scholarly journals Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development

2019 ◽  
Author(s):  
Marshall Lukacs ◽  
Tia Roberts ◽  
Praneet Chatuverdi ◽  
Rolf W. Stottmann
Keyword(s):  
Neural Crest ◽  
Neural Development ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Folate Receptor ◽  
Neural Crest Cell ◽  
Specific Expression ◽  
Hypomorphic Mutation ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

AbstractThe glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

scholarly journals Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Marshall Lukacs ◽  
Tia Roberts ◽  
Praneet Chatuverdi ◽  
Rolf W Stottmann
Keyword(s):  
Neural Crest ◽  
Heart Development ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Neural Crest Cell ◽  
Neural Tube Closure ◽  
Specific Expression ◽  
Pathogenic Variants ◽  
Median Cleft ◽  
Cleft Lip Palate

Glycosylphosphatidylinositol (GPI) anchors attach nearly 150 proteins to the cell membrane. Patients with pathogenic variants in GPI biosynthesis genes develop diverse phenotypes including seizures, dysmorphic facial features and cleft palate through an unknown mechanism. We identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypo-morphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2), a component of the GPI biosynthesis pathway. The Clpex mutation decreases surface GPI expression. Surprisingly, Pgap2 showed tissue-specific expression with enrichment in the brain and face. We found the Clpex phenotype is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium. We showed folinic acid supplementation in utero can partially rescue the cleft lip phenotype. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency. These mutants developed median cleft lip and palate demonstrating a previously undocumented cell autonomous role for GPI biosynthesis in NCC development.

Cleft Lip and Palate in Ectodermal Dysplasia

2020 ◽  
pp. 105566562094912
Author(s):  
Ingrid M. Ganske ◽  
Tim Irwin ◽  
Olivia Langa ◽  
Joseph Upton ◽  
Wen-Hann Tan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Ectodermal Dysplasia ◽  
Phenotypic Expression ◽  
Velopharyngeal Insufficiency ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Outcomes Measures ◽  
Cleft Lip Palate ◽  
Dentofacial Orthopedics

Objective: Ectodermal dysplasia (ED) comprises multiple syndromes that affect skin, hair, nails, and teeth, and sometimes are associated with orofacial clefting. The purpose of this study is to (1) identify the prevalence and characteristics of cleft lip and/or palate (CL/P) in patients with ED and (2) describe the management and outcomes. Design: Retrospective review from 1990 to 2019. Patients: All patients with ED treated at Boston Children's Hospital. Main Outcomes Measures: Prevalence of CL/P was calculated and clinical details recorded: phenotypic anomalies, cleft type, operative treatment, and results of repair. Results: Of 170 patients with a purported diagnosis of ED, 24 (14%) had CL/P. Anatomic categories were bilateral CL/P (67%), unilateral CL/P (8%), and cleft palate only (25%). The most common ED syndrome (37%) was ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC). Pathogenic variants in TP63 were the most frequent finding in the 11 patients who had genetic testing. Aberrations from a typical clinical course included failure of presurgical dentofacial orthopedics, dehiscence of nasolabial adhesion, and total palatal absence requiring free-flap construction. Two patients had prolonged postoperative admission for respiratory infection. High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected the predominance of bilateral complete forms. Conclusions: As in other types of syndromic CL/P, cleft phenotypic expression in ED is more severe than the general cleft population. Further studies are needed to correlate genotype and phenotype for the distinct syndromes included in the ED spectrum.

scholarly journals Alveolar cleft and maximum cleft width as predictors for difficult laryngoscopy and intubation in patients with unilateral complete cleft lip and palate

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Gamal A. Abdelhameed ◽  
Wael A. Ghanem ◽  
Simon H. Armanios ◽  
Tamer Nabil Abdelrahman
Keyword(s):  
Body Weight ◽  
Odds Ratio ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Difficult Laryngoscopy ◽  
Secondary Outcome ◽  
Pediatric Airway ◽  
Alveolar Cleft ◽  
Cleft Lip Palate ◽  
Width Measurements

