La Déficience Intellectuelle liée au chromosome X (X-LID), anciennement appelée RMLX (retard mental lié au chromosome X) est une pathologie fréquente (3 % de la population) et handicapante. Cette déficience se manifeste par la réduction de la capacité à comprendre les informations nouvelles ou complexes, des difficultés d’acquisition de nouvelles compétences et l’échec dans la gestion de sa vie en toute autonomie ; celle-ci est souvent accompagnée par un dysmorphisme corporel. Cette pathologie s’installe dès l’enfance (avant l'âge de 18 ans) et a des répercussions sur le développement de l’individu (QI<70). La pathogénie de la déficience intellectuelle reste obscure et dans 50 % des cas, la cause n’est pas connue. Dix pour-cent (10 %) des cas de la déficience intellectuelle seraient liés à des gènes localisés sur le chromosome X, avec une mutation transmise par les mères et affectant principalement les garçons. Parmi les 931 gènes du chromosome X, seulement 114 gènes ont été identifiés comme gènes de déficience intellectuelle. Le dernier (le gène SSR4) fut caractérisé en mars 2014. À l’heure des technologies du séquençage de haut débit, le laboratoire de génétique moléculaire de l’hôpital Necker de Paris s'est doté d’une plateforme d’identification de mutation génétique humaine par séquençage à haut débit permettant le diagnostic des maladies rares. L’objectif de mon travail de thèse était d’appliquer l’approche du séquençage à très haut débit (technique SOLiD) dans l’identification de nouveaux gènes de la déficience intellectuelle liée au chromosome X chez des familles ayant des garçons atteints de déficience intellectuelle non-syndromique, d’identifier les mutations des gènes qui sont déjà connus et d’en discuter la corrélation génotype-phénotype. L’approche que j’ai utilisée dans cette étude est le diagnostic génétique par séquençage à haut débit de l’exome du chromosome X de vingt sujets appartenant à dix familles (X-LID) françaises. La procédure consiste à capturer l’exome du chromosome X des patients atteints, à l’enrichir par la technologie Rain-Dance, puis à le séquencer dans notre plateforme avec un séquenceur à haut débit de la technologie SOLiD5500 afin d’analyser les résultats et pour ne retenir que les nouvelles mutations et commenter leur pouvoir pathogène. Cette étude a mis en évidence de nouvelles mutations dans 21 gènes, dont neuf gènes ne sont pas encore décrits parmi les gènes X-LID et a révélé l’importance de l’hétérogénéité génétique tout en relevant la possibilité de l’effet des charges mutationnelles et le rôle gènes modificateurs. Certaines nouvelles mutations, nous les avons identifiées dans des gènes connus pour leur implication dans la déficience intellectuelle et les avons publiées durant les études doctorales. Pour confirmer la causalité des nouveaux gènes ayant muté chez les familles atteintes, des études fonctionnelles supplémentaires in vivo doivent être appliquées tout en suivant les publications sur le même sujet afin de comparer avec des cas similaires. / X linked Intellectual deficiency (X - LID); formerly X-LMR (X Linked Mental Retardation) is a common pathology (3 % of the population). Intellectual Deficiency (ID) is the most frequent cause of serious handicap in children and young adults. Defining features of ID include an overall intelligence quotient (IQ) of less than 70 together with associated functional deficits in adaptive behavior (such as daily living, social and communication skills), which manifest before18 years of age. ID pathogenesis remains obscure and 50% of cases have no known cause. Ten percent of the intellectual intellectual deficiency would be related to genes located on the X chromosome, and subsequently inherited by affected boys. Among the 931 genes of the X chromosome, only 114 genes have been identified as X-LID genes. The last (SSR4 gene) was characterized in March 2014. At the time of the Next Generation Sequencing (NGS), the laboratory of molecular genetics of Necker hospital in Paris is equipped with a platform for the identification of human genetic mutation by high-throughput sequencing for the diagnosis of rare diseases. The objective of my thesis work was to seek new genes for X linked intellectual deficiency in families with non-syndromes cognitive disorder affected boys and to identify mutations in the genes that are already known and to discuss the genotype, phenotype correlation. The approach that I have used in this study is genetic diagnosis by high-throughput sequencing of chromosome X exomes of 20 subjects belonging to ten X-LID French families. The procedure is to capture and enrich the exome of the X chromosome of patients, then to sequence it in our platform with a high throughput sequencer of SOLid technology then analyze the results and retain that new mutations to discuss their pathogenity. This study has highlighted new mutations in 21 genes, including nine that are not yet described among the X-LID genes. Some new mutations, we identified in genes known through their involvement in cognitive impairment were published during my doctoral studies. To confirm causality of new genes that were found mutated in families, additional studies in vivo must be applied while following the literature to make comparisons with similar cases.

