Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. ...We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median range age at last follow-up: 16.3 years (1.2-41.0 years) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
•At least 65% of cases of pES may be genetically determined.•Genetic findings have prognostic significance and may guide the physician's choice of a targeted treatment.
Summary
Despite major therapeutic improvements, children with relapsed/refractory Acute Myeloid Leukaemia still have poor outcomes and overall survival does not exceed 40%. New treatments are ...required to improve their outcome; Gemtuzumab ozogamicin (GO), an anti‐CD33 immunoconjugate antibody, is a potent cytotoxic agent whose efficacy has been demonstrated mainly in adults. The main objective of this retrospective multicentre study was to assess the outcome of children treated, between February 2008 and August 2019, with GO at a single 4.5 mg/m2 dose, in combination with Fludarabine, Cytarabine and antssshracyclines, in context of a first relapse (n = 26) or refractory disease (n = 3). The remission rate was 83% (24/29 children) and 20 children (69%) were allografted. With a median follow‐up of 1.2 years (range: 0.1–8), the overall survival was 49% (CI95% = 33; 72). Most common adverse event was febrile neutropenia with microbiological identification in 55% of cases. Veno‐occlusive disease occurred in 6 patients (21%), of which 5 subvened after bone marrow transplantation, and resolved within 2–32 days (median 10.5 days). Administration of GO in combination with FLA‐anthracyclines chemotherapy appears to be a good reinduction regimen for relapsed or refractory AML with a good safety profile. These results warrant larger prospective study.
Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or ...extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reported GATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome.
•Mutations of key transcription factor in myeloid malignancies.
We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the “CysPed ...equation”). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units.
In 2005-2006 Reunion Island experienced a massive outbreak of chikungunya, a mosquito-borne alphavirus infection. During this epidemic, early neonatal cases were observed with a highly probable ...mother-to-child transmission.
A retrospective descriptive study was conducted in 5 neonatal medicine departments. Chikungunya virus infection was confirmed by reverse transcription-polymerase chain reaction or specific serology in mothers and their newborns. Mothers were screened if they presented signs at delivery or if their neonates became ill on the first days of life.
Thirty-eight neonates were enrolled. All mothers, except 2 asymptomatic mothers, presented signs during the perinatal period (range, day(D) -4 to D+1). All neonates were symptomatic and presented symptoms on D3 to D7 (mean, D4). The mean interval between onset of maternal illness and onset of neonatal illness was 5 days (range, 3-9). The most frequent clinical signs in neonates were fever (79%), pain (100%), rash (82%), and peripheral edema (58%). Thrombocytopenia (76%), lymphopenia (47%), decreased prothrombin value (65%), and elevation of aspartate aminotransferase (77%) were detected. Complications included seizures (6), hemorrhagic syndrome (6), and hemodynamic disorders (10). Reverse transcription-polymerase chain reaction in cerebrospinal fluid was positive in 22 of 24 cases, and abnormal findings on brain magnetic resonance imaging (14 of 25) with white matter lesions or intraparenchymal hemorrhages or both were found. Echocardiography (16) showed myocardial hypertrophy (5), ventricular dysfunction (2), pericarditis (2), and coronary artery dilatation (6). One neonate died of necrotizing enterocolitis.
The chikungunya epidemic that occurred on La Reunion Island revealed for the first time the possibility of mother-to-child transmission in the perinatal period with a high rate of morbidity.
Persistence of rubella live vaccine has been associated with chronic skin granuloma in 3 children with primary immunodeficiency. We describe 6 additional children with these findings, including 1 ...with visceral extension to the spleen.
B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms ...stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.
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