Tesis sobre el tema "Anomalie dentaire"

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The objective of this retrospective study was evaluate the prevalence of anomalies in tooth position (palatal ectopic eruption of the maxillary canine, dental transposition, distal angulation of mandibular second premolars, mesial angulation of mandibular permanent second molar and infra-occlusion of deciduous molars), number (supernumerary teeth) and size (microdontia) in patients with permanent tooth agenesis, by comparing them with the rates expected for the general population; in addition, the hypothesis was tested that patients with agenesis of permanent teeth have increased prevalence of enamel hypoplasia. To that end, the sample of this study consisted of 351 patients with agenesis of at least one permanent tooth, ranging between 8 and 30 years of age and with full clinical records. The sample was collected by examining orthodontic records belonging to the archives of a professional institution of specialization in Orthodontics, a dental radiology clinic and private orthodontic practices. Study materials included panoramic and periapical view radiographs, plaster cast models, intra- and extraoral photographs and filled-out medical records. First, the reproducibility of evaluations was analyzed through the rate of concordance using the Kappa test, at a 95% confidence interval. The Chi-square test was used to compare the prevalence of agenesis and anomalies in the sample to the expected rates according to scientific literature, considering a 5% level of significance. The study also analyzed the degree of the associations using the odds ratio and the respective 95% confidence interval. The prevalence of dental agenesis in the sample, excluding third molars, was 88.6%. Of the 351 patients, 128 (36.4%) had agenesis in the maxillary arch, 108 (30.8%) in the mandibular arch, and 115 (32.8%) in both arches. A total of 52.4% had agenesis in the maxillary left hemiarch, 55.0% in the maxillary right hemiarch, 48.7% in the mandibular left hemiarch and 47.3% in the mandibular right hemiarch. With regard to the associated anomalies evaluated, 28.5% microdontia, 28.2% had enamel hipoplasia, 7.4% had palatal ectopic eruption of the canine, 6.6% had distal angulation, 4.3% infra-occlusion, 3,9% transposition of canine/premolar, 3.7% supernumerary teeth, 3.7% medial angulation, 0,6% transposition of incisive/canine, and, when compared to the general population, they were 96.1 times more likely to feature mesial angulation of the mandibular second molar; 34.6 times more likely to have distal angulation; 15,9 times more likely to show transposition of canine/premolar; 14,3 times more likely to show transposition of incisive/canine; 9 times more likely to show hipoplasia; 8,1 times more likely to show microdontia of the lateral incisor; 5,2 times more likely to have palatal ectopic eruption of the canine; and with regard to infra-occlusion, there was a lower likelihood than the general population. From the obtained results, a strong association was observed between agenesis of permanent teeth with significant dental anomalies. It was detected that permanent tooth agenesis showed an increased prevalence of enamel hypoplasia, and that agenesis and other associated anomalies are genetically interlinked.
