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1.
Artigo em Inglês | MEDLINE | ID: mdl-31484767

RESUMO

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

2.
Syst Rev ; 8(1): 165, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296266

RESUMO

BACKGROUND: Seriously ill children suffer from numerous symptoms at the end of their lives, including pain, anxiety, and restricted communication. There are currently no comprehensive overviews of which health interventions have proven benefits and which have proven detrimental effects on the quality of life of children in an end-of-life context. In order to identify potential quality indicators to eventually improve care, a systematic review of available evidence is needed. The aim of the current systematic review will be to make an overview of the influence of health interventions on associated outcomes related to quality of life at the end of life in seriously ill children. METHODS: A systematic search will be conducted in MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science. We will include quantitative empirical designs looking into the influence of a health intervention on (proxies of) quality of life at the end of life in seriously ill children. Three independent authors will review titles and abstracts and screen full texts against eligibility criteria. One reviewer will carry out full data extraction and quality assessment, and a 20% random sample will be extracted and assessed by two independent reviewers. We will use the QualSyst Tool for assessment of the quality of the included studies (QualSyst Tool) for quality assessment; overall strength of the body of evidence will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. An overview table of health interventions will be discussed through narrative synthesis. Should sufficient homogeneous publications arise, we will perform meta-analyses with a random-effects model. Our protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist for study protocols. DISCUSSION: As part of a larger project, we will use the results of this review to identify a first set of quality indicators for the care for children at the end of life. Reviewing the current span of evidence and identifying research gaps will uncover future research priorities into the care for children at the end of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018105109.

3.
Br J Haematol ; 186(5): 741-753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31124581

RESUMO

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2 /day) versus prednisolone (60 mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109 /l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 109 /l, representing approximately 50% of T-ALL patients.

4.
Mol Cell Proteomics ; 18(4): 760-772, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30630937

RESUMO

Neutrophil granulocytes are critical mediators of innate immunity and tissue regeneration. Rare diseases of neutrophil granulocytes may affect their differentiation and/or functions. However, there are very few validated diagnostic tests assessing the functions of neutrophil granulocytes in these diseases. Here, we set out to probe omics analysis as a novel diagnostic platform for patients with defective differentiation and function of neutrophil granulocytes. We analyzed highly purified neutrophil granulocytes from 68 healthy individuals and 16 patients with rare monogenic diseases. Cells were isolated from fresh venous blood (purity >99%) and used to create a spectral library covering almost 8000 proteins using strong cation exchange fractionation. Patient neutrophil samples were then analyzed by data-independent acquisition proteomics, quantifying 4154 proteins in each sample. Neutrophils with mutations in the neutrophil elastase gene ELANE showed large proteome changes that suggest these mutations may affect maturation of neutrophil granulocytes and initiate misfolded protein response and cellular stress mechanisms. In contrast, only few proteins changed in patients with leukocyte adhesion deficiency (LAD) and chronic granulomatous disease (CGD). Strikingly, neutrophil transcriptome analysis showed no correlation with its proteome. In case of two patients with undetermined genetic causes, proteome analysis guided the targeted genetic diagnostics and uncovered the underlying genomic mutations. Data-independent acquisition proteomics may help to define novel pathomechanisms in neutrophil diseases and provide a clinically useful diagnostic dimension.

5.
Pediatr Blood Cancer ; 66(5): e27605, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623572

RESUMO

BACKGROUND: Children with acute myeloid leukemia (AML) have a 70% survival rate with treatment regimens containing high doses of cytarabine and anthracyclines and, in some, hematopoietic stem cell transplantation (allo-HSCT). PROCEDURE: In this multicenter Dutch-Belgian protocol (DB AML-01), 112 children with de novo AML were included. Treatment was stratified according to day 15 bone marrow response after the first induction course. Poor responders received a second course without delay while good responders awaited hematological recovery. Patients achieving CR after two induction courses continued with three consolidation courses without HSCT in CR1. RESULTS: The overall remission rate was 93.5%. After a median follow-up of 4.1 years, three-year event-free survival (EFS) was 52.6% (95% CI, 42.9%-61.3%), three-year cumulative incidence of relapse 39.7% (95% CI, 30.1%-49.0%), and three-year overall survival (OS) 74.0% (95% CI, 64.8%-81.2%). Significantly more events occurred in patients with high WBC at diagnosis or FLT3-ITD/NPM1-WT, whereas core binding factor (CBF) leukemia had a significantly better EFS. KMT2A rearrangements and age > 10 years negatively impacted OS. CONCLUSIONS: DB AML-01 response-guided therapy results in a favorable OS, particularly for children with CBF leukemia, children younger than 10 years or with initial WBC counts below 100 × 109 /L. Outcome of patients with FLT3-ITD/NPM1-WT remains poor and warrants alternative treatment strategies.

