RESUMO
Introduction: Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, characterized by microcephaly, immunodeficiency, and impaired DNA repair. NBS is most prevalent among Slavic populations, including Ukraine. Our study aimed to comprehensively assess the prevalence, diagnosis, clinical data, immunological parameters, and treatment of NBS patients in Ukraine. Methods: We conducted a retrospective review that included 84 NBS patients from different regions of Ukraine who were diagnosed in 1999-2023. Data from the Ukrainian Registry of NBS and information from treating physicians, obtained using a developed questionnaire, were utilized for analysis. Results: Among 84 NBS patients, 55 (65.5%) were alive, 25 (29.8%) deceased, and 4 were lost to follow-up. The median age of patients was 11 years, ranging from 1 to 34 years. Most patients originate from western regions of Ukraine (57.8%), although in recent years, there has been an increase in diagnoses from central and southeastern regions, expanding our knowledge of NBS prevalence. The number of diagnosed patients per year averaged 3.4 and increased from 2.7 to 4.8 in recent years. The median age of NBS diagnosis was 4.0 years (range 0.1-16) in 1999-2007 and decreased to 2.7 in the past 6 years. Delayed physical development was observed in the majority of children up to the age of ten years. All children experienced infections, and 41.3% of them had recurrent infections. Severe infections were the cause of death in 12%. The second most common clinical manifestation of NBS was malignancies (37.5%), with the prevalence of lymphomas (63.3%). Malignancies have been the most common cause of death in NBS patients (72% of cases). Decreased levels of CD4+ and CD19+ were observed in 89.6%, followed by a reduction of CD3+ (81.8%) and CD8+ (62.5%). The level of NK cells was elevated at 62.5%. IgG concentration was decreased in 72.9%, and IgA - in 56.3%. Immunoglobulin replacement therapy was administered to 58.7% of patients. Regular immunoglobulin replacement therapy has helped reduce the frequency and severity of severe respiratory tract infections. Conclusion: Improvements in diagnosis, including prenatal screening, newborn screening, monitoring, and expanding treatment options, will lead to better outcomes for NBS patients.
Assuntos
Síndrome de Quebra de Nijmegen , Humanos , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/imunologia , Ucrânia/epidemiologia , Masculino , Feminino , Criança , Adolescente , Pré-Escolar , Adulto , Estudos Retrospectivos , Lactente , Adulto Jovem , Prevalência , Sistema de RegistrosRESUMO
Patients with Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.
Assuntos
Síndrome de Quebra de Nijmegen/imunologia , Linfócitos T/citologia , Adolescente , Adulto , Diferenciação Celular , Senescência Celular , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Lactente , Masculino , Adulto JovemRESUMO
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 RetrospectivosRESUMO
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 TransplanteRESUMO
Patients with an immunodeficiency in the course of Nijmegen breakage syndrome (NBS) that is caused by mutations in the NBN/NBS1 gene are prone to recurrent infections and malignancies, due to a defective DNA double-strand breaks repair mechanism. Four-color flow cytometry was used to analyze changes in B lymphocyte subsets reflecting the most important stages of peripheral B cell maturation. It was demonstrated that the humoral immune defect observed in NBS patients was caused by reduced numbers of B lymphocytes, but also by their aberrant maturation. Reduced relative and absolute counts of naïve and memory B cells were accompanied by a significant accumulation of the natural effector B lymphocytes. The elevated proportion of IgM-only memory and reduced proportion of IgM-negative cells within the memory B cell pool suggests that there is class-switch recombination defect in this population of cells in NBS patients, resulting in inadequate production of immunoglobulins. Because of the reduced T-cell counts, the T-cell dependent antigen response is severely impaired resulting in a lower frequency of memory B-cells. The T-cell independent B-cell differentiation pathway seems less affected. The reduced IgG and IgA levels in patients with NBS are caused both by ineffective class switch, at least due to poor T cell help, and low number of memory B cells. This study illustrates that the NBN gene product nibrin plays an important role at different levels in the B-cell system.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Proteínas de Ciclo Celular/imunologia , Imunidade Humoral , Síndrome de Quebra de Nijmegen/imunologia , Proteínas Nucleares/imunologia , Adolescente , Subpopulações de Linfócitos B/patologia , Linfócitos B/patologia , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Imunoglobulina A/sangue , Switching de Imunoglobulina , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Memória Imunológica , Imunofenotipagem , Lactente , Contagem de Linfócitos , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/patologia , Proteínas Nucleares/genética , Linfócitos T/imunologia , Linfócitos T/patologiaAssuntos
Granuloma/patologia , Transtornos Necrobióticos/patologia , Síndrome de Quebra de Nijmegen/patologia , Criança , Feminino , Granuloma/tratamento farmacológico , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Transtornos Necrobióticos/tratamento farmacológico , Transtornos Necrobióticos/imunologia , Transtornos Necrobióticos/microbiologia , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/imunologia , Pele/imunologia , Pele/microbiologia , Pele/patologiaRESUMO
Se presenta el caso de un paciente masculino que a los 6 años de edad es derivado a Neurología Infantil para su estudio por presentar microcefalia y retardo mental. Tras ser evaluado por Inmunología y Genética se realiza en el Laboratorio de citogenética humana, programa de genética ICBM, Facultad de Medicina Universidad de Chile, PCR para deleción 657 del5 que confirma el diagnóstico de Nijmegen dando como resultado deleción nucleótido 5, mutación 657 del5, característico del Síndrome de Nijmegen. Actualmente el niño tiene 13 años y es tratado en el Servicio de Oncología infantil por el desarrollo de linfoma difuso de células grandes B, patología frecuente en este sindrome.