O objetivo deste estudo retrospectivo foi avaliar a prevalência de anomalias de posição (irrupção ectópica de canino superior para palatino, transposição dental, distoangulação de segundos pré-molares inferiores, mesioangulação de segundo molar inferior permanente e infraoclusão de molares decíduos), de número (supranumerários) e de tamanho (microdontias) em pacientes com agenesias de dentes permanentes, comparando-as com as prevalências esperadas para a população em geral, além de testar a hipótese de que pacientes com agenesia de dentes permanentes apresentem uma prevalência aumentada de hipoplasia de esmalte. Para tanto, a amostra deste estudo foi composta por 351 pacientes, com a presença de agenesia de no mínimo um dente permanente, na faixa etária entre 8 e 30 anos e com prontuários clínicos preenchidos. A amostra foi coletada a partir do exame das documentações ortodônticas pertencentes aos arquivos de uma escola de aperfeiçoamento profissional em Ortodontia, de uma clínica radiológica odontológica e de consultórios particulares de ortodontistas. O material de estudo englobou radiografias panorâmicas e periapicais, modelos de gesso, fotografias intra e extraorais e prontuários clínicos devidamente preenchidos. Inicialmente foi analisada a reprodutibilidade das avaliações pela porcentagem de concordância utilizando Kappa, com intervalo de confiança de 95%. O teste de qui-quadrado foi utilizado para comparar as prevalências de agenesias e anomalias na amostra com as prevalências esperadas segundo a literatura científica, considerando o nível de significância de 5%. Analisou-se, ainda, o grau das associações pela razão de chances ( odds ratio ) e o respectivo intervalo de confiança de 95%. A prevalência de agenesias dentais na amostra, excluindo os terceiros molares, foi de 88,6%. Dos 351 pacientes, 128 (36,4%) apresentavam agenesia no arco maxilar, 108 (30,8%) no mandibular e 115 (32,8%) nos dois arcos. Em relação ao hemiarco maxilar esquerdo, 52,4% apresentavam agenesia, no direito 55,0%, no mandibular esquerdo 48,7% e no direito 47,3%. Das anomalias associadas avaliadas, 28,5% microdontia, 28,2% hipoplasia de esmalte, 7,4% apresentavam irrupção ectópica de canino superior por palatino, 6,6% distoangulação, 3,9% transposição de canino/pré-molar superior, 4,3% infraoclusão, 3,7 supranumerário, 3,7% mesioangulação, 0,6% transposição de incisivo/canino inferior, e, quando comparadas com a população em geral, observou que 96,1 vezes mais chance de apresentar mesioangulação do segundo molar inferior; 34,6 vezes mais chance de apresentar distoangulação; 15,9 vezes mais chance de apresentar transposição canino/pré-molar superior; 14,3 vezes mais chance de apresentar transposição de incisivo/canino inferior; 9 vezes mais chance de hipoplasia; a microdontia do incisivo lateral apresentou 8,1 vezes mais chance; 5,2 vezes mais chance de apresentar irrupção ectópica do canino superior por palatino, e, em relação à infraoclusão, apresentando uma menor chance do que a população geral. A partir dos resultados obtidos, verificou-se uma forte associação entre a agenesia de dentes permanentes, correlacionando com outras anomalias dentais importantes. Foi constatado de que pacientes com agenesia de dentes permanentes apresentam uma prevalência aumentada de hipoplasia de esmalte e de que agenesias e outras anomalias associadas apresentam-se interligadas geneticamente entre si.

Les anomalies de croissance maxillo-faciale résultent de variations du processus normal de croissance. Après les caries, elles représentent les problèmes bucco-dentaires les plus fréquents chez les jeunes et peuvent entraîner des troubles fonctionnels (mastication, phonation, respiration), esthétiques et parfois psychologiques. Le traitement orthodontique vise à corriger les anomalies de croissance maxillo-faciale. L'objectif de cette thèse est de rechercher des facteurs de risque précoces d'anomalies de croissance maxillo-faciale et d'étudier le rôle des facteurs socio-économiques, culturels et géographiques de l'accès au traitement orthodontique en France. Les enfants de la cohorte EPIPAGE, qui avait inclus toutes les naissances survenues entre 22 et 32 semaines d'aménorrhée dans neuf régions françaises en 1997, ont été examinés à 5 ans. Nous avons étudié les relations entre les caractéristiques néonatales et la déformation du palais à 5 ans chez 1711 enfants. Le sexe masculin, le petit âge gestationnel, le petit poids pour l'âge gestationnel et peut-être l'intubation de longue durée sont identifiés comme des facteurs de risque de déformation du palais à 5 ans chez les grands prématurés ; de plus, les enfants avec des déficiences neuro-motrices semblent particulièrement à risque. La cohorte mère-enfant EDEN, a inclus des femmes enceintes en 2002-2003 et leur enfant à la naissance. Nous avons recherché les facteurs de risque précoces de l'occlusion postérieure inversée et de la béance antérieure chez 422 enfants de 3 ans. En plus d'une tétine encore utilisée à 3 ans et de la respiration buccale qui sont des facteurs connus, un