Nathalie Aladjidi

Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30‐year nationwide cohort of 1478 patients under 18 years of age

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15‐year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five‐year survival was 96·6% (95% confidence interval: 95·4–97·5%) overall, improving from 92% pre‐1998 to 99% post‐1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5‐year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single‐system patients, extended therapy duration, and more efficient second‐line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.

Cutaneous and visceral chronic granulomatous disease triggered by a Rubella Virus vaccine strain in children with primary immunodeficiencies

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.

Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort

Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2–17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1–16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1–28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7–28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

Class I phosphoinositide-3-kinases (PI3Ks) convert phosphoinositol-4,5-bisphosphate to phosphoinositol3,4,5-trisphosphate, a lipid second messenger produced mainly at plasma membranes where it recruits and activates pleckstrin homology domain-containing proteins, including the well known protein kinase AKT. Class IA PI3Ks are heterodimers composed of a catalytic subunit (p110a, p110β or p110δ) and a regulatory subunit (p85a, p85β or p85g, p50a and p55a). The catalytic subunits consist of an adaptor-binding domain (ABD), a Ras-binding domain (RBD), a protein kinase C homology-2 (C2) domain, a helical domain and a kinase domain. All of the class IA regulatory subunits contain two Src homology 2 domains, nSH2 and cSH2, separated by a coiled-coil domain known as inter-SH2 domain (iSH2). The p110δ catalytic subunit encoded by the PIK3CD gene is predominantly expressed in leukocytes. So far, six heterozygous germline gain-of-function mutations affecting either C2, helical or kinase domains of p110δ have been described to be responsible for the autosomal dominant “Activated PI3K-δ Syndrome 1” (APDS1): N334K, C416R, E525K, E525A, E1021K and E1025G (Figure 1A, B). A clinically and biologically similar disease “Activated PI3K-δ Syndrome 2” (APDS2) is caused by mutations in the PIK3R1 gene encoding the regulatory subunit p85a, p55a and p50a: splice site mutations responsible for amino acid 434-475 deletion. Both diseases although heterogeneous share a common phenotype characterized mainly by recurrent respiratory tract infections since childhood, bronchiectasis, lymphoproliferative disorder, and predisposition to development of B-cell lymphoma as main clinical complications. Biologically, APDS patients present with hypogammaglobulinemia and B-cell lymphopenia with an increased percentage of transitional B cells and decreased naive T-cell counts, especially T CD4 cells. Here, we report three unrelated patients with novel heterozygous mutations in PIK3CD (E81K and G124D) located in the ABD and the ABD-RBD linker region of p110δ as cause for APDS1. These two gain-of-function mutations thus affect domains not previously shown to be important in the increased p110δ activity characteristic of this syndrome. The patients were born at term and presented with recurrent upper and lower respiratory tract infections since childhood. For patient 1 (P1), a 13-year-old boy, no relevant family history was reported. He presented with hypogammaglobulinemia with decreased IgG and IgA but normal IgM serum levels (Table 1). Current complications include bronchiectasis, a lymphoproliferative syndrome with splenomegaly and hepatic fibrosis responsible for portal hypertension associated with gastrointestinal bleedings. P2, a 10-year-old boy, presented with recurrent otitis media and sinusitis since his first year of life. He had an adenoidectomy at 3 years of age. He presented with high IgM but normal IgG and IgA serum levels (Table 1). The serum levels of IgG2 (0.23; N: 0.56) and IgG4 (<0.002; N: 0.018) subclasses were low. P3, a 9-year-old girl, presented with growth retardation since 6 months of age (currently -

Physical health conditions and quality of life in adults with primary immunodeficiency diagnosed during childhood: A French Reference Center for PIDs (CEREDIH) study

Background: Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health‐related quality of life (HRQoL). Objective: To investigate long‐term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long‐term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. Methods: Patients were asked to complete health status questionnaires. A severity score (grade 1 [mild] to grade 4 [life‐threatening]) was assigned to each health condition. The HRQoL of patients was compared with age‐ and sex‐matched French normal values by using the 36‐item Short‐Form Survey (SF‐36) HRQoL questionnaire. Results: Among 329 participants, the mean age at evaluation was 27.6 years, with a 21‐year mean follow‐up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty‐five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3‐4 health conditions was highly significant for all physical and mental domains. Conclusion: Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.

Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes

Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months.

Reliable assessment of the incidence of childhood autoimmune hemolytic anemia

Childhood autoimmune hemolytic anemia (AIHA) is a rare and severe disease characterized by hemolysis and positive direct antiglobulin test (DAT). Few epidemiologic indicators are available for the pediatric population. The objective of our study was to reliably estimate the number of AIHA cases in the French Aquitaine region and the incidence of AIHA in patients under 18 years old.

Benefits of rituximab as a second-line treatment for autoimmune haemolytic anaemia in children: a prospective French cohort study

Childhood autoimmune haemolytic anaemia (AIHA) requires second‐line immunosuppressive therapy in 30–50% of cases. It appears that rituximab is indicated in such circumstances. This prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty‐one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 [interquartile range (IQR) 1·6–28·5] months. Forty‐six patients responded (75%) and the 6‐year relapse‐free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9–18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6‐year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6‐year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit‐risk ratio, allowing steroid withdrawal, with 37% of long‐term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long‐term results indicate the baseline to be challenged by new treatment approaches.

Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond–like syndrome

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Treatment with cyclosporin in auto-immune cytopenias in children: The experience from the French cohort OBS'CEREVANCE

Binal N. Shah, Chinedu A. Ezekekwu, Omowunmi Sonubi, Lewis L. Hsu, Richard S. Cooper, Victor R. Gordeuk Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois Department of Hematology, College of Medicine, University of Ibadan, Ibadan, Nigeria Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois