Publications by authors named "Isabelle Pellier"

72 Publications

[Consequences of childhood cancer in the quest for first job in the Grand Ouest inter-region: A mixed-method study designed from the Grand Ouest Cancer de l'Enfant (GOCE) organization in childhood cancer survivors and professionals].

Bull Cancer 2021 Oct 13. Epub 2021 Oct 13.

CHU de Poitiers, unité d'onco-hématologie pédiatrique, Inserm CIC 1402, 86000 Poitiers, France. Electronic address:

Introduction: The professional situation of patients treated for childhood cancer differs from country to country. The aim of the study is to study, with the French sociocultural specificities, the first professional integration of these young people.

Methods: A sequential quantitative-qualitative mixed approach associates 16 individual interviews and responses to a self-questionnaire of 254 young cancer survivors (sex-ratio=1, median age 23.5 years diagnosed between 2000 and 2010; 68% leukemia) to 30 individual and collective interviews of professionals. Results They seem to have had fewer difficulties than the general population to find their first job (33% vs. 44%). Young women had more difficulties, young people thought they had stopped studying too early and those who mentioned their sequelae (mainly psychological and neurocognitive). The qualitative phase shows that, in this context, the information provided during the job interview plays an important role in access to the first job.

Discussion: The study showed a need for information, communication and training for all actors whose main axes could be: i) for young people: learn to introduce themselves and adapt speeches and postures, be aware of their non-obligation to reveal a situation relating to health and to the handicap; ii) for the medical profession: to promote communication and to find spaces for exchanges between specialists, generalists, occupational physicians; iii) for employers: better know the disease and the laws to adapt their eyes and practices.
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http://dx.doi.org/10.1016/j.bulcan.2021.06.015DOI Listing
October 2021

Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study.

J Pediatr 2021 Sep 13;236:204-210. Epub 2021 May 13.

Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, University Lyon 1, Lyon, France; Apoptosis, Cancer and Development Laboratory, INSERM U1052, CNRS UMR5286, CRCL, Lyon, France.

Objective: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT).

Study Design: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units.

Results: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents.

Conclusions: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.
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http://dx.doi.org/10.1016/j.jpeds.2021.05.016DOI Listing
September 2021

Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.

Clin Microbiol Infect 2021 Aug 1;27(8):1124-1130. Epub 2021 Apr 1.

Département de Médecine Intensive-Réanimation, CHU d'Angers, Université d'Angers, Angers, France.

Objectives: To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening.

Methods: We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10.

Results: The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58-86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45-2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points.

Conclusion: In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo.

Trial Registration: ClinicalTrials.gov Identifier: NCT04325893 (https://clinicaltrials.gov/ct2/show/NCT04325893).
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http://dx.doi.org/10.1016/j.cmi.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015393PMC
August 2021

Testosterone deficiency in men surviving childhood acute leukemia after treatment with hematopoietic stem cell transplantation or testicular radiation: an L.E.A. study.

Bone Marrow Transplant 2021 06 16;56(6):1422-1425. Epub 2021 Jan 16.

Department of Pediatric Hematology and Oncology, Timone Enfants Hospital and Aix-Marseille University, Marseille, France.

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4-6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).
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http://dx.doi.org/10.1038/s41409-020-01180-yDOI Listing
June 2021

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

Haematologica 2021 Jan 14. Epub 2021 Jan 14.

Pediatric Oncology Immunology Hematology Unit, Armand-Trousseau University Hospital, AP-HP, Paris.

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 (IMs). 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 (6.8-50.0) years and the median follow-up period was 11.3 (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 IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs 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 (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, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
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http://dx.doi.org/10.3324/haematol.2020.271106DOI Listing
January 2021

[What should we remember from 2020?]

Bull Cancer 2021 Jan 6;108(1):55-66. Epub 2021 Jan 6.

Université de Bordeaux, Inserm U1218, 33000 Bordeaux, France.

The editorial committee of the Bulletin du Cancer is proud to comply with his annual analysis of some of the worldwide updates in oncology that emerge in 2020. We know that all new breakthroughs will not be addressed and apologise for not being comprehensive, but we hope that the topics deciphered herein will bring the reader interesting information in his daily practice in gyneco-oncology, uro-oncology, neuro-oncology, digestive oncology, pneumo-oncology, hemato-oncology, pediatric oncology, or in palliative care.
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http://dx.doi.org/10.1016/j.bulcan.2020.12.002DOI Listing
January 2021

[Interactions optimization between pediatricians and adults' physicians for patient benefit in oncology].

