AUTHOR=Sharapova Svetlana O. , Pashchenko Olga E. , Bondarenko Anastasiia V. , Vakhlyarskaya Svetlana S. , Prokofjeva Tatjana , Fedorova Alina S. , Savchak Ihor , Mareika Yuliya , Valiev Timur T. , Popa Alexander , Tuzankina Irina A. , Vlasova Elena V. , Sakovich Inga S. , Polyakova Ekaterina A. , Rumiantseva Natalia V. , Naumchik Irina V. , Kulyova Svetlana A. , Aleshkevich Svetlana N. , Golovataya Elena I. , Minakovskaya Nina V. , Belevtsev Mikhail V. , Latysheva Elena A. , Latysheva Tatiana V. , Beznoshchenko Alexander G. , Akopyan Hayane , Makukh Halyna , Kozlova Olena , Varabyou Dzmitry S. , Ballow Mark , Ong Mei-Sing , Walter Jolan E. , Kondratenko Irina V. , Kostyuchenko Larysa V. , Aleinikova Olga V. 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.602482

DOI=10.3389/fimmu.2020.602482

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Nibrin</italic> (<italic>NBN)</italic> 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%; <italic>p</italic>=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) (<italic>n</italic>=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%, <italic>p</italic>=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 (<italic>n</italic>=7) and immunodeficiency (<italic>n</italic>=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.</p>