Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey

Fanconi anemia (FA) is a recessively inherited disease characterized by multiple symptoms including growth retardation, skeletal abnormalities, and bone marrow failure. The FA diagnosis is complicated due to the fact that the clinical manifestations are both diverse and variable. A chromosomal breakage test using a DNA cross-linking agent, in which cells from an FA patient typically exhibit an extraordinarily sensitive response, has been considered the gold standard for the ultimate diagnosis of FA. In the majority of FA patients the test results are unambiguous, although in some cases the presence of hematopoietic mosaicism may complicate interpretation of the data. However, some diagnostic overlap with other syndromes has previously been noted in cases with Nijmegen breakage syndrome. Here we present results showing that misdiagnosis may also occur with patients suffering from two of the three currently known cohesinopathies, that is, Roberts syndrome (RBS) and Warsaw breakage syndrome (WABS). This complication may be avoided by scoring metaphase chromosomes—in addition to chromosomal breakage—for spontaneously occurring premature centromere division, which is characteristic for RBS and WABS, but not for FA.

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Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage syndrome

Mutation Research/DNA Repair Reports ◽

10.1016/0167-8817(83)90021-4 ◽

1983 ◽

Vol 112 (1) ◽

pp. 23-32 ◽

Cited By ~ 38

Author(s):

R.D.F.M. Taalman ◽

N.G.J. Jaspers ◽

J.M.J.C. Scheres ◽

J. de Wit ◽

T.W.J. Hustinx

Keyword(s):

Ionizing Radiation ◽

Nijmegen Breakage Syndrome ◽

Chromosomal Breakage

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Non-Hodgkin Lymphoma in Children with Primary Immunodeficiencies: Clinical Manifestations, Diagnosis, and Management, Belarusian Experience

Lymphoma ◽

10.1155/2015/123548 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Alina Fedorova ◽

Svetlana Sharapova ◽

Taisia Mikhalevskaya ◽

Svetlana Aleshkevich ◽

Inna Proleskovskaya ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Clinical Manifestations ◽

B Cell Lymphoma ◽

Large Cell ◽

Cell Types ◽

Nijmegen Breakage Syndrome ◽

Primary Immune Deficiency ◽

Chromosomal Breakage ◽

Hematopoietic Stem ◽

Non Hodgkin Lymphoma

Introduction. Non-Hodgkin lymphoma (NHL) is the most frequent malignancy associated with primary immune deficiency disease (PID). We aimed to present the clinical characteristics and outcomes of Belarusian children with PID who developed NHL. Procedure. We reviewed 16 patients with PID and NHL. Eight patients had combined PID: 5—Nijmegen breakage syndrome, 1—Bloom syndrome, 1—Wiskott-Aldrich syndrome, and 1—Х-linked lymphoproliferative syndrome. Results. In 75% cases PID was diagnosed simultaneously or after the NHL was confirmed. PID-associated NHL accounted for 5.7% of all NHL and was characterized by younger median age (6.3 versus 10.0 years, P<0.05) and by prevalence of large-cell types (68.8% versus 24.5%, P<0.001). Children with combined PID had median age of 1.3 years; 5 of them developed EBV-associated diffuse large B-cell lymphoma with lung involvement. Five of 6 patients with chromosomal breakage syndrome developed T-NHL. Six patients died of infections; two died after tumor progression; one child had early relapse; two died of second NHL and one of secondary hemophagocytic syndrome. Overall, 4 children are alive and disease-free after a follow-up from 1.4 to 5.7 years. Conclusions. PID needs to be diagnosed early. Individualized chemotherapy, comprehensive supportive treatment, and hematopoietic stem cell transplantation may improve survival of children with PID and NHL.

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

Annals of Agricultural and Environmental Medicine ◽

10.26444/aaem/143541 ◽

2021 ◽

Author(s):

Aleksandra Filipiuk ◽

Agata Kozakiewicz ◽

Kamil Kośmider ◽

Monika Lejman ◽

Joanna Zawitkowska

Keyword(s):

Therapeutic Approach ◽

Nijmegen Breakage Syndrome ◽

Lymphoid Malignancies

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Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2016.01.007 ◽

2016 ◽

Vol 59 (3) ◽

pp. 126-132 ◽

Cited By ~ 16

Author(s):

Agata Pastorczak ◽

Tomasz Szczepanski ◽

Wojciech Mlynarski

Keyword(s):

Clinical Course ◽

Nijmegen Breakage Syndrome ◽

Therapeutic Implications ◽

Lymphoid Malignancies

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Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage–modified chromatin

The Journal of Cell Biology ◽

10.1083/jcb.200708210 ◽

2008 ◽

Vol 181 (2) ◽

pp. 213-226 ◽

Cited By ~ 145

Author(s):

Fredrik Melander ◽

Simon Bekker-Jensen ◽

Jacob Falck ◽

Jiri Bartek ◽

Niels Mailand ◽

...

Keyword(s):

Adaptor Protein ◽

Nijmegen Breakage Syndrome ◽

Local Concentration ◽

Dna Double Strand Breaks ◽

Phosphate Binding ◽

Chromosomal Breakage ◽

Mrn Complex ◽

N Terminus

DNA double-strand breaks (DSBs) trigger accumulation of the MRE11–RAD50–Nijmegen breakage syndrome 1 (NBS1 [MRN]) complex, whose retention on the DSB-flanking chromatin facilitates survival. Chromatin retention of MRN requires the MDC1 adaptor protein, but the mechanism behind the MRN–MDC1 interaction is unknown. We show that the NBS1 subunit of MRN interacts with the MDC1 N terminus enriched in Ser-Asp-Thr (SDT) repeats. This interaction was constitutive and mediated by binding between the phosphorylated SDT repeats of MDC1 and the phosphate-binding forkhead-associated domain of NBS1. Phosphorylation of the SDT repeats by casein kinase 2 (CK2) was sufficient to trigger MDC1–NBS1 interaction in vitro, and MDC1 associated with CK2 activity in cells. Inhibition of CK2 reduced SDT phosphorylation in vivo, and disruption of the SDT-associated phosphoacceptor sites prevented the retention of NBS1 at DSBs. Together, these data suggest that phosphorylation of the SDT repeats in the MDC1 N terminus functions to recruit NBS1 and, thereby, increases the local concentration of MRN at the sites of chromosomal breakage.

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