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1.
Front Immunol ; 11: 602482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33488600

RESUMO

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.


Assuntos
Proteínas de Ciclo Celular , Efeito Fundador , Neoplasias Hematológicas , Transtornos Linfoproliferativos , Síndrome de Quebra de Nijmegen , Proteínas Nucleares , Adolescente , Adulto , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Criança , Pré-Escolar , Europa Oriental/epidemiologia , Feminino , Seguimentos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Humanos , Incidência , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/imunologia , Síndrome de Quebra de Nijmegen/mortalidade , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Prevalência , Qualidade de Vida , Estudos Retrospectivos
2.
J Pediatr Hematol Oncol ; 39(4): e203-e206, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28267077

RESUMO

BACKGROUND: X-linked lymphoproliferative disease type I (XLP I) is caused by mutations in the SH2D1A gene and characterized mainly by hypogammaglobulinemia and abnormal response to Epstein-Barr virus with a high predisposition to B-cell non-Hodgkin lymphoma development. OBSERVATIONS: In this article, we describe the experience of 2 centers in Belarus and in Russia that follow 3 male patients who were diagnosed with XLP I after lymphoma development and treatment. Three novel mutations c.51G>C (p.E17D), c.192G>T (p.W64C), and c.53insA (p.K18KfsX67) were found in 3 males patients with XLP I. Two of them did not have any signs of immunodeficiency before B-cell non-Hodgkin lymphoma development. CONCLUSIONS: We propose SH2D1A mutational screening be considered in male patients with or without hypogammaglobulinemia who received rituximab treatment for lymphoma and did not recover immunoglobulin G in a year after B-depleting therapy.


Assuntos
Linfoma não Hodgkin/complicações , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/genética , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Agamaglobulinemia , Criança , Humanos , Imunoglobulina G/sangue , Linfoma não Hodgkin/tratamento farmacológico , Transtornos Linfoproliferativos/diagnóstico , Masculino , Mutação , Rituximab/uso terapêutico
3.
Clin Immunol ; 163: 108-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26774591

RESUMO

INTRODUCTION: Here we present an unusual case of DNA ligase IV deficiency syndrome without dysmorphic facial findings and microcephaly complicated with Epstein-Barr virus-associated large B-cell lymphoma with the right lung involvement and a massive brain tumor lesion in a two-year-old female. METHODS: PID panel was used for sequencing 55 genes. Most genes have >98% exon coverage including splicing sites. LIG4 gene has 100% exon and splicing site coverage. This was used in Ion Torrent PGM system, the library kit was made by Agilent with Haloplex technology. The sequence analysis software was Alamut, direct sequencing of LIG4 gene was performed after NGS results. RESULT: We identified three heterozygous mutations in LIG4 gene c.2736+3delC and c.8 C>T (p.A3V) inherited from mother and c.26C>T (p.T9I) - from father after PID panel sequencing and some additional polymorphisms in ATM, NOD2 and NLRP3 genes. CONCLUSION: This case broadens the clinical spectrum of DNA ligase IV deficiency.


Assuntos
Neoplasias Encefálicas/imunologia , DNA Ligases/deficiência , Infecções por Vírus Epstein-Barr/imunologia , Síndromes de Imunodeficiência/imunologia , Neoplasias Pulmonares/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Encefálicas/virologia , Pré-Escolar , DNA Ligase Dependente de ATP , DNA Ligases/genética , Feminino , Herpesvirus Humano 4 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/genética , Neoplasias Pulmonares/virologia , Linfoma Difuso de Grandes Células B/virologia , Mutação , Neoplasias Primárias Múltiplas/virologia , Análise de Sequência de DNA
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