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Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The first consultation of a heterosexual couple for infertility should lead to the prescription of a spermiological assessment. In the first instance, it consists of a spermogram and a spermocytogram. It will provide information on macroscopic and microscopic parameters. The survival migration test guides the MPA technique; the sperm culture and the clinical examination complete this assessment. In a second phase, we will be able to continue the analysis of the sperm with: the search for anti-sperm antibodies, the analysis of the seminal biochemistry, and the evaluation of the DNA fragmentation rate. Blood samples will enrich the exploration: hormonal assays of endocrine and exocrine testicular functions; genetic analyses (karyotype, search for micro deletion of the Y chromosome, search for CFTR variants and search for the MTHFR gene mutation). Finally, imaging will complete this exploration with an ultrasound and scrotal venous doppler, and an MRI of the urogenital carrefour. Fertility assessment in men must be early, exhaustive and oriented. [ABSTRACT FROM AUTHOR]

The observation of vacuoles in hematopoietic cells on bone marrow aspiration may challenge the cytologist and lead to discussion of their specificity and the interest of reporting them. These vacuoles are observed in many pathological situations, of hematological origin or not, and since 2020, they represent an argument to evoke the diagnosis of VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic) that associate clonal hematopoiesis and systemic auto-inflammation. We report 3 patients with VEXAS syndrome in whom repeat myelograms found vacuoles in more than 10% of granular precursors with an average of more than 3 vacuoles per cell. All these cases presented macrocytic anemia and lymphopenia associated or not with other cytopenias. They all have a mutation of UBA1. The current data of the literature are synthesized in order to show the contours of this pathology. The association of macrocytic anemia, skin lesions, and fever in an autoinflammatory context in a male patient may lead to the suspicion of VEXAS syndrome. A Bone marrow aspiration might be done to search vacuoles in the myeloid precursors as well as a UBA1 gene mutation. The association with a myelodysplastic syndrome worsens the prognosis. Cytologists are therefore in the front line to evoke this diagnosis by reporting the presence of significant numbers of vacuoles in order to orientate the complementary examinations to be performed. [ABSTRACT FROM AUTHOR]

Introduction: from a genetic point of view P. falciparumis extremely polymorphic. There is a variety of parasite strains infesting individuals living in malaria endemic areas. The purpose of this study is to investigate the relationship between polymorphisms in Plasmodium falciparum parasites and Pfcrt and Pfmdr1 gene mutations in Nanoro area, Burkina Faso. Methods: blood samples from plasmodium carriers residing in the Nanoro Health District were genotyped using nested PCR. Parasite gene mutations associated with resistance to antimalarial drugs were detected by PCR-RFLP. Results: samples of 672 patients were successfully genotyped. No msp1and msp2allelic families exhibited an increase in developing mutations in resistance genes. However, mutant strains of these genes were present at greater levels in monoclonal infections than in multi-clonal infections. Conclusion: this study provides an overview of the relationship between polymorphisms in Plasmodium falciparum parasites and mutations in resistance genes. These data will undoubtedly contribute to improving knowledge of the parasite´s biology and its mechanisms of resistance to antimalarial drugs. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia is a genetic and rare bone disorder affecting the young subject. Its pathophysiology involves genetic mutations leading to defective skeletal development with fibrous and medullary proliferations. Cephalic extremity is involved in one third of cases. We here report a case of surgically treated fibrous dysplasia of the frontal and ethmoid sinuses. The study involved a 31-year-old man presenting with chronic holocranial headaches. Computed tomography (CT) scan showed voluminous bilateral hyperdense expansive process in the frontal and ethmoid sinuses. Surgery was performed on the basis of functional signs and imaging data. Anatomopathological examination of bone fragments confirmed the diagnosis of fibrous dysplasia. Fibrous dysplasia is rare and characterized by slow disease progression. In the absence of a consensus on therapy, surgery remains the treatment of choice for unifocal forms. [ABSTRACT FROM AUTHOR]

Résumé: Bien qu'étant peu pathogène chez l'humain, le réovirus de mammifère a été, et demeure, un modèle privilégié d'étude de la réplication et de la pathogenèse virale. Généralement considéré comme étant cytolytique, ce virus peut parfois établir des infections persistantes à long terme en culture cellulaire. Dans ce contexte, il constitue en fait un des modèles parmi les plus utilisés pour démontrer la coévolution entre virus et cellules. Bien qu'initialement surtout limitées au modèle des cellules fibroblastiques de souris L929, les dernières années ont vu apparaître d'autres études au sein de différents types cellulaires. L'utilisation de la persistance virale pourrait devenir un outil de prédilection pour isoler de nouveaux virus mieux adaptés à des utilisations virothérapeutiques, par exemple en tant qu'agents oncolytiques contre des cancers humains ou animaux. Une meilleure compréhension du phénomène de persistance, spécialement des gènes viraux impliqués, s'avère donc essentielle. Le développement de nouveaux outils, tel que l'utilisation de la génétique inverse, apparaît très prometteur pour l'atteinte de ces objectifs. Cette dernière approche permet en effet d'établir la signification biologique de mutations retrouvées chez les virus sélectionnés lors de la persistance virale. Although mammalian reovirus exhibits only limited pathogenicity in humans, it has been, and still remains, instrumental in studies of viral replication and pathogenesis. Generally considered as cytolytic, this virus can sometimes establish long-term persistent infections in tissue culture. In fact, in this context, it constitutes one widely used model to demonstrate coevolution between virus and host cells. Initially limited to the murine L929 fibroblasts model, further studies in different cell types appeared in the last few years. Establishment of viral persistence could also become a preferred approach to isolate new viruses that are better adapted to their applications in virotherapy, for example as oncolytic agents against human or animal cancers. A better understanding of the persistence phenomenon, especially of viral genes involved, is thus essential. The development of new tools, such as reverse genetics, appears very promising to achieve these objectives. Actually, this last approach allows us to establish the biological significance of mutations found on viruses selected during viral persistence. [ABSTRACT FROM AUTHOR]