6.
Dev Neurorehabil ; : 1-8, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30015543

RESUMO

OBJECTIVE: To discover short-term changes in perspectives of parents and teachers of childhood brain tumour survivors on school reintegration, in order to reveal similarities and differences between them over time. METHODS: Semi-structured interviews were conducted with parents and teachers of five children at the start and the end of a 1-year period following the child's school re-entry. RESULTS: Thematic analysis of data resulted in three main themes: 'the child's performance and wellbeing', 'the school's attitude and approach' and 'communication and working together'. Parental concerns about child-specific changes and the school's approach to the child could either decrease or increase over time. Teachers remained focused on assessing their pupil's learning potential and finding ways of appropriate support. Their different perspectives on communication and working together became more pronounced. CONCLUSIONS: This study emphasizes the importance of clear communication and collaboration, coordinated follow-up and availability of healthcare professionals during the child's school reintegration.

7.
Cell Rep ; 23(13): 3946-3959.e6, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949776

RESUMO

Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPα checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPα interactions.

8.
Blood ; 132(4): 405-412, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29789356

RESUMO

Pediatric acute promyelocytic leukemia (APL) can be cured with all-trans retinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 109/L or ≥10 × 109/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m2 and 405 mg/m2, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients (P = .002 and P = .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov as EudractCT 2008-002311-40.

9.
J Mol Diagn ; 20(2): 195-202, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29269280

RESUMO

In addition to Sanger sequencing, next-generation sequencing of gene panels and exomes has emerged as a standard diagnostic tool in many laboratories. However, these captures can miss regions, have poor efficiency, or capture pseudogenes, which hamper proper diagnoses. One such example is the primary immunodeficiency-associated gene IKBKG. Its pseudogene IKBKGP1 makes traditional capture methods aspecific. We therefore developed a long-range PCR method to efficiently target IKBKG, as well as two associated genes (IRAK4 and MYD88), while bypassing the IKBKGP1 pseudogene. Sequencing accuracy was evaluated using both conventional short-read technology and a newer long-read, single-molecule sequencer. Different mapping and variant calling options were evaluated in their capability to bypass the pseudogene using both sequencing platforms. Based on these evaluations, we determined a robust diagnostic application for unambiguous sequencing and variant calling in IKBKG, IRAK4, and MYD88. This method allows rapid identification of selected primary immunodeficiency diseases in patients suffering from life-threatening invasive pyogenic bacterial infections.

11.
Front Immunol ; 9: 2912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619276

RESUMO

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

12.
J Clin Immunol ; 37(8): 801-810, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28993958

RESUMO

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1ß, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1ß or TNF-α. Transduction of wild-type and variant NEMO in NEMO-/- deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1ß and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.


Assuntos
Imunodeficiência de Variável Comum/genética , Displasia Ectodérmica/genética , Fibroblastos/fisiologia , Quinase I-kappa B/genética , Mutação/genética , Infecções por Pseudomonas/diagnóstico , Pseudomonas/fisiologia , Agamaglobulinemia , Células Cultivadas , Pré-Escolar , Imunodeficiência de Variável Comum/diagnóstico , Displasia Ectodérmica/diagnóstico , Hemizigoto , Humanos , Quinase I-kappa B/metabolismo , Interleucina-6/metabolismo , Masculino , Mastoidite , Otite , Polimorfismo Genético
13.
J Health Psychol ; : 1359105317733534, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28988492

RESUMO

Reintegration into school is a milestone for childhood brain tumor survivors, as well as for their parents, teachers, and healthcare providers. We explored their experiences following the school re-entry by conducting semi-structured interviews. Thematic analysis resulted in four main themes: "school performance," "psychosocial well-being," "support and approach," and "communication and collaboration." Children were pleased to return to school despite confrontation with adverse outcomes. Parents, teachers, and healthcare providers identified current and future concerns and challenges, as well as opportunities for academic and personal development. Their experiences highlight the importance of coordinated and systematic follow-up in close collaboration with healthcare providers.

14.
Clin Case Rep ; 5(4): 486-490, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28396774

RESUMO

22q11.2DS is a significant health problem because of its fairly high incidence. It is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk, especially amongst patients with the 22q11.2 distal deletion syndrome.

