Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management

International audienceSHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

<p>Abstract</p> <p>Objective</p> <p>To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children.</p> <p>Study design</p> <p>Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.</p> <p>Results</p> <p>21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications.</p> <p>Conclusion</p> <p>Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.</p

Les récepteurs des facteurs de croissance fibroblastique de type 3 (implications thérapeutiques et inhibition)

PARIS-BIUP (751062107) / SudocSudocFranceF

Synthèse d'analogues des liposidomycines et évaluation de leur activité biologique

La translocase bactérienne MraY est une protéine qui catalyse la première étape membranaire de biosynthèse du peptidoglycane bactérien. Les liposidomycines sont des inhibiteurs naturels de cette enzyme possédant une bonne activité in vitro mais faible in vivo, ceci en raison probablement du caractère trop hydrophile de ces composés. L'objectif de la thèse a été de synthétiser des analogues de structure simplifiée de liposidomycines, en utilisant une stratégie répartiteur. Dans un premier temps, l'élaboration de trois châssis moléculaires de type l,4-diazépan-2-one, motif commun aux liposidomycines, a été réalisée. Dans un second temps, trois motifs structuraux, analogues à ceux présents dans les liposidomycines, ont été répartis autour de ces châssis. Enfin, les molécules ont été testées à une concentration finale de 2 mM sur l'enzyme MraY. Elles présentent des pourcentages d'inhibition de l'activité enzymatique compris entre 25% et 100%. Le meilleur inhibiteur présente un IC50 de 150 M.Goal of my thesis is the inhibition of the bacterial translocase MraY which catalyses the first membrane step of peptidoglycan biosynthesis. We developed a straightforward route to three enantiomerically pure polyfunctionalised diazepanone scaffolds from easily available L-serine derivative and azido epoxide resulting from L-ascorbic or D-isoascorbic acid. In a second time, three structurals motifs, analogs of liposidomycins, were synthesized. The compounds were tested on MraY enzyme at 2mM. The best compound has an IC50 of 150 M.PARIS-BIUP (751062107) / SudocSudocFranceF

Stratégies de synthèse pour l'élaboration d'une chimiothèque d'analogues des liposidomycines, antibiotiques naturels dédiés à la translocase MraY

PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Vers de nouveaux inhibiteurs de la transférase bactérienne MraY (Conception et synthèse de bioisostères de pyrophosphate)

Afin de lutter contre l'émergence continue de résistances aux antibiotiques, le développement de nouveaux agents antibactériens et l'identification de nouvelles cibles enzymatiques s'avèrent nécessaires. La transférase bactérienne MraY, impliquée dans la biosynthèse du peptidoglycane, constitue une telle cible. Les objectifs de cette thèse ont été la conception et la synthèse d'analogues de l'UDP-Mur/VAc-pentapeptide, substrat nucléotidique naturel de MraY. La principale modification envisagée a concerné le groupement pyrophosphate, motif clé responsable de la réactivité du substrat. Deux familles de bioisostères ont été ciblées : des analogues de type b-cétophosphonate et de type phosphmoylméthylphosphonate. L'élaboration de ces structures a nécessité la préparation de synthons phosphores et de C-glycosides diversement fonctionnalisés. Le développement de bioisostères de type thiophosphophosphate a aussi été initié afin d'approfondir l'étude du mécanisme d'action de MraY.In order to contain the expansion of bacterial resistance against antibiotics, development of new antibacterial agents and research for new enzymatic targets are required. The bacterial transferase MraY, involved in the peptidoglycan biosynthesis, is such a target. The aim of this work was to design and synthesize analogs of UDP-Mur/VAc-pentapeptide, the natural nucleotidic substrate of MraY. The main modification was directed towards the pyrophosphate group, which is the key moiety responsible for the substrate reactivity. Two bioisosteres families were targeted: b-ketophosphonate analogs and phosphinoylmethylphosphonate analogs. Synthesis of these structures required preparation of phosphorus synthons and C-glycosides variously fonctionalised. Development of thiophosphophosphate bioisosteres was also initiated in order to investigate the MraY mechanism.PARIS-BIUP (751062107) / SudocSudocFranceF

Conception d'antidiabétiques potentiels, inhibiteurs d'alpha-D-glucosidase, de structure carbosucre ou analogue

Le diabète est une pathologie qui affecte 5% de la population mondiale, et le diabète non-insulino dépendant représente 90% des cas. L'objectif de la thèse a été la conception et la synthèse de nouveaux antidiabétiques potentiels de structure apparentée à celle d'inhibiteurs connus de glycosidases tels que le voglibose, l'acarbose, le miglitol ou la castanospermine. La stratégie est basée sur une méthode originale de carbocyclisation de bis-époxydes dérivés deu D-mannitol via une réaction tandem d'alkylation-cyclisation mettant en jeu le réarrangement de Brook, qui conduit a la formation de cyclohexanones et de cycloheptanones polyhydroxylées...Diabetes is a pathology which concerns 5% of the population of the world, and non-isulino dependant diabetes represents 90% of the cases. The goal of the thesis was the design and the synthesis of new potential antidiabetics displaying a structure related to that encountered in voglibose, acarbose, miglitol or castanospermine, which are known inhibitors of glycosidases...PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Synthesis of a β-Ketophosphonate Bioisostere of UDP- N -acetylglucosamine

International audienc