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1.
Haematologica ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33440924

RESUMO

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.

2.
J Pediatr ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33340549

RESUMO

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.

3.
Haemophilia ; 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32842170

RESUMO

BACKGROUND: Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications. OBJECTIVES: To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population. PATIENTS/METHODS: The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres. RESULTS: During the 5 years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4 IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum. CONCLUSION: In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149.

4.
Br J Haematol ; 189(5): 931-942, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32130726

RESUMO

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.

5.
J Thromb Haemost ; 17(12): 2211-2215, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31565851

RESUMO

BACKGROUND: Macrothrombocytopenia (MTP) is a rare but enigmatic complication of Glanzmann thrombasthenia (GT), an inherited bleeding disorder caused by the absence of platelet aggregation due to deficiencies of the αIIbß3 integrin. OBJECTIVES: We report a family with type I GT and a prolonged bleeding time but unusually associated with congenital mild thrombocytopenia and platelet size heterogeneity with giant forms. METHODS AND RESULTS: Sanger sequencing of DNA from the propositus identified 2 heterozygous ITGB3 gene mutations: p.P189S and p.C210S both of which prevent αIIbß3 expression and are causative of GT but without explaining the presence of enlarged platelets. High-throughput screening led to the detection of a predicted disease-causing heterozygous mutation in the TUBB1 gene: p.G146R, encoding ß1-tubulin, a component of the platelet cytoskeleton and a gene where mutations are a known cause of MTP. CONCLUSIONS: Family screening confirmed that this rare phenotype results from oligogenic inheritance while suggesting that the GT phenotype dominates clinically.


Assuntos
Plaquetas/patologia , Hemostasia/genética , Integrina beta3/genética , Mutação , Trombastenia/genética , Trombocitopenia/genética , Tubulina (Proteína)/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Integrina beta3/sangue , Integrina beta3/química , Masculino , Modelos Moleculares , Herança Multifatorial , Linhagem , Fenótipo , Conformação Proteica , Fatores de Risco , Relação Estrutura-Atividade , Trombastenia/sangue , Trombastenia/diagnóstico , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Tubulina (Proteína)/sangue , Tubulina (Proteína)/química
6.
J Clin Immunol ; 39(7): 702-712, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

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.


Assuntos
Serviços Médicos de Emergência , Hospitalização , Doenças da Imunodeficiência Primária/epidemiologia , Adulto , Criança , Controle de Doenças Transmissíveis , Doenças Transmissíveis/etiologia , Gerenciamento Clínico , França/epidemiologia , Humanos , Incidência , Profilaxia Pré-Exposição , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/terapia , Vigilância em Saúde Pública , Resultado do Tratamento
7.
Br J Haematol ; 187(4): 530-542, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31338833

RESUMO

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/patologia , Criança , Estudos de Coortes , Europa (Continente) , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Mutação , Nucleotidiltransferases/genética , Estudos Retrospectivos
8.
Am J Med Genet A ; 179(6): 993-1000, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30888095

RESUMO

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome da Deleção Distal 11q de Jacobsen/diagnóstico , Síndrome da Deleção Distal 11q de Jacobsen/genética , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-fli-1/genética , RNA Longo não Codificante , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Cariotipagem , Masculino , Linhagem , Fenótipo
9.
Mol Genet Metab ; 128(3): 342-351, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30660387

RESUMO

Non-syndromic microcytic congenital sideroblastic anemia (cSA) is predominantly caused by defective genes encoding for either ALAS2, the first enzyme of heme biosynthesis pathway or SLC25A38, the mitochondrial importer of glycine, an ALAS2 substrate. Herein we explored a new case of cSA with two mutations in GLRX5, a gene for which only two patients have been reported so far. The patient was a young female with biallelic compound heterozygous mutations in GLRX5 (p.Cys67Tyr and p.Met128Lys). Three-D structure analysis confirmed the involvement of Cys67 in the coordination of the [2Fe2S] cluster and suggested a potential role of Met128 in partner interactions. The protein-level of ferrochelatase, the terminal-enzyme of heme process, was increased both in patient-derived lymphoblastoid and CD34+ cells, however, its activity was drastically decreased. The activity of ALAS2 was found altered and possibly related to a defect in the biogenesis of its co-substrate, the succinyl-CoA. Thus, the patient exhibits both a very low ferrochelatase activity without any accumulation of porphyrins precursors in contrast to what is reported in erythropoietic protoporphyria with solely impaired ferrochelatase activity. A significant oxidative stress was evidenced by decreased reduced glutathione and aconitase activity, and increased MnSOD protein expression. This oxidative stress depleted and damaged mtDNA, decreased complex I and IV activities and depleted ATP content. Collectively, our study demonstrates the key role of GLRX5 in modulating ALAS2 and ferrochelatase activities and in maintaining mitochondrial function.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Ferroquelatase/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Glutarredoxinas/genética , Heme/biossíntese , Mutação de Sentido Incorreto , 5-Aminolevulinato Sintetase/metabolismo , Aconitato Hidratase/metabolismo , Adolescente , Sequência de Aminoácidos , Anemia Sideroblástica/enzimologia , Linhagem Celular Transformada , Feminino , Ferroquelatase/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Glutationa/metabolismo , Humanos , Mitocôndrias/enzimologia , Estresse Oxidativo , Linhagem , Estrutura Terciária de Proteína
10.
Eur J Epidemiol ; 34(5): 521-532, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30515664

RESUMO

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project's progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18-50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs' cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4-21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7-11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%).


Assuntos
Transtornos Herdados da Coagulação Sanguínea/epidemiologia , Adolescente , Adulto , Transtornos de Proteínas de Coagulação/epidemiologia , Feminino , Seguimentos , França/epidemiologia , Hemofilia A/epidemiologia , Hemofilia B/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem , Doenças de von Willebrand/epidemiologia
11.
BMJ Open ; 8(7): e022409, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30049701

RESUMO

INTRODUCTION: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life. METHODS AND ANALYSIS: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag. ETHICS AND DISSEMINATION: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public. TRIAL REGISTRATION NUMBER: NCT02866526; Pre-results.


Assuntos
Hemofilia A/terapia , Transição para Assistência do Adulto , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Desempenho Acadêmico , Adolescente , Adulto , Atitude Frente a Saúde , Estudos Transversais , Relações Familiares , Feminino , França , Hemofilia A/psicologia , Humanos , Masculino , Satisfação do Paciente , Fatores de Proteção , Pesquisa Qualitativa , Qualidade de Vida , Fatores de Risco , Classe Social , Cooperação e Adesão ao Tratamento/psicologia , Adulto Jovem
12.
Haematologica ; 102(7): 1192-1203, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385783

RESUMO

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.


Assuntos
Transtornos Plaquetários/congênito , Transtornos Plaquetários/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Plaquetários/diagnóstico , Criança , Pré-Escolar , Feminino , Hemorragia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação/métodos , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/métodos , Resultado do Tratamento , Adulto Jovem
13.
Br J Haematol ; 177(5): 751-758, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28444729

RESUMO

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


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Hematínicos/uso terapêutico , Rituximab/uso terapêutico , Adolescente , Transfusão de Sangue/estatística & dados numéricos , Criança , Pré-Escolar , Substituição de Medicamentos , Feminino , França , Humanos , Masculino , Estudos Prospectivos , Esteroides/uso terapêutico , Resultado do Tratamento
15.
Orphanet J Rare Dis ; 11: 49, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27112265

RESUMO

BACKGROUND: Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered. METHODS: We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015. RESULTS: Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation. CONCLUSIONS: Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Adulto Jovem
16.
Front Pediatr ; 3: 79, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26484337

RESUMO

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

17.
Haematologica ; 99(8): 1387-94, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24763399

RESUMO

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.


Assuntos
Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/epidemiologia , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações Hematológicas na Gravidez/genética , Estudos Retrospectivos , Trombocitopenia/genética , Adulto Jovem
18.
J Pediatr ; 158(1): 135-41, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20813381

RESUMO

OBJECTIVE: To assess school performance in an unselected group of childhood cancer survivors and study risk factors for impairment. STUDY DESIGN: Rates of repeating a grade were compared for patients with cancer, their siblings, and the general population. Phone questionnaires were administered to patients about the school career of their child in remission and their siblings. Responses about cancer survivors were compared with those concerning their siblings and various registries provided by the national board of education. The primary outcome was the rate of repeating a grade. RESULTS: A total of 148 children in remission with a mean age of 15 ± 5.3 years and a mean follow-up period since diagnosis of 6.3 ± 1.3 years were included. More patients than siblings repeated a grade (33% versus 21%; P = .02), with a mean delay since diagnosis of 2 years. Risk factors were an older age at diagnosis, attending a secondary school, low education level of parents, bone marrow transplantation, cerebral surgery, and physical sequelae. In multivariate analysis, risk for repeating was associated with low educational level of the father, attending secondary school at diagnosis, and requiring school-organized educational support on return to school. CONCLUSION: After cancer, repeating a grade is not an exceptional occurrence, especially for teenagers; follow-up and supportive interventions before returning to school would be beneficial.


Assuntos
Escolaridade , Neoplasias , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fatores de Risco , Sobreviventes
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