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Blood ; 130(12): 1456-1467, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28679735


X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

Transplante de Células-Tronco Hematopoéticas , Quinase I-kappa B/genética , Mutação/genética , Pré-Escolar , Estudos de Coortes , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Inflamação/patologia , Doenças Inflamatórias Intestinais/etiologia , NF-kappa B/metabolismo , Fenótipo , Transdução de Sinais/genética , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Resultado do Tratamento
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28598545


BACKGROUND: The frequency of common cytogenetic abnormalities in pediatric acute lymphoblastic leukemia (ALL) is known to vary by geographic location and ethnic origin. This study aimed to determine the frequency of hypodiploidy, ETV6-RUNX1, BCR-ABL1, and MLL rearrangement within New Zealand's pediatric ALL population and to assess whether the frequency of these ALL prognostic markers varies according to ethnicity. PROCEDURE: The New Zealand Children's Cancer Registry provided information for all registered pediatric ALL patients that were diagnosed between 2000 and 2009, with medical records available for 246 patients. Each patient's medical record was reviewed to determine the frequency of hypodiploidy, ETV6-RUNX1, BCR-ABL1, MLL rearrangement, and cell lineage. Chi-square tests for independence were undertaken to compare the frequencies of cytogenetic abnormalities according to prioritized ethnicity. RESULTS: The frequency of cytogenetic ALL abnormalities in the New Zealand pediatric population were consistent with international reference values. A low frequency of ETV6-RUNX1 was evident for Maori pediatric ALL patients (5.4%, P = 0.018), when compared to Pacific peoples (21.1%) and non-Maori/non-Pacific peoples (27.4%). This has not impacted on outcome, however, with equivalent 5-year overall survival being observed in Maori (89.4%) compared to Pacific peoples (92.0%) and non-Maori/non-Pacific peoples (90.2%). CONCLUSIONS: A lower frequency of the favorable prognostic marker ETV6-RUNX1 was observed in Maori pediatric ALL patients. This did not translate into poorer survival. Future research into biological and nonbiological prognostic factors in this patient population may assist in explaining this finding.

Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Fusão Oncogênica/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Linfocítica Crônica de Células B/etnologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino
J Paediatr Child Health ; 48(10): 921-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22900528


AIMS: The aim of this study was to review patterns of requests for heritable thrombophilia and to audit these findings against an international standard. METHODS: Review of requests for antithrombin, protein C, protein S, activated protein C resistance, Factor V Leiden and prothrombin G20210A mutation analysis in children <16 years between 1/1/2004 and 31/12/2009. Data for patient characteristics, test results, origin of request, requesting department and indication were obtained. The 2010 British Committee for Standards in Haematology (BCSH) clinical guidelines for testing for heritable thrombophilia was used as the standard for the audit. RESULTS: On 269 patients, 379 requests were made. Thirty-four per cent of tests were abnormal but only 36% of abnormal tests were repeated. Seven per cent of patients were confirmed with a heritable thrombophilia. Thirty-four tests were performed on patients on anticoagulation. The median age was 6.903 years. Fifty-three per cent of requests came from a ward, 28% from outpatients, 14% from an intensive care department and 5% from the emergency department. Departments most frequently requesting tests were neurology (20%), paediatric intensive care (15%) and cardiology (12%). Indications for testing were arterial thrombosis (5%), cerebral vein thrombosis (4%), deep vein thrombosis (12%), stroke (23%), asymptomatic relative (6%), intra-abdominal vein thrombosis (8%), start oestrogen containing medication (2%), purpura fulminans (0.2%), heparin resistance (8%) and other (35%). DISCUSSION: The large majority of requests did not satisfy the BCSH criteria. Requesting behaviours are haphazard. Better appreciation of the difficulties of interpreting results in children of different ages and in different clinical settings amongst paediatricians is required.

Fidelidade a Diretrizes/estatística & dados numéricos , Hospitais Pediátricos/normas , Auditoria Médica , Padrões de Prática Médica/estatística & dados numéricos , Trombofilia/diagnóstico , Adolescente , Biomarcadores/metabolismo , Criança , Pré-Escolar , Testes Genéticos/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Nova Zelândia , Guias de Prática Clínica como Assunto , Trombofilia/complicações , Trombofilia/metabolismo , Procedimentos Desnecessários/estatística & dados numéricos
Hemoglobin ; 32(3): 247-53, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18473240


The 5' untranslated region (5'UTR) of beta-globin has been well characterized and is often used as a model for eukaryotic transcription/translation, but there are still questions regarding the mechanism of translational control. Mutations affecting the Cap site at + 1 and at positions +10, +22, +33 and +40-43 have been described, and it is thought that the initiator element required for transcription stretches from -2 to +7 relative to the Cap site with a downstream element situated from +10 to +15. The influence on initiation or translation of sequences between +7 and +10 is unknown. We report here a family with beta-thalassemia (beta-thal) who have a + 8 (CT) mutation. Molecular studies indicate that this mutation leads to a reduction in mRNA levels and we discuss the implications of a CT change at this position on the transcription/translation process.

Regiões 5' não Traduzidas/genética , Globinas/genética , Mutação , Transcrição Genética/genética , Talassemia beta/genética , Regiões 5' não Traduzidas/metabolismo , Grupo com Ancestrais do Continente Asiático , Globinas/biossíntese , Humanos , Talassemia beta/metabolismo