Sequência didática para o ensino de fendas labiopalatinas / Didactic sequence for the teaching of cleft lip and palate / Secuencia didáctica para la enseñanza de labio leporino y paladar hendido

Introdução: A fenda labial e a fissura palatina, apresentam elevada prevalência na população brasileira, sendo necessária uma formação acadêmica de cirurgiões que gere saberes que transformem a realidade. Diante do exposto, o presente manuscrito objetivou descrever o desenvolvimento, a aplicação e a avaliação de uma sequência didática sobre fissuras labiais, palatinas e labiopalatais com enfoque em aprendizagem significativa em que houve a associação de duas metodologias ativas, a construção de modelos didáticos e a sala de aula invertida. Metodologia: A sequência didática foi realizada na educação superior, com equipes de discentes de Odontologia, seguindo três etapas: planejamento; confecção do modelo didático semiplano de fissuras labiais, palatinas e labiopalatais; apresentação em roda de conversa. O desempenho dos acadêmicos foi avaliado em cada etapa. Resultados: Inicialmente, os discentes possuíam pouco conhecimento sobre o tema. Os modelos didáticos foram construídos com facilidade e durante a roda de conversa foram utilizados os modelos didáticos e compartilhados os conhecimentos sobre Embriologia, Teratologia, aspectos clínicos e tratamento odontológico para cada fenda representada, evidenciando a eficácia do método. Conclusões: As metodologias ativas adotadas utilizadas no processo de planejamento, confecção e debate sobre fissuras labiais, palatinas e labiopalatais foram ferramentas valiosas no processo ensino-aprendizagem na educação em Odontologia... (AU)

Introduction: Cleft lip and cleft palate showed prevalence in the Brazilian population, being an academic training of surgeries that generates knowledge that transforms reality. Given the above, this manuscript aimed to describe the development, application and evaluation of a didactic sequence on cleft lip, palate and lip and palate with a focus on meaningful learning with the association of two active methodologies, the construction of didactic models and the inverted classroom. Methodology: The didactic sequence was carried out in Higher Education with teams of Dentistry students following three stages: planning; making the semiplane didactic model of cleft lip, palate and lip and palate; presentation in conversation circle. Academic performance was assessed at each stage. Results: Initially, the students had little knowledge on the topic. Didactic models were easily built. During the conversation, didactic models were used and knowledge about Embryology, Teratology, clinical aspects and dental treatment was shared for each gap represented, showing the effectiveness of the method. Conclusions: The active methodologies adopted used in the process of planning, making and debating cleft lip, palate and lip and palate were valuable tools in the teaching-learning process in Dentistry Education... (AU)

Introducción: Labio leporino y paladar hendido, presentan elevada prevalencia en la población brasileña, es necesária una formación académica de los cirujanos para generar conocimientos que transformen la realidad, dado lo anterior, este manuscrito tuvo como objetivo describir el desarrollo, la aplicación y la evaluación de una secuencia didáctica sobre el lábio leporino, fisura palatina y paladar hendido con un enfoque de aprendizaje significativo en el que hubo la asociación de dos metodologias activas, la construcción de modelos didácticos y el aula invertida. Metodología: La secuencia didáctica se realizo en la enseñanza superior, con equipos de estudiantes de odontologia, siguiendo tres etapas: Planificación; realización de um modelo didáctico semiplano de lábio leporino y paladar hendido; presentación del circulo de conversación. Se evaluo el desempeño de los académicos en cada etapa. Resultados: Inicialmente, los estudiantes tenían poco conocimiento sobre el tema. Los modelos didácticos se construyeron facilmente y durante la conversación se utilizaron los modelos didácticos y se compartieron sobre Embriologia, Teratología, aspectos clínicos y tratamiento odontológico de cada fisura representada, evidenciando la efectividad del método. Conclusiones: Las metodologias activas adoptadas y utilizadas en el proceso de planificación, realización y debate sobre lábio leporino, paladar hendido y fisura palatina fueron herramientas valiosas en el proceso de enseñanza-aprendizaje en la formación odontológica... (AU)

Surgical Treatment of Lip Pits in Van der Woude Syndrome: A Preliminary Retrospective Study of 24 Patients.