As fissuras orais são as malformações craniofaciais mais freqüentes ao nascimento e apresentam incidências variáveis entre as diversas populações. Essas fissuras são subdivididas em dois grupos principais, as fissuras labiais com ou sem fissura de palato (FL&plusmn;P) e as fissuras palatinas (FP), consideradas entidades distintas do ponto de vista embriológico, epidemiológico e etiológico. Estas malformações podem ser classificadas em sindrômicas ou não sindrômicas (NS) a depender da existência de outras alterações clínicas associadas. Para as FL&plusmn;PNS e FPNS, o padrão de herança multifatorial e o modelo &ldquo;doenças comuns-variantes comuns&rdquo; foram propostos. Diversos estudos têm sido realizados na tentativa de se identificar os fatores genéticos de predisposição a estas malformações, particularmente para as FL&plusmn;PNS. Entre estes fatores, o IRF6, comprovadamente associado à síndrome de Van der Woude (SVW), é um gene candidato associado às fissuras NS. Em algumas situações, a SVW torna-se clinicamente indistinguível das fissuras não sindrômicas, o que pode dificultar o aconselhamento genético destas famílias afetadas por fissuras. A associação entre FL&plusmn;P e variantes comuns no IRF6 tem sido observada em vários estudos em diferentes populações, porém os resultados obtidos não explicam a alta herdabilidade das FL&plusmn;P. Frente a este quadro, foi proposto mais um modelo genético para as fissuras NS, o modelo de &ldquo;doenças comuns-variantes raras&rdquo;. Diante destas questões, o presente trabalho foi realizado para tentar avaliar o impacto fenotípico de variantes no IRF6 em famílias com fissuras NS, através da verificação da ocorrência de mutações patogênicas, do tipo perda de função no IRF6, causativas da SVW entre casos não sindrômicos e da identificação da associação de variantes do IRF6 raras e comuns à predisposição de fissuras NS em casos familiais. Para testarmos estas hipóteses, foi realizado o sequenciamento do IRF6 em 304 pacientes com fissuras orais, não relacionados entre si, e com história familiar positiva para fissuras. Os resultados foram comparados com controles da população brasileira e com bancos de dados internacionais. A avaliação dos resultados sugere uma freqüência de aproximadamente 1% de mutações patogênicas para SVW entre os casos não sindrômicos familiais. Foram também encontradas variantes novas raras, de significado clínico ainda desconhecido, em 3,3% dos casos e observamos um excesso de variantes na região 5\'UTR entre os fissurados sugerindo que estas tenham um efeito funcional na regulação do IRF6 e eventual envolvimento com a ocorrência das fissuras orais NS. Além disso, foram detectadas novas associações com fissuras NS entre as variantes comuns já conhecidas. Além da análise mutacional do IRF6 entre pacientes com FL&plusmn;P e FP, estudamos as FP isoladamente, com o objetivo de verificar a contribuição genética nas fissuras palatinas não sindrômicas, através de um estudo epidemiológico. Entende-se que estes estudos podem fornecer informações relevantes para o delineamento de estudos genéticos e para associações com possíveis fatores ambientais predisponentes à malformação. Entretanto, há um número limitado de estudos epidemiológicos sobre FP na literatura e em particular no Brasil, por isso, objetivamos estimar dados relacionados à consanguinidade, risco de recorrência e herdabilidade das FPNS a partir de uma amostra de 331 casos de FPNS na população brasileira. A frequência de casamentos consanguíneos foi semelhante à da população controle e os riscos de recorrência para irmãos dos probandos (&sim;1,5%) foi menor que o estimado na literatura mundial. Foi estimada uma herdabilidade de 95,81%, o que sugere grande atuação de componentes genéticos na etiologia das FP nesta população. Estes resultados sugerem a validade de maiores estudos na identificação dos fatores genéticos para as FPNS e demonstram a importância de se estudar o efeito dos diversos tipos de variantes no IRF6 em pacientes com fissuras orais / Oral clefts are the most common congenital craniofacial malformation and have different incidences rates among different populations. These oral clefts are subdivided into two main groups, cleft lip with or without palate cleft (CL&plusmn;P) and cleft palate (CP), regarded as separate entities from embryological, epidemiological and etiological perspectives.These malformations are classified into syndromic or nonsyndromic (NS) depending on the existence of other associated clinical changes. For NSCL&plusmn;P and NSCP, the multifactorial inheritance pattern and the &ldquo;common disease-common variants&rdquo; model have been proposed. Several studies have been conducted in an attempt to identify the genetic factors predisposing to these malformations, particularly for NSCL&plusmn;P. Among these factors, the IRF6, demonstrably associated with Van der Woude (SVW) syndrome, is a candidate gene associated to NS clefts. In some situations, SVW becomes clinically indistinguishable from nonsyndromic clefts, which can hamper genetic counseling of cleft affected families. The association between CL&plusmn;P and IRF6 common variants has been observed in several studies in different populations, but the results do not explain the high heritability of CL&plusmn;P. Thus, an additional Another genetic model was proposed for NS clefts, the &ldquo;common disease-rare variant&rdquo; model. Given these issues, the present study tries to assess the phenotypic impact of variants in IRF6 in families with NS clefts by verifying the occurrence of loss-of-function mutations in IRF6, causative of SVW among nonsyndromic cases and also by the indentification of rare and common IRF6 variants predisposing NS clefts in familial cases. To test these hypotheses, the sequencing of IRF6 was performed for 304 unrelated cases of oral clets, with positive family history of clefts. results were compared with Brazilian population controls as well as international databases. The results suggests a prevalence of 1% for pathogenic mutations of SVW among nonsyndromic familial cases. It was also observed new rare variants of still unknown clinical significance in 3.3% of cases and it was observed an excess of variants in the 5\'UTR region among the cleft cases suggesting that they have a functional effect on the regulation of IRF6. Furthermore, new associations with NS clefts were detected among common variants already known. Besides mutational analysis of IRF6 for patients with CL&plusmn;P and CP, the CP cases were studied, in order to verify the genetic contribution in nonsyndromic CP, by means of an epidemiological study. It is understood that these studies may provide relevant information for genetic study guidelines and for possible associations with environmental factors predisposing the malformation. However, there is a limited number of epidemiological studies on CP in the literature and mainly in Brazil, so this study also aims to estimate data related to inbreeding, recurrence risk and heritability of NSCP from a sample of 331 cases from a Brazilian population. The frequency of consanguineous marriages was similar to the control frequency and recurrence risks for siblings of probands (about 1.5%) was lower than estimated in the literature. A heritability of 95.81% was estimated, suggesting a high genetic component interaction in the etiology of CP in this population. Finally these results indicate the relevance of further studies on the identification of genetic factors for NSCP and demonstrate the importance of studying the effect of different types of variants in IRF6 in patients with oral clefts

