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.
Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive ...long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IM). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 years (range, 6.8-50.0 years) and the median follow-up period was 11.3 years (range, 5.1-38.0 years). At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15-1.60, P=0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
Summary
Among 143 patients with elastase, neutrophil‐expressed (ELANE)‐related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic ...neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte‐colony stimulating factor (G‐CSF), on G‐CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem‐cell transplantation. During the disease’s natural history period (without G‐CSF; 1913 person‐years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3), high lymphocyte count (>3000/mm3) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G‐CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.
Refractory chronic immune thrombocytopenia (r‐cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r‐cITP is inconsistently defined in literature, ...contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r‐cITP including five pediatric definitions in 886 patients with cITP (median min‐max follow‐up 5.3 1.0–29.3 years). The pediatric definitions identified overlapping groups of various sizes (4%–20%) but with similar characteristics (higher proportion of immunopathological manifestations IM and systemic lupus erythematosus SLE), suggesting that they adequately captured the population of interest. Based on the 79 patients with r‐cITP (median follow‐up 3.1 0–18.2 years) according to the CEREVANCE definition (≥3 second‐line treatments), we showed that r‐cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r‐cITP. One patient (1%) experienced two grade five bleeding events after meeting r‐cITP criteria and while not receiving second‐line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r‐cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48–19.84, p = 7.8 × 10−4). In sum, children with cITP may be diagnosed with r‐cITP at any time point of the follow‐up and are at increased risk of IM and SLE. Second‐line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR.
Heterozygous germline
mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients ...in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.
Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe ...five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in
, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.
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