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1.
J Appl Oral Sci ; 27: e20180649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596367

RESUMO

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.


Assuntos
Fissura Palatina/genética , Metilação de DNA , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Proteínas com Domínio T/genética , Animais , Fissura Palatina/embriologia , Fissura Palatina/patologia , Feminino , Fatores de Crescimento de Fibroblastos/análise , Masculino , Camundongos Endogâmicos C57BL , Domínios e Motivos de Interação entre Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Análise de Sequência de DNA , Proteínas com Domínio T/análise
2.
Am J Orthod Dentofacial Orthop ; 156(2): 257-265, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375236

RESUMO

INTRODUCTION: Children with unilateral cleft lip and palate (UCLP) exhibit snoring and mouth breathing. They are also reported to show obstructive sleep apnea syndrome. However, their upper airway ventilation condition is not clearly understood. Therefore, this study was performed to evaluate upper airway ventilation condition in children with UCLP with the use of computational fluid dynamics. METHODS: Twenty-one children (12 boys, 9 girls; mean age 9.1 years) with UCLP and 25 children (13 boys, 12 girls; mean age 9.2 years) without UCLP who required orthodontic treatment underwent cone-beam computed tomography (CBCT). Nasal resistance and upper airway ventilation condition were evaluated with the use of computational fluid dynamics from CBCT data. The groups were compared with the use of Mann-Whitney U tests and Student t tests. RESULTS: Nasal resistance of the UCLP group (0.97 Pa/cm3/s) was significantly higher than that of the control group (0.26 Pa/cm3/s; P < 0.001). Maximal pressure of the upper airway (335.02 Pa) was significantly higher in the UCLP group than in the control group (67.57 Pa; P < 0.001). Pharyngeal airway (from choanae to base of epiglottis) pressure in the UCLP group (140.46 Pa) was significantly higher than in the control group (15.92 Pa; P < 0.02). CONCLUSIONS: Upper airway obstruction in children with UCLP resulted from both nasal and pharyngeal airway effects.


Assuntos
Fenda Labial/patologia , Fissura Palatina/patologia , Tomografia Computadorizada de Feixe Cônico/métodos , Hidrodinâmica , Laringe/anatomia & histologia , Nariz/anatomia & histologia , Tonsila Faríngea/anatomia & histologia , Pontos de Referência Anatômicos , Criança , Fenda Labial/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Epiglote/anatomia & histologia , Epiglote/diagnóstico por imagem , Feminino , Humanos , Osso Hioide/anatomia & histologia , Imagem Tridimensional/métodos , Laringe/diagnóstico por imagem , Má Oclusão de Angle Classe I , Nasofaringe/anatomia & histologia , Nasofaringe/diagnóstico por imagem , Nariz/diagnóstico por imagem , Respiração , Apneia Obstrutiva do Sono
3.
J Appl Oral Sci ; 27: e20180434, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31215598

RESUMO

This study aimed to compare the linear dimensions of the dental arches of adult patients with complete unilateral cleft lip and palate (UCLP) after orthodontic and prosthetic treatment with fixed partial dentures (FPD) to patients without clefts, using 3D technology. This retrospective longitudinal study sample consisted of 35 subjects divided into two groups. Included in this sample were 15 complete UCLP individuals who had received orthodontic treatment before rehabilitation with a fixed partial denture (FG), as well as 20 patients without cleft as control group (CG). All patients were aged between 18 and 30 years. Digital dental casts were obtained in two stages: (T1) end of orthodontic treatment and (T2) one year after prosthetic rehabilitation (FG); and (T1) end of orthodontic treatment and (T2) one year after removal of the orthodontic appliance (CG). Intercanine, interfirst premolar and intermolar distances, and incisor-molar length were obtained. A precalibrated and trained examiner performed the assessments. Intergroup differences between T2 and T1 were compared between the groups using the t test or Mann-Whitney test with a significance level of 5% (p<0.05). The intercanine distance variation (T2-T1) showed statistical difference (p=0.005) increasing in the FG group and decreasing in the CG group. In the interfirst premolar distance variation, FG decreased, while CG increased with statistically significant difference (p=0.008). The intercanine distance of individuals with cleft showed stability, while that of the CG had no stability. The CG showed stability in the interfirst premolar distance, while FG had no stability. These findings showed that the FPD is capable of restricting orthodontic results, leading to a stabilization of the dental arches.