A case of a male patient at 6 years old was referred to child neurology for study due to microcephaly and mental retardation. After being evaluated for Immunology and Genetics Laboratory is performed in human cytogenetics, genetic program ICBM, Faculty of Medicine University of Chile, PCR for deletion 657 of the 5 that confirms the diagnosis of Nijmegen nucleotide deletion resulting in 5, 657 mutation del 5 Characteristic of the syndrome of Nijmegen. Currently the child is 13 and is treated at the Childrens Oncology Service in the development of lymphoma diffuse large B cell, common pathology in this syndrome.
Assuntos
Humanos , Masculino , Adolescente , Deficiência Intelectual , Microcefalia , Síndrome de Quebra de Nijmegen/diagnóstico , Instabilidade Cromossômica , Deficiência de IgA , Mutação , Síndrome de Quebra de Nijmegen/complicações , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/imunologia , Vitiligo/etiologiaRESUMO
Immunodeficiency and lymphoid malignancy are hallmarks of the human disease Nijmegen breakage syndrome (NBS; OMIM 251260), which is caused by NBS1 mutations. Although NBS1 has been shown to bind to the T-cell receptor alpha (TCRα) locus, its role in TCRß rearrangement is unclear. Hypomorphic mutations of Nbs1 in mice and patients result in relatively mild T-cell deficiencies, raising the question of whether the truncated Nbs1 protein might have clouded a certain function of NBS1 in T-cell development. Here we show that the deletion of the entire Nbs1 protein in T-cell precursors (Nbs1(T-del)) results in severe lymphopenia and a hindrance to the double-negative 3 (DN3)-to-DN4 transition in early T-cell development, due to abnormal TCRß coding and signal joints as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation (ChIP) analysis of the TCR loci reveals that Nbs1 depletion compromises the loading of Mre11/Rad50 to V(D)J-generated DNA double-strand breaks (DSBs) and thereby affects resection of DNA termini and chromatin conformation of the postcleavage complex. Although a p53 deficiency relieves the DN3âDN4 transition block, neither a p53 deficiency nor ectopic expression of TCRαß rescues the major T-cell loss in Nbs1(T-del) mice. All together, these results demonstrate that Nbs1's functions in both repair of V(D)J-generated DSBs and proliferation are essential for T-cell development.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA/genética , Reparo do DNA/fisiologia , Genes de Cadeia Pesada de Imunoglobulina , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Sequência de Bases , Diferenciação Celular , Proliferação de Células , Quebras de DNA , Primers do DNA/genética , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Genes p53 , Humanos , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/metabolismo , Camundongos , Camundongos Knockout , Mutação , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/imunologia , Síndrome de Quebra de Nijmegen/metabolismo , Proteínas Nucleares/deficiência , Recombinação Genética , Linfócitos T/citologiaRESUMO
The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.
Assuntos
Diferenciação Celular/imunologia , Imunoglobulinas/imunologia , Síndrome de Quebra de Nijmegen/imunologia , Células Precursoras de Linfócitos B/imunologia , Hipermutação Somática de Imunoglobulina/imunologia , Adolescente , Adulto , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Criança , Pré-Escolar , Quebras de DNA de Cadeia Dupla , Feminino , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Lactente , Masculino , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/metabolismo , Síndrome de Quebra de Nijmegen/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Recombinação Genética/genética , Recombinação Genética/imunologia , Hipermutação Somática de Imunoglobulina/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
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 DNARESUMO
Selected viruses and immune parameters were monitored in 57 patients with Nijmegen breakage syndrome as a proposed tool for early detection of changes preceding development of malignancy. The following parameters were analysed: (1) viral infections; (2) monoclonal proteins; and (3) B-cell and T-cell receptor gene rearrangements in peripheral blood lymphocytes. Viral infections were detected in 68.4% of patients with a predominance of EBV (63.2%), followed by HBV (19.2%) and HCV (8.8%). Monoclonal gammopathy detected in 38.6% of cases correlated with the presence of EBV DNA (p=0.002) and HCV RNA (p=0.04). Clonal Ig and/or TCR gene rearrangements occurred in 73.9% of patients. The presence of at least one of the studied parameters preceded the development of malignancy in 22 patients. Systematic PCR analysis for viral infections and Ig/TCR gene rearrangements, supplemented by detection of monoclonal proteins, is advantageous in monitoring NBS patients before severe complications of the disease, including cancer, appear.