15.
J Med Case Rep ; 11(1): 47, 2017 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-28215183

RESUMO

BACKGROUND: Pediatric germ cell tumors account for approximately 3.5 % of all childhood cancers for children under the age of 15 years. Up to one-third are extragonadal neoplasms. Germ cell tumors are a heterogeneous group of malignant tumors with a wide variety of histopathological features. Yolk sac tumor is the predominant variant in newborns and younger children. We report for the first time, the presentation of a primary yolk sac tumor in the abdominal wall of a small child. CASE PRESENTATION: An 18-month-old white girl underwent resection of a small, round subcutaneous lump (1.5×1.3×0.8 cm) of the abdominal wall in her right hypochondriac region. The histopathology was compatible with yolk sac tumor. Her alpha-fetoprotein was initially elevated but normalized after the resection. Magnetic resonance imaging of her abdomen was normal. The surgeon decided to observe and follow her alpha-fetoprotein level closely. One year after resection a local recurrence appeared and her alpha-fetoprotein rose to 58 ng/mL. The surgeon performed a wide resection of the lesion with normalization of her alpha-fetoprotein. Follow-up consisted of measuring alpha-fetoprotein, clinical evaluation, and abdominal ultrasound. CONCLUSIONS: Clinicians should be aware that a yolk sac tumor can present in an unusual extragonadal place, for example in this case it was subcutaneous. In some cases, conservative treatment can be carried out with careful monitoring of the patient and their alpha-fetoprotein.


Assuntos
Parede Abdominal/patologia , Tumor do Seio Endodérmico/patologia , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/análise , Tratamento Conservador , Tumor do Seio Endodérmico/diagnóstico , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Recidiva Local de Neoplasia/cirurgia , Ultrassonografia , alfa-Fetoproteínas/análise
16.
Clin Case Rep ; 4(7): 643-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27386119

RESUMO

A general practitioner faces regularly soft tissue swelling in otherwise healthy children. Delay in diagnosis of soft tissue malignancies is often due to asymptomatic nature and the unfamiliarity with the age-dependent differential diagnosis. Hence, an accurate knowledge is important to prevent important delay in diagnosis of potential malignancies.

17.
Eur J Med Genet ; 59(12): 647-653, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26975585

RESUMO

It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID.


Assuntos
Predisposição Genética para Doença , Neoplasias Hematológicas/patologia , Síndromes de Imunodeficiência/patologia , Criança , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/genética , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Fatores de Risco
18.
Exp Hematol ; 43(12): 1072-1076.e2, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26320718

RESUMO

Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is a rare genetic disorder caused by mutations in STXBP2/Munc18-2. Munc18-2 plays a role in the degranulation machinery of natural killer cells and cytotoxic T lymphocytes. Mutations in STXBP2/Munc18-2 lead to impaired killing of target cells by natural killer cells and cytotoxic T lymphocytes, which in turn results in elevated levels of the inflammatory cytokine interferon γ, macrophage activation, and hemophagocytosis. Even though patients with FHL-5 present with anemia and hemolysis, no link between the disease and the erythroid lineage has been established. Here we report that red blood cells express Munc18-2 and that erythroid cells from patients with FHL-5 exhibit intrinsic defects caused by STXBP2/Munc18-2 mutations. Red blood cells from patients with FHL-5 expose less phosphatidylserine on their surface upon Ca(2+) ionophore ionomycin treatment. Furthermore, cultured erythroblasts from patients with FHL-5 display defective erythropoiesis characterized by decreased CD235a expression and aberrant cell morphology.


Assuntos
Eritroblastos/metabolismo , Eritropoese , Linfo-Histiocitose Hemofagocítica/metabolismo , Proteínas Munc18/biossíntese , Mutação , Fosfatidilserinas/metabolismo , Eritroblastos/patologia , Feminino , Humanos , Ionomicina/farmacologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Proteínas Munc18/genética , Fosfatidilserinas/genética
19.
Haematologica ; 100(10): 1311-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26137961

RESUMO

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.


Assuntos
Antígenos CD/genética , Deleção de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores Imunológicos/genética , Adolescente , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Ensaios Clínicos como Assunto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva
20.
Nat Genet ; 46(9): 1021-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25129144

RESUMO

The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils.


Assuntos
Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Células Mieloides/metabolismo , Neutropenia/congênito , Adolescente , Adulto , Apoptose/genética , Diferenciação Celular/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Feminino , Glicosilação , Homeostase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/metabolismo , Mutação , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/metabolismo , Receptores de Fator Estimulador de Colônias de Granulócitos/genética , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Transdução de Sinais , Adulto Jovem
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