Assuntos
Fenda Labial/reabilitação , Fissura Palatina/reabilitação , Arco Dental/patologia , Prótese Dentária Fixada por Implante/métodos , Imagem Tridimensional/métodos , Ortodontia Corretiva/métodos , Adolescente , Adulto , Pontos de Referência Anatômicos , Fenda Labial/patologia , Fissura Palatina/patologia , Feminino , Humanos , Masculino , Maxila/patologia , Aparelhos Ortodônticos , Valores de Referência , Estudos Retrospectivos , Estatísticas não Paramétricas , Resultado do Tratamento , Adulto Jovem
4.
Lasers Med Sci ; 34(8): 1699-1703, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187297

RESUMO

Post-surgical scars of cleft lip patients can lead to abnormal lip activity, which causes deficient maxillary growth. The aim of the present study was to assess the effect of laser therapy on the appearance and electrical activity of the upper lip in cleft lip and palate patients. Twelve patients with cleft lip and palate participated in this study. All patients had surgically repaired the cleft lip at the age of about 3-6 months. The lip scars underwent five fractional CO2 laser treatment sessions with a 4-week interval. Improvement of the quality of the skin texture was recorded according to quartile grading scale based on photographs taken before and 1 month after treatment. Patients' satisfaction survey was also recorded using Patient Scar Assessment Questionnaire (PSAQ) before and after laser therapy. Moreover, the EMG activity of the upper lip muscle was measured before and after treatment. According to dermatologists, the improvement of scar appearance ranged from 0.5 to 3, with a mean of 1.29 ± 0.86. Mean scores of the scar appearance (p < 0.001), symptoms (p = 0.003), and scar consciousness (p < 0.001) subscales of the PSAQ questionnaire had significantly increased after treatment. The EMG recording of the upper lip had decreased significantly after laser treatment at rest (p = 0.009) and maximum lip compression (p = 0.007). The fractional CO2 laser is an effective method for treating old scars of the cleft lip with a significant change in the opinion of patients about their scar appearance. Also, the therapy can help to reduce the EMG activity of the upper lip at rest.


Assuntos
Cicatriz/etiologia , Cicatriz/cirurgia , Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Lasers de Gás/uso terapêutico , Cicatriz/patologia , Fissura Palatina/patologia , Eletrodos , Eletromiografia , Feminino , Humanos , Lábio/patologia , Lábio/fisiopatologia , Lábio/cirurgia , Resultado do Tratamento , Adulto Jovem
5.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172578

RESUMO

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.


Assuntos
Encéfalo/anormalidades , Fenda Labial/classificação , Fenda Labial/genética , Fissura Palatina/classificação , Fissura Palatina/genética , Loci Gênicos , Marcadores Genéticos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Encéfalo/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Humanos , Transcriptoma
6.
BMC Genomics ; 20(1): 349, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068123

RESUMO

BACKGROUND: Palatoschisis or cleft palate is a known anomaly in pigs resulting in their death. However, little is known about its aetiology. A detailed description of the phenotype was derived from necropsy and by computed tomography revealing that all 20 cases also exhibited hypodontia and renal cysts. Furthermore, a genetic origin was assumed due to dominant inheritance as all 20 recorded cases were confirmed offspring of a single boar. RESULTS: Single nucleotide variant (SNV) genotyping data were used to map the defect in the porcine genome and led to the detection of a chromosomal imbalance in the affected offspring. Whole genome sequencing of an affected piglet and a normal full sib was used to identify a chromosomal translocation and to fine map the breakpoints in the genome. Finally, we proved that the boar, which sired the malformed piglets, carried a balanced translocation. The detected translocation of Mb-sized segments of chromosome 8 and 14 had not been previously observed during karyotyping. All affected offspring were shown to be carriers of a partial trisomy of chromosome 14 including the FGFR2 gene, which is associated with various dominant inherited craniofacial dysostosis syndromes in man, and partial monosomy of chromosome 8 containing MSX1 known to be associated with tooth agenesis and orofacial clefts in other species. CONCLUSIONS: This study illustrates the usefulness of recently established genomic resources in pigs. In this study, the application of genome-wide genotyping and sequencing methods allowed the identification of the responsible boar and the genetic cause of the observed defect. By implementing systematic surveillance, it is possible to identify genetic defects at an early stage and avoid further distribution of congenital disorders.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Fissura Palatina/genética , Polimorfismo de Nucleotídeo Único , Suínos/genética , Anormalidades Múltiplas/patologia , Animais , Fissura Palatina/patologia , Feminino , Masculino , Síndrome , Sequenciamento Completo do Genoma
7.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052503

