A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair

Immunoglobulin class switch recombination (CSR) deficiencies are rare primary immunodeficiencies, characterized by a lack of switched isotype (IgG, IgA, or IgE) production, variably associated with abnormal somatic hypermutation (SHM). Deficiencies in CD40 ligand, CD40, activation-induced cytidine deaminase, and uracil-N-glycosylase may account for this syndrome. We previously described another Ig CSR deficiency condition, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) μ regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, SHM was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events

Stroke without cerebral arteriopathy in sickle cell disease children: causes and treatment

Cerebral arteriopathy (CA) in children with sickle cell disease (SCD) is classically described as chronic stenosis of arteries in the anterior brain circulation, leading to ischemic stroke. Some studies have however reported strokes in children with SCD but without CA. In order to better understand the etiology and risk factors of these strokes, we retrospectively analyzed ischemic strokes occurring in a large cohort of children over a 13 year-period. Between 2007 and 2020, 25/1500 children with SCD had an ischemic stroke in our center. Among them, 13 (52%) had CA, described as anatomical arterial stenosis, while 12 (48%) did not. Patients with stroke without CA were older than patients with stroke attributed to SCD-CA (9.0 years old vs 3.6 years old, p=0.008), and had more frequently a SC genotype (25% vs 0% respectively). Their stroke involved posterior circulation more frequently, with cerebellar involvement in 42%. Retained stroke etiologies in patients without typical SCD-related CA were reversible cerebral vasoconstriction syndrome, cerebral fat embolism, arterial thrombosis or thromboembolism, hyperviscosity, vasculitis in a context of infectious meningoencephalitis, and severe hemodynamic failure. No recurrence was observed in the 24 months following stroke, even though 67% of the patients were no longer receiving exchange transfusions in this group. In conclusion, in a cohort of pediatric SCD patients with efficient stroke screening strategy, half of occurring ischemic strokes were related to causes other than CA. They affected a different population of SCD children and systematic long-term transfusion programs may not be necessary in these cases

Early splenectomy in a large cohort of children with sickle cell anemia: risks and consequences

In children with sickle cell anemia (SCA), early splenic complications can require splenectomy, but the benefit-to-risk ratio and the age at which splenectomy may be safely performed remain unclear. To address this question, we analyzed the rate of post-splenectomy events in children with SCA splenectomized between 2000-2018 at the Robert Debré University Hospital, Paris, France. A total of 188 children underwent splenectomy, including 101 (11.9%) from our newborn cohort and 87 referred to our center. Median (Q1-Q3) age at splenectomy was 4.1 years (range 2.5-7.3 years), with 123 (65.4%) and 65 (34.6%) children splenectomized at ≥3 years of age or <3 years of age, respectively. Median postsplenectomy follow-up was 5.9 years (range 2.7-9.2 years) yielding 1192.6 patient-years (PY) of observation. Indications for splenectomy were mainly acute splenic sequestration (101 [53.7%]) and hypersplenism (75 [39.9%]). All patients received penicillin prophylaxis; 98.3% received 23-valent polysaccharic pneumococcal (PPV-23) vaccination, and 91.9% a median number of 4 (range 3-4) pneumococcal conjugate vaccine shots prior to splenectomy. Overall incidence of invasive bacterial infection and thrombo-embolic events were 0.005 / PY (no pneumococcal infections) and 0.003 / PY, respectively, regardless of age at splenectomy. There was an increased proportion of children with cerebral vasculopathy in children splenectomized <3 years of age (0.037 / PY vs. 0.011 / PY; P<0.01). A significantly greater proportion of splenectomized than non-splenectomized children were treated with hydroxycarbamide (77.2% vs. 50.1%; P<0.01), suggesting a more severe phenotype in children who present spleen complications. If indicated, splenectomy should not be delayed in children, provided recommended pneumococcal prophylaxis is available. Spleen complications in childhood may serve as a marker of severity

The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients

Infections graves chez l enfant drépanocytaire (apport du dosage des antibiotiques dans la prise en charge)

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Thérapeutiques transfusionnelles dans la prise en charge de la vasculopathie cérébrale de l enfant drépanocytaire : échanges transfusionnels versus saignées-transfusions, bénéfice/risque des deux méthodes

