Congenital diaphragmatic hernia and cleft lip and palate: looking for a common genetic etiology.

PURPOSE: Congenital diaphragmatic hernia (CDH) and cleft lip and/or palate (CL/P) are inborn closure defects. Genetic factors in and outcomes for patients with both anomalies (CDH+CL/P) remain unclear. We aimed to investigate associated genetic aberrations, prevalence of, and outcomes for, CDH+CL/P. METHODS: Data from Congenital Diaphragmatic Hernia Study Group (CDHSG) registry were collected. CL/P prevalence in CDH patients was determined. Genetic abnormalities and additional malformations in CDH+CL/P were explored. Patient characteristics and outcomes were compared between CDH+CL/P and isolated CDH (CDH-) using Fisher's Exact Test for categorical, and t-test or Mann-Whitney U-test for continuous, data. p < 0.05 was considered statistically significant. RESULTS: Genetic anomalies in CDH+CL/P included trisomy 13, 8p23.1 deletion, and Wolf-Hirschhorn syndrome (4p16.3 deletion). CL/P prevalence in CDH was 0.7%. CDH+CL/P had lower survival rates than CDH-, a nearly fourfold risk of death within 7 days, were less supported with extracorporeal life support (ECLS), had higher non-repair rates, and survivors had longer length of hospital stay. CONCLUSION: Genetic anomalies, e.g. trisomy 13, 8p23.1 deletion, and Wolf-Hirschhorn syndrome, are seen in patients with the combination of CDH and orofacial clefts. CL/P in CDH patients is rare and associated with poorer outcomes compared to CDH-, influenced by goals of care decision-making.

Religiosity and alcohol use in adolescents with orofacial cleft: correlational study.

OBJECTIVE: To evaluate the correlation between religiosity and alcohol use among adolescents with orofacial clefts. METHODS: Cross-sectional study, developed in a Brazilian public and tertiary hospital, between December 2021 and March 2022. Data collection was hybrid, and three instruments were used: Sociodemographic Questionnaire, Durel Religiosity Scale, and the Alcohol Use Disorders Identification Test. For statistical analysis, the following tests were used: χ2, Fisher's Exact, Mann-Whitney and Spearman's Correlation Coefficient, in addition to analyses of linear correlation strength and bivariate logistic regression. The significance level adopted for all tests was 5% (p≤0.05). RESULTS: 370 adolescents participated, with a mean age of 15.2 years (±1.8). Among them, 23 (5.4%) used alcohol riskly or harmfully, being more frequent among male adolescents (p=0.001), those of mixed race (p=0.046), attending high school (p=0.011), with no religion (p<0.001), or who did not attend religious services (p<0.001). Levels of organizational, non-organizational and intrinsic religiosity were significantly lower among adolescents with risky or harmful alcohol use (p=0.005; p<0.001 and p=0.002, respectively). There was a moderate correlation between risky or harmful alcohol use and non-organizational (r=0.31; p=0.002) and intrinsic (r=0.36; p<0.001) religiosity. Male adolescents (p<0.001; OR=6.58), closest in age to 18 years (p<0.001; OR=1.37), and non-practitioners of religion (p<0.001; OR=6. 48) presented higher odds of risky or harmful alcohol use. CONCLUSIONS: Adolescents with higher levels of organizational and intrinsic religiosity used less alcohol, while males, closest in age to 18 years, and non-practitioners of religion presented higher odds of using alcohol riskly or harmfully.

Cleft lip and palate and periconception COVID-19 infection in five arab countries.

BACKGROUND: Little is known about factors associated with the severity of cleft lip with or without cleft palate (CL/P) especially during the COVID-19 pandemic with its dramatic changes. OBJECTIVES: The aim of this multi-national study is to measure the association between CL/P severity, COVID-19 infection, and fear of COVID-19 in five Arab countries. METHODS: This cross-sectional study took place in major governmental hospitals in five Arab countries from November 2020 to April 2023. Participants were infants born with CL/P and their mothers who were in their 1st trimester during the COVID-19 pandemic. Clinical examination was carried out, and CL/P cases were grouped according to phenotype: cleft lip and palate (CLP) versus cleft lip (CL), cleft extension (incomplete versus complete), and site (unilateral versus bilateral) to assess severity. Information on maternal COVID-19 infection and fear of COVID-19 were gathered. RESULTS: The study recruited 273 CL/P infants. Maternal COVID-19 infection during one-month pre-gestation and 1st trimester was significantly associated with higher odds of CL/P severity (AOR = 2.707; P = 0.002) than mothers without the COVID-19 infection. Using supplements during pregnancy showed a protective effect (AOR = 0.573; P = 0.065). CONCLUSION: Mothers infected with COVID-19 before and during pregnancy had more than twofold higher odds of having an infant with a more severe CL/P phenotype.

