Fisura labio palatina: revisión de la literatura / Cleft lip and palate: literature review

La formación del paladar ocurre entre la quinta y undécima semana de vida intrauterina producto de la unión del paladar primario y secundario. Por otra parte, la formación del labio superior ocurre entre la quinta y sexta semana del desarrollo, y se configura en su parte media por la fusión de los procesos nasales mediales y lateralmente, a expensas de los procesos maxilares. La prevalencia de las fisuras labiales y/o fisura palatina varía según las distintas etnias, con cifras entre 0,7 hasta 1,1 casos por 1000 nacidos vivos. El objetivo de este trabajo fue realizar una revisión bibliográfica sobre aspectos epidemiológicos, mecanismos genéticos moleculares y ambientales que influyen en la ocurrencia de la fisura labial, fisura palatina y fisura labio palatina. La búsqueda bibliográfica se realizó en las bases de datos PUBMED, SCOPUS, SPRINGER, SCIENCEDIRECT utilizando los términos en inglés "cleft lip and palate", "cleft lip", "cleft palate" y "embriology". Entre los criterios de inclusión se consideraron estudios realizados en humanos y animales, publicados entre los años 2015 y 2021. La búsqueda arrojó un total de 407 trabajos, de los cuales tras un filtro por título y resumen quedaron un total de 38 artículos, en los cuales se realizó un análisis de texto completo para finalmente seleccionar 26 artículos que abarcan temas genéticos-moleculares, ambientales, epidemiológicos y sindrómicos. Además se incorporaron por búsqueda manual, 6 documentos asociados a libros de texto, y artículos científicos, sin considerar el criterio inclusión de tiempo. Dentro de esta revisión se describe la fuerte asociación entre las fisuras orales y las mutaciones de genes Msx1, sonic hedgehog, proteínas morfogenéticas óseas y factor de crecimiento fibroblástico durante la migración de las células de la cresta neural y la modelación y formación del paladar. La ausencia de ácido fólico durante el desarrollo del paladar y la presencia de hipoxia por exposición a humo, son los factores ambientales observados con mayor frecuencia en malformaciones orofaciales.

SUMMARY: Palate formation occurs between the fifth and eleventh week of intrauterine life as a result of the union of the primary and secondary palate. On the other hand, the formation of the upper lip occurs between the fifth and sixth week of development, and is configured in its middle part by the fusion of the medial and lateral nasal processes, at the expense of the maxillary processes. The prevalence of cleft lips and / or cleft palate varies according to the different ethnic groups, with figures ranging from 0.7 to 1.1 cases per 1000 live births. The aim of this work was to carry out a literature review on epidemiological aspects, molecular and environmental genetic mechanisms that influence the occurrence of cleft lip, cleft palate and its embriology. The literature search was carried out in the databases PUBMED, SCOPUS, SPRINGER, SCIENCEDIRECT using the English terms "cleft lip and palate", "cleft lip", "cleft palate" and "embryology". Inclusion criteria included studies carried out in humans and animals, published between 2015 and 2021. The search yielded a total of 407 works, of which after a filter by title and abstract, a total of 38 articles remained, in which a text analysis was carried out complete to finally select 26 articles that cover genetic-molecular, environmental, epidemiological and syndromic topics. In addition, 6 documents associated with textbooks and scientific articles were incorporated by manual search, without considering the inclusion criterion of time. This review describes the strong association between oral fissures and mutations of genes Msx1, sonic hedgehog, bone morphogenetic proteins and fibroblast growth factor during migration of neural crest cells and palate shaping and formation. Lack of folic acid during palae development dar and the presence of hypoxia due to exposure to smoke, are the environmental factors most frequently observed in orofacial malformations.

DNA hypermethylation of Fgf16 and Tbx22 associated with cleft palate during palatal fusion

Abstract Objective: Cleft palate (CP) is a congenital birth defect caused by the failure of palatal fusion. Little is known about the potential role of DNA methylation in the pathogenesis of CP. This study aimed to explore the potential role of DNA methylation in the mechanism of CP. Methodology: We established an all-trans retinoic acid (ATRA)-induced CP model in C57BL/6J mice and used methylation-dependent restriction enzymes (MethylRAD, FspEI) combined with high-throughput sequencing (HiSeq X Ten) to compare genome-wide DNA methylation profiles of embryonic mouse palatal tissues, between embryos from ATRA-treated vs. untreated mice, at embryonic gestation day 14.5 (E14.5) (n=3 per group). To confirm differentially methylated levels of susceptible genes, real-time quantitative PCR (qPCR) was used to correlate expression of differentially methylated genes related to CP. Results: We identified 196 differentially methylated genes, including 17,298 differentially methylated CCGG sites between ATRA-treated vs. untreated embryonic mouse palatal tissues (P<0.05, log2FC>1). The CP-related genes Fgf16 (P=0.008, log2FC=1.13) and Tbx22 (P=0.011, log2FC=1.64,) were hypermethylated. Analysis of Fgf16 and Tbx22, using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), identified 3 GO terms and 1 KEGG pathway functionally related to palatal fusion. The qPCR showed that changes in expression level negatively correlated with methylation levels. Conclusions: Taken together, these results suggest that hypermethylation of Fgf16 and Tbx22 is associated with decreased gene expression, which might be responsible for developmental failure of palatal fusion, eventually resulting in the formation of CP.