Although mammalian reovirus exhibits only limited pathogenicity in humans, it has been, and still remains, instrumental in studies of viral replication and pathogenesis. Generally considered as cytolytic, this virus can sometimes establish long-term persistent infections in tissue culture. In fact, in this context, it constitutes one widely used model to demonstrate coevolution between virus and host cells. Initially limited to the murine L929 fibroblasts model, further studies in different cell types appeared in the last few years. Establishment of viral persistence could also become a preferred approach to isolate new viruses that are better adapted to their applications in virotherapy, for example as oncolytic agents against human or animal cancers. A better understanding of the persistence phenomenon, especially of viral genes involved, is thus essential. The development of new tools, such as reverse genetics, appears very promising to achieve these objectives. Actually, this last approach allows us to establish the biological significance of mutations found on viruses selected during viral persistence. [ABSTRACT FROM AUTHOR]

Kallmann-de Morsier syndrome (KS) is a genetic disease of the olfactory system characterized by the association of hypogonadotropic hypogonadism also referred to as gonadotropin-releasing hormone (GnRH) deficiency and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs). Apart from sporadic cases that occur most often, familial Kallmann’s syndrome is being described with increasing frequency. Diagnosis is mainly made in adolescents with absence of spontaneous puberty associated with smell disorders with hypoplasia or even aplasia of the bulbs and/or of the olfactory lobes on MRI. Sometimes, the diagnosis may be suspected in early childhood due to the association of cryptorchidism and micropénis. A mutation in one of known genes is only found in less than 30% of cases and, therefore, many other genes are still to be found. Hormone therapy allows pubertal growth in all cases and fertility can be obtained in most of the cases. We here report 3 cases of patients with this syndrome. [ABSTRACT FROM AUTHOR]

Acquired endocrine resistance remains one of the main obstacles in the treatment of estrogen receptor (ER) positive, HER2 negative advanced breast cancer. Recently, activating ESR1 gene mutations affecting the ligand-binding domain have been identified as a keymechanismin aromatase inhibitor (AI) resistance. These mutations can be detected on histological samples or circulating tumour DNA, using PCRbased assays or next-generation sequencing. They induce a constitutive activation of ER, leading to acquired resistance to AI; tamoxifen, fulvestrant and targeted therapies against mTOR or CDK4/6 retain their efficacy. The use of monitoring ESR1 mutations in clinical practice is still to be defined. [ABSTRACT FROM AUTHOR]

Alterity is questioned within three Russian films which are about genetic mutation and the coming of a new era for Humanity: Tarkovsky's Stalker, Lopuchanski's The Ugly Swans and Iufit's Bipedalism. Stalker defends the idea that a spiritual renewal is necessary to save the world through a mutant girl possessing paranormal capacities. The Ugly Swans adds that mutation should not be considered as pathological, and thus must be accepted with trust in its spiritual power. Nevertheless, Bipedalism recalls that attempts to create a new human being, made in the 1920's-1930's in the USSR, have proved to lead to dead ends and human disasters. The comparison between those three films leads to a temporal point of view about alterity which challenges the more conventional spatial conception of it. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer diagnosed and the first leading cause of cancer death among women in France. A population of women at high risk of breast cancer (more than 3% risk at 5 years and 20-25% lifetime) can nowadays be identified and benefit from an appropriate personalized prevention and monitoring program. The French national health authority (HAS, Haute Autorité de Santé) considers personal germline mutation of BRCA1/2, TP53, PTEN, CDH1 or STK11/LKB1 genes, but also recently personal breast cancer history, personal history of atypical breast lesion, history of high-dose chest irradiation and striking family breast/ovarian cancer history but without identified mutation, as criteria of high breast cancer risk and provides screening recommendations for these women. [ABSTRACT FROM AUTHOR]

BRCA1 and BRCA2 germline mutations explain only a small proportion of breast cancer predispositions. More genes are obviously involved. Some are causative of predispositions with broader tumor spectrum and have been studied for many years. Other genes have been recently discovered, thanks to technological evolutions and the growing knowledge of the functions of BRCA genes and their partners. The transfer to clinical practice requires an accurate evaluation of the consequences of each gene mutation. In most of the cases, available data are not sufficient to consider an immediate use of genetic counselling. [ABSTRACT FROM AUTHOR]