Cleft Lip and/or Palate: Children's Experiences of Stigma in Colombia.

OBJECTIVE: Given prior craniofacial research reporting higher risk for negative social interactions, this study aimed to explore experiences of stigma described by children with cleft lip and/or palate (CL/P). DESIGN: Qualitative interviews were conducted with children in three sessions (totaling 90-180 min) using creative activities in their homes and/or and walking interviews in their neighborhood. Interview transcriptions were interpreted primarily with thematic analysis following theoretical frameworks of the stigmatization process and self-stigma concept. SETTING: Participants were recruited through Operation Smile Colombia. Interviews took place at children's homes and neighborhoods within three Colombian regions (Boyacá, Bogotá and Cundinamarca). PARTICIPANTS: Children (N = 12) with CL/P aged between 6-12 years were interviewed. RESULTS: Themes fit within the stigmatization process, starting with labeling and stereotyping, such as a range of mockery, and group separation by peers highlighting their not belonging and being socially 'other'. Status loss themes included negative appraisals of cleft-related differences and being perceived as 'ill' and 'imperfect'. Social exclusion themes reflected limited social interactions and loneliness. Self-stigma themes included shame about speaking with peers and anticipation of negative social interactions. CONCLUSIONS: The study results suggest that the process of stigmatization and self-stigma adversely affect social interactions for children with a cleft in multiple ways. Healthcare practitioners and policy makers can help address the potential consequences of stigma by implementing interventions at micro, meso and macro levels.

Single-cell transcriptome and chromatin accessibility mapping of upper lip and primary palate fusion.

Cleft lip and/or primary palate (CL/P) represent a prevalent congenital malformation, the aetiology of which is highly intricate. Although it is generally accepted that the condition arises from failed fusion between the upper lip and primary palate, the precise mechanism underlying this fusion process remains enigmatic. In this study, we utilized transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) to interrogate lambdoidal junction tissue derived from C57BL/6J mouse embryos at critical stages of embryogenesis (10.5, 11.5 and 12.5 embryonic days). We successfully identified distinct subgroups of mesenchymal and ectodermal cells involved in the fusion process and characterized their unique transcriptional profiles. Furthermore, we conducted cell differentiation trajectory analysis, revealing a dynamic repertoire of genes that are sequentially activated or repressed during pseudotime, facilitating the transition of relevant cell types. Additionally, we employed scATAC data to identify key genes associated with the fusion process and demonstrated differential chromatin accessibility across major cell types. Finally, we constructed a dynamic intercellular communication network and predicted upstream transcriptional regulators of critical genes involved in important signalling pathways. Our findings provide a valuable resource for future studies on upper lip and primary palate development, as well as congenital defects.

Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts.

OBJECTIVE: N6-methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes which is associated with many cellular processes and diseases. Here, our objective is to explore whether genetic variants in m6A modification genes are associated with the risk of non-syndrome orofacial clefts (NSOCs). METHODS: The transmission disequilibrium test (TDT) was performed to calculate the association between single nucleotide polymorphisms (SNPs) in m6A modification genes and NSOCs risk in 944 case-parent trios. The function of SNP was predicted by HaploReg, RegulomeDB and histone enrichment data. The expression quantitative trait locus (eQTL) analysis was examined using Genotype-Tissue Expression (GTEx) and eQTLGen. The role of gene in the development of NSOCs was assessed with correlation and enrichment analysis based on gene expression data in mice craniofacial tissue and zebrafish embryo. RESULTS: We identified that rs8078195 (A > C) in METTL16 was suggestively associated with the increased risk of NSOCs (OR = 1.32, p = 1.80E - 03). The region surrounding rs8078195 was subjected to deoxyribonuclease hypersensitivity and enriched with multiple histone modifications. In addition, it had a significant eQTL effect with METTL16 in skin tissue and human peripheral blood, which played an important role in NSOCs development. Bioinformatic analysis indicated that METTL16 contributed to the development of NSOCs probably by regulating cell cycle process. CONCLUSIONS: Rs8078195 in METTL16 was associated with the occurrence of NSOCs.

