Estudo de polimorfismos em genes relacionados ao metabolismo do ácido fólico e sua associação com o desenvolvimento de fendas orais não-sindrômicas

The congenital facial clefts are characterized by incomplete formation of the structures that separate the oral and nasal cavity. It is known that several environmental and genetic factors are involved in its development, among these, polymorphisms associated with folic acid metabolism have been investigated. In this sense, the objective was to observe the frequency of polymorphisms C677T and A1298C methylenetetrahydrofolate reductase gene (MTHFR), methionine synthase A2756G of (MTR), A66G of methionine synthase reductase (MTRR) A80G and the reduced folate carrier (RFC1) in patients with non-syndromic oral clefts, trying to match them with their development. Methods: We studied 140 patients with non-syndromic oral clefts and their mothers and 175 control subjects with their mothers, who underwent a questionnaire to obtain family information. Were collecting blood for DNA extraction from patients and their mothers to identify the genotypes of both by PCRRFLP, in addition to carrying out the determination of glucose, AST, ALT and serum creatinine, folic acid and vitamin B12 Serum and plasma homocysteine, and the hemogram. Results: Most patients have cleft lip and palate (55.8%), followed by isolated cleft palate (24.2%) and cleft lip (20%). Regarding gender, 62% of patients were male and 48% female and, after subdivision of the type of screwdriver according to sex was found a prevalence of males in the cracks of the type lip and palate (69 %) and lip (69.2%) and in the case of cleft palate was a female predominance (59%). The average concentration of serum folate in the group of mothers of cleft patients was significantly lower (13.8 ± 2.4 ng / mL) compared with the group of mothers of control subjects (18.8 ± 3.4 ng / mL) This was also observed for the group of cleft children as compared to controls, the dosage of folic acid had a significant difference with values of 15.6 ± 0.6 (ng / mL) and 17.9 ± 0.6 (ng / mL), respectively. For the biochemical measurements of glucose, AST, ALT and creatinine were not statistically different, nor was observed for haematological parameters performed. In assessing the frequency of polymorphisms C677T and A1298C MTHFR, A2756G MTR, MTRR A66G and A80G of the RFC1 there was no statistically significant difference in genotype distribution between cases and controls both for mothers and in the cleft. Conclusion: Although not observed association of polymorphisms with the development of cracks, the decrease in serum folate in the group of cleft patients and their mothers may reflect a disturbance in the metabolism of this metabolite, necessitating further studies such as studies methylation and expression to further elucidate the involvement of folate in the development of oral clefts

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection(1), but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits(4), and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies(5). Phenotypic overlap(6) and linkage data(7) suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.

Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta

Amelogenesis imperfecta (AI) is a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Mutations in several enamel proteins and proteinases have been associated with AI. The object of this study was to evaluate evidence of etiology for the six major candidate gene loci in two Brazilian families with AI. Genomic DMA was obtained from family members and all exons and exon-intron boundaries of the ENAM, AMBN, AMELX, MMP20, KLK4 and Amelotin gene were amplified and sequenced. Each family was also evaluated for linkage to chromosome regions known to contain genes important in enamel development. The present study indicates that the AI in these two families is not caused by any of the known loci for AI or any of the major candidate genes proposed in the literature. These findings indicate extensive genetic heterogeneity for non-syndromic AI.

Bone augmentation and autogenous transplantation of premolar to the site of the fissure in a cleft palate patient

This article presents a case report of autogenous tooth transplantation to the site of the fissure, in addition to bone augmentation with graft of autogenous bone harvested from the iliac crest, performed in a cleft palate patient, who had insufficient bone volume. A non-syndromic 10-year-old girl, with a unilateral cleft lip and palate, incisal transforamen fissures, agenesis of the maxillary left central incisor and both maxillary lateral incisors, was treated with autogenous bone graft in the cleft area. The orthodontic treatment plan was to replace the missing lateral incisors with the maxillary canines and to extract the mandibular first premolars. One of the mandibular premolars was extracted from its site with 2/3 of its root formation completed and transplanted to the maxillary left central incisor area. After orthodontic treatment, the anatomic crowns were characterized with composite resin. Autogenous tooth transplantation can be performed in the area of the fissure in young cleft palate patients, by performing bone graft augmentation before transplantation of the tooth, to gain sufficient recipient alveolar bone volume. A multidisciplinary approach is mandatory for the success of this clinical procedure, especially in cleft palate patients. © 2012 John Wiley & Sons A/S.