nouveau facteur de risque d'occlusion postérieure inversée en denture temporaire est mis en évidence : la prématurité. Enfin, l'étude chez les 5988 enfants et les adolescents de l'enquête sur la santé et la consommation de soins en France réalisée par l'Insee en 2002-2003, enquête transversale sur échantillon représentatif de la population vivant en France, montre que 23% des 12-15 ans ont un traitement orthodontique. En plus du facteur économique, le moindre recours au traitement orthodontique est aussi lié à l'environnement social et culturel moins favorisé de l'enfant, à l'absence de couverture complémentaire et à l'habitation en zone rurale.En conclusion, pour mieux comprendre les inégalités dans le traitement orthodontique, il faudrait en évaluer les besoins en amont. Nous avons étudié des facteurs liés à la présence d'anomalies de croissance maxillo-faciale à des âges très jeunes afin de pouvoir identifier tôt des enfants à risque de ces anomalies. Il est nécessaire de vérifier leur évolution pour savoir si elles sont de réels marqueurs précoces de besoin en traitement orthodontique.

Les anomalies bucco-dentaires et crânio-faciales sont des manifestations phénotypiques des maladies rares. Ce doctorat combine les approches cliniques, précliniques et translationnelles en particulier par l’étude des modèles murins génétiquement modifiés reproduisant les maladies rares étudiées. Ce doctorat vise ainsi à identifier des gènes impliqués dans la morphogenèse et la signalisation inter-cellulaire en s’intéressant aux facteurs environnementaux et génétiques. Une étude détaille les effets d’un facteur d’environnement l’acide rétinoïque en excès sur du développement dentaire et la formation de l’émail. Les anomalies dentaires et de la formation de l'émail sont analysées dans des modèles murins, de maladies rares génétiques, inactivés pour Ltbp3 et Smoc2. Ces résultats permettent une meilleure compréhension du développement dentaire et crânio-facial, pourraient déboucher sur la mise au point et l’amélioration de traitements appropriés et de stratégies thérapeutiques applicables à la prise en charge de patients atteins de maladies rares. L’approche via les modèles murins des maladies rares est tout à fait pertinente pour suivre la régénération osseuse et les pathologies associées
The goal of this thesis is to investigate genetic and environmental factors, both initiating and influencing signaling centers that regulate tooth development and thus producing associated defects. Essentially, my research program utilizes patient-based rare disease phenotypes to create novel mouse models. This study also involved investigating the developmental effects of excess retinoic acid on enamel formation to gain understanding of the mechanisms by which environmental factors can alter enamel development. Other studies investigated enamel and dental anomalies in Ltbp3 and Smoc2 mutant mice. These results advance our understanding of tooth development, and may translate towards optimizing clinical diagnosis, and improving treatment strategies for several human rare diseases. An improved understanding of rare disease models and our testing of clinically relevant approaches using rodent models is a feasible approach to address bone degeneration problems

Les Amélogenèses imparfaites constituent un groupe d’altération de l’émail dentaire d’origine génétique. Cette pathologie peut exister de manière isolée ou associée à d’autres symptômes dans le cadre de syndromes. Certains gènes impliqués sont déjà connus, cependant de nouvelles mutations et de nouveaux gènes restent à identifier. L’étude de familles informatives dans le cadre de ce projet de recherche sur le massif crânio-facial et bucco-dentaire, associée à des stratégies d’identification génétique telles que la sélection de gènes candidats, les zones d’homozygotie, le séquençage haut débit, ont permis d’obtenir des résultats probants. Des investigations futures passant par l’augmentation des cohortes, le développement des outils de séquençage de nouvelle génération, l’étude des modèles cellulaires et animaux permettront d'améliorer la compréhension de l’amélogenèse
Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. This disease can exist in isolation or in association with other symptoms in the form of syndromes. Several genes involved in AI are already known, however mutations in these genes are not sufficient to explain all cases of AI. This suggests that mutations in yet unidentified genes underlie AI. The study of informative families included in this research project on cranio-facial and oro-dental anomalies, by using genetic strategies such as candidate gene mutational analysis,homozygosity mapping and next generation sequencing, allowed the discovery of novel genes and mutations in AI. Future investigations based on the recruitment of new families, the development of new next generation sequencing tools and the establishment of cellular and animal models will improve our understanding of amelogenesis

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2007.