[Single nucleotide polymorphism heritability of non-syndromic cleft lip with or without cleft palate in Chinese population].

OBJECTIVE: To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). METHODS: Utilizing summary statistics data from genome-wide association studies (GWAS), a thorough investigation to evaluate the impact of common variations on the genome were undertook. This involved assessing single nucleotide polymorphism (SNP) heritability across the entire genome, as well as within specific genomic regions. To ensure the robustness of our analysis, stringent quality control measures were applied to the GWAS summary statistics data. Criteria for inclusion encompassed the absence of missing values, a minor allele frequency ≥1%, P-values falling within the range of 0 to 1, and clear SNP strand orientation. SNP meeting these stringent criteria were then meticulously included in our analysis. The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression. Additionally, hierarchical linkage disequilibrium score regression to partition SNP heritability within coding regions, promoters, introns, enhancers, and super enhancers were employed, and the enrichment levels within different genomic regions using LDSC (v1.0.1) software were further elucidated. RESULTS: Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios, comprising a total of 2 418 individuals from the Chinese population. Following rigorous quality control procedures, 490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations. The observed SNP heritability of NSCL/P was 0.55 (95%CI: 0.28-0.82). Adjusting for the elevated disease pre-valence within our sample, the SNP heritability scaled down to 0.37 (95%CI: 0.19-0.55) based on the prevalence observed in the general Chinese population. Notably, our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions (15.70, P=0.04) and super enhancer regions (3.18, P=0.03). CONCLUSION: Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population. By elucidating the SNP heritability landscape across different genomic regions, we contribute valuable insights into the genetic basis of NSCL/P. The significant enrichment of SNP heritability within enhancer and super enhancer regions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P. This paves the way for further research aimed at uncovering novel genetic pathogenic factors underlying NSCL/P pathogenesis.

Physicochemical and biocompatibility characterisation of a 3D lyophilised platelet-rich fibrin scaffold for cleft lip and palate repair.

Craniofacial bone defects result from various disorders such as trauma, congenital malformations and infections. Cleft lip and palate are the most prevalent congenital craniofacial birth defect in humans. Growth factors (GFs) are soluble proteins secreted by cells that regulate various cellular processes and tissue regeneration. At present, developing three-dimensional scaffolds for delivering GFs to the site of injury has become an important aspect in craniofacial bone regeneration. This study aims to develop a novel 3D bone substitute using lyophilized-platelet-rich fibrin (LyPRF) biocomposite scaffolds for potential application for CLP repair. Collagen (C), bioglass (BG), and LyPRF were used to fabricate a biocomposite (C-BG-LyPRF) scaffold. The physical, chemical, and biocompatibility properties of the scaffold were evaluated. The C-BG-LyPRF scaffold demonstrated a mean pore diameter of 146 µm within a porosity of 87.26%. The FTIR spectra verified the presence of am-ide I, II, and III functional groups. The inorganic phase of the C-BG-LyPRF scaffold was composed of sodium, calcium, silicon, and phosphorus, as determined by EDX analysis. Furthermore, C-BG-LyPRF scaffold was biocompatible with MC3T3-E1 cells in both the Live/Dead and prolif-eration assays. Data demonstrate the developed C-BG-LyPRF scaffold exhibits biomimetic and biocompatibility properties, establishing it as a promising biomaterial for craniofacial regeneration.

Across-surface distances after one- and two-stage palatoplasty in children with oral cleft.

The goal of this study was to digitally evaluate the development of maxillary dental arches of children with unilateral cleft lip and palate treated with one- and two-stage palatal closure. One hundred and sixty-eight digitized dental models of cheiloplasty and one-stage palatoplasty (G1) and cheiloplasty and two-stage palatoplasty (G2) were evaluated at preoperative time 1 (T1), preoperative time 2 (T2), and postoperative (T3). The following surface distances were evaluated: across surface distance; cleft widths anterior (P-P') and posterior (U-U') cleft widths, intercanine width (C-C'), and intertuberosity width (T-T'); smallest (P'-T') and largest (P-T) segment lengths; and smallest (C'-D') and largest (C-D) segment cleft depths. In G1, P-P', U-U', and C-C' reduced at T2, unlike P'-T' (P<0.05). P-T and C'-D' distances increased at T3 (P<0.05), while C-D increased at all stages (P<0.001). In G2, U-U' and C-C' reduced at T2 (P<0.05), while P'-T', P-T, C'-D', and C-D' increased at T3 (P<0.001). In an intergroup analysis of growth rate, G2 showed higher growth percentages compared to G1, in which C'-D' was significant (P=0.038). Furthermore, C'-D' presented a coefficient of determination of 0.076 (P=0.039). In conclusion, dental arch development is influenced by the rehabilitation protocol. However, in the sample evaluated, the comparison suggested that individuals whose palate was operated on in two stages had the most favorable palatal growth.