The treatment of women for hereditary forms of breast cancer with no identified mutation is a common and complex situation and one that poses problems, particularly when it comes to adapting the level of screening within the family with regard to the residual risk associated with family history. Recent Haute Autorité de santé (French Health Authority) guidelines will enable progress to be made in the treatment of these families, by at least partly structuring the risk assessment process, in order to homogenise the adaptation of the level of monitoring in these families. From this process, carried out in collaboration with oncogenetic specialists, two levels of screening are defined: high risk or very high risk of breast cancer; breast monitoring methods take into account this level of risk and the degree of kinship in relation to the cases of breast cancer in the family. [ABSTRACT FROM AUTHOR]

Hereditary ovarian carcinomas represent 10% of cases of the around 4,500 yearly ovarian cancers in France. They principally consist of high-grade serous carcinomas. They are especially observed in mutation carriers on genes BRCA1 or 2 and, at a lesser degree, on genes of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Due to the absence of an effective screening method for this highly lethal disease, laparoscopic prophylactic adnexectomy is strongly recommended as soon as possible, after a genetic counselling session. However, not all women accept the outcomes of an early menopause, especially if a substitutive treatment is contra-indicated. Recent data obtained from the thorough examination of risk-reducing salpingo-oophorectomy (RRSO) specimens highlight the pivotal role of the Fallopian tube in the pathogenesis of most ovarian carcinomas, especially its fimbrial end for the high-grade serous subtype, so frequent with mutation carriers. Thus, for these at-risk women, reluctant to RRSO, the idea of a temporary prophylactic surgery, limited to a bilateral radical fimbriectomy until oophorectomy at menopause, is being assessed in a prospective study. Meanwhile, due to these informations, it is advocated as well to perform salpingectomies in non-at-risk patients, candidates for a conservative hysterectomy or a surgical tubal ligation, as a primary prophylaxis of this dreadful disease. [ABSTRACT FROM AUTHOR]

Résumé: Nous présentons les avancées thérapeutiques survenues dans la prise en charge des patients atteints de mucoviscidose. Cela concerne des améliorations, essentiellement en termes de qualité de vie, sur des traitements antibiotiques inhalables et des agents pouvant améliorer les caractéristiques rhéologiques des secrétions bronchiques. Nous détaillerons surtout les perspectives innovantes, à savoir les modulateurs de la protéine Cystic Fibrosis Transmembrane conductance Regulator (CFTR) ; ces molécules d’intérêt confirmé ou encore à l’étude, visent la correction des anomalies de fonctionnement de la protéine CFTR mutée responsables des manifestations de la maladie. L’espérance de vie des patients atteints de mucoviscidose nés après 2000 se situerait aux alentours de 50ans. Cette amélioration de survie s’est faite grâce à l’organisation des soins au sein des Centre de ressource et de compétences de la mucoviscidose (CRCM) et reste encore basée sur des traitements symptomatiques à visée respiratoire et nutritionnelle. Mais la charge en soin est lourde et les résultats restent insuffisants. La mise à disposition d’antibiotiques en poudre sèche utilisables par inhalation constitue un gain de temps non négligeable pour des patients chez qui l’ensemble des soins peut atteindre deux heures quotidiennement. Depuis 2012, les modulateurs de CFTR, molécules permettant une approche pharmacologique ciblée en fonction du type des mutations, autorisent une approche plus spécifique de la maladie. L’ivacaftor (Kalydeco®), qui potentialise la fonction de la protéine CFTR correctement exprimée à la surface cellulaire a obtenu une autorisation de mise sur le marché chez des patients porteurs de la mutation G551D. Le lumacaftor va être testé en association avec l’ivacaftor chez les patients porteurs de la mutation F508del, mutation présente chez 75 % des malades. L’ataluren qui permet la production d’une protéine CFTR fonctionnelle chez des patients porteurs d’une mutation non-sens est le 3e représentant de cette nouvelle classe thérapeutique. Nous disposons actuellement de nombreux traitements symptomatiques de la mucoviscidose qui ont permis d’améliorer le pronostic de la maladie. L’apparition des modulateurs de CFTR, même s’ils sont pour l’instant limités avec Kalydeco® à un nombre restreint de patients, laisse envisager une nouvelle ère dans la prise en charge thérapeutique des patients. Des traitements personnalisés en fonction du génotype ou du type de dysfonctionnement de CFTR devraient se multiplier et modifier les stratégies thérapeutiques et le pronostic de la maladie. [ABSTRACT FROM AUTHOR]

Progress in genomics with, in particular, high throughput next generation sequencing is revolutionizing oncology. The impact of these techniques is seen on the one hand the identification of germline mutations that predispose to a given type of cancer, allowing for a personalized care of patients or healthy carriers and, on the other hand, the characterization of all acquired somatic mutation of the tumor cell, opening the door to personalized treatment targeting the driver oncogenes. In both cases, next generation sequencing techniques allow a global approach whereby the integrality of the genome mutations is analyzed and correlated with the clinical data. The benefits on the quality of care delivered to our patients are extremely impressive. [ABSTRACT FROM AUTHOR]

