The lip was thicker at rest and thinner in the forced smile, as also evaluated by the group not experienced with cleft care. The curve of the upper lip in natural and forced smiles was considered as close to straight by both groups, regardless of the cleft. Conclusion. The smile in individuals with clefts was regarded as average for both cleft and noncleft sides. The thickness was characterized as average to thin, being thinner in forced smile and when analyzed by the group not experienced with cleft care. In the average, the curve of the upper lip was considered as straight. The present study elucidates some characteristics related to the smile in individuals with repaired unilateral cleft lip, alveolus, and palate.
Van der Woude Syndrome is the most common form of syndromic orofacial clefting, accounting for 2% of all cases, and has the phenotype that most closely resembles the more common non-syndromic forms. The syndrome has an autosomal dominant hereditary pattern with variable expressivity and a high degree of penetrance with cardinal clinical features of lip pits with a cleft lip, cleft palate, or both.
This case report describes van der Woude syndrome in a 19 year old male patient with a specific reference to the various aspects of this condition, as clinical appearance, etiological factors (genetic aspects), differential diagnosis, investigative procedures and management.
Key words:Cleft palate, cleft lip, lip pits, van der Woude syndrome, syndromic clefting.
Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.
Cleft palate; Genetic; IRF6; Non-syndromic cleft lip; PPS; VWS
Cleft lip with or without cleft palate is one of the most common congenital malformations in newborns. While numerous studies on secondary palatogenesis exist, data regarding normal upper lip formation and cleft lip is limited. We previously showed that conditional inactivation of Tgf-β type I receptor Alk5 in the ectomesenchyme resulted in total facial clefting. While the role of Tgf–β signaling in palatal fusion is relatively well understood, its role in upper lip fusion remains unknown. In order to investigate a role for Tgf-β signaling in upper lip formation, we used the Nes-Cre transgenic mouse line to delete the Alk5 gene in developing facial prominences. We show that Alk5/Nes-Cre mutants display incompletely penetrant unilateral or bilateral cleft lip. Increased cell death seen in the medial nasal process and the maxillary process may explain the hypoplastic maxillary process observed in mutants. The resultant reduced contact is insufficient for normal lip fusion leading to cleft lip. These mice also display retarded development of palatal shelves and die at E15. Our findings support a role for Alk5 in normal upper lip formation not previously reported.
Tgf-β; cleft lip; Transforming growth factor-beta; Nes-Cre; development; mouse
Cleft lip with or without cleft palate (CLP) and cleft palate only (CP) are severe disruptions affecting orofacial structures. Patients with orofacial clefts require complex interdisciplinary care, which includes nursing, plastic surgery, maxillofacial surgery, otolaryngology, speech therapy, audiology, psychological and genetic counseling, orthodontics and dental treatment, among others. Overall, treatment of clefts of the lip and palate entails a significant economic burden for families and society. Therefore, prevention is the ultimate objective and this will be facilitated by a complete understanding of the etiology of this condition. Here we review the current concepts regarding the genetic and environmental factors contributing to orofacial clefts and emphasize on the roles of BMP signaling pathway components in the normal and aberrant development of the lip and palate.
Clefts of the lip and/or palate (CLP) are common birth defects of complex etiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian, or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the etiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translation research.