Abstract Background Cleft lip and palate is one of the commonest congenital anomalies, which have an impact on feeding, speech, and dental development away from the significant psychosocial sequel. Early surgical repair aims to restore appearance and function, and the modern techniques can leave many defects undetectable. Therefore, the anesthetic challenge facing the pediatric airway with such abnormalities is still of a great impact. The aim of our study among 189 patients enrolled is to correlate alveolar gap and maximum cleft width measurements as predictors of difficult laryngoscopy and intubation in infants with unilateral complete cleft lip/palate aging from 1 to 6 months. As a secondary outcome, their weight is to be correlated too as another parameter. Results The alveolar gap and maximum cleft width are both of equal high predictive power (p value ≤ 0.001) with 100% sensitivity for both and specificity of 76.10% and 82.39% respectively, with a cut off value of ≤ 10 mm and 11 mm for these dimensions respectively, and odds ratio of incidence of difficult intubation is 4.18 and 5.68 respectively, while body weight ≤ 5.75 kg has an odds ratio of 2.32. Conclusion Alveolar cleft and maximum cleft width can be used as predictors for anticipation of difficult laryngoscopy and intubation infant patients with unilateral complete cleft lip and palate, while body weight ≤ 5.75 kg increases the risk more than twice.

scholarly journals How is the face formed and when it goes wrong: In relation to Cleft Lip/Palate

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Fozia Khan
Keyword(s):  
Cleft Lip ◽  
Normal Development ◽  
Cleft Lip And Palate ◽  
Complex Structure ◽  
First Trimester ◽  
Facial Defect ◽  
Facial Defects ◽  
The Face ◽  
Embryonic Life ◽  
Cleft Lip Palate

The normal development of the face relies upon the correct morphogenesis of structures in utero that usually occurs within the first trimester of embryonic life. The face is a very complex structure involving many genes and factors and with it being such a crucial part of life, both physically and aesthetically and therefore mentally, its important for everything to be just right. However, when the normal process doesn’t go to plan this results in dysmorphogenesis, which cleft lip and palate (CLP) is an example of as the lip/palate doesn’t fuse together and the infant is left with a gap. Although the exact cause of CLP is unknown, it is thought to be a mixture of genetics, environment and the teratogens the mothers are exposed to within the environment. This report will demonstrate the normal development of the face for the purpose of understanding how it goes wrong, resulting in CLP. Since there is still a lot to be understood about CLP it will also shed light on recent advances in relating SHH and certain genes as a possible cause for this dysmorphogenesis. The report will also briefly look at the relation of CLP with the genes associated with syndromic and non-syndromic diseases and the different types of CLP. There are many other facial defects that are a result of dysmorphogenesis, however as CLP is one of the most common yet poorly understood facial defect, it will be the main focus of this report.

The aetiology and pathogenesis of craniofacial deformity

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 207-212
Author(s):  
David Poswillo
Keyword(s):  
Neural Crest ◽  
Animal Studies ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Treacher Collins Syndrome ◽  
Apert Syndrome ◽  
Craniofacial Malformations ◽  
Craniofacial Microsomia ◽  
Animal System ◽  
Isolated Cleft Palate

Craniofacial malformations have been recorded since time immemorial. While observational studies have assisted in the recognition of syndromes, little light has been shed on the causal mechanisms which interfere with craniofacial development. Animal studies in which malformations occur spontaneously or have been induced by teratogenic agents have permitted step-by-step investigation of such common deformities as cleft lip and palate. The role of the ectomesenchymal cells of the neural crest and the possible phenomenon of disorganized spontaneous cell death are described in relation to lip clefts. The factors associated with isolated cleft palate, Pierre Robin syndrome and submucous clefts are described by reference to animal models. The haemorrhagic accident preceding the onset of craniofacial microsomia is discussed as is the distinctly different phenomenon of disturbance to the migration or differentiation of neural crest cells in the pathogenesis of Treacher Collins syndrome. The more severe anomalies of the calvarium such as plagiocephaly, Crouzon and Apert syndrome still defy explanation, in the absence of an appropriate animal system to study; some thoughts on the likely mechanism of abnormal sutural fusions are discussed.

Prevalence of Cleft Lip/Palate in the Fangshan District of Beijing, 2006-2012

2018 ◽  
Vol 55 (9) ◽  
pp. 1296-1301 ◽  
Author(s):  
Yanfen Yang ◽  
Hui Liu ◽  
Ruixin Ma ◽  
Lei Jin
Keyword(s):  
Data Analysis ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Upward Trend ◽  
Live Births ◽  
Cleft Lip Palate ◽  
Obstetric Services ◽  
Permanent Residents ◽  
Beijing China

