Abstract Background Inborn errors of immunity (IEI) with atopy (IEI-A) are a subgroup of IEIs with eczema as a prominent clinical feature that can mimic atopic dermatitis (AD). However, IEI-A-associated eczema can differ from that of classic AD, and its frequency, genotype-specific clinical patterns and temporal relationships with other manifestations of IEI-A (infections, allergic manifestations, autoimmunity) remain poorly defined. Objectives To characterize the frequency of eczema, timing and phenotypes in patients with IEI-A, and to explore the relationship of eczema with other clinical manifestations of IEI-A. Methods This retrospective study used data from the French National Referral Center for Primary Immunodeficiency Diseases (CEREDIH), focusing on patients with genetically defined IEI-A followed in three large CEREDIH-participating centres and available clinical data. Eczema frequency and onset in relationship to other clinical events, particularly severe-or-unusual infections, was assessed, as were eczema phenotypes, concomitant allergic manifestations, treatments and autoimmunity. Clustering analyses were computed to identify distinct IEI-A eczema-associated clinical phenotypes. Results Among 373 patients with IEI-A, varying widely by genotype, 50.9% (n = 190) had eczema. All patients deficient in DOCK8 (dedicator of cytokinesis-8) were affected, followed by those deficient in FOXP3 (n = 22/30; 73%) and those with STAT3 loss of function (n = 44/59; 75%). Onset was usually early (median 4 months). Eczema frequency and clinical presentation varied markedly across IEI-A genotypes; four phenotypic clusters were identified, with particular localizations and severe pruritus being strongly associated with pathogenic STAT3 or DOCK8 variants. For children with isolated eczema at 24 months, the risk of developing IEI-related severe or unusual infections was lower than that of persistent isolated eczema until the age of 6.8 years. Conclusions Eczema is a common, early feature of IEI-A, often preceding infections by years. While 38.4% (n = 73/190) of patients with IEI-A with eczema fulfilled the UK Working Party diagnostic criteria for AD, some clinical pictures may differ from that of classic AD. At a time when systemic AD treatments are rapidly advancing in paediatrics, recognizing these patterns to identify patients with IEI-A could refine diagnostic strategies, improve IEI detection among children with eczema, shorten the time to IEI-A diagnosis, guide tailored management and ensure patients receive the optimal care.

Background Autoimmune neutropenia (AIN) is the main cause of chronic neutropenia in children, but its infectious consequences remain poorly studied. The primary objective of this study was to evaluate infectious events leading to emergency department or hospital admissions during the first 2 years following the diagnosis of AIN in children.Methods We performed a retrospective, multicentre analysis of medical records from 21 French university hospitals of patients aged under 18 years diagnosed with AIN with positive antineutrophils autoantibodies. We collected data on emergency room visits and hospitalisations in the 2 years following diagnosis, causes of these events, microbiology results, management and outcome.Results One hundred and sixty-eight patients were enrolled. Median age at diagnosis of AIN was 13 months. AIN was predominantly diagnosed during an infectious episode (n=120, 71%). In the 2 years of follow-up after diagnosis, 248 events of emergency room visits and/or hospitalisations were reported (0.77 per patient-year). The most frequent diagnoses were common childhood viral or bacterial infections. The incidence rate of severe infections was 0.003 per patient-year. Despite the predominance of viral infections, 177 episodes (71%) led to hospitalisation and 166 (68%) to the initiation of antibiotic therapy, for a median duration of 7 days (IQR 3-10).Conclusion The risk of severe infections in children with AIN is low. During follow-up, we suggest being attentive to signs of severity during fever, particularly in children over 3 years of age and/or with other immunological comorbidities but not proposing systematic hospitalisation or additional antibiotic therapy.

Life-threatening hypereosinophilic syndrome (HES) is a rare medical emergency with limited therapeutic options in corticosteroid-refractory cases. Preliminary reports suggest that Janus kinase inhibitors may be beneficial in eosinophil-associated disorders, including HES. We conducted a nationwide multicenter retrospective study to assess ruxolitinib. Thirteen patients with severe acute HES and organ- or life-threatening involvement were included, most requiring intensive care, with massive baseline absolute eosinophil counts (AEC, median 45 × 109/L) and major involvement including eosinophilic myocarditis, ischemic strokes, and vascular thromboses. Ruxolitinib was initiated after a median of 7 days of corticosteroids. A rapid decline in absolute eosinophil counts was observed after initiation of ruxolitinib, with hematologic response rates of 54%, 85%, and 92% at Days 7, 14, and 30. Clinical improvement was observed across organ systems. Adverse events were manageable, although three deaths occurred during follow-up, only one of which occurred on ruxolitinib.