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A finalidade desta pesquisa foi de avaliar a prevalência das agenesias dentárias em pacientes com idades de 9 a 16 anos, do município de Dourados, MS, por meio da análise dos prontuários clínicos do CROIF - Centro de Radiologia Oro Facial "Dr. Mike Bueno" e da Clínica de Ortodontia "Kary Sampaio Mei"; atendidos no período de 1999 a 2006. Especificamente o objetivo principal foi de verificar a relação das agenesias dentárias entre os gêneros feminino e masculino; estimar qual a freqüência do envolvimento dos elementos dentários neste tipo de anomalia e determinar a localização mais freqüente. Foram analisadas 1300 radiografias panorâmicas cujos resultados mostraram que existe uma maior prevalência desta anomalia no gênero feminino (55,9%) e que do total da amostra, 22,8% dos pacientes tinham agenesia dentária e 77,2% não apresentavam esta anomalia de desenvolvimento. O dente que apresenta maior freqüência deste tipo de anomalia dentária é o terceiro molar, o segundo mais prevalente em nossa amostra é o segundo pré-molar, principalmente os inferiores, em seguida o incisivo lateral superior; e por último dos mais prevalentes, o primeiro pré-molar superior; o único dente que não apresentou nenhuma ocorrência de agenesia é o primeiro molar. A localização mais freqüente neste tipo de anomalia dentária é na maxila, no quadrante direito, seguido do quadrante superior esquerdo. Na mandíbula temos que os resultados dos dois quadrantes são equivalentes e menores que na maxila. A análise estatística dos resultados usando o teste do 2 (Qui-Quadrado) de Pearson mostrou que não existe influência do gênero na ocorrência da agenesia dentária. A análise pelo teste T de Student, da amostra em relação ao tipo de dente, localização da agenesia dentária, mostrou que não existe diferença estatística em nenhuma das comparações executadas. _________________________________________________________________________________________ ABSTRACT
The purpose of this research was to evaluate the prevalence of the dental agenesies in patients with ages of 9 the 16 years, of the city of Dourados, MS, by means of the analysis of clinical handbooks of the CROIF - Clínica de Radiologia Crânio Facial "Dr. Mike Bueno" and of the Clínica de Ortodontia "Kary Sampaio Mei"; taken care of in the period between 1999 and 2006. Specifically, the main objective was to verify the relation of the dental agenesies between the sorts feminine and masculine; esteem which the frequency of the involvement of the dental elements in this type of anomaly and to determine the most frequent localization . 1300 panoramic xrays had been analyzed and had shown that a bigger prevalence of thi s anomaly in the feminine sort exists (55,9%) and that of the total of the sample, 22.8% of the patients had dental agenesy and 77.2% did not present this anomaly of development. The tooth that presents greater frequency of this type of dental anomaly is the third molar one, as more prevalent in our sample he is as the daily pay -molar one, mainly the inferiors, after that the superior lateral incisor; e finally of most prevalent, first the daily pay-molar superior; the only tooth that did not present no occurrence of agenesy is first the molar one. The localization most frequent in this type of dental anomaly is in the jaw, in the right quadrant, followed of the left superior quadrant. In the jaw we have that the results of the two quadrants are lesser equivalents and that in the jaw. The analysis statistics of the results using the test of 2 (Qui-Quadrado) of Pearson showed that influence of the sort in the occurrence of the dental agenesy does not exist. The analysis for test T of Student, of the sample in relation to the type of tooth, localization of the dental agenesy, showed that difference does not exist statistics in none of the executed comparisons.