BACKGROUND: Van der Woude syndrome (VWS) is a rare congenital malformation characterized by lower lip pits among patients with a lip and/or palate cleft. It is transmitted by an autosomal dominant inheritance with variable expressivity. METHODS: The study group consisted of 24 consecutive patients (13 males and 11 females) with VWS operated on at a single center between 2009 and 2022. They suffered from: bilateral cleft lip and palate - 6 patients; unilateral cleft lip and palate - 9 patients; cleft lip - 1 patient; and isolated cleft palate - 8 patients. RESULTS: In 16 (66%) cases pits of lower lip occurred on both side of midline, while in 8 (34%) the pits were detected unilaterally. The primary cleft repairs were performed according to one-stage principle at the mean age of 8.6 months (SD 1.4, range 6-12). In all patients lower lip pits repairs were performed after the primary cleft repairs as a separate procedure at the mean age of 37 months (SD 11.3 range 14-85). The mean number of all primary repairs of the syndrome-both cleft defect and lower lip pits repairs-was 2.46. Nine patients (37.5%) required additional secondary corrections of the lower lip due to the poor aesthetic post-operative outcome. CONCLUSIONS: The frequent need for secondary corrections of residual lower lip deformities indicates the considerable difficulties in obtaining a satisfactory outcome of the repairs to lip pits caused by VWS. The average number of the primary surgical interventions in evaluated material remained low.

Congenital Upper Lip Sinus.

Congenital upper lip sinus (CULS) is an extremely rare anomaly. The aim of the study is to present a new case and compile the present knowledge of CULS to help foster a deeper understanding of this disease. A 9-year-old girl with a midline CULS, a prolonged maxillary labial frenulum, and a palatal epulis is presented. Thirty-nine papers met the eligibility criteria and 45 cases were included in the systematic review. CULS shows typical clinical and pathologic characteristics. It tends to occur at the midline region horizontally (n=35; 78%) and the upper part of the white lip (n=23; 51%) vertically. No ethnic predilection is found, but it tends to show a female predilection (n=28; 62%). Twenty-six cases (58%) are symptomatic. Thirteen cases (29%) are accompanied by other maxillofacial defects. In all cases, the sinus was lined with stratified squamous epithelium. The etiology remains unknown but 3 theories have been put forward: the fusion theory, the merging theory, and the invagination theory. The authors believe that CULS shows homogeneity with cleft lip to some extent and maybe a microform of it. Primary treatment is surgical excision and the prognosis is favorable, with no complications or recurrence.

Congenital midline upper lip sinus in an infant.

Congenital lip sinus is a rare entity with upper lip sinus being rarer than the lower lip sinus. It can be an isolated entity or associated with cleft lip, palate or Van der Woude syndrome. Syndromic association requires proper evaluation and aggressive surgical treatment. Preoperative delineation of the sinus tract with ultrasound sonography or MRI is mandatory. Simple excision is sufficient in cases of isolated sinuses. In this article, we report an infant with upper lip sinus managed successfully with simple excision and reviewed the literature.

Embryological approach to philtral hair sparsity in bilateral cleft lip deformities.

OBJECTIVE: In bilateral cleft lip cases, surgeons have long known that the medial nasal prominence or prolabium is devoid of muscle. Despite cheiloplasty restoring orbicular muscle continuity, moustache hair growth is less developed on the philtral skin. We sought to understand this hair disparity. BASIC PROCEDURES: The authors conducted a comprehensive literature search using reference materials on the physiological and pathological development of the face in utero and the PubMed database using the keywords 'embryology', 'bilateral cleft lip' and 'hair'. MAIN RESULTS: In bilateral cleft lip, the normal fusion between the maxillary and intermaxillary process does not occur, and the migration of cranial neural crest cells (CNCC) is disturbed. CNCCs from different locations and with different myoblastic differentiation potential are arrested on each side of the cleft. Therefore, a reduced concentration of myoblasts and myocytes as well as hormone receptors in the medial process could hinders the normal physiological development of the different layers of the philtral skin and especially the skin appendages. CONCLUSION: Philtral hair sparsity in patients with bilateral cleft lip can be explain by a defect in the migration of CNCCs to the prolabium, whose cells are not able to develop hair follicles, due to a disruption of the exchange of Wnt/ß-catenin, EDA, and or Noggin signals and due to the absence of androgen receptor.

Longitudinal Morphological Changes in the Mucosal Free Margin After Unilateral Cleft Lip Repair.