Three-dimensional Analysis of Skeletal Stability in Cleft Lip and Palate Patients Undergoing Bimaxillary Surgery With Le Fort I Osteotomy and Intraoral Vertical Ramus Osteotomy.

Orthognathic surgery in patients with lip and palate clefts is challenging owing to scar tissue from primary repairs and severe deformities. In this study, we evaluated the stability of Le Fort I osteotomy with intraoral vertical ramus osteotomy (IVRO) in patients with cleft lip and palate using 3-dimensional (3D) analysis. This retrospective study comprised 14 cleft lip and palate patients (3 females, 11 males; the average age at surgery: 23.8 y) who underwent bimaxillary orthognathic surgery involving Lefort I osteotomy and IVRO. Cone-beam computed tomography (CBCT) images were obtained at preoperative (T0), 1-month postoperative (T1), and 1-year follow-up (T2) periods. The 3D analysis assessed the transitions and rotations of the maxilla and mandible using a virtual triangle. The maxilla showed stability in all directions at the 1-year follow-up with minimal relapse. The distal segment of the mandible exhibited clinically acceptable anterior (1.15 mm relapse) movements and pitch rotation (2.88° counterclockwise relapse) during the first year postoperatively. The proximal mandibular segment underwent anterior-inferior transition (1.21 and 2.01 mm, respectively) and lateral-outward rotation (4.90° and 7.51°, respectively) postsurgery, remaining unchanged 1 year postoperation. Le Fort I osteotomy with IVRO provides skeletal stability in patients with cleft lips and palates. This study demonstrated a minimal maxillary relapse and clinically acceptable movements in the distal mandibular segment during the first postoperative year. The proximal mandibular segment moved anteriorly and inferiorly, rotated laterally and outward after surgery, and remained unchanged at the 1-year follow-up.

Influence of Preoperative Inflammatory Status on Outcomes of Alveolar Bone Grafting in Patients With Cleft Lip.

After secondary alveolar bone grafting, the outcome of bone formation is always a problem that leads to repeat surgery. Bone formation is closely related to the inflammatory and immune status of patients. To achieve better bone formation results, this study aimed to investigate the influence of preoperative inflammatory indicators on the bone survival ratio (BSR) of secondary alveolar bone grafting. A retrospective study was conducted on 62 patients who underwent surgery by the same surgeon between January 2016 to December 2022. Demographic and laboratory data were included as independent variables. The BSR calculated from computed tomography data was included as the dependent variable. Pearson correlation analysis, Spearman correlation analysis, and multiple linear regression analysis were performed. The analysis results revealed significant correlations between BSR and preoperative inflammatory markers, including neutrophil percentage, neutrophil-to-lymphocyte ratio, lymphocyte percentage (L%), lymphocyte count, and monocyte-to-lymphocyte ratio. Multiple linear regression identified L% as an independent factor of BSR, with lower L% associated with higher BSR. Preoperative inflammatory markers may influence BSR after alveolar bone grating. A lower value of L% indicates a better postoperative bone formation outcome. Understanding these associations can aid clinicians in treatment planning and patient stratification.

Hospitalization Trends for Airway Infections and In-Hospital Complications in Cleft Lip and Palate.