Objective: To estimate the cleft lip with or without cleft palate (CL/P) prevalence among births between 2006 and 2012 in Fangshan district of Beijing, China. Design: Surveillance data analysis. Setting: All hospitals that provide obstetric services in the district. Patients: The CL/P cases presented for this report were from 13 weeks’ gestation to 7 days postpartum. Main Outcome Measures: The CL/P prevalence was defined as the number of cases per 10 000 births, including live births and stillbirths at 28 weeks’ gestation or beyond. Results: The overall CL/P prevalence was 18.9 (95% confidence interval [CI]: 15.1-22.7) per 10 000 births. From 2006 to 2012, the CL/P prevalence was 19.3, 20.2, 10.9, 16.1, 17.5, 25.4, and 22.3 per 10 000 births; annually, no significant change was noted ( Pfor trend = .311). The prevalence of cleft palate, cleft lip, and cleft lip and palate were 3.4 (95% CI: 2.0-5.4), 6.2 (95% CI: 4.2-8.8), and 9.4 (95% CI: 6.9-12.4) per 10 000 births, respectively. The CL/P prevalence among the nonpermanent residents (31.4 per 10 000 births) was 2.31 times that of permanent residents (13.6 per 10 000 births). Among nonpermanent residents, the CL/P prevalence showed an upward trend over the study period ( Pfor trend = .036), that increased from 38.8 (95% CI: 16.5-76.6) per 10 000 births in 2006 to 54.6 (95% CI: 25.7-100.4) per 10 000 births in 2012. Conclusions: The overall CL/P prevalence was stable in the Fangshan district. However, the CL/P prevalence of the nonpermanent residents increased significantly.

Hard Palate Repair Timing and Facial Growth in Cleft Lip and Palate: A Systematic Review

2006 ◽  
Vol 43 (5) ◽  
pp. 563-570 ◽  
Author(s):  
Yu-Fang Liao ◽  
Michael Mars
Keyword(s):  
Systematic Review ◽  
Hard Palate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Case Reports ◽  
Case Series ◽  
Long Term Results ◽  
Facial Growth ◽  
Cleft Lip Palate ◽  
Palate Repair

Objective: To evaluate the effect of timing of hard palate repair on facial growth in patients with cleft lip and palate, with special reference to cranial base, maxilla, mandible, jaw relation, and incisor relation. Design: A systematic review. Methods: The search strategy was based on the key words “facial growth,” “cleft lip palate,” and “timing of (hard) palate repair.” Case reports, case-series, and studies with no control or comparison group in the sample were excluded. Results: Fifteen studies met the selection criteria. All the studies were retrospective and nonrandomized. Five studies used cephalometry and casts, seven used cephalometry, and three used casts. Methodological deficiencies and heterogeneity of the studies prevented major conclusions. Conclusion: The review highlights the importance of further research. Prospective well-designed, controlled studies, especially targeting long-term results, are required to elucidate the effect of timing of hard palate repair on facial growth in patients with cleft lip and palate.

Pattern of Cleft Lip and Palate in Hospital-Based Population in Saudi Arabia: Retrospective Study

2008 ◽  
Vol 45 (6) ◽  
pp. 592-596 ◽  
Author(s):  
Aziza Aljohar ◽  
Kandasamy Ravichandran ◽  
Shazia Subhani
Keyword(s):  
Saudi Arabia ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Tertiary Care ◽  
Positive Family History ◽  
Care Hospital ◽  
Associated Anomalies ◽  
Cleft Lip Palate ◽  
Isolated Cleft Palate

Objective: To report the patterns of cleft lip and/or cleft palate in Saudi Arabia from data collected at a tertiary care hospital. Design and Setting: King Faisal Specialist Hospital and Research Center, Riyadh. Patients: All the cleft lip and/or cleft palate patients registered in the Cleft Lip/Palate and Craniofacial Anomalies Registry from June 1999 to December 2005. Results: Retrospectively, 807 cases of cleft lip and/or palate were registered. There were 451 boys and 356 girls. Cleft lip and palate was more common (387) than isolated cleft palate (294) and isolated cleft lip (122). Boys predominated in cleft lip and palate and cleft lip; whereas, girls predominated in isolated cleft palate, with boy to girl ratios of 1.6:1, 1.2:1, and 0.9:1 for cleft lip and/or palate, isolated cleft lip, and isolated cleft palate, respectively. The Riyadh region had more cases (32.0%) than the Asir (15.6%) and Eastern (14.6%) regions. Parents of 439 individuals had consanguineous marriages. A positive family history of cleft was seen in 224 cases. Of 238 cases with associated anomalies, 91 had congenital heart disease. Of the children with isolated cleft palate, 40.5% had associated anomalies, whereas only 23.0% of the children with isolated cleft lip or cleft lip and palate had associated malformations. Conclusion: The pattern of cleft observed in this study does not differ significantly from those reported in the literature for Arab populations.

