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1.
Pediatrics ; 142(4)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30209074

RESUMO

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, severe immunodeficiency, and predisposition to lymphoid malignancy. In this report, we describe a case of a 9-year-old boy, previously diagnosed with NBS and symptoms of dyspnea, dry cough, and fever. Despite initial recognition of pneumonia, there was no response to broad spectrum antimicrobial treatment, negative results from microbiological tests, and unclear changes in lung imaging were observed. Therefore, further diagnostics were focused on suspected lymphoid malignancy and involved lung biopsy. Unexpectedly, histopathological examination revealed noncaseating granulomas. The introduction of systemic steroids resulted in significant improvement of the patient's clinical condition. This is the first description of primary pulmonary noncaseating granulomas without nodular involvement in a child with NBS.


Assuntos
Granuloma/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Síndrome de Quebra de Nijmegen/diagnóstico por imagem , Criança , Granuloma/complicações , Granuloma/terapia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Masculino , Síndrome de Quebra de Nijmegen/complicações , Síndrome de Quebra de Nijmegen/terapia
2.
Eur J Med Genet ; 59(3): 126-32, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26826318

RESUMO

Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Anticancer treatment among patients with NBS is challenging because of a high risk of life threatening therapy-related toxicity including severe infections, bone marrow failure, cardio- and nephrotoxicity and occurrence of secondary cancer. Based on systemic review of available literature and the Polish acute lymphoblastic leukemia database we concluded that among patients with NBS, these who suffered from clinically proven severe immunodeficiency are at risk of the complications associated with oncological treatment. Thus, in this group it reasonable to reduce chemotherapy up to 50% especially concerning anthracyclines methotrexate, alkylating agents and epipodophyllotoxines, bleomycin and radiotherapy should be omitted. Moreover, infection prophylaxis using intravenous immunoglobulin supplementation together with antifungal and antibacterial agent is recommended. To replace radiotherapy or some toxic anticancer agents targeted therapy using monoclonal antibodies and kinase inhibitors or bone marrow transplantation with reduced-intensity conditioning should be considered in some cases, however, this statement needs further studies.


Assuntos
Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Síndrome de Quebra de Nijmegen/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Predisposição Genética para Doença , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Leucemia Linfoide/epidemiologia , Leucemia Linfoide/etiologia , Linfoma/epidemiologia , Linfoma/etiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Síndrome de Quebra de Nijmegen/complicações , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/terapia , Fenótipo , Radioterapia/efeitos adversos , Radioterapia/métodos , Risco , Resultado do Tratamento
3.
Mol Ther ; 24(1): 117-24, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26265251

RESUMO

Over 90% of patients with Nijmegen breakage syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5 bp deletion in the NBN gene involved in the cellular response to DNA damage. This hypomorphic mutation leads to a carboxy-terminal protein fragment, p70-nibrin, with some residual function. Average age at malignancy, typically lymphoma, is 9.7 years. NBS patients are hypersensitive to chemotherapeutic and radiotherapeutic treatments, thus prevention of cancer development is of particular importance. Expression of an internally deleted NBN protein, p80-nibrin, has been previously shown to be associated with a milder cellular phenotype and absence of cancer in a 62-year-old NBS patient. Here we show that cells from this patient, unlike other NBS patients, have DNA replication and origin firing rates comparable to control cells. We used here antisense oligonucleotides to enforce alternative splicing in NBS patient cells and efficiently generate the same internally deleted p80-nibrin protein. Injecting the same antisense sequences as morpholino oligomers (VivoMorpholinos) into the tail vein of a humanized NBS murine mouse model also led to efficient alternative splicing in vivo. Thus, proof of principle for the use of antisense oligonucleotides as a potential cancer prophylaxis has been demonstrated.