As fissuras orais são as malformações craniofaciais mais freqüentes ao nascimento e apresentam incidências variáveis entre as diversas populações. Essas fissuras são subdivididas em dois grupos principais, as fissuras labiais com ou sem fissura de palato (FL&plusmn;P) e as fissuras palatinas (FP), consideradas entidades distintas do ponto de vista embriológico, epidemiológico e etiológico. Estas malformações podem ser classificadas em sindrômicas ou não sindrômicas (NS) a depender da existência de outras alterações clínicas associadas. Para as FL&plusmn;PNS e FPNS, o padrão de herança multifatorial e o modelo &ldquo;doenças comuns-variantes comuns&rdquo; foram propostos. Diversos estudos têm sido realizados na tentativa de se identificar os fatores genéticos de predisposição a estas malformações, particularmente para as FL&plusmn;PNS. Entre estes fatores, o IRF6, comprovadamente associado à síndrome de Van der Woude (SVW), é um gene candidato associado às fissuras NS. Em algumas situações, a SVW torna-se clinicamente indistinguível das fissuras não sindrômicas, o que pode dificultar o aconselhamento genético destas famílias afetadas por fissuras. A associação entre FL&plusmn;P e variantes comuns no IRF6 tem sido observada em vários estudos em diferentes populações, porém os resultados obtidos não explicam a alta herdabilidade das FL&plusmn;P. Frente a este quadro, foi proposto mais um modelo genético para as fissuras NS, o modelo de &ldquo;doenças comuns-variantes raras&rdquo;. Diante destas questões, o presente trabalho foi realizado para tentar avaliar o impacto fenotípico de variantes no IRF6 em famílias com fissuras NS, através da verificação da ocorrência de mutações patogênicas, do tipo perda de função no IRF6, causativas da SVW entre casos não sindrômicos e da identificação da associação de variantes do IRF6 raras e comuns à predisposição de fissuras NS em casos familiais. Para testarmos estas hipóteses, foi realizado o sequenciamento do IRF6 em 304 pacientes com fissuras orais, não relacionados entre si, e com história familiar positiva para fissuras. Os resultados foram comparados com controles da população brasileira e com bancos de dados internacionais. A avaliação dos resultados sugere uma freqüência de aproximadamente 1% de mutações patogênicas para SVW entre os casos não sindrômicos familiais. Foram também encontradas variantes novas raras, de significado clínico ainda desconhecido, em 3,3% dos casos e observamos um excesso de variantes na região 5\'UTR entre os fissurados sugerindo que estas tenham um efeito funcional na regulação do IRF6 e eventual envolvimento com a ocorrência das fissuras orais NS. Além disso, foram detectadas novas associações com fissuras NS entre as variantes comuns já conhecidas. Além da análise mutacional do IRF6 entre pacientes com FL&plusmn;P e FP, estudamos as FP isoladamente, com o objetivo de verificar a contribuição genética nas fissuras palatinas não sindrômicas, através de um estudo epidemiológico. Entende-se que estes estudos podem fornecer informações relevantes para o delineamento de estudos genéticos e para associações com possíveis fatores ambientais predisponentes à malformação. Entretanto, há um número limitado de estudos epidemiológicos sobre FP na literatura e em particular no Brasil, por isso, objetivamos estimar dados relacionados à consanguinidade, risco de recorrência e herdabilidade das FPNS a partir de uma amostra de 331 casos de FPNS na população brasileira. A frequência de casamentos consanguíneos foi semelhante à da população controle e os riscos de recorrência para irmãos dos probandos (&sim;1,5%) foi menor que o estimado na literatura mundial. Foi estimada uma herdabilidade de 95,81%, o que sugere grande atuação de componentes genéticos na etiologia das FP nesta população. Estes resultados sugerem a validade de maiores estudos na identificação dos fatores genéticos para as FPNS e demonstram a importância de se estudar o efeito dos diversos tipos de variantes no IRF6 em pacientes com fissuras orais / Oral clefts are the most common congenital craniofacial malformation and have different incidences rates among different populations. These oral clefts are subdivided into two main groups, cleft lip with or without palate cleft (CL&plusmn;P) and cleft palate (CP), regarded as separate entities from embryological, epidemiological and etiological perspectives.These malformations are classified into syndromic or nonsyndromic (NS) depending on the existence of other associated clinical changes. For NSCL&plusmn;P and NSCP, the multifactorial inheritance pattern and the &ldquo;common disease-common variants&rdquo; model have been proposed. Several studies have been conducted in an attempt to identify the genetic factors predisposing to these malformations, particularly for NSCL&plusmn;P. Among these factors, the IRF6, demonstrably associated with Van der Woude (SVW) syndrome, is a candidate gene associated to NS clefts. In some situations, SVW becomes clinically indistinguishable from nonsyndromic clefts, which can hamper genetic counseling of cleft affected families. The association between CL&plusmn;P and IRF6 common variants has been observed in several studies in different populations, but the results do not explain the high heritability of CL&plusmn;P. Thus, an additional Another genetic model was proposed for NS clefts, the &ldquo;common disease-rare variant&rdquo; model. Given these issues, the present study tries to assess the phenotypic impact of variants in IRF6 in families with NS clefts by verifying the occurrence of loss-of-function mutations in IRF6, causative of SVW among nonsyndromic cases and also by the indentification of rare and common IRF6 variants predisposing NS clefts in familial cases. To