La drépanocytose est une maladie génétique de l hémoglobine, exposant notamment les patients à un risque d accident vasculaire cérébral, qui peut être prévenu par la réalisation de transfusions sanguines ou d échanges transfusionnels itératifs. Nous avons décrit et comparé, en termes d efficacité et de tolérance, les protocoles transfusionnels proposés aux enfants drépanocytaires ayant une vasculopathie cérébrale dans 2 centres hospitaliers : dans l un, un programme d échanges transfusionnels manuels ou automatisés, et dans l autre un programme de transfusions itératives et de saignées-transfusions. L échange transfusionnel automatisé est la méthode qui permet la meilleure diminution du taux d HbS par séance en comparaison avec l échange transfusionnel manuel et la transfusion simple. En ce qui concerne la normalisation de la vasculopathie cérébrale, il n existait pas de supériorité des échanges transfusionnel, manuels et automatisés, par rapport aux transfusions simples. Le taux d allo-immunisation était plus important dans le groupe de transfusions itératives que dans le groupe d échanges transfusionnels. Les patients sous transfusions itératives présentaient une surcharge martiale plus fréquente et plus importante que les patients sous échanges transfusionnels. En conclusion, la réalisation de transfusions itératives chez les enfants drépanocytaires permet d améliorer la vasculopathie cérébrale de manière aussi efficace que les échanges transfusionnels manuels et automatisés. En revanche, cette méthode comporte d avantages de risques en termes d allo-immunisation, et surtout de surcharge martiale, difficilement accessible ensuite au traitement médicamenteux chélateurPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Dépistage néonatal de la drépanocytose en France

International audienceLe dépistage néonatal de la drépanocytose, la plus fréquente des maladies rares en France, a permis, entre 1984 et 2019, l’identification de 9 260 nouveau-nés atteints de drépanocytose (dont 586 en 2019) et de 180 687 hétérozygotes AS. Ce dépistage a permis la mise en œuvre précoce de mesures prophylactiques chez ces enfants, grâce à un tissu sanitaire et social structuré. Depuis que ce dépistage est organisé, on a pu observer, dès l’âge pédiatrique, une diminution majeure de la mortalité et de la morbidité de la drépanocytose, qui concerne notamment les complications infectieuses invasives, anémiques et neuro-vasculaires. En métropole, ce dépistage garde la particularité d’être ciblé vers les nouveau-nés dont les parents sont originaires de régions à risque. La fréquence croissante de la drépanocytose (1/1 303 nouveau-nés identifiés en 2019 contre 1/2 089 en 2009) et l’augmentation de la fréquence des hétérozygotes plaident aujourd’hui pour un dépistage systématique étendu à tous les nouveau-nés et pour une meilleure information sur cette maladie, devenue un enjeu majeur de santé publique

Douleurs et souffrances de jeunes drépanocytaires en Île-de-France

La drépanocytose est une maladie génétique qui s’est développée dans les zones impaludées. Du fait de la traite négrière et de la migration, elle est maintenant présente dans les pays occidentaux et notamment en France. Cette pathologie présente la particularité de provoquer des douleurs atroces. Cet article cherche dans un premier temps à comprendre les sensations douloureuses de jeunes drépanocytaires franciliens de 18 à 26 ans dans toute leur singularité, mais aussi à identifier quelques invariants communs. Face à ces sensations douloureuses, les jeunes cherchent du sens à leur malheur. Aussi, dans un second temps, nous analysons leurs postures face à la souffrance, et notamment le recours aux dimensions religieuses. Le refuge auprès d’une ou plusieurs religions aide les jeunes à ne pas se laisser engloutir par la maladie, à se projeter dans un avenir meilleur, à s’inscrire dans une vie qui a un sens au sein d’une communauté spirituelle.Sickle cell anemia is a genetic disorder that originally emerged in regions of the world where malaria is endemic. With the spread of populations out of these regions because of the slave trade and migration, sickle cell disease is now present in Western countries including France. This pathology has the peculiarity of causing excruciating pain. This article first seeks to understand the painful sensations of Ile-de-France sickle cell patients aged 18 to 26 in all their particularity, while also identifying some common invariants. We then analyze young people’s attitudes towards their suffering and in particular their recourse to spirituality. Turning towards one or more religious traditions helps young people to surmount their illness, to plan for a better future, and to find a meaningful life in a spiritual community