RESUMO

Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Fenda Labial/terapia , Fissura Palatina/terapia , Medicina Regenerativa/métodos , Animais , Fenda Labial/epidemiologia , Fenda Labial/patologia , Fenda Labial/fisiopatologia , Fissura Palatina/epidemiologia , Fissura Palatina/patologia , Fissura Palatina/fisiopatologia , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Osteogênese/efeitos dos fármacos , Transplante de Células-Tronco/métodos , Engenharia Tecidual/métodos
8.
Mol Med Rep ; 20(1): 513-528, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115538

RESUMO

Non­syndromic orofacial clefts (NSOC), which include cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are common congenital birth defects in humans. Accumulating evidence indicates that long non­coding RNAs (lncRNAs) and microRNAs (miRNAs or miRs) play important roles in NSOC; however, the potential regulatory associations between them remain largely unknown. In this study, we performed next­generation RNA sequencing (RNA­seq) to identify transcriptome profiles, including mRNAs, lncRNAs and miRNAs, in patients with CL/P and CPO. A total of 36 lncRNAs, 1,341 mRNAs and 60 miRNAs were found to be differentially expressed in the CL/P group compared to the control group, and 57 lncRNAs, 1,255 mRNAs and 162 miRNAs were found to be differentially expressed in the CPO group compared to the control group. Subsequently, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to validate the expression of selected lncRNAs, miRNAs and mRNAs. In addition, bioinformatics methods were employed to explore the potential functions of ncRNAs and to construct lncRNA­miRNA­mRNA regulatory networks. To the best of our knowledge, this is the first study to comprehensively analyze regulated non­coding RNAs (ncRNAs) in CL/P and CPO, providing a novel perspective on the etiology of NSOC and laying the foundation for future research into the potential regulatory mechanisms of ncRNAs and mRNAs in NSOC.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Encéfalo/patologia , Pré-Escolar , Fenda Labial/sangue , Fenda Labial/patologia , Fissura Palatina/sangue , Fissura Palatina/patologia , Biologia Computacional , Feminino , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , MicroRNAs/sangue , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , Transcriptoma/genética
9.
Ann Anat ; 224: 41-46, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953811

RESUMO

AIM: The aim of this study was to evaluate palatal vertical bone thickness and density in relation to soft tissue on the hard palate for better selection of adequate bone regions for the insertion of orthodontic mini-implants (MIs) in cleft palate patients. MATERIALS AND METHODS: Cone beam computed tomography scans (CBCT) were obtained from 60 patients (mean age range 9-12). The study population included patients with isolate right side cleft palate formation (n = 20; 6 females; 14 males), left side cleft palate formation (n = 20; 9 females; 11 males) and without cleft formation as control group (n = 20; 15 females; 5 males). Bone and soft tissue measurements were performed vertical at a 90° angle to the bone surface, on previously defined measurement points (n = 88) on the hard palate. Bone density was measured on ten vertical layers in caudo-cranial direction. RESULTS: In non-cleft patient the highest bone thickness was in the anterior palate and decreased significantly in posterior direction. In patients with right and left cleft palate, the highest vertical bone level could be observed at the palatal premaxillary border opposite to the cleft side. Patients in the control group showed a significantly lower vertical soft tissue thickness than patients with palatal cleft formation. The evaluation of bone density showed no significant differences in all three groups. CONCLUSION: The results suggest that the favorable region for orthodontic MI placement is in the similar anatomical region compared to non-cleft patients, but differs from one side in each group. In unilateral cleft palate patients, the highest bone level was found on the anterior palate side opposite to the cleft side, indicating the most effective region for MIs placement.


