Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Abstract

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.

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

“…Median age at diagnosis of NBS ranged from 4-5 years. This is about average for all the countries [2,3]. Delay in diagnosis can result from the absence of unambiguous symptoms of NBS.…”

“…The disease likely occurs worldwide, but the highest occurrence of NBS has been described in Central and Eastern Europe due to the homozygous c.657_661del5 mutation in NBN gene. Most patients with NBS originate from Poland (137 patients), followed by Russia (81 patients), Ukraine (56 patients), the Czech Republic (33 patients), Belarus (22 patients) and Slovakia (14 patients) [1,2,3]. An unexpectedly high incidence of NBS patients has also been reported in regions of southeast Germany, which is linked to Slavic origin and migration in the Middle Ages [10].…”

“…The majority of patients are diagnosed with five base pair deletion in NBN gene (c.657_661del5) which is a founder mutation in Slavic populations [1]. NBS seems to occur worldwide, but most patients originated from Poland and Russia [2,3].…”

“…Profound immunodeficiency both cellular and humoral response develops among most patients [4]. Patients with NBS have cumulative cancer incidence by the age of 20 years and amounted to over 70% [2,3]. Non-Hodgkin lymphomas (NHLs) are most common with a similar number of lymphomas developed from abnormal T-cells and B-cells.…”

“…Non-Hodgkin lymphomas (NHLs) are most common with a similar number of lymphomas developed from abnormal T-cells and B-cells. T-cell acute lymphoblastic leukemia (T-ALL) is most frequently diagnosed among leukemias [2,3,7,8,9].…”