Ulcerations digestives péri-anastomotiques post-chirurgicales

Introduction et objectifs : Les ulcérations digestives péri-anastomotiques après une chirurgie réalisée dans l'enfance sont une entité rare dans la littérature. Elles se rapprochent par certains aspects des ulcérations de la maladie de Crohn. L'objectif est de décrire une série de cas d'ulcérations péri-anastomotiques et de proposer une hypothèse physiopathologique. Patients et méthodes : Il s'agit d'une étude rétrospective bi-centrique de 12 patients opérés dans l'enfance. Les caractéristiques cliniques, biologiques, radiologiques, endoscopiques et histologiques sont étudiées. Onze patients ont eu un génotypage NOD2. Résultats : Nous décrivons 12 cas d'ulcérations péri-anastomotiques majoritairement iléo-coliques (n=8) survenues en médiane à 11 ans [5-26 ans] d'une chirurgie réalisée dans l'enfance, le plus souvent dans le cadre d'une entérocolite ulcéro-nécrosante chez un prématuré (n=7). La présentation clinique associe le plus souvent diarrhée (n=8), anémie ferriprive (n=10) et hémorragie digestive (n=5). Huit sur 11 patients ont un polymorphisme NOD2. Six sur 12 patients reçoivent un traitement immunosuppresseur et 4 ont une défection de l'anastomose. Discussion et conclusion : A l'issue de notre étude, et en accord avec les données de la littérature, il semble se dégager des facteurs de risque de survenue d'ulcérations péri-anastomotiques post-chirurgicales, en particulier la suppression de la valvule iléo-caecoale. La prise en charge des ulcérations péri-anastomotiques post-chirurgicales n'est pas codifiée dans la littérature. Les immunosuppresseurs semblent une option intéressante. Notre étude fait évoquer la possibilité d'un "modèle" mimant la maladie de Crohn chez des patients, opérés dans l'enfance avec la réalisation d'une anastomose grêle-colique. Le polymorphisme NOD2 dans ce modèle serait la prédisposition génétiqueIntroduction and objectives : few reports describe digestive perianastomotic ulcerations that develop after digestive resection in infancy. Some of their features may mimic Crohn's disease. the aim of this study is to describe a small cohort of digestive peranastomotic ulcerations and to propose a physiopathological hypothesis. Patients and methods : Our study is a retrospective bi-center study of 12 patients operated during infancy. Clinical, biological, radiological, endoscopic and histological features were collected. Eleven patients were investigated for NOD2 polymorphism. Results : We describe 12 cases of perianastomotic ulcerations mostly at the ileocolonic anastomosis (n=8). The median interval onset of symptoms and surgery was 11 years (range 5-26 years). Necrotizing enterocolitis in preterm infants is the most frequent underlying disease (n=7). Patients mostly presented with diarrhea (n=8), iron deficiency anemia (n=10) and gastrointestinal blood loss (n=5). Among 11 patients, 8 carry a polymorphism in NOD2 gene. Six of 12 patients are treated with immunosuppressive drugs and 4 have resection and revision of anastomosis. Discussion and conclusion : In agreement with literature data, risk factors appear to predispose to postchirurgical perianastomotic ulcerations such as ileocaecal valve loss. Management of postchirurgical perianastomotic ulcerations is not well established in the literature. The use of immunosuppressive drugs seems interesting. Our study proposes a Crohn's-like "model" for patients with a particular microbiota, who underwent surgery in infancy especally with ileocaecal valve loss. NOD2 polymorphism could act as a genetic predispositionST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF

COPA syndrome as a cause of lupus nephritis

International audienceGenetic kidney diseases are rare situations resulting from mutations in genes expressed in major structures of the kidney, including podocytes, tubular cells, and basement membrane.1 More recently, a new field of monogenic inflammatory diseases has been identified2; these immune-mediated diseases can affect all organs, including the kidney. Here we report on a young girl diagnosed with lupus nephritis and carrying a mutation in the COPA gene encoding for coatomer protein complex subunit alpha

COPA syndrome restricted to life-threatening alveolar hemorrhages: clinical, pathological, molecular and biological characterization

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HETEROZYGOUS MUTATIONS IN COPA ARE ASSOCIATED WITH ENHANCED TYPE I INTERFERON SIGNALLING

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Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.Peer reviewe

Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry

International audienceBackground : The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.Methods : Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.Results : Median age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn’s disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound ( A /p.Trp83*) was detected in one pedigree.Conclusions : Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER–Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age