Assuntos
Fissura Palatina/patologia , Palato Duro/patologia , Âncoras de Sutura/normas , Densidade Óssea , Estudos de Casos e Controles , Criança , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/cirurgia , Tomografia Computadorizada de Feixe Cônico , Implantes Dentários/normas , Feminino , Humanos , Imagem Tridimensional , Masculino , Ortodontia/métodos , Palato Duro/diagnóstico por imagem , Palato Duro/fisiologia , Palato Duro/cirurgia , Projetos Piloto , Estudos Retrospectivos
10.
Mol Genet Genomic Med ; 7(5): e635, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924295

RESUMO

BACKGROUND: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family. METHODS: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two. RESULTS: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p < 0.05 of SATB2, COL21A1, and TOX3 copy number in extended families compared to the normal controls. CONCLUSION: Novel linkage evidence and significant low copy number of COL21A1 and TOX3 in NSCLP family was confirmed. These genes increased the risks toward NSCLP formation in that family traits.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Colágenos Fibrilares/genética , Receptores de Progesterona/genética , Fenda Labial/patologia , Fissura Palatina/patologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Malásia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Linhagem , Fatores de Transcrição/genética
12.
J Dermatol ; 46(5): 422-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809829

RESUMO

A Chinese female infant presented with ectodermal dysplasia, cleft palate and severe skin erosions at birth. Although all the typical clinical features of ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome were present, the ankyloblepharon was not very marked. We misdiagnosed epidermolysis bullosa and congenital ichthyosiform erythroderma at first and confirmed the diagnosis of AEC syndrome only when she presented with the typical clinical manifestation of recurrent infected scalp erosions at 1 year of age. Mutation analysis of exon 13 of the p63 gene revealed a missense mutation Ile482Thr (c.1445T>C) in the sterile alpha motive domain. In this work we review the clinical features, differential diagnosis and prognosis in AEC syndrome.


Assuntos
Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Erros de Diagnóstico , Displasia Ectodérmica/diagnóstico , Epidermólise Bolhosa/diagnóstico , Anormalidades do Olho/diagnóstico , Pálpebras/anormalidades , Eritrodermia Ictiosiforme Congênita/diagnóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Biópsia , Fenda Labial/genética , Fenda Labial/patologia , Fenda Labial/terapia , Fissura Palatina/genética , Fissura Palatina/patologia , Fissura Palatina/terapia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Displasia Ectodérmica/terapia , Epidermólise Bolhosa/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/terapia , Pálpebras/patologia , Feminino , Testes Genéticos , Heterozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/patologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Mutação de Sentido Incorreto , Pele/patologia
13.
J Craniomaxillofac Surg ; 47(2): 245-254, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600197

RESUMO

PURPOSE: To analyze three-dimensional (3D) nasolabial forms and upper lip surface symmetry after primary lip repair in children with unilateral cleft lip and palate (UCLP). METHODS: Subjects were 22 Japanese children with complete UCLP who underwent primary lip repair and were followed-up for 4-6 years. The 3D coordinates of facial landmarks and the angle and radius of the approximate nasal alar circle were calculated. Upper lip surface symmetry was analyzed using histogram intersection. RESULTS: The nasal tip and columella base were slightly dislocated to the cleft side, and the midpoint of Cupid's bow shifted to the non-cleft side. The nasal alar and the top of Cupid's bow were reconstructed at the same height, while the approximate nasal alar circle was smaller on the cleft side. The mean value of similarity for upper lip surface symmetry was 0.82; a subject with a higher value had more symmetrical contour lines in the visualized surface image. CONCLUSIONS: Postoperative nasolabial forms were almost restored to symmetrical levels, while retaining a small nasal alar. Histogram intersection is applicable as a method for the quantitative evaluation of upper lip surface symmetry in UCLP.


