RESUMEN

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.

Asunto(s)

Síndrome de Nijmegen , Humanos , Síndrome de Nijmegen/genética , Síndrome de Nijmegen/terapia , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/inmunología , Ucrania/epidemiología , Masculino , Femenino , Niño , Adolescente , Preescolar , Adulto , Estudios Retrospectivos , Lactante , Adulto Joven , Prevalencia , Sistema de Registros

RESUMEN

BACKGROUND: Hyperdopaminergic state (HS), especially impulse control behaviors (ICBs), are not rare in Parkinson's disease (PD). Controversial data regarding HS prevalence one year following sub-thalamic nucleus deep brain stimulation (STN-DBS) are reported. OBJECTIVE: Our objectives were to describe early postoperative HS (PoOHS) including ICBs, hypomania and psychotic symptoms during the first 3 months following STN-DBS (V1) and their prognosis at 1 year (V2). METHODS: This descriptive study included 24 PD patients treated successively with bilateral STN-DBS between 2017 and 2019. The primary endpoint was prevalence of PoOHS at V1 according to the Ardouin Scale of Behaviour in Parkinson's Disease. RESULTS: Prior to STN-DBS (V0), 25% patients had HS (only ICBs) whereas at V1 (during the 3 first months), 10 patients (41.7%) had one or several HS (P=0.22) (de novo in 29.2%): 7 (29.2%) ICBs, 4 (16.7%) hypomanic mood, 1 (4.7%) psychotic symptoms. At V2, all V0 and V1 HS had disappeared, while 1 patient (4.2%) presented de novo HS (P<0.01). No correlation was found between the occurrence of PoOHS at V1 and any V0 data. Higher levodopa equivalent dose of dopamine agonists at V1 was correlated with ICB at V1 (P=0.04). CONCLUSION: We found that early PoOHS are frequent in PD after STN-DBS, mostly de novo, with ICBs and hypomania being the most frequent. Despite a good prognosis of PoOHS at one year, our work emphasizes the importance of both a cautious adjustment of dopamine agonist doses and a close non-motor monitoring pre- and post-STN-DBS in PD.

Asunto(s)

Estimulación Encefálica Profunda , Síndrome de Nijmegen , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/epidemiología , Núcleo Subtalámico/fisiología , Estimulación Encefálica Profunda/efectos adversos , Manía , Síndrome de Nijmegen/etiología , Síndrome de Nijmegen/terapia , Resultado del Tratamiento

RESUMEN

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to malignancies. HSCT appears to cure immunodeficiency, but remains challenging due to limited experience in long-term risks of transplant-associated toxicity and malignancies. Twenty NBS patients received 22 allogeneic HSCTs with TCRαß/CD19+ graft depletion with fludarabine 150 mg/m2, cyclophosphamide 20-40 mg/kg and thymoglobulin 5 mg/kg based conditioning regimens (CRs). Twelve patients additionally received low-dose busulfan 4 mg/kg (Bu group) and 10 patients (including 2 recipients of a second HSCT) treosulfan (Treo group) 30 g/m2. Overall and event-free survival were 0.75 vs 1 (p = 0.16) and 0.47 vs 0.89 (p = 0.1) in the Bu and Treo groups, respectively. In the Bu group, four patients developed graft rejection, and three died: two died of de novo and relapsed lymphomas and one died of adenoviral hepatitis. The four living patients exhibited split chimerism with predominantly recipient myeloid cells and predominantly donor T and B lymphocytes. In Treo group, one patient developed rhabdomyosarcoma. There was no difference in the incidence of GVHD, viral reactivation, or early toxicity between either group. Low-dose Bu-containing CR in NBS leads to increased graft failure and low donor myeloid chimerism. Treo-CR followed by TCRαß/CD19-depleted HSCT demonstrates a low level of early transplant-associated toxicity and enhanced graft function with stable donor chimerism.

Asunto(s)

Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/métodos , Depleción Linfocítica , Agonistas Mieloablativos/uso terapéutico , Síndrome de Nijmegen/terapia , Acondicionamiento Pretrasplante/métodos , Antígenos CD19/metabolismo , Busulfano/administración & dosificación , Busulfano/efectos adversos , Busulfano/uso terapéutico , Femenino , Rechazo de Injerto , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Depleción Linfocítica/métodos , Masculino , Agonistas Mieloablativos/administración & dosificación , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/mortalidad , Cuidados Posoperatorios , Pronóstico , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Estudios Retrospectivos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Resultado del Tratamiento

RESUMEN

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.

Asunto(s)

Granuloma/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Síndrome de Nijmegen/diagnóstico por imagen , Niño , Granuloma/complicaciones , Granuloma/terapia , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/terapia , Masculino , Síndrome de Nijmegen/complicaciones , Síndrome de Nijmegen/terapia

RESUMEN

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.

Asunto(s)

Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Síndrome de Nijmegen/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Predisposición Genética a la Enfermedad , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Infecciones/etiología , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Linfoma/epidemiología , Linfoma/etiología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Síndrome de Nijmegen/complicaciones , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/terapia , Fenotipo , Radioterapia/efectos adversos , Radioterapia/métodos , Riesgo , Resultado del Tratamiento

RESUMEN

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.

Asunto(s)

Empalme Alternativo , Proteínas de Ciclo Celular/genética , Síndrome de Nijmegen/terapia , Proteínas Nucleares/genética , Oligonucleótidos Antisentido/administración & dosificación , Eliminación de Secuencia , Empalme Alternativo/efectos de los fármacos , Animales , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular , Niño , Replicación del ADN , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Persona de Mediana Edad , Síndrome de Nijmegen/genética , Proteínas Nucleares/antagonistas & inhibidores , Oligonucleótidos Antisentido/farmacología

RESUMEN

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.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Síndrome de Nijmegen/diagnóstico , Factores de Tiempo , Adolescente , Adulto , Niño , Preescolar , Inestabilidad Cromosómica , Femenino , Humanos , Síndromes de Inmunodeficiencia , Lactante , Linfoma no Hodgkin , Masculino , Microcefalia , Síndrome de Nijmegen/genética , Síndrome de Nijmegen/terapia , Pronóstico , Estudios Retrospectivos , Adulto Joven

RESUMEN

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.

Asunto(s)

Trasplante de Células Madre de Sangre del Cordón Umbilical , Síndrome de Nijmegen/terapia , Acondicionamiento Pretrasplante , Preescolar , Aberraciones Cromosómicas , Femenino , Sangre Fetal/citología , Genotipo , Humanos , Sistema Inmunológico/fisiopatología , Síndromes de Inmunodeficiencia/terapia , Mutación , Síndrome de Nijmegen/inmunología , Reacción en Cadena de la Polimerasa , Donantes de Tejidos , Quimera por Trasplante

RESUMEN

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.

Asunto(s)

Proteínas de Ciclo Celular/genética , Inmunidad Innata/genética , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/genética , Proteínas Nucleares/genética , Adolescente , Biomarcadores/sangre , Niño , Diagnóstico Diferencial , Femenino , Humanos , Síndrome de Nijmegen/sangre , Síndrome de Nijmegen/inmunología , Síndrome de Nijmegen/fisiopatología , Síndrome de Nijmegen/terapia , Linaje , Análisis de Secuencia de ADN

RESUMEN

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.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Síndrome de Nijmegen/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos , Quimera por Trasplante