test these hypotheses, the sequencing of IRF6 was performed for 304 unrelated cases of oral clets, with positive family history of clefts. results were compared with Brazilian population controls as well as international databases. The results suggests a prevalence of 1% for pathogenic mutations of SVW among nonsyndromic familial cases. It was also observed new rare variants of still unknown clinical significance in 3.3% of cases and it was observed an excess of variants in the 5\'UTR region among the cleft cases suggesting that they have a functional effect on the regulation of IRF6. Furthermore, new associations with NS clefts were detected among common variants already known. Besides mutational analysis of IRF6 for patients with CL&plusmn;P and CP, the CP cases were studied, in order to verify the genetic contribution in nonsyndromic CP, by means of an epidemiological study. It is understood that these studies may provide relevant information for genetic study guidelines and for possible associations with environmental factors predisposing the malformation. However, there is a limited number of epidemiological studies on CP in the literature and mainly in Brazil, so this study also aims to estimate data related to inbreeding, recurrence risk and heritability of NSCP from a sample of 331 cases from a Brazilian population. The frequency of consanguineous marriages was similar to the control frequency and recurrence risks for siblings of probands (about 1.5%) was lower than estimated in the literature. A heritability of 95.81% was estimated, suggesting a high genetic component interaction in the etiology of CP in this population. Finally these results indicate the relevance of further studies on the identification of genetic factors for NSCP and demonstrate the importance of studying the effect of different types of variants in IRF6 in patients with oral clefts

Foodborne illnesses continue to have a negative impact on the nation's health, accounting annually for an estimated 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths in the United States. Syndromic surveillance systems that analyze pre-diagnostic data, such as pharmaceutical sales data are being used to monitor diarrheal disease. The purpose of this study is to evaluate the usefulness of a poison control center (PCC) data collection and triage system for early detection of increases in foodborne illnesses.Data on calls to the Arizona Poison and Drug Information Center (APDIC) reporting suspected foodborne illnesses, and Pima County Health Department (PCHD) enteric illness reports were obtained for July 1, 2002 - June 30, 2007. Prediction algorithms were constructed using the first two and a half years, and validated in the remaining two and a half years. Multiple outcomes were assessed using unadjusted and adjusted raw counts, five and seven day moving averages, and exponentially weighted moving averages. Sensitivity analyses were conducted to evaluate model performance. Increases in PCHD laboratory reports of enteric illnesses were used as a proxy measure for foodborne disease outbreaks.Over the five year study period there were 1,094 APDIC calls reporting suspected foodborne illnesses, and 2,433 PCHD enteric illness cases. Seventy-five percent of cases were reported to PCHD within 23 days of symptom onset. In contrast, 62% of callers contacted APDIC within 24 hours of symptom onset. Forty percent of PCHD cases were missing symptom onset dates, which necessitated constructing and validating predictive algorithms using only those PCHD cases with known symptom onset dates.None of the prediction models performed at sensitivity levels considered acceptable by public health department standards. However, it is possible that a temporal relationship actually exists, but data quality (lack of outbreak dates, and missing symptom onset dates) may have prevented its detection. The study suggests that current surveillance by PCCs is insufficient as a univariate model for syndromic surveillance of diarrheal illness because of low caller volume reporting suspected foodborne illnesses; this can be improved. Methods were discussed to utilize PCCs for active surveillance of foodborne illnesses that are of public health significance.

La surveillance syndromique est un concept récent en épidémiologie. Fondée sur le suivi automatisé d’indicateurs de santé non spécifiques, cette nouvelle approche offre des perspectives intéressantes pour la détection de phénomènes pathologiques émergents. Nous nous sommes basés sur les données actuellement collectées en France sur la mortalité bovine pour évaluer la faisabilité et la pertinence d’un système de surveillance syndromique basé sur cet indicateur. Nous avons d’abord modélisé le niveau de référence de la mortalité bovine en France puis proposé des méthodes pour identifier et quantifier d’éventuels excès de mortalité. Nous avons d’abord analysé des données réelles pour estimer rétrospectivement les conséquences sur la mortalité de l’épizootie de fièvre catarrhale ovine qui a touché le cheptel bovin français en 2007 et 2008. Nous avons ensuite proposé une méthode visant à identifier des regroupements d’unités spatiales présentant des augmentations inhabituelles de mortalité, et évalué ses performances pour détecter des foyers d’une maladie infectieuse dont nous avons simulé la propagation dans le cheptel bovin. Sur la base de ces travaux, nous discutons finalement de l’intérêt pour la protection de la santé animale d’un système de surveillance non spécifique basé sur la mortalité, et émettons des propositions pour la mise en place opérationnelle d’un tel système. / Syndromic surveillance is a recent concept in epidemiology. Based on automated monitoringof non-specific health indicators, this new approach offers interesting prospects for the detection of various health events. We analyzed data on cattle mortality routinely collected inFrance to assess the feasibility and relevance of a syndromic surveillance system based on this indicator. We modeled the baseline of cattle mortality in France and proposed methods to identify and quantify excess mortality. First we analyzed real data to retrospectively estimate the effects on mortality of the bluetongue outbreak which affected the French cattle in 2007 and 2008. We then proposed a method to detect unusual increases mortality, and evaluated its performance for the detection of outbreaks of an infectious disease of which we simulated the spread in the cattle population. We finally discuss the interest of a surveillance system based on non-specific mortality for the protection of animal health, and make proposals for the operational implementation of such a system.