Assuntos
Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Lábio/cirurgia , Nariz/patologia , Pontos de Referência Anatômicos/diagnóstico por imagem , Pontos de Referência Anatômicos/patologia , Fenda Labial/diagnóstico por imagem , Fenda Labial/patologia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/patologia , Feminino , Humanos , Imagem Tridimensional , Lactente , Lábio/diagnóstico por imagem , Lábio/patologia , Masculino , Nariz/diagnóstico por imagem
14.
Growth Horm IGF Res ; 44: 17-19, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30583238

RESUMO

OBJECTIVE: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. PATIENTS AND METHODS: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. RESULTS: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). CONCLUSION: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.


Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Mutação da Fase de Leitura , Hipopituitarismo/congênito , Hipopituitarismo/genética , Proteínas Nucleares/genética , Proteína Gli2 com Dedos de Zinco/genética , Anormalidades Múltiplas/patologia , Fissura Palatina/patologia , Humanos , Hipopituitarismo/patologia , Recém-Nascido , Masculino , Fenótipo , Prognóstico , Síndrome
15.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071673

RESUMO

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.


Assuntos
Artrogripose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Processamento de RNA/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Pré-Escolar , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Pé Torto Equinovaro/metabolismo , Pé Torto Equinovaro/patologia , Feminino , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Domínios Proteicos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
16.
Biomed Pharmacother ; 103: 240-247, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29655165

RESUMO

The fibroblast growth factors (FGFs) play a critical role during palatogenesis by mediating a variety of cellular responses. Extensive epidemiological and genetic studies over several decades in humans have revealed members of the FGF family function as candidate genes for syndromic and nonsyndromic cleft lip and cleft palate. The findings that FGFs signaling work delicately in the development of palate have been confirmed in mice carrying targeted mutations. Here we try to review recent progress toward a detailed understanding of FGF signaling including FGF7, FGF8, FGF9, FGF10, FGF18 and their receptors FGFR1, FGFR2 in palate development studies and discuss how they interact with other factors on the basis of animal studies regarding cleft palate.


Assuntos
Fator 10 de Crescimento de Fibroblastos/metabolismo , Palato/embriologia , Palato/metabolismo , Transdução de Sinais , Animais , Fissura Palatina/genética , Fissura Palatina/patologia , Humanos , Organogênese
17.
Ann Anat ; 218: 59-68, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29604388

RESUMO

INTRODUCTION: Craniofacial development in mammals is a complex process that involves a coordinated series of molecular and morphogenetic events. Folic acid (FA) deficiency has historically been associated with congenital spinal cord malformations, but the effect that a maternal diet deficient in FA has on the development of other structures has been poorly explored. In the present study, the objective was to describe and quantify the alterations of craniofacial structures presented in mouse foetuses from dams fed a FA deficient (FAD) diet compared with controls that were given a regular maternal diet. MATERIAL AND METHODS: E17 mouse foetuses were removed from dams that were fed with a control diet or with a FAD diet for several weeks. Foetuses with maternal FAD diets were selected for the study when they showed an altered tongue or mandible. Histological sections were used to quantify the dimensions of the head, tongue, mandibular bone and masseter muscle areas using ImageJ software. The muscles of the tongue, suprahyoid muscles, lingual septum, submandibular ducts, and lingual arteries were also analysed. RESULTS: The heads of malformed foetuses were smaller than the heads of the controls, and they showed different types of malformations: microglossia with micrognathia (some of which were combined with cleft palate) and aglossia with either micrognathia or agnathia. Lingual and suprahyoid muscles were affected in different forms and degrees. We also found alterations in the lingual arteries and in the ducts of the submandibular glands. Summarised we can state that pharyngeal arches-derived structures were affected, and the main malformations observed corroborate the vulnerability of cranial neural crest cells to FA deficiency. CONCLUSION: The present study reveals alterations in the development of craniofacial structures in FAD foetuses. This study provides a new focus for the role of FA during embryological development.