Bull Cancer 2021 Feb 17;108(2):137-138. Epub 2020 Dec 17.

Centre hospitalo-universitaire d'Angers, immunologie-hématologie-oncologie pédiatrique, 4, rue Larrey, 49933 Angers, France.

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http://dx.doi.org/10.1016/j.bulcan.2020.10.012DOI Listing
February 2021

Prospective Evaluation of the First Option, Second-Line Therapy in Childhood Chronic Immune Thrombocytopenia: Splenectomy or Immunomodulation.

J Pediatr 2021 04 17;231:223-230. Epub 2020 Dec 17.

Pediatric Hematology Unit, CIC1401, INSERM CICP, University Hospital of Bordeaux, Bordeaux, France; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE), University Hospital of Bordeaux, Bordeaux, France. Electronic address:

Objective: To describe 4 subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine, or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia.

Study Design: Selection of patients with chronic immune thrombocytopenia from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine, or rituximab as a first second-line treatment.

Results: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years, respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years, respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival was 62% (95% CI 55; 71). It was 85% (95% CI 77; 95) for the 56 patients treated with splenectomy, 60% (95% CI 44; 84) for the 23 patients treated with rituximab, 46% (95% CI 30; 71) for the 24 patients treated with azathioprine, and 37% (95% CI 24; 59) for the 34 patients treated with hydroxychloroquine (log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve event-free survival (P = .05). Female teenagers with antinuclear antibody positivity benefited from hydroxychloroquine therapy.

Conclusions: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.018DOI Listing
April 2021

Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

J Exp Med 2020 11;217(11)

Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
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http://dx.doi.org/10.1084/jem.20192262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596820PMC
November 2020

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol 2020 Jul;40(5):786-787

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-EnfantsMalades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.
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http://dx.doi.org/10.1007/s10875-020-00793-8DOI Listing
July 2020

Environmental exposures related to parental habits in the perinatal period and the risk of Wilms' tumor in children.

Cancer Epidemiol 2020 06 1;66:101706. Epub 2020 Apr 1.

CRESS, UMR1153, INSERM, Université de Paris, Villejuif, France; National Registry of Childhood Cancers, APHP, CHU Paul Brousse, Villejuif and CHU de Nancy, France.

Introduction: Wilms' tumor is the most frequently diagnosed renal tumor in children. Little is known about its etiology. The aim of this study was to investigate the potential role of specific exposures related to parental habits such as parental smoking, maternal alcohol consumption and the use of household pesticides during pregnancy.

Methods: The ESTELLE study was a nationwide case-control study that included 117 Wilms' tumor cases and 1100 control children from the general French population, frequency-matched by age and gender. Unconditional logistic regression was used to estimate odds ratios and 95 % confidence intervals.

Results: After controlling for matching variables and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with the risk of Wilms' tumor in children (OR 1.6 [95 % CI 1.1-2.3]). Insecticides were the most commonly reported type of pesticide and there was a positive association with their use (OR 1.7 [95 % CI 1.1-2.6]. The association was stronger when they were used more often than once a month (OR 1.9 [95 % CI 1.2-3.0]. Neither maternal smoking during pregnancy nor paternal smoking during preconception/pregnancy was associated with a risk of Wilms' tumor (ORs 1.1[95 % CI 0.7-1.8] and 1.1 [95 % CI 0.7-1.7], respectively). No association was observed with maternal alcohol intake during pregnancy (OR 1.2 [95 % CI 0.8-2.0]).

Conclusion: Our findings suggest an association between the maternal use of household pesticides during pregnancy and the risk of Wilms' tumor.
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http://dx.doi.org/10.1016/j.canep.2020.101706DOI Listing
June 2020

In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Autoimmun Rev 2020 Sep 30;19(9):102525. Epub 2020 Mar 30.

Synapse Research Institute, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.
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http://dx.doi.org/10.1016/j.autrev.2020.102525DOI Listing
September 2020

Liver metastasis at diagnosis in children with nephroblastoma enrolled in SIOP2001 protocol: A French multicentric study.

Pediatr Blood Cancer 2020 06 24;67(6):e28201. Epub 2020 Mar 24.

Children and Adolescents Oncology Department, Gustave Roussy, Villejuif, France.

Background: Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear.

Patients And Methods: The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed.

Results: From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively.