Weakness of the mucosal free margin is common in secondary cleft lip deformities. However, the incidence is rarely reported after a long-term follow-up. We evaluated the evolution of patient mucosal free margin after primary repair and until the end of growth.Blinded retrospective study (photography and chart reviews).Tertiary care hospital; private practice.Forty-eight patients with unilateral cleft lip with or without cleft palate who underwent primary nasolabial repair between 1996 and 2004 were followed up until their end of growth marked at 18 and 16 years of age for male and female patients, respectively.Primary nasolabial repair using a straight-line closure without a triangular flap on the vermilion was performed; if needed, a revision surgery was performed at 5 years of age (85%).The contour of the mucosal free margin was classified into nodular, smooth, and recessed types at 1, 5, and 10 years and at the end of growth.At 1 year of age, the nodular type was more common (58%). However, the recessed type was more common (75%) at the end of growth. The mucosal free margin continued to change after 10 years of age. At the end of growth, half of the patients with incomplete cleft experienced center weakness, and the others had cleft-side weaknesses.Patients with incomplete clefts showed favorable results at early ages. However, two-thirds of the patients with complete and incomplete clefts showed focal weakness at the end of growth.

Mutations in Van Der Woude Families From Ethiopia.

BACKGROUND: Van der Woude syndrome (VWS) is the most common syndromic orofacial cleft which accounts for approximately 2% of all cleft lip (CL) and/or palate cases. It is characterized by the presence of lower lip pits, in addition to CL, CL with or without cleft palate, cleft palate only, and hypodontia. It is inherited as an autosomal-dominant trait with almost complete penetrance but variable expressivity, and different variants in IRF6 gene have been reported in different populations around the world including African populations (Ethiopian, Ghanaian, and Nigerian). METHODS AND FINDINGS: The authors investigated the role of IRF6 in Ethiopian families with VWS. The DNA of 7 families with VWS from Ethiopia were screened by Sanger sequencing. The authors screened all 9 exons of IRF6 and found a novel missense variant in exon 4 (p. Gly65Glu). This variant was predicted to be deleterious/probably damaging by Sift and PolyPhen, respectively. The IRF6 variant (p. Gly65Glu) segregates in the family since it was identified in the father and a sibling. CONCLUSION: Several of the individuals with lower lip pits in this study did not seek treatment. This is due to lack of awareness about the significance of this minor looking deformity and its consequences, and availability of treatment for birth defects. Therefore, it is important to educate families. Finally, screening for novel variants in known genes has a role in counseling and prenatal diagnosis for high-risk families.

A Novel IRF6 Frameshift Mutation in a Large Chinese Pedigree With Van der Woude syndrome.

AIMS: Van der Woude syndrome (VWS) is one of the most common craniofacial anomalies, causing significant functional and psychological burden to the patients. This study aimed to identify the genetic cause of VWS in a Chinese family. METHODS: Whole genome sequencing (WGS) was performed to screen for pathogenic mutations. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Cosegregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics guidelines. RESULTS: A novel frameshift duplication c.373_374dupAA (p.Asn125Lys fs*43) was identified in exon 4 of the interferon regulatory factor 6 (IRF6) gene in all 3 affected members, which were not found in unaffected family members. The novel mutation leads to a frameshift and a premature stop codon which caused putative truncated protein. Protein alignment indicated high evolutionary conservation of the p.N125 residue, and this mutation was predicted by online tools to be damaging and deleterious. CONCLUSIONS: This study demonstrates that the novel mutation c.373_374dupAA (p.Asn125Lysfs*43) in the IRF6 gene corresponds to the VWS in this family. The discovery of this pathogenic variant enriches the genotypic spectrum of IRF6 gene and contributes to genetic diagnosis and counseling of families with VWS.

Dental age, agenesis, and morphological anomalies in individuals with Van der Woude syndrome and isolated cleft palate.

OBJECTIVES: To analyse the differences between dental age and chronological age and dental anomalies in individuals with Van der Woude syndrome (VWS) and compare with non-syndromic cleft palate (NSCP) and non-cleft controls. MATERIALS AND METHODS: In total, 204 oral panoramic radiographs (118 girls and 86 boys) consisting of 51 VWS patients (age x̅ = 8.17 ± 1.34 years), 51 NSCP patients (age x̅ = 8.09 ± 1.41 years), and 102 normative non-cleft children (age x̅ = 8.62 ± 1.24 years) were collected. Dental stages were assessed by the Demirjian method, with the local dental maturity index as reference. Dental anomalies including agenesis were investigated. Statistical differences were determined by One-way ANOVA and regression. Repeatability was calculated by an intra-class correlation test and 95% confidence interval. RESULTS: The difference between dental age and chronological age of the VWS group (0.12 years) and the NSCP group (0.09 years) was significantly lower than the non-cleft group (0.40 years) (P = 0.002). There was no significant difference between the VWS and NSCP groups (P = 0.885). Hypodontia was more prevalent in both the VWS group (37.25%, P = 0.0001) and the NSCP group (19.60%, P = 0.035) compared with the non-cleft group (5.88%). The odds for hypodontia in the VWS group were approximately double compared with the NSCP group. In VWS patients, the most commonly missing teeth were the permanent second premolars and the maxillary permanent laterals incisors. Peg-shaped teeth had a prevalence of 13.70% in VWS patients. CONCLUSIONS: In VWS and NSCP patients compared with non-cleft children, the difference in dental age compared with chronological age decreased. Hypodontia occurs at a high prevalence in VWS and NSCP patients compared with non-cleft children.