Thymic malignancies are tumors which necessitate a multimodal approach. Twenty percent of these tumors are associated with auto-immune disorders. Surgery remains the treatment of choice for localized lesions. Complete resection represents the main prognostic factor. Postoperative radiation could be considered for patients with residual disease. Chemotherapy is standard in locally advanced and metastatic disease. In current practice the most common regimen for adult patients is anthracycline-based chemotherapy. The combination of carboplatin and paclitaxel seems to be efficient in recent studies and could be used as first-line. Several targeted therapies, such as KIT inhibitors, anti-VEGF, CDK inhibitors, or more recently mTOR inhibitors, have been developed with promising results. In the age of personalized medicine, including patients in phase I studies may help to identify rare mutations and treat them specifically. In France, monthly national web conferences are performed by RYTHMIC (Réseau Tumeurs Thymiques et Cancer) group to optimize the management of these tumors. [ABSTRACT FROM AUTHOR]

Résumé: Les thromboses splanchniques surviennent chez 30 % des patients atteints de thrombocytémie essentielle, mais sont rarement présentes lors du diagnostic. Nous rapportons 2 cas pédiatriques ayant présenté une thrombocytémie essentielle révélée par une thrombose splanchnique atypique. Dans le premier cas, une jeune fille de 16ans avait présenté un syndrome de Budd-Chiari révélé par un choc hémorragique sur rupture de varices œsophagiennes. L’examen clinique avait mis en évidence une splénomégalie isolée. La recherche d’une thrombophilie avait permis de diagnostiquer une mutation homozygote du facteur V Leiden associée à une mutation de Jak2. La biopsie médullaire avait confirmé le diagnostic de syndrome myéloprolifératif. Dans le deuxième cas, une jeune fille de 17ans avait consulté son médecin traitant pour une visite de routine, et l’examen clinique avait révélé une splénomégalie isolée. L’échographie avait montré l’existence d’un thrombus des veines splénique et portale. Une mutation isolée de Jak2 avait été mise en évidence et le syndrome myéloprolifératif avait été confirmé sur la biopsie médullaire. Le diagnostic de syndrome myéloprolifératif a donc été évoqué chez ces deux jeunes-filles devant une thrombose veineuse atypique associée à une mutation de Jak2, et confirmé par la biopsie médullaire. Ces présentations initiales de syndrome myéloprolifératif sont rares chez l’enfant et probablement sous-diagnostiquées. [ABSTRACT FROM AUTHOR]

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the catabolism of fluoropyrimidines. Its activity follows a Gaussian curve in the general population and some mutations have been identified in the gene reported to cause early severe related adverse events, in 2 to 5% of the patients. It is clearly a problem of public healthcare that cannot be underestimated. We review the performances of assays that assess DPD status. The combination of 2 complementary techniques, genotyping and enzyme phenotyping, suitable for routine clinical applications is crucial for reliably detecting DPD deficiency and avoiding early severe toxicity associated with fluoropyrimidines. [ABSTRACT FROM AUTHOR]

The identification of KRAS mutations as a predictive marker of resistance to anti-EGFR antibodies has been considered as a major step in the personalized treatment of metastatic colorectal cancer. Recently, other mutations in genes of the RAS family have demonstrated their role in identifying patients who may benefit from anti-EGFR. Meanwhile, more fundamental works have led to better understand the mechanisms of secondary resistance to anti-EGFR antibodies and also to consider the possibility to a rapid research of KRAS or RAS mutations in peripheral blood. [ABSTRACT FROM AUTHOR]

Résumé: Les thromboses artérielles des membres se produisent rarement in utero. Le diagnostic se fait facilement par l’examen clinique au moment de la naissance ou dans les heures qui suivent. L’exploration radiologique repose en première intention sur l’échographie doppler. L’étiopathogénie est souvent complexe et multifactorielle. Nous rapportons 2 cas de thrombose artérielle du membre supérieur droit survenue in utero. Le bilan de thrombophilie avait objectivé chez les 2 enfants un état hétérozygote pour le polymorphisme 677C>T de la 5,10-méthylène-tétrahydrofolate-réductase (MTHFR). Le premier cas concernait un prématuré ayant présenté dès sa naissance une cyanose du membre. L’angioscanner avait confirmé la présence d’une thrombose axillaire droite. L’évolution avait été favorable après un traitement anti-thrombotique. Le second cas était un nouveau-né à terme qui avait présenté dès la naissance une ischémie avec un début de gangrène du membre. L’échographie doppler avait montré une thrombose complète de l’artère sous-clavière droite. Une amputation du membre avait été réalisée après échec du traitement médical. Les particularités épidémio-cliniques et étiopathogéniques de cette affection néonatale rare sont discutées. [ABSTRACT FROM AUTHOR]