CAALL-F01 is a French prospective multicentric cohort study focused on children and adolescents, aged 1-17 years, with acute lymphoblastic leukemia (ALL). Patients with BCP-ALL were initially stratified based on age, white blood cell count, central nervous system (CNS) and/or testis involvement, genetics, and response to a prednisone prephase (PP). This stratification defined three risk groups: standard (B-SR), medium (B-MR), and high risk (B-HR). T-cell ALL patients were stratified into two groups, T-SR and T-HR, depending on CNS status and response to PP. As asparaginase is a major drug for childhood ALL and the pegylated form, pegaspargase (PEG), was not registered in the EU, a two-parallel-arm randomized clinical trial (RCT) was conceived and embedded in the cohort study. Randomization occurred before the first PEG infusion (D12), in the B-SR, B-MR, and T-SR groups. Patients were allocated (1:1) to either receive one infusion of PEG 2500 IU/m² on D12 (Arm A) or two infusions of 1250 IU/m² on D12 and D26 (Arm B) during induction. The dose assigned at randomization was used in subsequent treatment phases. Patients in the B-HR and T-HR groups received two infusions of PEG 2500 IU/m² during induction and 2500 IU/m² per infusion afterwards. The study had two primary objectives: 1) to assess the superiority of the fractionated scheme in terms of pharmacokinetics, 2) to assess the equivalence in tolerance of the two schemes. The co-primary endpoints were: 1) the incidence of adequate (>100 IU/L) asparaginase activity (AA) at the end of induction (D33 ± 1 day), 2) the incidence of severe (CTCAE Grade ≥ 3) asparaginase-related toxicities (CNS thrombosis, pancreatitis, severe allergy/anaphylaxis, and bilirubin elevation) from D12 of induction to D49. Results: From September 2016 to February 2022, 2032 patients (mean age, 5.4 years, 57% male) were included. Among these, 1624 patients in the B-SR (942 pts), B-MR (518 pts), or T-SR (164 pts) groups were randomly allocated to Arm A (814 pts) or Arm B (810 pts). The 2 arms were well balanced for baseline characteristics and prognostic features. The median follow-up was 44.6 months. The D33 AA was evaluable in 1475 (86.7%) randomized patients. The two-infusion arm was superior to the one-infusion arm, as D33 AA was ≥ 100 U/L in 87.9% of the patients in Arm A (653/743) versus 96.6% in Arm B (707/732) (p<.0001). The cumulative incidence of any of the four targeted toxicities was 15.9% in Arm A (129/814 pts) versus 14.1% in Arm B (114/810 pts) (difference, 1.78%, 95% confidence interval (CI) -1.70 to +5.26%); as the equivalence margin was set to 4%, equivalence was not demonstrated. Minimal residual disease levels assessed by clone-specific IG-TCR PCR at the end of induction and consolidation did not differ between the 2 arms, nor did the 48-month event-free survival (EFS, 95.5% CI 95 94.7-97.4 vs 97% CI 95.78-98.12). Post hoc analyses revealed that 48-month EFS in Arms A and B were not significantly different for patients with B-ALL (94.0%, 95CI 92.0-95.9 for Arm A vs 95.8%, 95CI 94.2-97.4 for Arm B, HR= 0.78, 95CI 0.51-1.20, p=0.26), nor for patients with T-cell ALL (88.0%, 95CI 81.2-95.2 for ArmA vs 87.2%, 95CI 80.1-94.9 for Arm B, HR=1.16, 96CI 0.49-2.72; p=0.74). Conclusion: For non-high-risk ALL, representing 80% of the study population, a fractionated scheme of pegaspargase (2 doses of 1250 IU/m²) is at least as well tolerated as a one-infusion scheme (1 dose of 2500 IU/m²) and more effective in terms of maintaining adequate AA throughout induction. However, at the current MFU of 44 months, this did not translate into superior long-term outcomes.

Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15–22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971–1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10–17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ITPR1 ), 2 ( ITPR2 ), and 3 ( ITPR3 ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant—NM_002224.3:c.7570C>T, p.Arg2524Cys—causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 + lymphopenia, a quasi-absence of naïve CD4 + and CD8 + cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg 2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Background Treatment summaries and a personalized survivorship care plans based on internationally approved, organ-specific follow-up care recommendations are essential in preserving the health and quality of life for cancer survivors. Cohorts made up of survivors of childhood cancer have made significant contributions to the understanding of early mortality, somatic late complications, and psychosocial outcomes among former patients. New treatment protocols are needed to enhance survival and reduce the potential risk and severity of late effects, and working with treatment databases is crucial in doing so. Construction and content In the GOCE (Grand Ouest Cancer de l’Enfant [Western Region Childhood Cancer]) network, in a participative approach, we developed the LOG-after medical tool, on which health data are registered and can be extracted for analysis. Its name emphasizes the tool’s goal, referring to ‘logiciel’ (the French word for software) that focuses on the period “after” the acute phase. This tool is hosted on a certified health data server. Several interfaces have been developed that can be used depending on the user’s profile. Here we present this innovative co-constructed tool that takes national aspects into account, including the results of the feasibility/satisfaction study and its perspective. Utility and discussion The database contains data relating to 2558 patients, with samples from 1702 of these (66.54%) being held in a tumor bank. The average year in which treatment started was 2015 (ranging from December 1967 to November 2022: 118 patients were treated before 2012 and registered retrospectively when seen in long-term follow-up consultations or for another cancer since November 2021). A short questionnaire was distributed to healthcare professionals using the tool (physicians and research associates or technicians, n = 14), of whom 11 answered and were all satisfied. Access to the patient interface is currently open to 124 former patients. This was initially offered to 30 former patients who were over 15 years old, affected by the disease within the last 5 years, and had agreed to test it. Their opinions were collected by their doctor by e-mail, telephone, or during a consultation in an open-ended question and a non-directive interview. All patients were satisfied with the tool, with interest in testing it in the long term. Some former patients found that the tool provided them with some ease of mind; one, for instance, commented: "I feel lighter. I allow myself to forget. I know I will get a notification when the time comes." Conclusions Freely available to all users, LOG-after: (1) provides help with determining personalized survivorship care plans for follow-up; (2) builds links with general practitioners; (3) empowers the patient; and (4) enables health data to be exported for analysis. Database URL for presentation: https://youtu.be/2Ga64iausJE

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.

La période post-traitement une part fondamental de la prise en charge du cancer pédiatrique. Durant cette période, les difficultés scolaires et psychologiques chez les survivants d’un cancer pédiatriques (SCP) sont connues et peuvent être pronostic sur la bonne réintégration sociale. Cette étude estime l’influence de la déprivation sociale du foyer de l’enfant sur ces difficultés. Notre étude se base sur une base de données multicentrique, et se concentre sur les SCP avant reçu une évaluation psychosociale au cours de leur suivi, de 2013 à 2020. Nous rapportons les données des difficultés scolaires et psychologiques. Le statut socio-économique du foyer de l’enfant a été estimé par un score de déprivation sociale. Nous rapportons les données de 1003 patients. Les difficultés scolaires ont été rapportés chez 22% d’entre eux. Une déprivation sociale plus importante était associée à la survenue de difficultés scolaires. La rechute tumorale, le traitement par greffe de cellules souches hématopoïétiques, et les tumeurs du système nerveux central étaient d’autres facteurs de risque. Dans le groupe des patients avec tumeurs du système nerveux central, la déprivation sociale était également un facteur associé à la survenue de difficultés scolaires. Les difficultés psychologiques n’étaient quant à elles pas associées avec le score de déprivation. Il existe un lien entre statut socio-économique et les difficultés scolaires chez les SCP. Des analyses complémentaires doivent être réalisées, notamment chez les enfants avec tumeurs du système nerveux central, qui est la population la plus concernée.

Autoimmune cytopenia (AIC) in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS'CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer >= 1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk [RR], 3.67; 95% confidence interval [CI], 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period.