Toutes altérations génétiques ou environnementales survenant lors du développement craniofacial et de l’odontogenèse peut aboutir à une fente orale et/ou à des anomalies dentaires. Un des syndromes les plus courants comprenant une fente orale est le syndrome de van der Woude (VWS) / des ptérygiums poplités (PPS) causé par des mutations du gène IRF6. Nous avons séquencé IRF6 dans 16 familles VWS et 2 familles PPS et analysé le phénotype dentaire des patients avec une mutation identifiée. Les individus atteints présentaient des fentes (76%), des dépressions de la lèvre inférieure (86%), des agénésies dentaires (68%) ainsi que des anomalies de morphologie dentaire (58%), telles que des dents fusionnées ou porteuses de cuspides supplémentaires, démontrant que la fréquence élevée des anomalies dentaires constatées chez les patients VWS/PPS avec une mutation IRF6 pourrait se révéler utile dans la pose du diagnostic, dans la mesure où les dépressions de la lèvre inférieure ne sont pas toujours présentes. Malgré le nombre considérable de gènes identifiés dans les fentes orales et/ou anomalies dentaires, la cause génétique de bon nombre de cas isolés reste sans réponse. Partir de patients syndromiques avec fente, porteurs d’anomalies chromosomiques, a permis la découverte de nouveaux gènes associés aux fentes : HDAC4, HIPK2, RBFOX1, SWSWAP et MMP17. En plus des mutations touchant la partie codante des gènes et des variants introniques prédisposants, l’altération d’éléments régulateurs distants peut aussi conduire à l’apparition de fentes, comme nous le montrons dans ce travail avec l’altération d’éléments régulateurs de SOX9. D’autre part, le tri minutieux de patients syndromiques basé sur un phénotypage précis et associé à des techniques de séquençage haut-débit peut conduire à l’identification de la cause génétique sous-jacente. En procédant ainsi, nous avons montré que des mutations récessives de FAM20A sont à l’origine du syndrome rein-dent (ERS). Les patients atteints présentent un phénotype oral pathognomonique caractérisé par une amélogénèse imparfaite, des retards d’éruption, des calcifications intra-pulpaires, des follicules dentaires surdéveloppés, une hyperplasie gingivale et une néphrocalcinose. Les mutations de FAM20A conduisent à une augmentation de chondroïtine sulfate et de la concentration de calcium extracellulaire ionisé, entraînant l’apparition de calcifications ectopiques. Notre travail montre qu’un phénotypage précis combiné à des méthodes d’investigations génétiques à haut-débit, contribue de manière significative à une meilleure compréhension des facteurs génétiques des fentes orales et/ou des anomalies dentaires
Any genetic or environmental disturbances during craniofacial development and odontogenesis can lead to orofacial clefts (OFC) and/or dental anomalies. One of the most common cleft syndrome is the Van der Woude / popliteal pterygium syndrome (VWS/PPS) caused by IRF6 mutations. We screened IRF6 in sixteen VWS and two PPS families and analyzed the dental phenotype of IRF6-mutated patients. Affected individuals had clefts (76%), lower lip pits (86%), dental agenesis (68%), and abnormal dental morphology (58%) such as fused teeth and additional cusps, demonstrating that the high frequency of dental anomalies in VWS/PPS patients mutated for IRF6 could be a useful clinical clue for correct diagnosis, as lips pits are not always present. Despite the large number of genes identified in oral cleft and/or dental anomalies, the genetic causes of many sporadic cases remain unknown. Starting from syndromic cleft patients presenting chromosomal abnormalities, new genes associated with oral cleft were discovered: HDAC4, HIPK2, RBFOX1, SWSWAP, and MMP17. In addition to protein coding mutations and predisposing intronic variants, alterations of long-range gene regulatory elements can also lead to OFC, illustrated in this work with the alteration of SOX9 regulatory elements. Careful stratification of syndromic patients based on a precise phenotype can lead to the identification of the underlying genetic causes, when combined