Objetivos: estabelecer o diagnóstico de uma amostra de indivíduos com deficiência auditiva (DA) e comprometimento de outras estruturas anatômicas e/ou sistemas fisiológicos, cadastrados no CEDALVI/HRAC-USP-Bauru; verificar possíveis fatores etiológicos envolvidos e investigar possível correlação do tipo de DA com as diferentes síndromes encontradas. Local: Serviço de Genética Clínica do CEDALVI/HRAC-USP, Bauru-SP. Participantes: 93 indivíduos com DA e comprometimento de outras estruturas anatômicas e/ou sistemas fisiológicos. Intervenções: Avaliação genética-clínica; estudo citogenético; avaliações radiológica, oftalmológica, otorrinolaringológica, audiológica e outras. Resultados: Dos 93 indivíduos, 51 eram do sexo masculino e 42, do feminino. Recorrência familial foi observada em 31 casos e, consangüinidade parental em 8. Na amostra, 25 síndromes gênicas conhecidas, 5 síndromes cromossômicas, 5 quadros de etiologia ambiental e 2 quadros de etiologia heterogênea foram estabelecidos em 87 indivíduos. Em 1 caso, não foi possível definir entre 2 condições gênicas e em 5, não foi possível se chegar a um diagnóstico. Conclusões: a casuística se compôs de síndromes etiologicamente heterogêneas, com maior freqüência de etiologia genética; o tipo de DA nas síndromes gênicas foi condizente com o quadro diagnosticado; 3 indivíduos apresentaram síndromes ambientais clássicas, com diferentes tipos de DA; 2 indivíduos apresentaram quadro clínico, possivelmente decorrente de efeito teratogênico; implicação direta de fatores de risco para DA, na etiologia dessa, nos indivíduos com síndromes gênicas conhecidas sem DA; 1 caso, possivelmente, representa uma síndrome nova de padrão único, de etiologia desconhecida; o aconselhamento genético está na dependência da fase em que se encontra o processo de delineamento das diferentes condições estabelecidas. / Objectives: The purposes of this study were to establish the diagnostic of the individuals with hearing loss and presenting other additional anatomic structures and/or physiologic systems involvement, recorded in the CEDALVI/HRAC-USP-Bauru; to verify possible etiologic factors involved and to investigate a possible correlation of the hearing loss type with the different diagnosis syndromes. Setting: Clinical genetic service of the CEDALVI/HRAC-USP, Bauru- P. Participants: The sample was comprised of 93 individuals with hearing loss and involvement of other anatomic structures and/or physiologic systems. Interventions: Clinical genetic evaluation; cytogenetic study; radiological, ophtalmological, othorinolaryngological, audiologycal evaluation, etc. Results: From the total of the sample, 51 were male and 42 were female. Familial recurrence was observed in 31 cases and parental consanguinity in 8. In the present sample, 25 known genic syndromes, 5 chromosomal syndromes, 5 environmental conditions, and 2 heterogeneous conditions were established in 87 individuals. The diagnosis was not established in 5 individuals and in 1 case it was not possible to define between 2 genic conditions. Conclusions: The casuistic was composed of etiologically heterogeneous syndromes with greater frequency of genetic etiology; the type of hearing loss in the genic syndromes was concordant with the diagnosed condition; 3 individuals presented classic environmental syndromes with different types of hearing loss; 2 individuals presented clinical picture, possibly due to teratogenic effect; hearing impairment related to risk factors of the hearing loss in the individuals with known genic syndromes without hearing loss; probable a new unique-pattern syndrome, of unknown etiology in 1 case; the genetic counseling will depend on the step of delineation process of the different diagnosed condition.

Um dos grupos de doenças mais importante que acomete o desenvolvimento da caixa craniana humana é o das craniossinostoses, caracterizado pelo fechamento prematuro de uma ou mais suturas cranianas. Entre as formas mendelianas das craniossinostoses sindrômicas, mutações dominantes em FGFR2 são uma das causas mais frequentes e estão associadas às síndromes de Apert, de Crouzon e de Pfeiffer. A sinalização intracelular subseqüente à ativação de FGFR2, tanto selvagem quanto mutante, é bastante intrincada e pode sofrer inúmeras bifurcações. As porções iniciais destas vias, imediatamente subsequentes à ativação do receptor, são relativamente bem compreendidas. Grande parte, porém, do controle dessas vias, principalmente no que tange a regulação transcricional e sua associação com alterações em comportamentos celulares, não é entendido. Assim sendo, os objetivos gerais deste trabalho foram: 1) estudar o potencial de diferenciação e o perfil diferencial de transcrição gênica de culturas primárias de células fibroblastóides isoladas a partir do periósteo das suturas coronais de pacientes acometidos por síndrome de Apert (heterozigotos para a mutação de ganho de função p.Ser252Trp em FGFR2, a mutação mais comum em pacientes com esta síndrome) e 2) estudar o potencial de diferenciação osteogênico e o perfil transcricional respectivamente de células mesenquimais e de tecido provenientes de sutura coronal de um modelo murino para Síndromes de Crouzon/Pfeiffer (heterozigotos para a mutação p.Cys342Tyr em Fgfr2, a mutação mais comum associada a estas síndromes). Certificamo-nos da expressão gênica e proteica de FGFR2 nas células fibroblastóides humanas e de Fgfr2 nas células mesenquimais murinas. Em seguida, testamos o potencial osteogênico (in vitro e in vivo ) e adipogênico (in vitro ) das células de pacientes com Síndrome de Apert, comparadas a células do mesmo tecido mas de indivíduos sem esta mutação e o potencial osteogênico (in vitro ) das células mesenquimais de camundongos portadores da mutação p.Cys342Tyr em Fgfr2, comparadas a células também das suturas coronais mas de animais selvagens. O potencial de diferenciação das células mutantes, nos dois grupos de experimentos, foi muito aumentado em relação ao potencial das células livres destas mutações. Conduzimos experimentos de microarrays de expressão gênica (sistema CodeLink) com 7 amostras de culturas primárias de células de pacientes com S. de Apert e as comparamos com 7 amostras de culturas primárias controles. Identificamos 263 genes com valores de expressão estatisticamente diferentes (SNR &#8805; |0.4|, P &#8804; 0,05) nas amostras de pacientes com S. de Apert quando comparadas às controles (118 superexpressos, 145 subexpressos). Categorias funcionais enriquecidas foram regulação de proliferação celular, metabolismo de nucleotídeos, regulação de expressão gênica, adesão celular, organização de matriz extracelular e cascata PI3K MAPK. Para a validação deste experimento constatamos superexpressão, por PCR em tempo real, de