Perfil audiológico e genético de pacientes com perda auditiva sensorioneural não sindrônica atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu-Universidade Estadual Paulista

Pós-graduação em Bases Gerais da Cirurgia - FMB

Ocorrência de microrganismos periodontopatogênicos e viruses herpéticos na cavidade bucal de pacientes portadores de Síndrome de Down

Pós-graduação em Ciência Odontólogica - FOA

Estudo comparativo em radiografias cefalométricas laterais das alterações craniofaciais em indivíduos portadores de síndrome de Down e em portadores da síndrome da apnéia obstrutiva do sono

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estudo de mutações no gene GJB2 e deleção delGJB6-D13S1830 em indivíduos com surdez não sindrômica da região Amazônica

A deficiência auditiva afeta cerca de 1 em cada 1000 recém-nascidos. Mutações no gene da conexina 26 (GJB2) são as causas mais frequentes de surdez não sindrômica em diferentes populações e é sabido que a mutação delGJB6-D13S1830 em DFNB30 é causadora de surdez neurossensorial. Muitos estudos descrevem o envolvimento de mutações no gene GJB2 com a deficiência auditiva em diferentes populações. Entretanto, existe pouca informação sobre a surdez genética no Brasil, especialmente na região Amazônica. OBJETIVO: Determinar a prevalência de mutações no gene GJB2 e da mutação delGJB6-D13S1830 em 77 casos esporádicos de surdez não sindrômicas. MÉTODO: A região codificante do gene GJB2 foi sequenciada e a PCR foi realizada para detectar a mutação delGJB6-D13S1830. RESULTADOS: O alelo 35delG foi encontrado em 9% dos pacientes (7/77). As mutações M34T e V95M foram detectadas em dois distintos pacientes heterozigotos. A mutação não patogênica V27I foi detectada em 28,6% (22/77). Não foi detectada a mutação delGJB6-D13S1830 em nenhum paciente estudado. CONCLUSÃO: Alelos mutantes no gene GJB2 foram observados em 40% (31/77) da amostra. Variantes patogênicas foram detectadas em apenas 12% (9/77). Mais estudos são necessários para elucidar causas genéticas de deficiência auditiva em populações miscigenadas.

Análise microbiológica e imunologica do fluido gengival e proteoma salivar de individuos com Sindrome de Down com doença periodontal

Pós-graduação em Odontologia - FOAR

Frontonasal dysplasia: clinical evaluation on audiological and brainstem electrophysiological profiles

Frontonasal dysplasia (FND) is a rare malformative complex affecting the frontal portion of the face, the eyes and the nose; it may occur singly or associated with other clinical signs. No systematic studies describing hearing in this condition were found. AIM: To evaluate hearing sensitivity and sound stimulus conduction from cochlea to brainstem in patients with clinical signs of FND. METHODS: 21 patients with isolated or syndromic FND were submitted to a clinical (otological/vestibular antecedents and otoscopy) and instrumental (pure tone and speech audiometry, tympanometry and brainstem auditory evoked response) hearing evaluation. DESIGN: A clinical, cross-sectional observational prospective study. RESULTS: Hearing thresholds were normal in 15 (70%) patients, abnormal in 5 (25%), mostly with conductive hearing loss; one patient did not cooperate with testing. The tympanometric curve was type A in 30 (72%) ears, type C in 5 (12%), type As in 4 (9%) and type B in 3 (7%). The auditory brainstem response (ABR) showed no abnormalities. CONCLUSION: Patients with FND showed no abnormalities in the auditory system from cochlea to brainstem in this study. Mild conductive hearing loss found in some is probably related to cleft palate. Further evaluation of hearing pathways at higher levels is recommended.

