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1.
Hum Genet ; 136(4): 463-479, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283832

RESUMO

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteínas Repressoras/genética , Humanos
2.
Rheumatology (Oxford) ; 56(8): 1358-1366, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444335

RESUMO

Objectives: The aim was to describe the epidemiological characteristics of childhood IgA vasculitis (IgAV) defined by the EULAR/PRINTO/Paediatric Rheumatology European Society criteria in a population-based sample from France and ascertain its incidence over 3 years by a four-source capture-recapture analysis. Methods: Cases were prospectively collected in Val de Marne county, a suburb of Paris, with 263 874 residents <15 years old. Children with incident IgAV living in this area from 2012 to 2014 were identified by four sources of case notification (emergency departments, paediatrics departments, private-practice paediatricians and general practitioners). Annual incidence was calculated, and a capture-recapture analysis was used with log-linear modelling to estimate case-finding completeness. Results: We identified 147 incident cases [78 boys; mean age 6.5 (s.d.:2.6) years]. The annual incidence (95% CI) was 18.6 (13.6, 24.5)/100 000 children. Although only 10% of children were exclusively identified by non-hospital sources, the completeness of case finding was 62%, with an undercount-corrected annual incidence (95% CI) of 29.9 (23.7, 37.3)/100 000 children. The annual distribution of diagnoses consistently showed a trough in summer months; 72% of children had infectious symptoms (mainly upper respiratory tract) a few days before IgAV onset; and 23% had a North African background. Conclusion: Our study supports secular and geospatial stability in childhood IgAV incidence and adds further indirect evidence for a possible role of a ubiquitous, non-emerging infectious trigger. Incidence studies from understudied areas are needed to disentangle the role of genetic factors better. Capture-recapture analysis suggests that a substantial portion of IgAV cases may remain unrecognized in epidemiological surveys.


Assuntos
Vasculite por IgA/epidemiologia , Imunoglobulina A , Adolescente , Criança , Pré-Escolar , Notificação de Doenças , Feminino , França/epidemiologia , Humanos , Vasculite por IgA/imunologia , Incidência , Modelos Lineares , Masculino , Estudos Prospectivos , Projetos de Pesquisa , Inquéritos e Questionários
3.
Br J Haematol ; 173(6): 927-37, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27062606

RESUMO

We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995-2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sß°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on-line guidelines was concomitant with an improvement in medical care in the 2006-2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).


Assuntos
Anemia Falciforme , Fidelidade a Diretrizes , Melhoria de Qualidade/normas , Síndrome Torácica Aguda/etiologia , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hidroxiureia/uso terapêutico , Recém-Nascido , Masculino , Paris , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Talassemia
4.
Pediatr Nephrol ; 31(12): 2299-2308, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27778092

RESUMO

BACKGROUND: The etiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been reported to be associated with INS onset and relapse. The aim of this study was to describe the epidemiology of a population-based cohort of children with INS and propose a spatiotemporal analysis. METHODS: All children aged 6 months to 15 years with INS onset between December 2007 and May 2010 and living in the Paris area were included in a prospective multicenter study. Demographic and clinical features at diagnosis and 2 years were collected. RESULTS: INS was diagnosed in 188 children, 93 % of whom were steroid sensitive. Annual incidence was 3.35/100,000 children. Standardized incidence ratio (SIR) was higher in one of the eight counties: Seine-Saint-Denis, with SIR 1.43 [95 % confidence interval (CI) 1.02-1.95]. A spatial cluster was further identified with higher SIR 1.36 (95 % CI 1.09-1.67). Temporal analysis within this overincidence area showed seasonal variation, with a peak during the winter period (p <0.01). In addition, partition of the Paris area into quintiles of the population showed that the average delay of occurrence, with regard to the first study case, followed a longitudinal progression (p <0.0001). CONCLUSION: The clustering of cases, the seasonal variation within this particular area, and the progression over the Paris area altogether suggest that INS may occur on an epidemic mode.


Assuntos
Síndrome Nefrótica/epidemiologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Coortes , Doenças Endêmicas , Epidemias , Feminino , Humanos , Incidência , Lactente , Masculino , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/virologia , Paris/epidemiologia , Estudos Prospectivos , Estações do Ano , Fatores Socioeconômicos , Esteroides/uso terapêutico
5.
Acta Paediatr ; 101(2): e86-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22040226

RESUMO

AIM: To describe a novel clinical observation and to provide a review the literature about lung involvement in children with Crohn disease (CD). METHODS: An 8-year-old girl presented with pulmonary and hepatic granulomatous lesions, followed 6 months later by abdominal and general symptoms, resulting in the diagnosis of CD. Differential diagnosis between CD and sarcoidosis and a review of the literature about lung lesions in children with CD are discussed. RESULTS: Crohn disease can be associated with pulmonary lesions, developing before, at the same time or after occurrence of digestive symptoms. CONCLUSIONS: This report highlights not only the importance of looking for lung lesions in CD but also underscores the necessity of considering the diagnosis of CD in incomplete presentation evoking sarcoidosis.


Assuntos
Doença de Crohn/diagnóstico , Hepatopatias/diagnóstico , Nódulos Pulmonares Múltiplos/diagnóstico , Criança , Doença de Crohn/complicações , Diagnóstico Diferencial , Feminino , Humanos , Sarcoidose/diagnóstico
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