genes identificados como superexpressos na assinatura de expressão associada às células mutadas, além de verificarmos o mesmo comportamento destes genes em células controles tratadas com FGF2 exógeno para superativação do receptor. Os experimentos de expressão gênica com os tecidos de suturas coronais do modelo murino foram feitos com 15 amostras de tecidos de animais mutantes em 3 grupos de 5 e comparadas a amostras de mesmo tecido de animais selvagens agrupadas da mesma forma. Identificamos três listas de genes diferencialmente expressos: a primeira contendo 188 transcritos (P &#8804;0,05, FC &#8805; 1,5,sendo 91 superexpressos e 97 subexpressos), e as outras duas filtradas previamente para coeficiente de variação &lt; 50% dentro de cada grupo, contendo 488 transcritos (P &#8804;0,05, FC &#8805; 1,2, sendo 183 superexpressos e 305 subexpressos) e 31 transcritos (P &#8804;0,05, FC &#8805; 1,5, sendo 11 superexpressos e 20 subexpressos). Categorias funcionais mais enriquecidas foram crescimento, proliferação e ciclo celular, diferenciação celular, sinalização célula-célula, resposta imune mediada por células e sinalização por receptor Wnt. Estes resultados nos permitiram: a) demonstrar que células fibroblastóides de periósteo craniano de paciente portadores de S. de Apert (mutação p.Ser252Trp em FGFR2) e células mesenquimais do modelo murino para S. de Crouzon e Pfeiffer, portador da mutação p.Cys342Tyr em Fgfr2, apresentam potencial osteogênico aumentado, agregando evidências que sugerem que esta alteração de comportamento celular tem função fundamental no desencadeamento das craniossinostoses nestas síndromes; b) revelar assinaturas de expressão gênicas associadas a estas mutações nas condições estudadas, que podem reger este comportamento celular anormal; c) identificar um novo grupo de genes associados à patofisiologia da Síndrome de Apert ou às características fenotípicas do modelo murino investigado, podendo também ser genes candidatos a outras craniossinostoses de causa desconhecida. / Craniosynostosis is one of the most important group of diseases linked to the development of the human skull and is characterized by the premature fusion of one or more cranial sutures. Dominant mutations in FGFR2 are frequent molecular causes amongst the mendelian inherited forms of the syndromic craniosynostosis and are associated to Apert, Crouzon and Pfeiffer syndromes. The intracellular signaling pathways following the activation of wild type or mutant FGFR2 are very complex due to several possible bifurcations. The initial portions of these pathways, immediately following the receptor activation, are relatively well delineated. However the great majority of the events related to the control of these pathways is still not well understood, mainly concerning its transcriptional regulation and its association to other cell behavior anomalies. Therefore the key scopes of this work were: 1) to study the differentiation potential and the differential gene expression profile of primary fibroblastoid cell cultures isolated from the periosteum of the coronal sutures of Apert Syndrome patients (heterozygous for the mutation p.Ser252Trp in FGFR2, the most common cause of the Apert Syndrome condition) and 2) to study the osteogenic differentiation potential and the transcriptional profile of mesenchymal cells and tissue isolated from the coronal sutures of a mouse model for the Crouzon and Pfeiffer Syndromes (heterozygous for the p.Cys342Tyr mutation in Fgfr2, the mutation most commonly associated to these syndromes). We assured the FGFR2 /FGFR2 gene and the protein expression in human fibroblastoid cells and Fgfr2 /Fgfr2 expression in the mesenchymal murine cells. We tested the (in vitro and in vivo ) osteogenic and the (in vitro ) adipogenic potentials of the Apert Syndrome patients cells compared to cells from the same tissue but from subjects without this mutation and the (in vitro ) osteogenic potential of mesenchymal cells from mice bearing the p.Cys342Tyr mutation in Fgfr2 compared to coronal suture cells but from wild type mice. On both experiments the differentiation potential of the mutant cells were very increased when compared to the potential of the wild type cells. We conducted gene expression microarray experiments (CodeLink system) using 7 samples from primary cultures of cells from Apert Syndrome patients compared to 7 samples from primary control cultures. We identified 263 genes with significantly different expression (SNR &#8805; |0.4|, P &#8804; 0,05) associated to the Apert Syndrome profile (118 upregulated, 145 downregulated). Enriched functional cathegories were regulation of cell proliferation, nucleotide metabolism, gene expression regulation, cell adhesion, extracellular matrix organization and PI3K MAPK cascades. In order to validate this gene expression signature we confirmed through Real-Time PCR the upregulation of genes identified as upregulated in the Apert cell profile in samples from the microarray experiment and in control cells treated with exogenous overactivate the receptor. The gene expression experiments with the coronal suture tissues from the mouse model were performed with 15 samples of mutant animal tissue in 3 groups of 5 and compared to samples from the same tissue of wild type animals, with identical grouping. We identified three sets of differentially expressed genes: the first set containing 188 transcripts (P &#8804;0,05, FC &#8805; 1,5, 91 upregulated e 97 downregulated), and the other two filtered for coeficient of variation &lt; 50% in each group, containing 488 transcripts (P &#8804;0,05, FC &#8805; 1,2, sendo 183 upregulated and 305downregulated) e 31 transcripts (P &#8804;0,05, FC &#8805; 1,5, 11 upregulated and 20 downregulated). The most enriched functional categories were growth, proliferation and cell cycle, cell differentiation, cell-to-cell signaling, cell mediated immune response and Wnt receptor signaling. These results allowed us: a) to demonstrate that fibroblastoid cells from coronal periosteum PF Apert Syndrome patients (p.Ser252Trp mutation in FGFR2) and mesenchymal cells from the coronal tissue of the mouse model for Crouzon and Pfeiffer syndromes (bearing the p.Cys342Tyr in Fgfr2) have enhanced osteogenic potential, summoning evidences suggesting that this cell behavior alteration have a fundamental role to the craniosynostotic process in these syndromes; b) to unravel gene expression signatures linked to these mutations in the studied conditions, that could orchestrate this abnormal cell behavior; c) to identify a ser of genes associated to the pathophysiology of Apert Syndrome and to the phenotypic characteristics of the animal model investigated, which might be candidate genes to other craniosynostosis of unknown cause.