with high-throughput sequencing. We identified FAM20A recessive mutations to be causative of the Enamel Renal Syndrome (ERS). Affected patients present a pathognomonic oral phenotype characterized by generalized hypoplastic enamel, delayed tooth eruption, pulp calcifications, hyperplastic dental follicles, gingival hyperplasia, and nephrocalcinosis. FAM20A mutations resulted in increased chondroitin sulfate and increased extracellular ionized calcium concentrations, eventually leading to ectopic calcification. Our work illustrates that precise phenotype combined with the power of high throughput genetic technologies contributes significantly to the understanding of the genetic factors underlying oral cleft and/or dental anomalies

La agenesia dental constituye la anomalía más común del desarrollo craneofacial, asociándose a maloclusiones y alteraciones funcionales. La hipodoncia puede ocurrir como una condición aislada (hipodoncia no sindrómica) o puede estar asociada a síndromes (hipodoncia sindromica), resaltando la heterogenicidad de esta condición. La alternativas terapéuticas se fundamentan en el cierre de espacios o en el aumento del mismo para la posterior colocación de prótesis sobre implante en la zona correspondiente. Cada una de las opciones ofrece ventajas e inconvenientes. Cada técnica puede llegar a excelentes resultados siempre que se establezca inicialmente un correcto diagnóstico, se cuente con un abordaje multidisciplinar y un plan de tratamiento preciso. El propósito de esta recopilación bibliográfica es presentar una breve revisión de literatura acerca de esta condición clínica la cual incluye: etiología, prevalencia, síndromes, anomalías dentales asociadas como su abordaje clínico interdisciplinar.
Dental agenesis is the most common anomaly of craneofacial development, frequently associated with malocclusion with functional consequences. Hypodoncia can either occurs as an isolated condition (non-syndromic hypodontia) or can be associated with syndrome (syndromic hypodontia), highlighting the heterogenecity of the condition. The therapeutic options are based on closing the space or increasing the distance to allow an implant over prosthesis in the area. Each of the options has its advantages and disadvantages. Each technique can achieve good results if there is a correct initial diagnosis and multidisciplinary treatment approach. The purpose of this report of literature about tooth agenesis, wich includes etiology, prevalence, associated syndromes and dental anomalies, as its interdisciplinary clinical approach.
Fil: Mas Fuchs, María Victoria. Universidad Nacional de Cuyo. Facultad de Odontología.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie
To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease

Orientador: Ricardo Della Coletta
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Fissuras do lábio e/ou palato (FL/P) representam a anomalia congênita mais comum em humanos. FL/P podem estar associadas a outras malformações, caracterizando uma síndrome, ou apresentar-se de forma isolada, recebendo a denominação não-sindrômica (FL/PNS). A etiologia das FL/PNS é complexa e envolve a participação de inúmeros genes, os quais estão sobre a influência de fatores ambientais. Alguns estudos demonstraram uma frequência elevada de anomalias dentais em pacientes com FL/PNS, sugerindo um defeito genético único para essas duas alterações. Os objetivos deste estudo foram: 1) verificar se polimorfismos nos genes responsáveis por síndromes que apresentam FL/P em seu espectro clínico, incluindo TP63, MID1, PVRL1, RUNX2 e TBX1, podem contribuir para a etiologia das FL/PNS, e 2) determinar a frequência de anomalias dentais em pacientes com FL/PNS. Sete regiões polimórficas foram genotipadas por PCR-RFLP (reação em cadeia da polimerase associada à análise de polimorfismo de fragmentos de restrição enzimática) em amostras de DNA provenientes de 367 pacientes afetados por FL/PNS (grupo experimental) e de 413 indivíduos clinicamente normais (grupo controle). Para determinar a frequência de anomalias dentais em pacientes com