Introduction: Hematological involvement (HI) is a life-threatening involvement of Langerhans cell histiocytosis (LCH). Since 1975, its definition is based on the Lahey criteria: Anemia (Hb <10 g/dL and <9 g/dL in infants) and/or thrombocytopenia (platelet count <100x10 9/l). Methods: Among 2,234 patients < 18 years enrolled in the French histiocytosis registry (cutoff date May 2023), 303 patients presented HI. We differentiated mild HI (MHI) (Hb > 7 g/dl and Platelets > 20x10 9/l) from severe HI (SHI) (Hb ≤ 7 g/dl and Platelets ≤ 20x10 9/l) by using usual cutoffs for transfusion requirements. Results: Median age at diagnosis was one year and sex was male in 49%. The median follow-up in the 258 survivors was 10.9 years, while death occurred after a median of 0.9 years in the 45 patients who died (Figure 1A). Only 3 patients died later than two years of initial diagnosis. The HI was mild in 150 cases and severe in 153 cases. BRAF v600E was found in 88 among the 101 patients for which mutation analysis was documented. Patients with SHI had significantly more lung involvement (35 % vs 19 %), more hepatic involvement (72 % vs 21 %), and more skin involvement (85 % vs 61 %). Morphological bone marrow infiltration by CD1a positive cells could not differentiate between SHI and MHI and bone marrow features were hardly informative. Signs of myelofibrosis were documented in 9 patients mostly later in the disease course. Lastly, 44 macrophage activation syndromes were observed exclusively in SHI. For 11 of those patients panel analyses of hemophagocytic lymphohistiocytosis genes did not show any bi-allelic pathogenic variants. 20 patients did not receive any therapy, including one with SHI and 19 with MHI. An intensive approach with hematologic stem cell transplantation (HSCT) (n=11) and 2-Cda-Cytarabine (2-Cda-AraC) (n=44) was proposed almost only for SHI. MAPK-inhibition was used in 40 patients. Three deaths were observed among the MHI and 42 among the SHI. From 1983 to 1998 mortality was about 50% and 30 of 63 patients died. With the establishment of the second-line treatment by 2-Cda-AraC mortality decreased drastically and from 1998 to 2014 only 13 of 194 patients died. From 2014 on patients received exclusively MAPK-inhibition as second line treatment and 2 of 46 patients died (one without therapy, one at the initiation). The overall survival is depicted in figure 1A. Neurodegenerative (ND) complications were observed in 32 patients (10.5%) with a median delay of 4.8 years after initial LCH diagnosis and incidence of ND was independent of the MHI or SHI group (Figure 1B). Conclusion: In Langerhans cell histiocytosis, the classic definition of hematological involvement by the Lahey criteria should be reconsidered. HI may be limited to severe HI that included almost all medical complications and warrants innovative approaches, while mild HI can be managed by the classic therapeutical approach. Even if progress has been achieved in the treatment of LCH patients with HI with more than 95% achieving short-term control, long term neurodegeneration remains a challenge in this group of patients, which warrants further research. Figure 1: A) Kaplan-Meier curve of cumulative incidence of death for all the 303 patients, regardless of therapy. B) Risk of clinical neurodegenerative symptoms in the same cohort (considering death as a censor).

Abstract Background Treatment summary and a personalized survivorship care plan based on internationally approved, organ-specific follow-up care recommendations are essential to preserve health and quality of life. Cohorts have made significant contributions to the understanding of early mortality, somatic late complications, and psychosocial outcomes among childhood cancer survivors. New treatment protocols have the goal to increase the cure and reduce the potential risk and severity of late effects. Therefore, pursue such databases with modern treatments are necessary. Construction and content In the GOCE network, in a participative approach, we developed the LOG-after medical tool, on which health data are registered and can be extracted for analysis. This tool is hosted on a web server, which is health data host certified and several interfaces have been developed depending on the user’s profile. Here we present the construction of the software, the results of the feasibility/satisfaction study with a descriptive analysis. Utility and discussion The database contains data of 2558 patients of which for 1702, a tumor bank exists (66.54%). The average treatment start period was April 2015 (ranging from December 1967 to November 2022; 118 patients were treated before 2012 and registered retrospectively when seen in long-term foloow-up consultations or for another cancer since November 2021). When questioned about their satisfaction of the tool, all health care professionals were satisfied. Access to the patient interface is currently open to 124 former patients. This was initially offered to 30 former patients, older than 15 years, affected by the disease within the last 5 years, who agreed to test it. All patients were satisfied with the tool, with an interest to test it in the long-term. Some of them testified to a decrease in mental load, as this verbatim : "I feel lighter. I allow myself to forget, I know I will get a notification when the time comes." Conclusions Freely available to all users, LOG-after enables (1) help with suggesting a personalized survivorship care plan for middle or long-term follow-up, (2) link with general practitioner, (3) empowerment of the patient, (5) an export of health data for analysis. Database URL for presentation: https://youtu.be/2Ga64iausJE