Dental anomalies in patients with down syndrome

The purpose of the present study was to evaluate the incidence of dental anomalies in Brazilian patients with Down syndrome. A sample with 49 panoramic x-rays of syndromic patients aged 3 to 33 years (22 male and 27 female) was used. The characteristics of dental anomalies were observed in the panoramic radiographs in both the primary and permanent dentition, according to the ICD (International Classification of Diseases). The corresponding tables and percentile analysis were elaborated. There was a high incidence of syndromic patients with different types of anomalies, such as taurodontism (50%), proven anodontia (20.2%), suspected anodontia (10.7%), conic teeth (8.3%) and impacted teeth (5.9%). In conclusion, patients with Down syndrome presented a high incidence of dental anomalies and, in most cases, the same individual presented more than one dental anomaly.

Condições de saúde bucal de crianças e adolescentes portadores de síndrome de Down

Patients with Down syndrome have shown different conditions of oral health, and there is a low occurrence of dental caries and a higher susceptibility to periodontal diseases. Thus, this study aimed to evaluate the prevalence of dental caries and periodontal diseases in subjects with Down syndrome. The population was composed of 40 patients with the syndrome, aged 6 to 18 years, of both genders, and an equal number of non-syndromic patients. The periodontal conditions were evaluated by mean of the criteria of PSR and dental conditions were registered following indexes dmft and DMFT. It was found that in children with Down syndrome, the dmft index was 1.17 and DMFT 3.53 while the control group was verified dmft 1.97 and DMFT 2.77. The results of PSR evidenced that 32.5% of children with Down syndrome were periodontally healthy, 65% were gingivitis patients and 2.5% were periodontitis patients, while in the control group, 50% healthy and 50% were gingivitis patients. The results evidenced similar populations of cariogenic cocci between patients with Down syndrome and non-syndromic subjects. It was concluded that the incidence of caries in children with Down syndrome was higher in permanent teeth compared with the control group, while in the occurrence of deciduous teeth caries was slightly higher in the control group, so when children with Down syndrome are subjected to periodic examinations, they present themselves periodontally healthy.

Avaliação funcional pré e pós programa de exercício físico de pacientes em hemodialise

Model Study: An experimental study Introduction: Chronic Kidney Disease (CKD) refers to a syndromic diagnosis which leads to a progressive and irreversible loss of renal function. A hemodialysis patient may have limitations in functional capacity, pulmonary function and respiratory musclular strength impacting in quality of life. Objective: To evaluate the effects of an exercise program on pulmonary function, functional capacity, quality of life and pain in patients undergoing hemodialysis. Methodology: The study included 28 patients of both genders, women and men aged between 40 and 60 years undergoing dialysis at the Kidney Institute, Santa Casa de Misericordia in Presidente Prudente-SP. Primary outcomes included respiratory muscular strength measurements assessed by manovacuometry. The functional capacity was evaluated by a six minute walking test. A life quality questionnaire was applied to evaluate quality of life (SF36-KDQOL). Lung function was evaluated by spirometry. Pain was assessed by a visual analogue scale. The exercise program consisted of training 3 times a week for 40 minutes on hemodialysis during eight weeks. At the end of the program all patients were reassessed. Results: There was no significant difference in the values of FVC and FEV1 before and after the exercise program as well as the index Tiffenau. The value of post MIP was significantly higher than the value obtained in the pre program. For variable MEP no significant difference was found. Functional capacity evaluations showed that there were no significant differences (p> 0.05). The evaluation of quality of life, about the domains of specific areas of CKD showed statistical significance when comparing the list of symptoms and problems with overloading of renal disease and professional role. Indicators related to pain were significantly reduced after the program (P <0.05). Discussion: A chronic kidney patient faces complex situations of physical, social and financial aspects. Although no statistically significant results were found in all variables, the study corroborates to others found in the literature, which suggests that an exercise program can be positive for this population. Conclusion: Although lung capacity and functional capacity did not submit changes to the end of the study, reduced levels of pain, fatigue and dyspnea suggest improvement in functional performance after exercise programs.

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease

Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the HoltOram syndrome (hearthand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned approximate to 700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the HoltOram syndrome, and identified a patient with a homozygous mutation in an enhancer approximate to 90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the HoltOram syndrome.

Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and beta-Catenin

Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal beta-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal beta-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized beta-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized beta-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis. (Ant J Pathol 2012, 181:1017-1033; http://dx.doi.org/10.1016/j.ajpath.2012.05.026)