RESUMO
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder, characterized by spontaneous chromosomal instability with predisposition to immunodeficiency and cancer. We present a repeated NBS in two sons from one woman after two marriages. We describe the clinical data, cytogenetic, and molecular findings of a prenatally diagnosed fetus, and his brothers with NBS. The first patient developed peripheral T-cell lymphoma at the age of 16 years and died 5 months after the protocol start. The diagnosis of NBS was established after his death. The second patient was born after the fifth pregnancy, third delivery in the second marriage; he developed cortical T-cell leukemia at the age of 3 years, received hematopoietic stem cells transplantation (HSCT) and he is alive now. In a year after repeated NBS case in this family, mother became pregnant again and the mutation was detected in the male fetus after the prenatal diagnosis; the pregnancy was aborted. At the age of 41 years, mother's seventh pregnancy finished by miscarriage. In three months, she was pregnant again, only one mutation in NBN gene was detected during the prenatal diagnostics in the female fetus; healthy female was born at term. To our knowledge, this is the first time to describe the repeated cases of two patients born with Nijmegen breakage syndrome from one mother and two different fathers. This case highlights the value of checking NBN carrier in Belarusian families during genetic counselling.
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.
