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

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. © Copyright © 2021 Sharapova, Pashchenko, Bondarenko, Vakhlyarskaya, Prokofjeva, Fedorova, Savchak, Mareika, Valiev, Popa, Tuzankina, Vlasova, Sakovich, Polyakova, Rumiantseva, Naumchik, Kulyova, Aleshkevich, Golovataya, Minakovskaya, Belevtsev, Latysheva, Latysheva, Beznoshchenko, Akopyan, Makukh, Kozlova, Varabyou, Ballow, Ong, Walter, Kondratenko, Kostyuchenko and Aleinikova.We thank all doctors for clinical help for patients. We also appreciate the support of patient and their parents for agreeing to take part in this study. TP thanks Sergey?Nikulshin, Marika Grutupa, and Zanna Kovalova. We thank Joseph Dasso for editing this manuscript, primarily for proper English

Clinical and genetic characteristics of acute myeloid leukemia with t(8;21) in children and results of therapy according to protocol AML-MM-2000

A t(8;21) is the most frequent abnormality in AML in children. Patients with this genetic abnormality are traditionally expected favorable prognosis with a probability of cure up to 80 %. Known additional cytogenetic abnormalities in AML with t(8;21) not affecting prognosis. These include loss of one sex chromosome and del(9q-). Prognosis impact of additional abnormalities involving chromosomes 7 and 11 in patients with t(8;21) is unknown. The purpose of this study was to analyse of additional anomalies, that occur in patients with t(8;21), and their influence on prognosis. During the study period 173 children with AML have received AML-MM-2000 treatment protocol in Russia and Belarus. Of these, in 33 patients (11 girls and 22 boys, median age — 10.5 years) t(8;21) was detected by chromosome banding or molecular-genetic analysis. In group with t(8;21) CNS leukemia in 8 patients was detected, extramedullary lesion — in 8 patients. In 4 patients CNS leukemia combined with presence of extramedullary lesions. These factors did not influence on therapy outcome. Overall survival of AML patients with t(8;21) was 0,67 ± 0,08 compared to 0,44 ± 0,04 in patients with AML without this translocation (p = 0,04). Special subgroup consist of 5 patients with t(8;21) and identified chromosomal abnormalities affecting chromosome 7 and 11, which were a poor prognostic factor: event-free survival in this subgroup of patients (n = 5) was 0,0 ± 0,0, compared to 0,34 ± 0,16 in patients with t(8;21) without additional anomalies (n = 28) (p = 0,027).</p