Conclusion: Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites.
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http://dx.doi.org/10.1002/pbc.28201DOI Listing
June 2020

Maternal and perinatal characteristics, congenital malformations and the risk of wilms tumor: the ESTELLE study.

Cancer Causes Control 2020 May 6;31(5):491-501. Epub 2020 Mar 6.

CRESS, UMR1153, INSERM, Université de Paris, Villejuif, France.

Purpose: Wilms tumor (WT), or nephroblastoma, is an embryonic tumor that constitutes the most common renal tumor in children. Little is known about the etiology of WT. The aim of this study was to investigate whether maternal or perinatal characteristics were associated with the risk of WT.

Methods: The ESTELLE study is a national-based case-control study that included 117 cases of WT and 1,100 controls younger than 11 years old. The cases were children diagnosed in France in 2010-2011 and the controls were frequency matched with cases by age and gender. The mothers of case and control children responded to a telephone questionnaire addressing sociodemographic and perinatal characteristics, childhood environment, and lifestyle. Unconditional logistic regression models adjusted on potential cofounders were used to estimate the odds ratios (OR) and their confidence intervals (95% CI).

Results: High birth weight and the presence of congenital malformation were associated with WT (OR 1.9 [95% CI 1.0-3.7] and OR 2.5 [95% CI 1.1-5.8], respectively). No association with breastfeeding or folic acid supplementation was observed.

Conclusions: Although potential recall bias cannot be excluded, our findings reinforce the hypothesis that high birth weight and the presence of congenital malformation may be associated with an increased risk of WT. Further investigations are needed to further elucidate the possible role of maternal characteristics in the etiology of WT.
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http://dx.doi.org/10.1007/s10552-020-01288-yDOI Listing
May 2020

Second-line treatment trends and long-term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years.

Br J Haematol 2020 06 4;189(5):931-942. Epub 2020 Mar 4.

Pediatric Hematology Unit, CIC1401, INSERM CICP, University Hospital of Bordeaux, Bordeaux, France.

Childhood chronic immune thrombocytopenic purpura (cITP) is a rare disease. In severe cases, there is no evidence for the optimal therapeutic strategy. Our aim was to describe the real-life management of non-selected children with cITP at diagnosis. Since 2004, patients less than 18 years old with cITP have been enrolled in the national prospective cohort, OBS'CEREVANCE. From 1990 to 2014, in 29 centres, 392 children were diagnosed with cITP. With a median follow-up of six years (2·0-25), 45% did not need second-line therapy, and 55% (n = 217) received one or more second lines, mainly splenectomy (n = 108), hydroxychloroquine (n = 61), rituximab (n = 61) or azathioprine (n = 40). The overall five-year further second-line treatment-free survival was 56% [95% CI 49·5-64.1]. The use of splenectomy significantly decreased over time. Hydroxychloroquine was administered to children with positive antinuclear antibodies, more frequently older and girls, and reached 55% efficacy. None of the patients died. Ten years after the initial diagnosis, 55% of the 56 followed children had achieved complete remission. Children with cITP do not need second-line treatments in 45% of cases. Basing the treatment decision on the pathophysiological pathways is challenging, as illustrated by ITP patients with positive antinuclear antibodies treated with hydroxychloroquine.
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http://dx.doi.org/10.1111/bjh.16448DOI Listing
June 2020

Depicting the genetic architecture of pediatric cancers through an integrative gene network approach.

Sci Rep 2020 01 27;10(1):1224. Epub 2020 Jan 27.

Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France.

The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of gene-disease relationship and have been performed on adult but not pediatric cancers. We performed a deep multi-layer understanding of pan-cancer transcriptome data selected from the Treehouse Childhood Cancer Initiative through a co-expression network analysis. We identified six modules strongly associated with pediatric tumor histotypes that were functionally linked to developmental processes. Topological analyses highlighted that pediatric cancer predisposition genes and potential therapeutic targets were central regulators of cancer-histotype specific modules. A module was related to multiple pediatric malignancies with functions involved in DNA repair and cell cycle regulation. This canonical oncogenic module gathered most of the childhood cancer predisposition genes and clinically actionable genes. In pediatric acute leukemias, the driver genes were co-expressed in a module related to epigenetic and post-transcriptional processes, suggesting a critical role of these pathways in the progression of hematologic malignancies. This integrative pan-cancer study provides a thorough characterization of pediatric tumor-associated modules and paves the way for investigating novel candidate genes involved in childhood tumorigenesis.
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http://dx.doi.org/10.1038/s41598-020-58179-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985191PMC
January 2020

Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

Pediatr Rheumatol Online J 2020 Jan 2;18(1). Epub 2020 Jan 2.