Assuntos
Processamento Alternativo , Proteínas de Ciclo Celular/genética , Síndrome de Quebra de Nijmegen/terapia , Proteínas Nucleares/genética , Oligonucleotídeos Antissenso/administração & dosagem , Deleção de Sequência , Processamento Alternativo/efeitos dos fármacos , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular , Criança , Replicação do DNA , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/antagonistas & inibidores , Oligonucleotídeos Antissenso/farmacologia
4.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271390

RESUMO

PURPOSE: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. METHODS: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. RESULTS: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies. CONCLUSIONS: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/diagnóstico , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Instabilidade Cromossômica , Feminino , Humanos , Síndromes de Imunodeficiência , Lactente , Linfoma não Hodgkin , Masculino , Microcefalia , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
5.
Pediatr Transplant ; 19(2): E51-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25523867

RESUMO

NBS is a rare autosomal recessive congenital disorder associated with chromosome instability caused by a mutation in the NBN gene (8q21). Clinical manifestations include microcephaly, growth retardation, combined immunodeficiency, and a strong predisposition to develop (mainly lymphatic) malignancies. There is no specific treatment for patients with NBS, and the prognosis is generally poor. The therapeutic option for some patients with NBS may be HSCT. We present a case of safe and successful non-myeloablative UCB transplantation in the 19th month of the life of a female child with NBS concomitant with SCID.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndrome de Quebra de Nijmegen/terapia , Condicionamento Pré-Transplante , Pré-Escolar , Aberrações Cromossômicas , Feminino , Sangue Fetal/citologia , Genótipo , Humanos , Sistema Imunitário/fisiopatologia , Síndromes de Imunodeficiência/terapia , Mutação , Síndrome de Quebra de Nijmegen/imunologia , Reação em Cadeia da Polimerase , Doadores de Tecidos , Quimeras de Transplante
6.
Orv Hetil ; 151(16): 665-73, 2010 Apr 18.
Artigo em Húngaro | MEDLINE | ID: mdl-20353920

RESUMO

Nijmegen Breakage syndrome is a rare, autosomal recessive disorder characterized by severe, combined immunodeficiency, recurrent sinopulmonary infections, chromosomal instability, radiosensitivity, predisposition to malignancy, a "bird-like" facial appearance, progressive microcephaly, short stature, and mental retardation. The syndrome is caused by mutations in the NBS1 gene, which encodes a DNA-repair protein, named nibrin. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inborn error of innate immunity.


Assuntos
Proteínas de Ciclo Celular/genética , Imunidade Inata/genética , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Adolescente , Biomarcadores/sangue , Criança , Diagnóstico Diferencial , Feminino , Humanos , Síndrome de Quebra de Nijmegen/sangue , Síndrome de Quebra de Nijmegen/imunologia , Síndrome de Quebra de Nijmegen/fisiopatologia , Síndrome de Quebra de Nijmegen/terapia , Linhagem , Análise de Sequência de DNA
7.
Bone Marrow Transplant ; 45(4): 622-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19684627

RESUMO

Nijmegen breakage syndrome (NBS) is characterized by chromosomal instability, radiation hypersensitivity, characteristic facial appearance, immunodeficiency and strong predisposition to lymphoid malignancy. Traditionally, NBS patients have not undergone hematopoietic SCT (HSCT) owing to concerns about increased toxicity. We therefore report on the HSCT experience in NBS patients in Europe. Six patients were transplanted either for resistant or secondary malignancy (four patients) or severe immunodeficiency (two patients). Five patients received reduced-intensity conditioning regimens. After a median follow-up of 2.2 years, five patients are alive and well. One patient who received myeloablative conditioning died from sepsis before engraftment. Acute GVHD grades I-II occurred in three of five patients, mild chronic GVHD in one. All five surviving patients exhibit restored T-cell immunity. The experience in these six patients suggests that HSCT in NBS is feasible, can correct the immunodeficiency and effectively treat malignancy. Acute toxicity seems to be reasonable with reduced-intensity conditioning regimens.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Quimeras de Transplante
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