Altered regulation of cell migration in IRF6-mutated orofacial cleft patients-derived primary cells reveals a novel role of Rho GTPases in cleft/lip palate development.

Orofacial clefts are the most common congenital craniofacial birth defects. They occur from a failure in cell proliferation and fusion of neural crest cells of the lip buds and/or palatal shelves. In this study, we investigate the genetic basis and molecular mechanisms in primary cells derived from a cleft and lip palate patient presenting van der Woude syndrome (VWS). Since mutations in the integrin genes are widely correlated with VWS, Interferon Regulatory Factor 6 (IRF6) screening was conducted in a cohort of 200 participants presenting with orofacial anomalies. Primary fibroblastic cells derived from the upper right gingiva and palatal regions were isolated and two cellular populations from two participants were obtained: a control with no cleft phenotype and a patient with a cleft phenotype typical of van der Woude syndrome (VWS). IRF6 targeted sequencing revealed mutations in two distinct families. Our results showed no alteration in the viability of the CLP/VWS patient cells, suggesting the phenotype associate with the disease is not secondary to a defect in cell proliferation. We did however detect a significant decrease in the migratory ability of the CLP with Van der Woude syndrome (CLP/VWS) patient cells, which could account for the phenotype. When compared to normal cells, patient cells showed a lack of polarization, which would account for their lack of mobility. Patient cells showed protrusions all around the cells and a lack of defined leading edge. This was reflected with actin staining, WAVE2 and Arp2 around the cell, and correlated with an increase in Rac1 activation. Consistently with the increase in Rac1 activation, patient cells showed a loss in the maturation of focal adhesions needed for contractility, which also accounts for the lack in cell migration. Our findings give increased understanding of the molecular mechanisms of VWS and expands the knowledge of van der Woude syndrome (VWS) occurrence by providing a strong molecular evidence that CLP with Van der Woude syndrome (CLP/VWS) phenotype is caused by a defect in normal physiological processes of cells.

Taurodontism in the first permanent molars in Van der Woude syndrome compared to isolated cleft palate.

OBJECTIVES: To analyse prevalence, pattern, and severity of taurodontism in individuals with Van der Woude syndrome (VWS) exhibiting cleft palate and compare with aged-matched non-syndromic cleft palate (NSCP) and non-cleft controls. MATERIALS AND METHODS: One hundred and seventy-eight dental panoramic tomographs (DPTs) (105 girls and 73 boys) consisting of 42 VWS patients (x¯=8.55±1.02 years), 42 NSCP patients (x¯=8.59±1.02 years), and 94 normative non-cleft children (x¯=8.79±1.16 years) were assessed and their first permanent molars evaluated. Measurement 3 of the taurodontism index developed by Shifman and Chanannel with the Tulensalo modification was used. Prevalence, pattern, and severity were compared between groups. Statistical differences were determined by one-way analysis of variance and Fisher test. Repeatability was calculated by Cohens Kappa test. RESULTS: The prevalence of taurodontic molars was 59.5% in VWS, 45.2% in NSCP, and 26.6% in non-cleft controls. The prevalence and severity of taurodontism in VWS and NSCP were significantly higher than in non-cleft children in all first permanent molars. There was no significant difference in prevalence and severity between VWS and NSCP. The odds for having taurodontism in the VWS group was approximately double compared to the NSCP group. Most of the taurodontic molars showed hypotaurodontism and taurodontism occurred bilaterally more frequently than unilaterally. CONCLUSION: This study shows a higher prevalence of taurodontism in VWS and NSCP. Most taurodontic molars are hypotaurodontic and most occur bilaterally.

Clinical Findings and Outcomes of Palatal Repair in 9 Patients With Van der Woude Syndrome.