Résumé: Le syndrome de Van der Woude (SVDW) représente la première cause de fente labio-alvéolopalatine d’origine syndromique. Il associe à ces fentes, des fistules de la lèvre inférieure et parfois des hypodonties. Des découvertes récentes ont permis de mettre en évidence des mutations du gène de l’IRF6 dans ce syndrome et, ainsi, de mieux comprendre les variabilités cliniques de ce syndrome. À la lumière des cas pris en charge récemment dans notre institution et d’une revue de la littérature, nous tentons de faire le point sur cette association syndromique. [ABSTRACT FROM AUTHOR]

Résumé: L’encéphalopathie aiguë nécrosante (EAN) est une maladie neurologique rare déclenchée à la suite d’une fièvre le plus souvent d’origine virale affectant des nourrissons ou des enfants jusque là en bonne santé. L’évolution clinique se caractérise par une détérioration rapide de l’état neurologique aboutissant presque toujours à un coma et nécessitant une prise en charge en réanimation. Le diagnostic est conforté par l’imagerie par résonance magnétique (IRM) cérébrale qui montre des lésions spécifiques de nécrose symétrique et focale des thalami. L’EAN a été associée dans de récentes études à l’existence d’une mutation autosomique dominante du gène de la protéine RAN-binding protein 2. Nous rapportons le cas d’une fratrie (trois enfants) d’origine tunisienne dans laquelle deux enfants ont présenté de façon certaine une EAN à l’âge de 9 mois dans les suites immédiates d’une infection virale. L’étude moléculaire a mis en évidence une mutation faux-sens du gène RAN-binding protein 2 chez les deux enfants pour lesquels un prélèvement était disponible. Parmi les tableaux d’encéphalopathie aiguë de l’enfant, la reconnaissance de cette nouvelle entité neurologique, rare, permet non seulement une prise en charge symptomatique précoce, mais aussi un conseil génétique plus précis. [ABSTRACT FROM AUTHOR]

Résumé: La prise en charge du syndrome de Budd-Chiari (SBC) a été transformée au cours des dix dernières années : diagnostic moins invasif grâce aux progrès de l’imagerie, identification d’un syndrome myéloprolifératif (SMP) dans 20 à 50 % des cas, facilitée par la mise en évidence de la mutation JAK2 V617F, stratégies thérapeutiques par étape en fonction de la réponse au traitement précédent. La présence d’une affection prothrombotique fréquente, comprenant les syndromes myéloprolifératifs, déficits en protéine C ou S, mutations du facteur V Leiden ou du facteur II, et le syndrome des anti-phospholipides, nécessite une exploration complète, sans oublier la recherche de maladies systémiques ou de causes plus rares associées. L’échographie-Doppler doit être effectuée par un opérateur expérimenté, informé de la suspicion diagnostique, pour documenter un obstacle ou des collatérales. Au cours du SBC, la survie à cinq ans des patients traités selon la stratégie thérapeutique par étapes (anticoagulant, traitement de la cause et reperméabilisation, puis transjugular intrahepatic portosystemic shunt [TIPS], puis greffe hépatique), en fonction de la réponse au traitement, est supérieure à 80 %. [ABSTRACT FROM AUTHOR]

Résumé: La trisomie 21 a été décrite par J. Langdon Down en 1866, d’où le nom de syndrome de Down utilisé dans la littérature médicale anglo-saxonne. L’individualisation relativement tardive de cette pathologie, dont J. Lejeune, M. Gautier et R. Turpin ont démontré en 1959 qu’elle était due à la trisomie du chromosome 21, a conduit à s’interroger sur son ancienneté. Trois approches permettent de répondre à cette question : la recherche de sa représentation dans les œuvres d’art les plus anciennes, la paléo – ostéologie et l’étude de l’apparition du chromosome 21 et de sa pathologie dans le cadre de l’évolution chromosomique. Des sculptures, des figurines évocatrices d’une trisomie 21 ont été observées dans l’antiquité gréco-romaine, dans différentes cultures méso-américaines, ainsi que dans des temples de la civilisation khmère. En Europe, à la Renaissance, elle est représentée par des peintres italiens et flamands sur des tableaux d’inspiration religieuse. Les recherches sur l’origine et la pathologie du chromosome 21 ont montré que la trisomie 21 remontait aux premiers temps de la lignée des primates et pourrait être la conséquence d’une mutation chromosomique datant de plusieurs millions d’années. [ABSTRACT FROM AUTHOR]