Assessing the association between hypoxia during craniofacial development and oral clefts

Abstract Objectives To evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families. Material and Methods The study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. Results For the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05). Conclusion Hypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.

Bases ambientales y genéticas de las fisuras orofaciales: revisión / Narrative review: environmental and genetic basis of orofacial clefts

El desarrollo embriológico de las estructuras orofaciales es un proceso complejo guiado por programas genéticos. Alteraciones en esos procesos dan lugar a anomalías estructurales. Un ejemplo de ellas son las fisuras de labio y el paladar. Las principales vías involucradas en las fisuras tienen como participantes a las familias del factor de crecimiento fibroblástico (FGF), Hedgehog (HH), Wingless (WNT) y la familia del factor de crecimiento transformante beta (TGFß), que incluye las proteínas morfogenéticas del hueso (BMPs) y activinas. En esta revisión narrativa se presentan algunos de los procesos celulares, moleculares y factores ambientales implicados en el desarrollo del complejo orofacial, finalizando con posibilidades terapéuticas para la evidencia acumulada.

Complex genetic process guides the embryonic head development. Alterations in these processes result instructural abnormalities. An example of these are the cleft lip and palate. The major pathways involved in the fissures are families: the Fibroblast Growth Factor (FGF) family, the Hedgehog (HH) family, the Wingless (WNT) family and the Transforming Growth Factor beta (TGF-ß) family, which includes the Bone Morphogenetic Proteins (BMPs) and Activins. In this review, we discuss some of the celular/molecular processes and environmental factors involved in the development of the orofacial complex, ending with therapeutic possibilities and potential clinical relevance to the accumulated evidence.

Expression analyses of human cleft palate tissue suggest a role for osteopontin and immune related factors in palatal development

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.

Lábio leporino unilateral e bilateral total (Tratamento cirúrgico num tempo único) / Unilateral and bilateral total cleft lip (in only time surgical treatment)

Os autores estudam sucintamente a grave malformação congênita labiopalatina (lábio leporino e fissura palatina) e o seu tratamento num tempo único. Discorrem sobre a histologia, embriologia, anatomofisiologia, etiologia e patogenia dessa malformação bem como sobre a orientação terapêutica (operação). Finalizam o trabalho fazendo alguns comentários gerais

Diferencias celulares y moleculares en la susceptibilidad a la fisura palatina en el ratón / Cellular and molecular differences in the susceptibility to cleft palate on mice

The aim of this study was to identify possible candidate genes for the susceptibility to cleft palate. We studied hyaluronic and glycoprotein levels with morphometric and histochemical techniques, in palatine process of 13 and 14 days old mouse embryos of strains A/Sn and C/57 BL, that are respectively susceptible and resistant to glucocorticoid and non steroid anti-inflammatory drug induced cleft palate. At 13 days, in palatine process of the resistant strain and when these are still vertical, there was a significantly higher amount of extracellular matrix, constituted principally by hyaluronic acid. These differences disappeared at 14 days, when the processes became horizontal. The basal membrane of the medial palatine epithelium of the susceptible strain, showed interruptions due to a lower amount of glycoproteins. It is concluded that the observed differences in the amount and quality of these molecules, are a consequence of genetic differences that could determine the susceptibility to cleft palate

Fissuras lábio-palatais: consideraçöes embriológicas / Cleft lip and palate: embryological considerations

A primeira parte deste ensaio aborda de forma suscinta o mecanismo de formaçäo embriogênica da face, acompanhado de painéis fotográficos que ilustram as malformaçöes faciais mais comuns no homem e os prováveis processos faciais embrionários envolvidos

Embriologia e epidemiologia das fissuras lábio-palatais / Embriology and epidemiology of the lip and palate fissures

As fendas lábio-palatais säo as mais comuns anormalidades congênitas da face. Säo malformaçöes distintas no que diz respeito à etiologia e épocas de desenvolvimento embrionário. Resultam sumariamente da deficiência de massas mesodérmicas, no que se refere à migraçäo e fusäo de seus processos. Estas anormalidades säo causadas principalmente por mutaçöes genéticas, porém fatores ambientais podem ser comumente envolvidos em alguns casos. Diversos fatores interferem na formaçäo, aumento ou diminuiçäo da incidência, associaçäo a outras deformidades e, säo abordados também nas interligaçöes entre sexos, tipos de fendas, e freqüência