Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate

AbstractNoonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate lay the groundwork for future molecular diagnosis research, and the development of novel treatment strategies

GATA4 molecular screening and assessment of environmental risk factors in a Moroccan cohort with tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD) with an incidence of 1/3600 live births. This disorder was associated with mutations in the transcription factors involved in cardiogenesis, like Nk2 homeobox5 (NKX2-5), GATA binding protein4 (GATA4) and T-BOX1 (TBX1). GATA4 contributes particularly to heart looping and differentiation of the second heart field.Objectives: The aim of this study was to screen a Moroccan cohort with tetralogy of Fallot for GATA4 mutations, and to assess environmental risk factors that could be involved in the occurrence of this disorder.Methods: Thirty-one non-syndromic TOF patients, enrolled between 5th April 2014 and 18th June 2015, were screened for GATA4 mutations using direct sequencing of GATA4 coding exons. Statistical assessment of different risk factors, which is a retrospective study, was carried out using Chi-square and Fisher’s exact tests. Results: We identified seven exonic variants in nine patients (two missense and five synonymous variants); in addition of eight intronic variants. Assessment of environmental risk factors shows significant association of maternal passive smoking with TOF in the Moroccan population.Conclusion: The present study allowed, for the first time, the molecular and environmental characterisation of Moroccan TOF population. Our findings emphasise particularly the strong association of passive smoking with the emergence of tetralogy of Fallot.Keywords: Tetralogy of Fallot, GATA4, molecular screening, risk factors

Embryonic paratesticular rhabdomyosarcoma: a case report

INTRODUCTION: An embryonic paratesticular rhabdomyosarcoma is a very rare mesenchymal tumor. It is an intrascrotal tumor that is localized in paratesticular structures such as the epididymis or spermatic cord. Rhabdomyosarcoma is most often observed in children and adolescents, presenting as a painless scrotal mass. CASE PRESENTATION: Our patient was an 18-year-old Moroccan man who presented with a painless left scrotal mass that had evolved over four months. An inguinal orchiectomy was performed. A histological examination of the excised tissue revealed an embryonic rhabdomyosarcoma. Our patient had three sessions of chemotherapy with vincristine, actinomycin C and cyclophosphamide. Each chemotherapy session was conducted over five days, with a cycle of 21 days. Our patient was assessed two months after the last chemotherapy session and demonstrated good clinical improvement. CONCLUSION: Paratesticular rhabdomyosarcoma is a rare aggressive tumor manifesting in children and very young adults. Localized forms have a good prognosis whereas metastatic tumors show very poor results. A well-defined treatment based on surgery and chemotherapy yields good results

GATA4 molecular screening and assessment of environmental risk factors in a Moroccan cohort with tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD) with an incidence of 1/3600 live births. This disorder was associated with mutations in the transcription factors involved in cardiogenesis, like Nk2 homeobox5 (NKX2-5), GATA binding protein4 (GATA4) and T-BOX1 (TBX1). GATA4 contributes particularly to heart looping and differentiation of the second heart field. Objectives: The aim of this study was to screen a Moroccan cohort with tetralogy of Fallot for GATA4 mutations, and to assess environmental risk factors that could be involved in the occurrence of this disorder. Methods: Thirty-one non-syndromic TOF patients, enrolled between 5th April 2014 and 18th June 2015, were screened for GATA4 mutations using direct sequencing of GATA4 coding exons. Statistical assessment of different risk factors, which is a retrospective study, was carried out using Chi-square and Fisher\u2019s exact tests. Results: We identified seven exonic variants in nine patients (two missense and five synonymous variants); in addition of eight intronic variants. Assessment of environmental risk factors shows significant association of maternal passive smoking with TOF in the Moroccan population. Conclusion: The present study allowed, for the first time, the molecular and environmental characterisation of Moroccan TOF population. Our findings emphasise particularly the strong association of passive smoking with the emergence of tetralogy of Fallot

Modélisation d'une terminologie médicale en langue arabe à des fins de médiation, d'extraction et de recherche d'information

Notre objectif, dans le cadre de ce projet de thèse, est la proposition d'un modèle terminologique à des fins d'extraction, de recherche d'information et de médiation dans un contexte multilingue. Le contexte multilingue a été choisi pour répondre aux besoins des utilisateurs dans la diffusion et la structuration de l'information spécialisée dans le domaine médical en langue arabe. Etant donnée la difficulté de traitement automatique de la terminologie médicale en langue arabe morphologiquement et/ou sémantiquement, nous avons voulu aborder ces problématiques en nous appuyant sur ce qui était déjà fait en Anglais, une autre langue qui connaît des avancées en TALN. Nous nous sommes focalisés sur le champ sémantique et pour ce faire, nous nous sommes appuyés sur la catégorisation sémantique internationale de l'UMLS. L'idée principale du projet est de refléter l'importance du rôle de l'outil terminologique dans les recherches en sciences de l'information et de la communication qui accorde plus d'importance à l'outil thésaurique qu'à l'outil terminologique au niveau de la structuration de l'information. Les résultats de notre expérience ont été satisfaisants étant donné les difficultés rencontrées au cours de l'évolution de notre projet. Ces difficultés étaient liées au manque de la documentation spécialisée en langue arabe, et d'outils permettant à la terminologie de s'appliquer dans le contexte d'un SRI. Nous avons constitué quelques échantillons de ces outils afin de consolider notre idée sur le plan pratique. Nos résultats ont été concrétisés par la proposition de deux méthodologies au niveau de la recherche de l'information, i) une méthodologie de reformulation des requêtes et ii) une autre en structuration de l'information au niveau de l'indexation. Et d'autres prometteuses, au niveau de l'acquisition des connaissances, nous avons exploré l'alignement phrastique pour but d'extraction des termes médicaux en langue arabe, et nous avons suggéré de considérer l'outil terminologique comme élément de médiation afin d'améliorer la communication spécialisée. Nous avons ainsi constaté à travers l'évolution de notre projet le rôle primordial de l'outil terminologique pour l'amélioration des recherches documentaires spécialisées en langue arabe et de façon générale, son rôle important dans le traitement de l'information dans le domaine médicalThe objective of our thesis is the proposal of a terminological model for the mediation, extraction and search information in multilingual context. The multilingual context was chosen to serve the needs of the users in the structuring and diffusion of specialized information in Arabic language. Given the difficulty of the automatic treatment of Arabic language in specialized domain, morphologically and semantically we have used existing NLP advanced developed in English language. We focused on semantic field, so we have used the semantic categorisation of UMLS. The main idea of the project is to reflect the importance of the role of terminology in the researches in information and communication sciences, which give more importance to the thesaurus than to the terminology in information structuring. The results of our project were satisfactory given the difficulties encountered and overcome throughout the course of our project. These difficulties were linked to the absence of medical documentation in Arabic language and of the tools, whic allow applying the terminology in the context of a SRI. Our work resulted in the proposition of main two methodologies at the level of the research i) a methodology of reformulation of the requests and ii) the other one in a methodology of indexation. We also developed others promising methodology in the field of the acquisition of knowledge, we investigated the field of the alignment for the purpose of extraction of medical terms in Arabic language. At the end in our project, we suggested to consider the terminology as element of mediation to improve specialized communication. Throughout the evolution of our project, we observed the essential role of terminology in the improvment of specialized retrieval systems in Arabic language and generally its important role in the treatment of information in the medical fieldLILLE3-BU (590092101) / SudocSudocFranceF

Williams-Beuren syndrome in diverse populations

Williams–Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses