RESUMO
ABSTRACT: 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. This trial was registered at www.ClinicalTrials.gov as #NCT05937828.
Assuntos
Citopenia , Lúpus Eritematoso Sistêmico , Adolescente , Adulto , Criança , Humanos , Adulto Jovem , Anticorpos Antinucleares , Lúpus Eritematoso Sistêmico/diagnóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Splenectomy is effective in â¼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS'CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10-7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.
Assuntos
Anemia Hemolítica Autoimune , Trombocitopenia , Anemia Hemolítica Autoimune/diagnóstico , Criança , Estudos de Coortes , Humanos , Esplenectomia/efeitos adversos , Trombocitopenia/complicaçõesRESUMO
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.
Assuntos
Púrpura Trombocitopênica Idiopática , Humanos , Criança , Púrpura Trombocitopênica Idiopática/terapia , Púrpura Trombocitopênica Idiopática/diagnóstico , Feminino , Masculino , Adolescente , Pré-Escolar , Doença Crônica , Esplenectomia , Seguimentos , Resultado do Tratamento , Lactente , Hemorragia/etiologia , Lúpus Eritematoso Sistêmico/complicações , Fatores EtáriosRESUMO
Nephrotic syndrome is a common condition characterized by filtration of large amounts of protein, hypoalbuminemia, reduced plasma oncotic pressure, sodium retention, and edema. The mechanism responsible for sodium retention in this condition is still controversial. Two different pathophysiological pathways have been proposed to explain edema formation: activation of neurohumoral effector mechanisms, including the renin-angiotensin-aldosterone system, or abnormal intrinsic/primary renal sodium retention. A 5-year-old boy with X-linked adrenoleukodystrophy presented with bilateral leg swelling, massive proteinuria, and hypoalbuminemia. Minimal change disease was diagnosed. The patient was initially treated with corticosteroids and experienced several relapses. The progression of fractional excretion of sodium correlated with proteinuria and undetectable aldosterone levels. This unusual finding suggests that the mechanism of tubular sodium avidity in this child with mineralocorticoid insufficiency was independent of the renin-angiotensin-aldosterone system.
Assuntos
Adrenoleucodistrofia , Síndrome Nefrótica , Humanos , Masculino , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/complicações , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/sangue , Pré-Escolar , Sistema Renina-Angiotensina , Sódio/sangue , Sódio/urina , Aldosterona/sangueRESUMO
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.
Assuntos
Lúpus Eritematoso Sistêmico , Púrpura Trombocitopênica Idiopática , Feminino , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Prospectivos , Fatores de Risco , Hemorragia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Estudos RetrospectivosRESUMO
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.
Assuntos
Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Doença de Erdheim-Chester/genética , Mutação , ÉxonsRESUMO
Ganglioglioma, pleomorphic xanthoastrocytoma (PXA) and pilocytic astrocytoma are rare brain neoplasms with frequent activation of mitogen-activated protein (MAP) kinase pathway. A downstream marker of MAP-kinase pathway activation is cyclin D1. However, the expression of cyclin D1 has not been studied in the differential diagnosis between these brain tumors. The aim of this work is to compare the expression of cyclin D1 in ganglioglioma, PXA, pilocytic astrocytoma. We also compared cyclin D1 expression in giant cell glioblastoma and in IDH wild type glioblastoma. Our work shows that roughly half of gangliogliomas have ganglion cells stained by cyclin D1 while two third of PXA have pleormophic cells stained by cyclin D1 and 15% of giant cell glioblastoma have pleomorphic cells stained by cyclin D1 (p < 0.001). Cyclin D1 never stains normal neurons either in the adjacent cortex of circumscribed tumor, or in entrapped neurons in IDH wild type glioblastomas. The expression of cyclin D1 is correlated to the presence of BRAF V600E mutation in ganglioglioma and PXA (p = 0.002). To conclude, cyclin D1 positivity might be used to confirm the neoplastic nature of ganglion cells. Cyclin D1 is expressed in most cases of BRAF V600E mutated gangliogliomas but also in cases without BRAF mutations suggesting an activation of MAP-kinase pathway through another way. Cyclin D1 immunohistochemistry has currently no or little role in the differential diagnosis of pilocytic astrocytoma. Its role in the differential diagnosis between PXA and giant cell glioblastoma needs to be further investigated on external series.
Assuntos
Astrocitoma/diagnóstico , Ciclina D1/metabolismo , Ganglioglioma/diagnóstico , Glioblastoma/diagnóstico , Mutação , Adolescente , Adulto , Astrocitoma/metabolismo , Ciclina D1/genética , Diagnóstico Diferencial , Feminino , Ganglioglioma/metabolismo , Glioblastoma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto JovemRESUMO
Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.
Assuntos
Catepsina C/antagonistas & inibidores , Membrana Celular/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Granulomatose com Poliangiite/patologia , Mieloblastina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/metabolismo , Humanos , Masculino , Mieloblastina/genética , Neutrófilos/enzimologia , Proteólise , Adulto JovemRESUMO
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, BRAFV600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002).
Assuntos
Histiocitose de Células de Langerhans/epidemiologia , Doenças Neurodegenerativas/epidemiologia , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Humanos , Incidência , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fatores de RiscoRESUMO
In this retrospective study, we evaluate long-term complications in nearly all ß-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Talassemia beta/complicações , Talassemia beta/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , França/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Inquéritos Epidemiológicos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Talassemia beta/terapiaRESUMO
BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8+ T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Cromossomos Humanos X/genética , Síndromes de Imunodeficiência/genética , Infecções/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Adolescente , Adulto , Idoso , Adesão Celular , Movimento Celular , Criança , Pré-Escolar , Estudos de Associação Genética , Humanos , Contagem de Linfócitos , Masculino , LinhagemRESUMO
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Fenótipo , Adolescente , Adulto , Alelos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Síndromes de Imunodeficiência/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Sítios de Splice de RNA , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto JovemRESUMO
BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a common pathology among adult patients, with an incidence ranging from 3-25 % depending on risk factors. Little information is available regarding CI-AKI incidence, risk factors, and prognostic impact in the pediatric population. METHODS: We performed a retrospective study of pediatric patients who underwent computed tomography (CT) scan with iodinated contrast media injection between 2005 and 2014 in five pediatric units of a university hospital. CI-AKI was defined according to Kidney Disease/Improving Global Outcomes (KDIGO) criteria. RESULTS: Of 346 identified patients, 233 had renal function follow-up and were included in our analyses. CI-AKI incidence was 10.3 % [95 % confidence interval (CI) 6.4-14.2 %]. CI-AKI was associated with 30-day unfavorable outcome before (45.8 % vs. 19.7 %, P = 0.007) and after [odds ratio (OR) 3.6; 95 % CI 1.4-9.5] adjustment for confounders. No independent risk factors of CI-AKI were identified. CONCLUSIONS: CI-AKI incidence was as high as 10.3 % following intravenous contrast media administration in the pediatric setting. As reported among adults, CI-AKI was associated with unfavorable outcome after adjustment for confounders. Although additional studies are needed in the pediatric setting, our data suggest that physicians should maintain a high degree of suspicion toward this complication among pediatric patients.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Meios de Contraste/efeitos adversos , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. RESULTS: Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. CONCLUSION: Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Nefropatias/etiologia , Poliangiite Microscópica/complicações , Adolescente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Criança , Etnicidade , Feminino , França/epidemiologia , Taxa de Filtração Glomerular , Humanos , Incidência , Nefropatias/epidemiologia , Nefropatias/mortalidade , Masculino , Poliangiite Microscópica/mortalidade , Poliangiite Microscópica/terapia , Prognóstico , Recidiva , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Rhabdomyosarcoma (RMS) occasionally occurs in a context of a predisposition syndrome. The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1. We report a national retrospective series of 16 RMS occurring in neurofibromatosis type 1 (NF1) patients during childhood, within a 20-year period. RESULTS: The mean age at diagnosis of the cancer was 2.5 years. All were embryonal subtype. Most tumours developed in the pelvis. One was metastatic. Chemotherapy and radiotherapy were normally scheduled without any specific toxicity. The 5-year event-free survival and overall survival were 67% and 87%, respectively. Long-term sequel related to chemotherapy consisted in two chronic tubulopathies, hence not obviously different from non-NF1 patients. No second cancer was reported so far with a median follow-up of 9.7 years. The genomic analysis performed on six samples revealed the abnormalities commonly observed in sporadic RMS: gain of chromosome 2 (5/6), 8 (6/6) and chromosome 11p loss of heterozygosity (5/6). Interestingly, we identified small deletions in tumour suppressor genes that may synergize with NF1 inactivation. CONCLUSIONS: Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases.
Assuntos
Neurofibromatose 1/complicações , Rabdomiossarcoma/complicações , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rabdomiossarcoma/genética , Rabdomiossarcoma/mortalidadeRESUMO
We studied the fecundity of 174 successive ALL (1987-2007) in females of the Childhood Cancer Registry of the Rhône-Alpes Region (ARCERRA) with a median age at follow-up of 25.6 years (18.0-37.4). We distinguished five treatment groups: Group Ia, chemotherapy only (n = 130); Ib, chemotherapy with cranial radiotherapy (n = 10); II, TBI conditioning allograft (n = 27); III, chemotherapy conditioning allograft (n = 4); IV, TBI conditioning autograft (n = 3). Twenty-three women had their first child at the mean age of 25.8 ±3.0 years, i.e., 2.0 ±2.9 years earlier than the general population of the Rhône-Alpes region (P = 0.003). The standardized fertility ratio (SFR), expressed as the number of actual births observed (O) to the number that would be expected in women of the same age in the general population (E) (SFR = O/E) was decreased for Group Ia (0.62; 95%CI, 0.52-0.74) and collapsed in Group II (0.17; 0.11-0.25). In univariate analysis, TBI (P = 0.013) and alkylating agents (P = 0.01) were negatively correlated with fecundity, but not with the age at diagnosis or the anthracyclines doses. In multivariate analysis including TBI and alkylating agents, we still found a negative correlation between TBI (P = 0.035), as well as alkylating agents (P = 0.028), and fecundity. More precisely, fecundity was negatively correlated with cumulative cyclophosphamide equivalent dose (P = 0.001), with a fecundity decreased for ≥1g/m(2), but without any dose effect; results not found in the Group Ia. Age at first child seems younger but the young median age of the cohort not allows concluding; fecundity is collapsed after fractionated total body irradiation and decreased after chemotherapy without any demonstrable cause. A delay of fertility is not excluded.
Assuntos
Fertilidade , Parto , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Estudos RetrospectivosAssuntos
Aspirina/administração & dosagem , Angiografia por Tomografia Computadorizada/métodos , Aneurisma Coronário , Processamento de Imagem Assistida por Computador/métodos , Imunoglobulinas Intravenosas/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Síndrome de Linfonodos Mucocutâneos , Adolescente , Idade de Início , Anticoagulantes/administração & dosagem , Antirreumáticos/administração & dosagem , Aneurisma Coronário/diagnóstico por imagem , Aneurisma Coronário/etiologia , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Síndrome de Linfonodos Mucocutâneos/terapia , Resultado do TratamentoRESUMO
Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.
Assuntos
Controle de Doenças Transmissíveis , Doenças Transmissíveis/etiologia , Síndromes de Imunodeficiência/complicações , Controle de Infecções , Infecções/etiologia , Humanos , Síndromes de Imunodeficiência/diagnóstico , Profilaxia Pré-ExposiçãoRESUMO
The primary manifestations of chronic hypothyroidism in children include growth arrest, delayed skeletal maturity, and delayed puberty. In 1960, Van Wyk and Grumbach reported three girls with hypothyroidism and a combination of incomplete isosexual precocious puberty (early breast development, menstruation, and absence of pubic hair), galactorrhea, delayed bone age, and pituitary enlargement. All abnormalities regressed after appropriate thyroid hormone replacement therapy. Over the years, an increasing number of reported cases has allowed for a more precise understanding of the clinical, biochemical, and radiological phenotypes of the Van Wyk-Grumbach syndrome (VWGS). These varying clinical manifestations are thought to result from a unique pathophysiological process where the thyroid-stimulating hormone (TSH) is a key element. We describe the cases of two patients (a boy and a girl) with severe autoimmune thyroiditis and VWGS. The clinical, biochemical, and radiological imaging characteristics were similar in both patients and included growth failure, absence of clinical goiter, markedly elevated TSH concentrations >100 mIU/L, undetectable free thyroxine levels, "normal" thyroglobulin levels, high follicle-stimulating hormone (FSH) and prolactin levels, prepubertal levels of luteinizing hormone (LH), delayed bone age, and hyperplasia of the pituitary gland. The two patients displayed differences, especially in the absence of clinical pubertal development, moderate anemia, abnormal renal function, and moderate goiter detected via ultrasonography (in the female patient). Thyroxine replacement therapy reversed the VWGS phenotype and hypothyroidism, with satisfactory growth velocity, strictly normal thyroid function, and normal pituitary size detected via magnetic resonance imaging at the 6-month follow-up visit.