Les maladies infectieuses demeurent l'une des causes majeures de décès dans le monde. Au Gabon, on estime que plus de la moitié des données disponibles ne sont pas collectées, et que plus de la moitié des données potentiellement collectées ne sont pas transmises au niveau central expliquant ainsi la lenteur à la réactivité du système de santé. Un réseau de surveillance syndromique des maladies infectieuses à potentiel épidémique (SuSyMIPE) a pu être mis en place dans quatre sites (Gamba, Koulamoutou, Libreville et Oyem) sentinelles. Pour chaque syndrome, un groupe de maladies était évoqué. Les notifications journalières de cas codifiées par "Short Message Service" (SMS) étaient transmis en fin d'après-midi. De janvier et octobre 2016, 5348 cas suspects des syndromes surveillés ont été enregistré, 28,1% (n = 1502) de Koulamoutou 24,5% (n = 1310) de Libreville, 24% (n = 1284) Gamba et 23,4% (n = 1252) d' Oyem. 71,3% (n = 3816) des cas étaient des fièvres, 19,7% (n = 1053) des syndromes respiratoires et les cas des syndromes diarrhéiques représentaient 9% (n = 479). Ce réseau nous a permis de détecter assez précocement l'épidémie de rougeole dans deux chefs-lieux de provinces (Libreville et Oyem) en 2016. Au total, entre les semaines 13 et 19, 79 cas suspects ont été notifiés, principalement 82,3% (n = 65) à Oyem et 17,7% (n = 14) à Libreville. Le sex-ratio M / F était de 0,88 (37/42), et l'âge moyen était de 49,37 ± 72.82 mois. Cependant, 53,3% (n = 16/30) seulement ont été confirmés pour la rougeole. La mise en place de ce système de surveillance syndromique nous a permis de répondre de manière plus rapide et plus efficiente aux épisodes de rougeole qui se sont manifestés. / Infectious diseases remain one of the leading causes of death in the world. In Gabon, it is estimated that more than half of the available data are not collected, and that more than half of the potentially collected data are not transmitted centrally, thus explaining the slowness of the responsiveness of the health system. A syndromic surveillance network for infectious diseases with epidemic potential (SuSyMIPE) has been set up in four sites (Gamba, Koulamoutou, Libreville and Oyem) sentinels. For each syndrome, a group of diseases was mentioned. The daily notifications of cases coded by "Short Message Service" (SMS) were transmitted at the end of the afternoon. From January to October 2016, 5348 cases of suspected syndromes were recorded, 28.1% (n = 1502) of Koulamoutou 24.5% (n = 1310) of Libreville, 24% (n = 1284) Gamba and 23, 4% (n = 1252) from Oyem. 71.3% (n = 3816) of the cases were fevers, 19.7% (n = 1053) of the respiratory syndromes and the cases of diarrheal syndromes accounted for 9% (n = 479). This network enabled us to detect the measles epidemic early in two provincial capitals (Libreville and Oyem) in 2016. In total, between weeks 13 and 19, 79 suspected cases were reported, mainly 82.3. % (n = 65) in Oyem and 17.7% (n = 14) in Libreville. The sex ratio M / F was 0.88 (37/42), and the mean age was 49.37 ± 72.82 months. However, only 53.3% (n = 16/30) were confirmed for measles. The implementation of this syndromic surveillance system allowed us to respond more quickly and more efficiently to the measles episodes that occurred.