Importance: Cleft lip or palate is a prevalent birth defect, occurring in approximately 1 to 2 per 1000 newborns and often necessitating numerous hospitalizations. Specific rates of hospitalization and complication are underexplored. Objective: To assess the rates of airway infection-associated hospitalization, overall hospital admissions, in-hospital complications, and mortality among children with a cleft lip or palate. Design, Setting, and Participants: This nationwide, population-based cohort study used in-hospital claims data from the Federal Statistical Office in Switzerland between 2012 and 2021. Participants included newborns with complete birth records born in a Swiss hospital. Data were analyzed from March to November 2023. Exposure: Prevalent diagnosis of a cleft lip or palate at birth. Main Outcomes and Measures: Outcomes of interest were monthly hospitalization rates for airway infections and any cause during the first 2 years of life in newborns with cleft lip or palate. In-hospital outcomes and mortality outcomes were also assessed, stratified by age and modality of surgical intervention. Results: Of 857 806 newborns included, 1197 (0.1%) had a cleft lip and/or palate, including 170 (14.2%) with a cleft lip only, 493 (41.2%) with a cleft palate only, and 534 (44.6%) with cleft lip and palate. Newborns with cleft lip or palate were more likely to be male (55.8% vs 51.4%), with lower birth weight (mean [SD] weight, 3135.6 [650.8] g vs 3284.7 [560.7] g) and height (mean [SD] height, 48.6 [3.8] cm vs 49.3 [3.2] cm). During the 2-year follow-up, children with a cleft lip or palate showed higher incidence rate ratios (IRRs) for hospitalizations due to airway infections (IRR, 2.33 [95% CI, 1.98-2.73]) and for any reason (IRR, 3.72 [95% CI, 3.49-3.97]) compared with controls. Additionally, children with cleft lip or palate had a substantial increase in odds of mortality (odds ratio [OR], 17.97 [95% CI, 11.84-27.29]) and various complications, including the need for intubation (OR, 2.37 [95% CI, 1.95-2.87]), extracorporeal membrane oxygenation (OR, 2.89 [95% CI, 1.81-4.63]), cardiopulmonary resuscitation (OR, 3.25 [95% CI, 2.21-4.78]), and respiratory support (OR, 1.94 [95% CI, 1.64-2.29]). Conclusions and Relevance: In this nationwide cohort study, the presence of cleft lip or palate was associated with increased hospitalization rates for respiratory infections and other causes, as well as poorer in-hospital outcomes and greater resource use.

Efficacy of modified anterior maxillary segmental distraction osteogenesis based on 3D visualisation for the treatment of maxillary hypoplasia among adolescents with cleft lip and palate.

BACKGROUND: This study evaluates a three-dimensional (3D) visualisation design combined with customized surgical guides to assist anterior maxillary segmental distraction osteogenesis (AMSDO) in correcting maxillary hypoplasia in adolescents with cleft lip and palate (CLP), focusing on treatment outcomes, satisfaction and the validity of 3D planning. METHODS: This retrospective cohort study was conducted at a single hospital in China. Between January 2020 and December 2023, 12 adolescents with CLP with maxillary hypoplasia were included. An advanced 3D simulation was used to convey the treatment strategy to the patients and their families. A customized surgical guide and distraction osteogenesis device were designed. Cephalometric analysis evaluated AMSDO changes and long-term stability. Patient satisfaction was assessed. The Chinese version of the Child Oral Health Impact Profile was used to evaluate the children's oral health-related quality of life before and after treatment. The postoperative outcomes were compared with the planned outcomes by superimposing the actual postoperative data onto the simulated soft tissue models and calculating the linear and angular differences between them. RESULTS: One patient experienced postoperative gingivitis, yielding an 8.33% complication rate. Most patients (83.33%) were highly satisfied with the target position, with the rest content. Cephalometric analysis showed significant improvements in various indices post-traction. Quality-of-life scores significantly improved post-treatment. The discrepancies in facial soft tissue between the simulated and actual results were within clinically satisfactory ranges. CONCLUSIONS: Digitally designed surgical guides effectively treat maxillary hypoplasia in adolescents with CLP, ensuring stability, reducing complications, reducing dependency on operator experience, and enhancing satisfaction and health outcomes. Although the simulated results were clinically acceptable, it is important to inform patients of potential variations in the predicted soft tissue.

Effects of bone anchored maxillary protraction on patients with unilateral cleft lip/palate or isolated cleft palate and hypoplastic maxilla: a 6-year follow-up case control study.

OBJECTIVES: To evaluate the effects of bone-anchored maxillary protraction (BAMP) treatment and longterm stability in growing cleft lip and palate and isolated cleft palate (CLP/CP) patients with mild maxillary hypoplasia and to compare maxillary growth patterns of BAMP-treated patients to matched control CLP/CP patients. MATERIALS AND METHODS: Ten patients with CLP/CP were treated with BAMP; they were compared to the maxillary growth pattern of 10 age-matched cleft control patients with no maxillary protraction treatment, who later received surgical Le Fort I maxillary advancement after the growth period. The assessment of maxillary growth and the occlusion started at mean 8 years of age and continued until mean 18 years of age. RESULTS: The use of BAMP orthopedic traction changed the growth pattern of mild hypoplastic maxilla toward a more anterior direction and advanced the face even above the level of Le Fort lll with only a minor effect on dentoalveolar units. The correction of occlusion and facial convexity were stable in the long term. CONCLUSIONS: The using BAMP may improve the position of the maxilla relative to the anterior cranial base for the correction of mild maxillary hypoplasia in adolescent patients with CLP/CP. The achieved results are rather stable in the long term.