Assuntos
Anormalidades Craniofaciais/patologia , Feto/patologia , Deficiência de Ácido Fólico/patologia , Animais , Fissura Palatina/etiologia , Fissura Palatina/patologia , Anormalidades Craniofaciais/etiologia , Dieta , Feminino , Mandíbula/anormalidades , Músculos da Mastigação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Língua/anormalidades , Doenças da Língua/patologia
18.
Biomed Res Int ; 2018: 5405376, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619373

RESUMO

Objective: The aim was to evaluate differences in the cervical vertebral skeletal maturity of unilateral cleft lip and palate (UCLP) and non-cleft lip/palate (non-CLP) Saudi male orthodontic patients. Method: This cross-sectional multicenter study took place at the dental school, King Saud University and King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between October 2014 and September 2015. The records of Saudi male orthodontic patients with UCLP (n = 69) were collected. Cervical vertebral maturation was assessed using their cephalometric radiographs. The records of 138 age-matched non-CLP Saudi male orthodontic patients served as controls. Results: There was a significant difference in skeletal maturity between the UCLP and non-CLP groups, as evident in the delayed skeletal development among the UCLP participants. Moreover, pubertal growth spurt onset was significantly earlier in the non-cleft participants in comparison with the UCLP participants (p = 0.009). Conclusions: There is delayed skeletal maturity among the UCLP Saudi male population in comparison with their non-CLP age-matched peers.


Assuntos
Vértebras Cervicais/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Ortodontia , Adolescente , Criança , Feminino , Humanos , Masculino , Arábia Saudita
19.
J Genet ; 97(1): 205-211, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666339

RESUMO

Emanuel syndrome is caused due to an additional derivative chromosome 22 and is characterized by severe intellectual disability, microcephaly, failure to thrive, preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and genital abnormalities in males. In 99% of the cases, one of the parents is a carrier of balanced translocation between chromosomes 11 and 22. It occurs due to malsegregation of the gametes with 3:1 segregation. In this case series, we describe four patients with diverse manifestations of this condition. The craniosynostosis observed in one case is a novel finding which has never been reported previously. This study aims to widen the phenotypic spectrum of Emanuel syndrome and provide cytogenetic microarray based breakpoints in two of the cases, thus supporting close clustering of the breakpoints of this common recurrent chromosomal rearrangement.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Criança , Transtornos Cromossômicos/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Cariotipagem , Masculino , Hipotonia Muscular/diagnóstico por imagem , Fenótipo
20.
J Craniomaxillofac Surg ; 46(4): 660-667, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29545028

RESUMO

Nasoalveolar Molding (NAM) is associated with ambivalent acceptance regarding effectiveness and unknown long-term results. Our purpose was to analyze the stress distribution patterns within the viscero- and neurocranium of neonates during the first phase of NAM therapy. A finite element (FE) model of a healthy four-week-old neonate was generated, derived from a computed tomography scan allowing the implementation of a bone-density-dependent material model. The influence of dental germs with variable material properties, the cleft width and area of expected force application were analyzed in a worst-case scenario. The resulting stress distribution patterns for each situation were analyzed using the software Ansys APDL. The established FE model was verified with a convergence analysis. Overall, stress patterns at the age of four weeks showed von Mises stress values below 60.000 Pa in the viscero- and neurocranium. The influences of the allocation of material properties for the dental germs, the area of force application, and the cleft width were negligible. A workflow to simulate the stress distribution and deformation in neonates attributable to various areas of force application has been established. Further analyses of the skulls of younger and older neonates are needed to describe the stress distribution patterns during NAM therapy.


Assuntos
Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Crânio/patologia , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/patologia , Processo Alveolar/fisiopatologia , Processo Alveolar/cirurgia , Fenda Labial/diagnóstico por imagem , Fenda Labial/patologia , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/patologia , Fissura Palatina/fisiopatologia , Análise de Elementos Finitos , Humanos , Recém-Nascido , Modelos Anatômicos , Nariz/diagnóstico por imagem , Nariz/patologia , Nariz/fisiopatologia , Nariz/cirurgia , Crânio/diagnóstico por imagem , Crânio/fisiopatologia , Estresse Mecânico , Tomografia Computadorizada por Raios X
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