BACKGROUND:Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype.OBJECTIVE:We revisited the significance of heterozygous FASLG mutations as a cause of ALPS.METHODS:Clinical features and biomarkers were analyzed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL.RESULTS:Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B12, and usually no soluble FasL. In contrast, heterozygous variants affected FasL function by reducing expression, impairing trimerization, or preventing Fas binding. However, they were not associated with elevated DNT and vitamin B12, and they did not affect FasL-mediated cytotoxicity. The dominant-negative effects of previously published variants could not be confirmed. Even Y166C, causing loss of Fas binding with a dominant-negative effect in biochemical assays, did not impair cellular cytotoxicity or cause vitamin B12 and DNT elevation.CONCLUSION:Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.

Pediatric Blood & CancerVolume 70, Issue 9 e30353 LETTER TO THE EDITOR Pediatric post-transplant lymphoproliferative disorder: Do not overlook digestive involvement Baptiste Le Calvez, Corresponding Author Baptiste Le Calvez [email protected] orcid.org/0000-0001-5148-3792 Pediatric Oncology, Nantes University Hospital, Nantes, France Nantes Université, Inserm UMR 1307, CNRS UMR 6075, CRCI2NA, Université d'Angers, Nantes, France Correspondence Baptiste Le Calvez, Pediatric Oncology, Nantes University Hospital, 9 quai Moncousu, Nantes, France. Email: [email protected]Search for more papers by this authorBatoul Samarji, Batoul Samarji Pediatric Gastroenterology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorGervaise Hubert, Gervaise Hubert Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorEric Lagrue, Eric Lagrue Department of Pathology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorMarion Eveillard, Marion Eveillard orcid.org/0000-0001-7206-5135 Hematology Biology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorCaroline Thomas, Caroline Thomas orcid.org/0000-0002-3939-9317 Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorAudrey Grain, Audrey Grain orcid.org/0000-0003-1547-8229 Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this author Baptiste Le Calvez, Corresponding Author Baptiste Le Calvez [email protected] orcid.org/0000-0001-5148-3792 Pediatric Oncology, Nantes University Hospital, Nantes, France Nantes Université, Inserm UMR 1307, CNRS UMR 6075, CRCI2NA, Université d'Angers, Nantes, France Correspondence Baptiste Le Calvez, Pediatric Oncology, Nantes University Hospital, 9 quai Moncousu, Nantes, France. Email: [email protected]Search for more papers by this authorBatoul Samarji, Batoul Samarji Pediatric Gastroenterology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorGervaise Hubert, Gervaise Hubert Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorEric Lagrue, Eric Lagrue Department of Pathology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorMarion Eveillard, Marion Eveillard orcid.org/0000-0001-7206-5135 Hematology Biology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorCaroline Thomas, Caroline Thomas orcid.org/0000-0002-3939-9317 Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this authorAudrey Grain, Audrey Grain orcid.org/0000-0003-1547-8229 Pediatric Oncology, Nantes University Hospital, Nantes, FranceSearch for more papers by this author First published: 19 April 2023 https://doi.org/10.1002/pbc.30353Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Absalon MJ, Khoury RA, Phillips CL. Post-transplant lymphoproliferative disorder after solid-organ transplant in children. Semin Pediatr Surg. 2017; 26(4): 257-266. 2Weisert M, Harake D, Hede S, Russell M, Alejos J, Menteer J. A multicenter survey on post-transplant lymphoproliferative disorders in pediatric heart transplant recipients: a case for development of consensus guidelines for screening, surveillance, and treatment? Pediatr Transplant. 2020; 24(5):e13730. 3Webber SA, Naftel DC, Fricker FJ, et al. Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet North Am Ed. 2006; 367(9506): 233-239. 4Ylinen E, Merras-Salmio L, Jahnukainen T. Gastrointestinal symptoms and endoscopy findings after pediatric solid organ transplantation: a case series. Pediatr Transplant. 2022; 26(7):e14374. 5Kocoshis SA. Endoscopic diagnosis of lymphoproliferative disease after solid organ transplantation. J Pediatr Gastroenterol Nutr. 1999; 28(4): 375-376. 6O'Connor JA, Cogley C, Burton M, Lancaster-Weiss K, Cordle RA. Posttransplantation lymphoproliferative disorder: endoscopic findings. J Pediatr Gastroenterol Nutr. 2000; 31(4): 458. 7Tai CC, Curtis JL, Szmuszkovicz JR, et al. Abdominal involvement in pediatric heart and lung transplant recipients with posttransplant lymphoproliferative disease increases the risk of mortality. J Pediatr Surg. 2008; 43(12): 2174-2177. 8Sharma A, Bennani NN, Habermann T, Murray JA. Post-transplant lymphoproliferative disorder involving the gastrointestinal tract: 1186. Am J Gastroenterol. 2017; 112: S651-S652. Volume70, Issue9September 2023e30353 ReferencesRelatedInformation