Tomographic Pharyngeal Dimensions in Individuals with Unilateral Cleft Lip/Palate and Class III Malocclusion are Reduced When Compared with Controls

2017 ◽  
Vol 54 (5) ◽  
pp. 502-508 ◽  
Author(s):  
Trindade-Suedam Ivy Kiemle ◽  
Freire Lima Thiago ◽  
Dominguez Campos Letícia ◽  
Faria Yaedú Renato Yassutaka ◽  
Filho Hugo Nary ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Outcome Measure ◽  
Cleft Lip And Palate ◽  
Cone Beam ◽  
Control Group ◽  
Craniofacial Anomalies ◽  
Class Iii ◽  
Class Iii Malocclusion ◽  
Cross Sectional ◽  
Cleft Lip Palate

Objective The objective of this study was to three-dimensionally evaluate the pharyngeal dimensions of individuals with complete nonsyndromic unilateral cleft lip and palate (UCLP) using cone beam computed tomography. Design This was a cross-sectional prospective study. Setting The study took place at the Laboratory of Physiology, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru-SP, Brazil. Patients and Participants The control group (CON) consisted of 23 noncleft adults with class III malocclusion, and the cleft group (UCLP) consisted of 22 individuals with UCLP and class III malocclusion. Two subgroups of individuals with class III malocclusion as a result of maxillary retrusion with (UCLP'; n = 19) and without (CON'; n = 8) clefts were also assessed. Interventions Pharyngeal volume, pharyngeal minimal cross-sectional area (CSA), location of CSA, pharyngeal length, sella-nasion-A point angle (SNA), sella-nasion-B point angle (SNB), and A point-nasion-B point angle (ANB), and body mass index were assessed using Dolphin software. Main Outcome Measure The pharyngeal dimensions of UCLP individuals are smaller when compared with controls. Results Mean pharyngeal volume (standard deviation) for the UCLP patients (20.8 [3.9] cm3) and the UCLP’ patients (20.3 [3.9] cm3) were significantly decreased when compared with the CON (28.2 [10.0] cm3) and CON’ patients (29.1 [10.2] cm3), respectively. No differences were found in the pharyngeal minimal CSA, ANB, or pharyngeal length values between groups (CON versus UCLP and CON’ versus UCLP'). CSAs were located mostly at the oropharynx, except in the UCLP’ patients, which were mainly at the hypopharynx. Mean SNA in the UCLP (76.4° [4.6°]) and UCLP’ groups (75.1 [3.1°]) were significantly smaller than those in the CON (82.8° [4.1°]) and CON’ groups (78.6° [1.2°]). SNB values were statistically smaller only for the comparison of CON versus UCLP patients. Conclusion The pharynx of individuals with UCLP and class III malocclusion is volumetrically smaller than that of individuals with class III malocclusion and no clefts.

No Evidence for Linkage and Association between 4q Microsatellite Markers and Nonsyndromic Cleft Lip and Palate in Chilean Case-Parents Trios

2005 ◽  
Vol 42 (3) ◽  
pp. 267-271 ◽  
Author(s):  
Rafael Blanco ◽  
José Suazo ◽  
JoséLuis Santos ◽  
Hernán Carreño ◽  
Hernán Palomino ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Microsatellite Markers ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Statistical Significance ◽  
P Value ◽  
Genetic Trait ◽  
Multiple Alleles ◽  
Cleft Lip Palate

Objective Nonsyndromic cleft lip/palate (NSCLP) has the characteristics of a complex genetic trait. Linkage and association studies have suggested that one or more clefting loci may be located on chromosome 4q. The goal of this study was to evaluate the possible linkage and association due to linkage disequilibrium between five microsatellite markers located on 4q28 to 4q33 and NSCLP, using the case-parent trio design. Subjects and Methods A total of 56 Chilean families (32 simplex and 24 multiplex) were recruited. Microsatellite markers were analyzed using polymerase chain reaction with fluorescent-labeled forward primers, followed by electrophoresis on a laser-fluorescent sequencer. Case-parents trios were ascertained to assess linkage and linkage disequilibrium through a multistage procedure. Transmission disequilibrium tests for multiple alleles were carried out to assess the statistical significance of 4q28 to 4q33 microsatellite markers. Results Only weak evidence for linkage was obtained for the FGA marker (asymptotic uncorrected p value = .08 and empirical p value = .05). Only the FGA and UCP1 markers were selected for association analysis in trios, with unrelated cases achieving a nearly significant result for the UCP1 marker (asymptotic uncorrected p value = .07 and empirical p value = .19). Conclusion Though the FGA and UCP1 markers showed nearly significant p values for linkage and association, respectively, the results of the present study provided insufficient evidence of the existence of a major susceptibility locus in the 4q region that was analyzed in the present study.

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