Changes in the upper airway and its surrounding structures after bimaxillary surgery in patients with cleft-related Class III deformity.

OBJECTIVES: To compare upper airway changes following bimaxillary surgery for correction of Class III deformity between patients with unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) and to compare the preoperative and postoperative upper airway among patients with UCLP and BCLP to healthy controls. MATERIALS AND METHODS: Sixty adults with CLP-related skeletal Class III deformity (30 UCLP and 30 BCLP) who consecutively underwent bimaxillary surgery were studied retrospectively. Cone-beam computed tomography (CBCT) was performed before and after surgery to measure upper airway and movements of facial skeletal and surrounding structures. CBCT images from 30 noncleft skeletal Class I adults, matched by age, gender, and body mass index and without surgical intervention, served as controls. RESULTS: After surgery, the volume of the nasopharynx increased in patients with CLP (both P < .001). Patients with CLP did not differ from controls in postoperative volume of the nasopharynx or oropharynx. However, the nasal cavity differed significantly between patients with CLP and controls (P < .001). CONCLUSIONS: After bimaxillary surgery, the nasal cavity of patients with CLP differed significantly compared with the controls. Volumes of the nasopharynx and oropharynx did not differ between patients with CLP after surgery and controls.

The state of systemic immunity in congenital cleft lip and palate patients with diseases of oral cavity tissues.

OBJECTIVE: Aim: To determine the state of dental health and the state of systemic immunity in patients in congenital cleft lip and palate patients. PATIENTS AND METHODS: Materials and Methods: The dental status and immunologic tests of 74 patients age 8-18 years old with congenital cleft lip and palate was analyzed: 43 children with unilateral and 31 children with bilateral complete combined cleft lip, alveolar process, hard and soft palate. RESULTS: Results: Indicators of the prevalence and intensity of the caries process in patients with congenital congenital complete cleft lip, alveolar process, hard and soft palate were high, especially in children with bilateral cleft lip and palate - the decompensated course of caries was determined in 41.93% patients, with unilateral - 23.25%. Сhronic catarrhal gingivitis was the most common in both groups of patients - the average severity of gingivitis prevailed - 51.16% with congenital unilateral cleft lip and palate and 51.61% - with bilateral. Atopic cheilitis, glossitis and chronic recurrent aphthous stomatitis were common. This patients have significant changes in the cellular chain of the immune system with a deficiency of the main phenotypes of lymphocytes - CD4+ CD8+ and inflammatory bacterial changes in blood serum. CONCLUSION: Conclusions: Patients of unilateral and bilateral complete combined cleft lip, alveolar process, hard and soft palate have significant changes in the dental status and in the cellular chain of the immune system. The level of manifestation of these changes is directly proportional to the extent of localization of the pathology - unilateral or bilateral.

Alterations of senescence-associated markers in patients with non-syndromic cleft lip and palate.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial anomalies. Abnormal Alu methylation in DNA of the pregnant mother may influence the abnormal development of the child. This study aimed to examine Alu methylation and cellular senescence in NSCL/P patients and their mothers as well as the correlation with the severity of NSCL/P. A total of 39 patients with NSCL/P and 33 mothers were enrolled. Of these patients, 6 were cleft lip only (CLO), 9 were cleft palate only (CPO), and 24 were cleft lip and palate (CLP). Alu methylation and senescence markers were determined in the white blood cells of NSCL/P patients, their mothers, and in the lip and palatal tissues of patients at the time of cheiloplasty and palatoplasty. Total Alu methylation was not significantly different between groups. However, a decrease in Alu hypermethylation, increased partial Alu methylation, RAGE, and p16 expression were shown in CLP, the most severe cleft type. Alu methylation in tissues did not differ between groups. In mothers, an increase in Alu methylation was observed only in the CLP. Therefore, the pathogenesis of NSCL/P may be related to Alu methylation of the mother promoting loss of Alu methylation and subsequently senescence in the children.