Unité d'Onco-Hémato-Immunologie pédiatrique, CHU Angers, 4 rue Larrey, 49933, Angers, France.

Background: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month.

Methods: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups.

Results: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 10/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 10/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99]).

Conclusions: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 10/L or platelets < 300 × 10/L.
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http://dx.doi.org/10.1186/s12969-019-0376-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941319PMC
January 2020

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

Family history of cancer and the risk of childhood brain tumors: a pooled analysis of the ESCALE and ESTELLE studies (SFCE).

Cancer Causes Control 2019 Oct 9;30(10):1075-1085. Epub 2019 Aug 9.

CRESS, UMR1153, Inserm, Paris Descartes University, Paris, France.

Purpose: Although some specific genetic syndromes such as neurofibromatosis (NF) have been identified as risk factor of childhood brain tumors (CBT), the potential role of inherited susceptibility in CBT has yet to be elucidated.

Methods: To further investigate this, we conducted a pooled analysis of two nationwide case-control studies ESCALE and ESTELLE. The mothers of 509 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency-matched by age and gender, responded to a telephone interview conducted by trained interviewers. Pooled odds ratio (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression.

Results: CBT was significantly associated with the family history of cancer in relatives (OR 1.2, 95% CI 1.0-1.5). The OR was slightly higher for maternal relatives than for paternal relatives, and when at least two relatives had a history of cancer. CBT was significantly associated with a family history of brain tumor (OR 2.1, 95% CI 1.3-3.7). This association seemed stronger for first-degree relatives (mother, father, and siblings), for whom, by contrast, no association was seen for cancers other than CBT. No specificity by CBT subtypes or by age of the children were found for any of these findings.

Conclusion: Our findings support the hypothesis of a familial susceptibility of CBT, not due to being a known NF carrier.
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http://dx.doi.org/10.1007/s10552-019-01214-xDOI Listing
October 2019

Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes.

Blood 2019 07 2;134(1):9-21. Epub 2019 Apr 2.

Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE) and.

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 (, , , , , , , , and ), 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.
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http://dx.doi.org/10.1182/blood-2018-11-887141DOI Listing
July 2019

Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front BB-SFOP chemotherapy-Analysis of a French pediatric historical cohort.

PLoS One 2019 8;14(3):e0212107. Epub 2019 Mar 8.

Department of Pediatric Oncology, University Hospital, Angers, France.

Background: Visual outcome is one of the main issues in the treatment of optic pathway glioma in childhood. Although the prognostic factors of low vision have been discussed extensively, no reliable indicators for visual loss exist. Therefore, we aimed to define initial and evolving factors associated with long-term vision loss.

Methods: We conducted a multicenter historical cohort study of children treated in France with up-front BB-SFOP chemotherapy between 1990 and 2004. Visual acuity performed at the long-term follow-up visit or within 6 months prior was analyzed. Logistic regression analysis was used to estimate the effects of clinical and radiological factors on long-term visual outcome.

Findings: Of the 180 patients in the cohort, long-term visual acuity data were available for 132 (73.3%) patients (median follow-up: 14.2 years; range: 6.1-25.6). At the last follow-up, 61/132 patients (46.2%) had impaired vision, and 35 of these patients (57.3%) were partially sighted or blind. Multivariate analysis showed that factors associated with a worse prognosis for long-term visual acuity were an age at diagnosis of < 1 year (OR 3.5 [95% CI: 1.1-11.2], p = 0.04), tumor extent (OR 4.7 [95% CI: 1.2-19.9], p = 0.03), intracranial hypertension requiring one or more surgical procedures (OR 5.6 [95% CI: 1.8-18.4], p = 0.003), and the need for additional treatment after initial BB-SFOP chemotherapy (OR 3.5 [95% CI: 1.1-11.9], p = 0.04). NF1 status did not appear as a prognostic factor, but in non-NF1 patients, a decrease in tumor volume with contrast enhancement after BB-SFOP chemotherapy was directly associated with a better visual prognosis (OR 0.8 [95% CI: 0.8-0.9], p = 0.04).

Interpretation: Our study confirms that a large proportion of children with optic pathway glioma have poor long-term outcomes of visual acuity. These data suggest new prognostic factors for visual acuity, but these results need to be confirmed further by large- and international-scale studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212107PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407847PMC
January 2020

[Use of blinatumomab in children acute lymphoblastic leukemia in the Grand Ouest interregion: A chance for all].

