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.
Highlights
Nijmegen breakage syndrome (NBS) is a syndromic combined immunodeficiency with an autosomal-recessive inheritance
Our analysis shows that adult NBS patients had substantially impaired quality of life (QoL) in both the physical and mental domains (Figure S2)
Our study shows that adult NBS patients find substantially impaired HRQoL in the physical and mental domains
Summary
Nijmegen breakage syndrome (NBS) is a syndromic combined immunodeficiency with an autosomal-recessive inheritance. It is a chromosome instability disorder with hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control and, high susceptibility to lymphoid malignancies. Most patients with NBS originate from Central and Eastern Europe with a Slavic background, and there is an accumulation of patients in Poland, Southeast Germany, Czech Republic, Ukraine, and Russia [3,4,5]. Sporadic cases have been published in patients of Middle Eastern origin [6, 7]. The majority of NBS patients are identified with a homozygous five base-pair deletion in the NBN gene (c.657_661del, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin [8]. Increased morbidity and mortality in this cohort are related to severe infections (in more than half of patients), autoimmune complications (in up to 1/3 of patients), and malignancies (in about half of patients) under the age of 20 years [9, 10]
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