Langerhans cell histiocytosis is a rare condition affecting the temporal bone in up to 60% of cases. Symptoms are non-specific and the differential diagnosis includes infection, benign lesions such as cholesteatoma, and malignant lesions of the skull base. Here, we report the case of a 14-yearold child referred with chronic ear discharge, and background of multifocal Langerhans cell histiocytosis 9 years prior. Recurrence of Langerhans cell histiocytosis was initially suspected and systemic treatment was considered. Further imaging workup and surgical exploration of the mastoid showed a secondary acquired cholesteatoma arising from a dehiscent posterior ear canal wall. Surgical removal of the cholesteatoma was performed with a canal wall down procedure. We review the presentation and management of temporal bone Langerhans cell histiocytosis. We recommend that cholesteatoma should be considered in case of recurrence of otological symptoms in patients with a background of Langerhans cell histiocytosis.

Abstract Background Thanks to an improved therapeutic regimen in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), 5 year‐overall survival now exceeds 90%. Unfortunately, the 25% of children who relapse have an initial poor prognosis, potentially driven by pre‐existing or emerging molecular anomalies. The latter are initially and essentially identified by cytogenetics. However, some subtle alterations are not visible through karyotyping. Methods Single nucleotide polymorphisms (SNP) array is an alternative way of chromosomal analysis allowing for a more in‐depth evaluation of chromosomal modifications such as the assessment of copy number alterations (CNA) and loss of heterozygosity (LOH). This method was applied here in retrospective diagnosis/relapse paired samples from seven children with BCP‐ALL and in a prospective cohort of 38 newly diagnosed childhood cases. Results In the matched study, compared to the initial karyotype, SNP array analysis reclassified two patients as poor prognosis cases. Modulation during relapse was seen for 4 CNA and 0.9 LOH. In the prospective study, SNP reclassified the 10 patients with intermediate karyotype as 7 good prognosis and 3 poor prognosis. Ultimately, in all the children tested, SNP array allowed to identify additional anomalies compared to conventional karyotype, refine its prognostic value and identify some druggable anomalies that could be used for precision medicine. Overall, the anomalies detected could be segregated in four groups respectively involved in B‐cell development, cell proliferation, transcription and molecular pathways. Conclusion SNP therefore appears to be a method of choice in the integrated diagnosis of BCP ALL, especially for patients initially classified as intermediate prognosis. This complementary method of both cytogenetics and high throughput sequencing allows to obtain further classified information and can be useful in case of failure of these techniques.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evo-lution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy -number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.

Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second-line treatment use, association with clinical and/or biological immunopathological manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex, or IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex, and IMs on cITP outcomes. We included 886 patients with a median (min-max) follow-up duration of 5.3 (1.0-29.3) years. We identified an age cutoff that dichotomized the risk of the outcomes and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four-fold higher risk of grade ≥3 bleeding, second-line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, second-line treatment use, and SLE diagnosis, respectively. The combination of these three risk factors defined outcome-specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long-term outcomes of pediatric cITP. We defined risk groups for each outcome, which will help clinical management and further studies.