Nijmegen Breakage syndrome

Debreceni Egyetem, Orvos- és Egészségtudományi Centrum Infektológiai és Gyermekimmunológiai Tanszék, Debrecen.
Orvosi Hetilap 04/2010; 151(16):665-73. DOI: 10.1556/OH.2010.28851
Source: PubMed


Nijmegen Breakage syndrome is a rare, autosomal recessive disorder characterized by severe, combined immunodeficiency, recurrent sinopulmonary infections, chromosomal instability, radiosensitivity, predisposition to malignancy, a "bird-like" facial appearance, progressive microcephaly, short stature, and mental retardation. The syndrome is caused by mutations in the NBS1 gene, which encodes a DNA-repair protein, named nibrin. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inborn error of innate immunity.

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    ABSTRACT: Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.
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    ABSTRACT: Appropriate cellular signaling responses to DNA damage and the ability to repair DNA are fundamental processes that are required for organismal survival. Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease that results from defective DNA damage signaling. Understanding the molecular basis of A-T has provided many critical insights into the cellular response to DNA double-strand breaks (DSBs). A-T is a syndrome that shows pronounced neurodegeneration of the nervous system coincident with immune deficiency, radiosensitivity, and cancer proneness. A-T results from inactivation of the A-T mutated (ATM) kinase, a critical protein kinase that regulates the response to DNA-DSBs by selective phosphorylation of a variety of substrates. Therefore, understanding the ATM signaling program has important biological ramifications for nervous system homeostasis. Underscoring the importance of the DNA-DSBs response in the nervous system are other diseases related to A-T that also result from defects in this signaling pathway. In particular, defects in the DNA damage sensor, the Mre11-RAD50-NBS1 complex, also lead to syndromes with neurological deficits and overlapping phenotypes to A-T. Collectively, these diseases highlight the critical importance of appropriate responses to DNA-DSBs to maintain homeostasis in the nervous system.
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    ABSTRACT: The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation. Serum levels of IgG, IgM, IgE, and/or IgA are low, although the type of immunoglobulin deficiency is variable. Recurrent infections are the presenting symptom, usually in early childhood. ICF always involves limited hypomethylation of DNA and often arises from mutations in one of the DNA methyltransferase genes (DNMT3B). Much of this DNA hypomethylation is in 1qh, 9qh, and 16qh, regions that are the site of whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. By an unknown mechanism, the DNMT3B deficiency that causes ICF interferes with lymphogenesis (at a step after class switching) or lymphocyte activation. With the identification of DNMT3B as the affected gene in a majority of ICF patients, prenatal diagnosis of ICF is possible. However, given the variety of DNMT3B mutations, a first-degree affected relative should first have both alleles of this gene sequenced. Treatment almost always includes regular infusions of immunoglobulins, mostly intravenously. Recently, bone marrow transplantation has been tried.
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