INTRODUÇÃO: A doença diarréica aguda é ainda importante causa de morbidade no mundo. Sua elevada incidência e a aceitação de sua ocorrência como fato "normal" impõem desafios para seu registro e implantação de seus sistemas de vigilância. OBJETIVOS: Conhecer as características epidemiológicas da diarréia aguda e avaliar a capacidade de detecção de surtos pelo Programa de Monitorização da Doença Diarréica Aguda, no município de Avaré. MÉTODOS: De 27 de fevereiro a 16 de julho 2005, realizou-se estudo prospectivo da diarréia em unidade sentinela do programa. Os surtos identificados foram investigados por estudos descritivos e analíticos. Amostras de fezes foram coletadas para os casos envolvidos nos surtos. A avaliação dos propósitos do programa embasou-se em indicadores de utilidade, sensibilidade e oportunidade. RESULTADOS: Foram identificados 408 casos (Coeficiente de Incidência = 4,7/1000 habitantes); idade mediana de 7 anos (variação de 1 mês a 89 anos) e 54% do sexo masculino. Dos quatro surtos de diarréia confirmados, dois ocorreram em uma creche e em um orfanato, devido à Giárdia lamblia e Cryptosporidum spp.; um intradomiciliar de origem alimentar, sem identificação do agente, e uma epidemia na comunidade associada ao rotavírus. Dos casos atendidos, 63 (15,5%) pertenciam a surtos, identificando-se mais 56 casos, em um total de 119 casos (Coeficiente de Incidência de Surtos=1,4/1000 habitantes). CONCLUSÕES: O estudo mostrou que o programa responde ao seu principal propósito, respeitando-se as condições de regularidade na informação, análises dos padrões da diarréia e investigação criteriosa. Intensificar treinamentos para aumentar a habilidade das equipes locais nas avaliações e investigações é uma das principais recomendações deste estudo. / BACKGROUND: Acute diarrheal illness remains an important cause of morbidity worldwide. Its high incidence and the acceptance of its occurrence as “normal" fact impose challenges for its report and implantation of its surveillance systems. OBJECTIVES: To describe the epidemiologic characteristics of the acute diarrhea and to evaluate the capacity of the Monitoring Program of the Acute Diarrheal Illness for early detection of outbreaks, in the city of Avaré, State of São Paulo, Brazil. METHODS: From February 16 to July 28, 2005, was a prospective study of the diarrhea in a sentinel health service of the program. Descriptive and analytical studies were developed to investigate the potential outbreaks identified in this period. Stool samples were collected from the involved cases in the outbreaks. The evaluation of purpose of the program was based on indicators of usefulness, sensitivity and timeliness. RESULTS: A total of 408 cases were identified (incidence rate=4.7/1000 inhabitants). The median age was 7 years (range 1-89 years) and 54% were male. Among four confirmed diarrhea outbreaks, two occurred in a day nursery and orphanage, due to Giardia lamblia and Cryptosporidum spp., respectively; one was caused by food in dwelling-house, without identification of the agent, and one caused by rotavirus spread citywide. Of all monitored cases, 63 (15.5%) were involved in outbreaks, linked to more 56 cases, in a total of 119 cases (outbreaks incidence rate=1.4/1000 inhabitants). CONCLUSIONS: The study showed that the program enables prompt detection and investigation of outbreaks, respected the conditions of reliability of the information, evaluation of the acute diarrhea trends and careful inquiry. To intensify training to increase the ability of local professionals to recognize patterns of possible outbreaks and for suitable investigations is one of the major recommendations of this study.

L'abattoir est un observatoire privilégié de la santé des bovins, permettant d'envisager une surveillance de la population bovine à partir des données d'inspection sanitaire qui y sont collectées. Mais la valorisation épidémiologique de ces données fait face à des difficultés (complexité des données, nombreux mouvements des bovins de leur naissance à l'abattoir). Afin de gérer cette complexité, une approche statistique (analyse multifactorielle et classification mixte) associée à des avis d'experts ont permis d'établir une typologie des lésions observées à l'abattoir. Une dizaine de groupes lésionnels ont été identifiés qui relèvent de divers domaines tels que la santé animale, la protection animale ou la santé publique. Les données d'abattoir peuvent être utilisées pour la surveillance de maladies ciblées telles que la cysticercose bovine. Des indicateurs de surveillance robustes ont été élaborés pour permettre la comparaison des prévalences de cette zoonose dans le temps et l'espace. Une méthode innovante de prise en compte de l'incertitude liée au lieu d'infestation des animaux a été mise en oeuvre pour identifier les zones à risque plus élevé d'infestation. Un tel outil sera mobilisable pour la mise en oeuvre ultérieure d'une inspection basée sur le risque visant à améliorer l'efficience de l'inspection en abattoir. L'utilisation des données d'abattoir pour la mise en place d'un dispositif de surveillance syndromique a par ailleurs été investiguée par modélisation de la proportion hebdomadaire de bovins ayant fait l'objet d'une saisie totale. Une évaluation des performances de plusieurs algorithmes de détection d'anomalies temporelles a été menée sur données simulées / The slaughterhouse is a unique dedicated vantage point from which to observe bovine health, making it possible to consider implementation of bovine surveillance based on meat inspection data. But the exploitation of these data for epidemiological purposes is not without difficulties (data complexity, large number of cattle movements from birth to slaughter). In order to deal with the data complexity issue, a statistical approach (multiple factor analysis in combination with clustering methods), in addition to the gathering of expert opinions, enables us to create a typology of the lesions detected at the slaughterhouse. Approximately ten lesion groups were identified which cover various areas including animal heath, animal welfare and public health. Meat inspection data can be used for the surveillance of targeted diseases such as bovine cysticercosis. Robust surveillance indicators have been created to enable prevalence comparisons of this zoonosis over time and space. An innovative approach that takes into account uncertainty regarding the location where the animal became infected was implemented to identify areas of higher risk of infection. A similar method could be used for the implementation of a future risk-based meat inspection initiative so as to improve meat inspection efficiency. The use of meat inspection data for the implementation of a syndromic surveillance system was investigated using a temporal analysis of the weekly proportion of whole carcass condemnations, and assessment of the performance of several algorithms for temporal aberration detection was conducted on simulated data