INTRODUCTION: Van der Woude syndrome (VWS), an autosomal dominant condition associated with clefts of the lip and/or palate and lower lip pits, is caused by mutations in interferon regulatory factor 6 gene. It is reported to be the most common syndromic cleft worldwide. This case series presents the phenotypic characteristics and treatment outcomes in a group of 9 patients diagnosed with VWS. METHODS: A retrospective review was performed on records of patients given a diagnosis of VWS presenting to the Department of Plastic Surgery of Sohag University between July 2009 and November 2019. Data analyses included age and sex of affected patients, type of the cleft, associated anomalies, presence of lower lip pits, and history of lower lip pits/cleft in the family and treatment outcomes. RESULTS: The study identified 9 patients (male = 2, female = 7). Age at first presentation ranged between 1 week and 7 years (mean = 1.3 years). Four patients had bilateral cleft lip and palate and 1 patient had unilateral cleft lip and palate (UCLP), whereas 4 patients had isolated cleft palate. Bilateral lower lip pits were presented in 8 patients, whereas the ninth patient has unilateral pit. Family history was positive in 3 patients. Most patients in this study developed after palatal repair speech problems with an increased rate of secondary surgical procedures needed for correction of velopharyngeal insufficiency. CONCLUSIONS: All reviewed cases of VWS presented with lower lip pits and cleft palate with or without cleft lip. A positive family history of similar conditions was demonstrated in 33.3% of our patients. This study suggests an increased incidence of secondary palatal surgeries for velopharyngeal insufficiency in patients with VWS; this warrant further studies including control group of nonsyndromic cleft patients.

A clinical and multi­omics study of Van der Woude syndrome in three generations of a Chinese family.

Previous studies have suggested that pathogenic variants in interferon regulatoryse factor 6 (IRF6) can account for almost 70% of familial Van der Woude Syndrome (VWS) cases. However, gene modifiers that account for the phenotypic variability of IRF6 in the context of VWS remain poorly characterized. The aim of this study was to report a family with VWS with variable expressivity and to identify the genetic cause. A 4­month­old boy initially presented with cleft palate and bilateral lower lip pits. Examination of his family history identified similar, albeit milder, clinical features in another four family members, including bilateral lower lip pits and/or hypodontia. Peripheral blood samples of eight members in this three­generation family were subsequently collected, and whole­exome sequencing was performed to detect pathogenic variants. A heterozygous missense IRF6 variant with a c.1198C>T change in exon 9 (resulting in an R400W change at the amino acid level) was detected in five affected subjects, but not in the other three unaffected subjects. Moreover, subsequent structural analysis was indicative of damaged stability to the structure in the mutant IRF protein. Whole­transcriptome sequencing, expression analysis and Gene Ontology enrichment analysis were conducted on two groups of patients with phenotypic diversity from the same family. These analyses identified significant differentially expressed genes and enriched pathways in these two groups. Altogether, these findings provide insight into the mechanism underlying the variable expressivity of VWS.

Non-random distribution of deleterious mutations in the DNA and protein-binding domains of IRF6 are associated with Van Der Woude syndrome.

BACKGROUND: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS: We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS: Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

Ascher Syndrome: Acquired Double Lower Lip Combined With Epulis Fissuratum.

Ascher syndrome is characterized by double lip, blepharochalasis, and non-toxic goiter triad. This condition of unknown etiology usually occurs in patients younger than 20 years of age. In this case report, the authors present the diagnostic process of Ascher syndrome and surgical procedure of double lower lip in a female patient who applied to our clinic for prosthetic reasons. A 70-year old female patient was referred to our clinic with the chief complaint of incompatible dentures. The patient had been using the same complete dentures for 40 years. Extraoral clinical examination revealed protruded, bulged lower lip at rest and bilateral blepharochalasis, defined as atrophy of the upper eyelid skin. The upper lip and lower eyelids were not affected. Intraoral examination revealed complete edentation of both jaws and a double lower lip, an accessory fold of excess mucosae inside the vermillion border. Furthermore, epulis fissuratum was observed in the lower jaw. There was no family history of double lip. The patient stated that she had noticed another lip inside her lip for several years. As Ascher syndrome was suspected, the patient was referred to the endocrinology department for thyroid examination, and the non-toxic goiter diagnosis was confirmed. Surgical removal of the redundant tissues was necessary because of deficiencies in speech, chewing, and aesthetics. The excess tissues were excised by transverse ellipse incision technique. Dentists should be familiar with Ascher syndrome, as they may be the first physicians to encounter patients with double lip.