Résumé: Introduction: La kératodermie palmoplantaire aquagénique (KPA) est une dermatose des paumes et des plantes dont les signes (œdème, majoration des plis et papules blanchâtres) sont déclenchés par immersion dans l’eau. Elle peut être observée chez des sujets sains, mais, alors que cette dermatose est peu connue des praticiens ayant en charge ces patients, la plupart des cas de KPA ont été décrits chez des patients mucoviscidosiques. Le but de ce travail était d’évaluer la fréquence de la KPA dans une population d’enfants mucoviscidosiques. Population et méthodes: Ce travail a été réalisé chez 60 enfants, 27 filles et 33 garçons, âgés de 4mois à 18ans, suivis au centre de ressources et de compétences de la mucoviscidose du centre hospitalier et universitaire d’Angers chez lesquels la mucoviscidose avait été confirmée par un test de la sueur positif supérieur à 60mmol de chlorures par litre de sueur. La recherche d’une KPA a été réalisée par un interrogatoire à la recherche de modifications des paumes et des plantes constatées par l’enfant ou sa famille après immersion dans l’eau et la recherche de ces mêmes signes par l’examen clinique avant et après immersion de la main droite dans une bassine d’eau tiède pendant 3minutes (signe du seau). Résultats: Quarante-sept des 60 enfants (78 %) avaient un signe du seau positif. Trente-huit de ces 47 enfants avaient déjà remarqué des modifications de la peau de leurs paumes ou de leurs plantes apparaissant rapidement au cours du bain et 6 avaient un œdème et une majoration des plis cutanés de la paume des mains avant même qu’ils ne plongent leur main dans l’eau. Conclusion: La KPA est très fréquente chez les enfants atteints de mucoviscidose. Elle est vraisemblablement une conséquence du dysfonctionnement de la protéine cystic fibrosis transmembrane conductance regulator (CFTR). Sa recherche devrait être systématique chez tous les enfants mucoviscidosiques. Sa découverte dans un autre contexte doit faire évoquer le diagnostic de mucoviscidose ou un portage à l’état hétérozygote d’une mutation impliquée dans la maladie. [ABSTRACT FROM AUTHOR]

Copyright of Population (00324663) is the property of Institut National d'Etudes Demographiques and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Several studies published during the last decade have shown that altered energy metabolism can lead to tumor development. Mutations in genes encoding for three Krebs cycle enzymes have been identified to contribute to the development of benign or malignant tumors: succinate dehydrogenase (SDH), fumarate hydratase ( FH gene), and isocitrate dehydrogenase ( IDH gene). We will review herein the clinical features associated with those mutations and we will discuss the mechanisms of tumorigenesis involved. [ABSTRACT FROM AUTHOR]

Résumé: L’utilisation récente du vémurafénib, inhibiteur spécifique du gène BRAF, a permis une amélioration significative de la survie sans récidive et de la survie globale des patients traités pour mélanome métastatique porteur de la mutation du gène BRAF. Cette nouvelle classe thérapeutique n’est cependant pas dénuée d’effets indésirables, notamment dermatologiques. Son association avec une radiothérapie concomitante doit être prise en considération, le vémurafénib apparaissant radiosensibilisant. L’oncologue radiothérapeute doit donc être informé de cette toxicité potentielle qui n’apparaît pas rare en pratique clinique. [ABSTRACT FROM AUTHOR]

Copyright of Biologie Aujourd'hui is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: We describe the case of a 4-year-old child with Mediterranean fever characterized by cutaneous features. Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent attacks of fever and polyserositis including peritonitis, pleuritis, and arthritis. Skin involvement is less common. In our case, the successively patient presented erysipelas-like erythema, edemas of the palmar and plantar regions, and purpuric lesions. From these clinical observations, several diagnoses were raised: infectious erysipelas, Kawasaki disease, Henoch-Schönlein purpura, and familial Mediterranean fever. Only the latter diagnosis was confirmed after exploration and then confirmed with genetic analysis, which found a M694V homozygous mutation. Erysipelas-like erythema is the most frequent cutaneous sign reported in the literature and the only one to be associated with the M694V homozygous mutation. The originality of this case is the dominancy and polymorphism of the skin lesions. [ABSTRACT FROM AUTHOR]

Abstract: Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid β-glucosidase. In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in 30 Tunisian patients with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing had shown that N370S was the most frequent mutation (22/50 mutant alleles, 44%), followed by L444P mutation, which is found in 16% (8/50 mutant alleles). The recombinant allele (RecNciI) represented 14%. Our findings revealed that the genotype N370S/RecNciI was mosst frequent in patients with childhood onset and it was associated with severe visceral involvement. The screening of these three mutations provided a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allowed also genetic counselling for their family members. [Copyright &y& Elsevier]

Copyright of Revue Francophone des Laboratoires is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recent advances in molecular genetics provide significant new therapeutics for advanced melanomas in the field of targeted therapies. New signaling pathways are described defining a personal genetic identity card. Three specific mutations have been identified: BRAF, NRAS, and c-KIT. Phase III studies evaluating Vemurafenib, a new anti-RAF (Dabrafenib) and anti-MEK as Trametinib, are promising. The preliminary results of the combination Dabrafenib/Trametinib are also encouraging. [ABSTRACT FROM AUTHOR]

Summary: Permanent neonatal diabetes mellitus is a rare disorder usually presenting within the first few weeks or months of life and defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency. Nonsyndromic neonatal diabetes is genetically heterogeneous and several genes have been linked to this disorder. Here, we report on a new homozygous recessive mutation in the INS gene in 2 siblings born to consanguineous parents and diagnosed with permanent neonatal diabetes without extrapancreatic features. Their clinically unaffected parents were heterozygous. Their phenotype was also characterized by severe intrauterine growth retardation, most likely reflecting severe insulin deficiency in prenatal life, hyperglycemia, and moderate dehydration in the first few days of life. Their clinical course was uneventful after introduction of insulin therapy with catch-up growth and acquisition of normal developmental milestones. [Copyright &y& Elsevier]