FL/PNS, 296 pacientes com idade entre 12 e 30 anos, sem história de extração dental e tratamento ortodôntico prévio e que apresentavam documentação radiográfica foram avaliados. Dos 7 prováveis polimorfismos, apenas 3 foram confirmados em nossa população. Após correção para múltiplas comparações pelo teste de Bonferroni, apenas o polimorfismo rs28649236 do gene TBX1 demonstrou diferença significante entre os grupos. O alelo G e os genótipos AG e GG ocorreram em uma frequência significantemente maior no grupo controle que no grupo experimental, e na presença do alelo G um efeito protetor para o desenvolvimento de FL/PNS foi observado (p=0,0002; OR: 0,41; IC 95%: 0,25-0,67). Anomalias dentais foram identificadas em 57,7% (n=296) dos pacientes com FL/PNS e pacientes com FL foram significantemente menos acometidos por anomalias dentais comparando-se com pacientes com FP ou FLP (p=0,004). Agenesia dental foi a mais frequentemente identificada entre os tipos de fissura, principalmente em pacientes com FLP e FP que em pacientes com FL (p=0,03). O presente estudo demonstrou que o polimorfismo rs28649236 do gene TBX1 apresenta um efeito protetor para o desenvolvimento de FL/PNS em uma população brasileira e que o risco de pacientes com FLP ou FP apresentar anomalias dentais é significantemente maior que o de pacientes com FL. Em adição, este estudo corrobora com evidências prévias que demonstraram a influência de genes responsáveis por síndromes contendo FL/P na etiopatogenia das FL/PNS.
Abstract: Cleft lip and/or cleft palate (CL/P) is the most common congenital anomaly in humans. CL/P may be associated with other malformations, featuring a syndrome, or present itself in an isolated form, denominated nonsyndromic (NSCL/P). NSCL/P etiology is complex and involves the participation of numerous genes, which are under the influence of environmental factors. Some recent studies have demonstrated a high frequency of dental anomalies in patients with NSCL/P, suggesting a common genetic defect for these two alterations. The objectives of this study were: 1) to verify whether polymorphic variants of genes responsible for syndromes that have CL/P in their clinical spectrum, including TP63, MID1, PVRL1, TBX1 and RUNX2, may contribute to the etiology of NSCL/P, and 2) to determine the frequency of dental anomalies in patients with NSCL/P. Seven polymorphic regions were genotyped by PCR-RFLP (restriction fragment length polymorphism-polymerase chain reaction) in DNA samples from 367 patients affected by NSCL/P (experimental group) and 413 clinically normal subjects (control group). To determine the frequency of dental anomalies in patients with NSCL/P, 296 patients aged between 12 and 30 years without history of tooth extraction and orthodontic treatment and with radiographic documentation were evaluated. Out of 7 probable polymorphisms, only 3 were confirmed in our population. After correction for multiple comparisons by Bonferroni test, only rs28649236 TBX1 polymorphism showed significant difference between groups. The allele G and the AG and GG genotypes occurred in a significantly higher frequency in controls than in the experimental group, and in the presence of the G allele a protective effect against NSCL/P was observed (p=0.0002; OR: 0.41; 95% CI: 0.25-0.67). Dental anomalies were identified in 57.7% (n= 296) of patients with NSCL/P and patients with CL were significantly less affected by dental anomalies compared with patients with CP or CLP (p=0.004). Dental agenesis was the most frequently identified among the cleft types, especially in patients with CLP and ICP than in patients with FL (p=0.03). The present study demonstrated that rs2864923 TBX1 polymorphism has a protective effect in NSCL/P development in a Brazilian population, and patients with CLP or CP are frequently more affected by dental anomalies than patients with CL. In addition, this study corroborates with previous evidences demonstrating the influence of genes related to syndromes containing CL/P on etiopathogenesis of the NSCL/P.
Doutorado
Patologia
Doutor em Estomatopatologia