Bull Cancer 2019 Mar 11;106(3):206-215. Epub 2019 Jan 11.

Hémato-immuno-oncologie pédiatrique, CHU de Nantes, 5, allée de l'île-Gloriette, 44093 Nantes cedex 01, France.

Introduction: Relapsed/refractory acute lymphoblastic leukemia (ALL) in children has a pejorative prognosis and justifies to be treated by hematopoietic stem cell transplantation (HSCT). A minimal residual disease (MRD) before transplantation is a major part of prognosis. Blinatumomab, a bispecific antibody CD19/CD3, allowed to achieve a cytologic and molecular complete remission in adults with refractory B-precursor ALL. This retrospective study analyses results from a pediatric cohort treated by blinatumomab thanks to an interregional structuring consortium.

Patients And Methods: Patients between 0 and 23 years old, from the 7 centers of the french "Grand Ouest" interregional network, treated by blinatumomab for a relapsed or refractory ALL, from January 2015 to January 2018, were included. The efficiency of blinatumomab was assessed in terms of complete remission, minimal residual disease, overall survival, and tolerability of treatment.

Results: Thirteen of 18 patients achieved a complete remission, with negative minimal residual disease for ten of them. Fourteen patients proceeded to stem cell transplantation,. Eight out of 14 patients obtained long term remission after HSCT. As far as tolerance is concerned, no serious adverse event, neurological or psychiatric disorder, was observed.

Conclusion: Thanks to an interregional network collaboration, all children with high risk ALL coming from the western french interregion could be treated by blinatumomab. Blinatumomab offered good hematological conditions to undergo HSCT with a good tolerability.
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http://dx.doi.org/10.1016/j.bulcan.2018.11.012DOI Listing
March 2019

Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study.

Br J Haematol 2018 11 12;183(4):608-617. Epub 2018 Nov 12.

EA4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France.

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAF status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAF mutation was present compared to 2·9% if it was absent (P = 0·002).
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http://dx.doi.org/10.1111/bjh.15577DOI Listing
November 2018

[Le Bulletin du Cancer: Developing adults - children partnership].

Bull Cancer 2018 Oct 20;105(10):849-850. Epub 2018 Sep 20.

Unité immuno-hemato-oncopédiatrie, Angers, France.

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http://dx.doi.org/10.1016/j.bulcan.2018.07.018DOI Listing
October 2018

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

Blood 2018 09 18;132(12):1318-1331. Epub 2018 Jun 18.

Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, Paris, France.

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 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the 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 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 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of -mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using -mutated primary cells and 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.
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http://dx.doi.org/10.1182/blood-2017-12-820308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536700PMC
September 2018

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Sci Immunol 2018 06;3(24)

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.

Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the transcription-dependent autoinduction and sustained activity of STAT3.
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http://dx.doi.org/10.1126/sciimmunol.aat4956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141026PMC
June 2018

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations.

Clin Immunol 2018 03 10;188:52-57. Epub 2018 Jan 10.

INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France.

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.
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http://dx.doi.org/10.1016/j.clim.2017.12.009DOI Listing
March 2018

Burden of Poor Health Conditions and Quality of Life in 656 Children with Primary Immunodeficiency.

J Pediatr 2018 03 6;194:211-217.e5. Epub 2017 Dec 6.

French National Reference Center for Primary Immune Deficiency (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR1163, Imagine Institute, Sorbonne Paris Cité, University Paris Descartes, Paris, France; Division of Médecine Expérimentale, Collège de France, Paris, France.

Objective: To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life.

Study Design: The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms.

Results: Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions.

Conclusions: Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood.

Trial Registration: ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.
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http://dx.doi.org/10.1016/j.jpeds.2017.10.029DOI Listing
March 2018

A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.

Blood 2018 02 16;131(7):717-732. Epub 2017 Nov 16.

Pediatric Hematology Immunology Unit, Necker-Enfants-Malades Hospital, Paris, France.

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (, ), telomeropathies (, , ), ribosome disorders (, , ), and DNA repair deficiency (). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as and (N = 16 of the 86 patients, 18.6%), (N = 6, 7.0%), and (N = 7, 8.1%), each of which was associated with a distinct natural history; and patients often experienced transient aplasia and monosomy 7, whereas patients presented early-onset severe aplastic anemia, and patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.
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http://dx.doi.org/10.1182/blood-2017-09-806489DOI Listing
February 2018
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