Abstract: Palindromic rheumatism is characterized by episodes of arthritis or para-arthritis leaving no residual or radiographic changes. Several diseases should be ruled out in the differential diagnosis. Evolution to rheumatoid arthritis is common, especially in patient with positive rheumatoid factor and anticitrullinated peptides. In seronegative patients, palindromic rheumatism could be part of the spectrum of autoinflammatory diseases because of a high frequency of MEFV mutations. Treatment remains discussed. The use of antimalarials could delay the development of rheumatoid arthritis or another connective tissue disease. [Copyright &y& Elsevier]

Summary: There is a need to find a cure for pulmonary disease in cystic fibrosis (CF), though full benefit of this approach will be restricted to those patients with well-preserved lungs. The most promising route is currently that of a pharmacological mutation-specific approach aiming at correcting the mechanism by which mutations lead to impairment of chloride conductance across respiratory epithelial cells. In the past 14years, 7 candidate drugs (CPX, 4PBA, gentamicin, PTC124, VX-770 or Ivacaftor, VX-809 or Lumacaftor, and Miglustat) have been investigated in CF patients. A postulate of 14 out of the 15 published studies has been that an effective agent had to improve total chloride secretion as assessed in vivo by nasal potential difference measurements. The present review casts a critical look at these studies. Apparent inconsistencies are discussed as well as possible limitations of nasal potential difference measurements as outcome parameters in these trials. Primarily targeting a mutation carried by less than 2% of French CF patients, the 2 Ivacaftor studies could well be a milestone on the long road toward a cure for CF. However, further data on safety and long-term efficacy are obviously needed and the current price of this medication in the US would make it unaffordable for European patients. [Copyright &y& Elsevier]

Summary: Distal spinal-muscular atrophy 1 (DSMA1) or spinal-muscular atrophy with respiratory distress type 1 (SMARD1) is a rare neuromuscular disorder resulting from IGHMBP2 mutations. It is an autosomal recessive disease. We present the case of a 1-year-old girl admitted for respiratory failure associated with pneumonia. Right hemidiaphragmic elevation on the chest radiograph and distal retractions suggested the diagnosis of DSMA1. It was confirmed by muscle biopsy and molecular analysis. This unrecognized diagnosis should be considered when respiratory failure develops in the first year of life and is associated with diaphragmatic paralysis and distal muscle atrophy. Electromyography with measurement of nerve conduction velocity and muscle biopsy suggest the diagnosis, which must be confirmed by genetic analysis. After identifying the mutations, it is possible to perform prenatal diagnosis. [Copyright &y& Elsevier]

Lung cancer is the leading cause of death by cancer worldwide. The vast majority of lung tumors are non-small cell lung carcinomas (NSCLC), and surgical resection remains the only effective treatment. According to the new WHO histological classification of lung cancer, NSCLC comprise three major histological subgroups; squamous cell carcinoma, adenocarcinoma, and large cell carcinoma and its variants. The recent discovery of EGFR tyrosine kinase inhibitor-sensitive mutations in a subset of adenocarcinomas has raised hopes toward the identification of new druggable molecular alterations in all subtypes of NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Numerous organs are involved in the metabolism of calcium and phosphorus, as well as numerous hormones and proteins. Therefore, many genes are involved in this metabolism and many genetic diseases may be observed. These diseases are frequently congenital or their symptoms appear during early infancy and some of them are rapidly lethal or are responsible of severe deformities. However, due to a variable penetrance or due to balancing mechanisms, some of them are diagnosed only during adulthood. Obviously, the treatment of these diseases may only be symptomatic today and it is based on the continuous correction of the metabolic disorder. The classification of these diseases is tricky as there are usually many consequences of a genetic mutation on the calcium and phosphorus metabolism and the phenotypic translation is heterogeneous. In front of varying or discreet clinical symptoms three criteria are very important in order to bring the diagnosis round to a genetic disease: the patient''s age, the family history, and a detailed analysis of the calcium and phosphorus parameters and regulating hormones. [Copyright &y& Elsevier]

Abstract: Hearing loss is the most common sensory disability with an incidence of one over 1000newborns. Hearing loss may be caused by environmental and genetic factors; inherited causes are assumed in two thirds of cases. There is a great clinical and genetic heterogenicity. All inheritance modes have been described. Mutations in the GJB2 gene, which encodes connexin 26, are mainly responsible for sensorineural deafness resulting in prelingual non syndromic autosomal recessive phenotypes DFNB1. The 35delG mutation of this gene is very frequent (70% of the cases). Thus, 35delG is, with the delta F508 mutation of the CFTR gene, the most frequent human pathogenic mutation known. Hearing loss might also be associated with other clinical features. Some of these syndromes, including hearing loss, have to be looked for systematically because of their frequency, of their possible clinical presentation as an isolated hearing loss and of the possibility of a medical treatment. [Copyright &y& Elsevier]

