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Wilson disease is a rare inherited disorder of copper metabolism that affects liver and brain due to copper tissue accumulation. The mechanism involved is based on mutations of the ATP7B gene. Children have predominant hepatic manifestations while adult are more often diagnosed by neurological and psychiatric symptoms. However, others features are tubulopathy, articular disorders and hemolytic anemia. We report the diagnostic of Wilson disease in a 14 years old girl and her sibling after investigation of hemolytic anemia, hepatic insufficiency, and hypophosphatemia.

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Introduction SMG9 deficiency is an extremely rare autosomal recessive condition originally described in three patients from two families harboring homozygous truncating SMG9 variants in a context of severe syndromic developmental disorder. To our knowledge, no additional patient has been described since this first report. Methods We performed exome sequencing in a patient exhibiting a syndromic developmental delay and in her unaffected parents and report the phenotypic features. Results Our patient presented with a syndromic association of severe global developmental delay and diverse malformations, including cleft lip and palate, facial dysmorphic features, brain abnormalities, heart defect, growth retardation, and severe infections. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous. Conclusions We confirm that bi-allelic truncating SMG9 variants cause a severe developmental syndrome including brain and heart malformations associated with facial dysmorphic features, severe growth and developmental delay with or without ophthalmological abnormalities, severe feeding difficulties, and life-threatening infections.

International audience; An infant botulism clinical course was characterized by several relapses despite therapy with amoxicillin and metronidazole. Botulism was confirmed by identification of botulinum toxin and C. botulinum in stools. A C. botulinum A2 strain resistant to penicillins and with heterogeneous resistance to metronidazole was isolated from stool samples up to 110 days after onset. Antibiotic susceptibility was tested by disk agar diffusion and minimum inhibitory concentrations were determined by Etest. Whole genome sequencing allowed detection of a gene cluster composed of blaCBP for a novel penicillinase, blaI for a regulator, and blaR1 for a membrane bound penicillin receptor in the chromosome of the C. botulinum isolate. The purified recombinant penicillinase was assayed. Resistance to β-lactams was in agreement with the kinetic parameters of the enzyme. In addition, the β-lactamase gene cluster was found in three C. botulinum genomes in databanks and in two out of 62 genomes of our collection, all the strains belonging to group I C. botulinum. This is the first report of a C. botulinum isolate resistant to penicillins. This stresses the importance of antibiotic susceptibility testing for adequate therapy of botulism.

We describe the case of a young patient with calcifying encephalopathy, born to asymptomatic parents. An extensive hypothesis-driven etiological assessment was performed and failed to detect the precise etiology during many years. We therefore decided to perform whole exome sequencing of the child-unaffected parents trio. A de novo pathogenic variant in the IFIH1 gene which has recently been shown to cause autosomal dominant forms of Aicardi-Goutieres syndrome was identified. This child presented with a severe form with neonatal thrombocytopenia and hepatomegaly, the latter having been detected during late gestation. Although first milestones were uneventful, he progressively lost motor skills from the age of 12 months and developed severe spastic paraplegia. Brain imaging revealed white matter abnormalities and extensive calcifications. He also presented atypical skin lesions, different from chilblains. His medical history was marked by two episodes of acute pancreatitis. We provide herein the results of pathological examination including detailed description of the neuropathological hallmarks. To our knowledge, this the first detailed clinico-pathological description of a patient with an IFIH1 pathogenic variant.

Introduction : Le malaise du nourrisson est un évènement pendant lequel un enfant de moins de 2 ans présente un changement de teint, de tonus musculaire, une apnée, un étouffement et/ou une suffocation. Il s’agit d’un symptôme et non d’un diagnostic précis. Les facteurs de risque de récidive ou d’événement sévère sont connus mais les facteurs de pathologie sous-jacente grave ne le sont pas. Objectif : Cette étude visait à évaluer les critères anamnestiques, cliniques et paracliniques associés à un diagnostic pouvant conduire à une urgence thérapeutique Méthode : Il s’agit d’une étude rétrospective, monocentrique, réalisée au CHU de Rouen. Les nourrissons de moins de 2 ans ayant été hospitalisés ou transférés au CHU de Rouen dans les suites d’un malaise ou pour lesquels l’hospitalisation a été prolongée du fait d’un malaise ont été inclus, sur la période du 1er janvier 2015 au 31 décembre 2017. Les patients ont été retrouvés par les codages d’hospitalisation selon la CIM 10. Les données recueillies étaient les antécédents personnels et familiaux, les données anamnestiques, cliniques et paracliniques des malaises ainsi que les conditions de sortie d’hospitalisation, la récidive et le décès avant l’âge de 2 ans. Résultats : 1213 patients ont été listés parmi lesquels 413 répondaient aux critères d’inclusion. Après exclusion, 346 patients ont été étudiés. L’âge médian au malaise était de 67 jours, les patients étaient de sexe masculin dans 56,1% des cas. Parmi nos patients, 84 (24,3 %) présentaient un diagnostic pouvant conduire à une urgence thérapeutique. Ces patients présentaient significativement un taux supérieur de sexe masculin, étaient plus âgés, présentaient plus souvent une perte de contact, avaient un taux de leucocytes, de neutrophiles, de CRP, de CPK et de lactates plus élevés. Les autres patients avaient plus souvent un malaise avec vomissement ou régurgitation ou au décours de l’alimentation, un examen clinique normal, une virologie respiratoire négative et une radiographie thoracique normale. Conclusion : Les facteurs significativement associés à ces diagnostics étaient un âge élevé au malaise, être de sexe masculin, présenter une hyperthermie ou une perte de contact, avoir un taux de leucocytes ou neutrophiles ou lactates augmenté.