Summary: A 10-year-old child was hospitalized for bradycardia during a viral infection with chikungunya. His history showed unexplored episodes of bradycardia. Cardiologic explorations revealed cardiac sinus node dysfunction (SD). Mutational screening of the SCN5A gene showed that this case was a compound heterozygote for p.Ala735Val and p.Asp1792Asn missense mutants. Five years later, the child underwent a pacemaker insertion after an electrophysiological study performed during an atrial flutter access. [ABSTRACT FROM AUTHOR]

Abstract: Lung cancer is in France, the leading cause of cancer death. Despite the dramatic advances that have allowed in a few years to go, for metastatic cancer, from a median survival without specific treatment of 4.5 months and now almost always more than one year, survival remains disappointing and further improvements are needed. Progress in the accumulated knowledge of the inner workings of normal and tumoral cells have paved the way for the development of targeted therapeutics called biological or simply targeted therapies. Two biological processes are already the target of marketed drugs, this is the way the receptor of epidermal growth factor (EGFR) and the path of neo-angiogenesis. It is almost assumed that, in the very near future, the inhibition of EML4-ALK will also be the subject of new drugs. In the medium term, it is conceivable that the molecular dissection of the tumors actually lead to the prescription of treatments tailored to mutations and other abnormalities that direct the growth of cancers. [Copyright &y& Elsevier]

Abstract: The tyrosine kinase inhibitors (TKI) are small molecules of low molecular weight that inhibit tyrosine kinases, enzymes responsible for the activation of signal transduction cascades. Currently, a number of TKI received approval in various cancers, while others are in clinical development process: TKI are specifically clinically active when they target a tyrosine kinase (TK) with constitutional activity subsequent to a mutation, being then a master-gene driving transformation and tumour progression. Already, this drug-family provides a major therapeutic weapon against cancer. [Copyright &y& Elsevier]

Abstract: Aim of the study: Platelet-activating factor interacts with its specific receptor and mediates leucocytes transmigration into central nervous system and expression of HLA molecules on antigens-presenting cells. These features are the major characteristics of multiple sclerosis pathology. In the present study, we investigated the role of platelet-activating factor receptor A224 mutation in the susceptibility to relapsing-remitting form of MS in a Tunisian population. Patients and methods: Forty-seven multiple sclerosis patients and 72 healthy controls were genotyped for platelet-activating factor receptor A224D mutation using polymerase chain reaction-restriction fragment length polymorphism technique. Results: We used three models of inheritance: the codominant, dominant and recessive models. Our results showed a predisposing effect of platelet-activating factor receptor 224D variant on susceptibility to relapsing-remitting multiple sclerosis (30% vs 48.1%, OR [IC 95%]=2.04 [1.04–3.99], P =0.023). Our results were also consistent with a dominant model of inheritance when comparing mild genotype (AA) with carriers of one or two copies of mutant allele (AD+DD) (55.7% vs 31.9%, OR [IC 95%]=2.92 [1.34–6.81], P =0.006). No effect of this mutation was shown when considering the age at disease onset, disease severity or gender. Conclusion: This first study reports an implication of platelet-activating factor receptor A224D mutation in the susceptibility to relapsing-remitting multiple sclerosis in Tunisian population. Further studies will be necessary to confirm the dominant role of PAFR A224D mutation and to elucidate the effect of this mutation on platelet-activating factor/platelet-activating factor receptor pathways. [Copyright &y& Elsevier]

Abstract: Objective: Coronary artery disease (CAD) is a complex multifactorial disease due to the interaction of multiple genes variations and environmental factors. Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysis of triglyceride rich particles, may contribute to CAD. We analysed here the frequency of LPL variants (p.Asp9Asn, p.Asn291Ser and p.Ser447X) in a Tunisian population as well as their association with circulating lipid level and risk of CAD. Patients and methods: LPL variations were investigated by PCR-RFLP and lipid parameters were measured in 135 patients and 109 controls. Results: The frequency of the p.Asp9Asn variation was 10.37% in CAD patients versus 3.66% in controls. The frequency for the p.Ser447X variation was 8.8% in CAD patients versus 13.7% in controls. There was no significant association between these two variants and CAD. The p.Asn291Ser mutation variation was absent in this population. In healthy subjects, heterozygote carriers of the p.Asp9Asn substitution had a significant increase level of total cholesterol (4.2±0.9mmol/L vs 5.6±1.2mmol/L; P =0.01) and a decreased level of HDL-cholesterol (1.36±0.3mmol/L vs 0.93±0.1mmol/L; P =0.045). Conclusion: There was no significant association between genetic variants of the LPL gene and CAD in this Tunisian population. The very low frequency of the p.Asn291Ser variation may be an ethnic specificity of Tunisians. [Copyright &y& Elsevier]

Copyright of IBS, Immuno-analyse & Biologie Specialisee is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)