Nijmegen breakage syndrome
- Andrew Gennery, MD
Andrew Gennery, MD
- Clinical Reader/Consultant
- Newcastle University
A number of human genetic disorders cause chromosomal breakage, which is characterized by genome instability that occurs in the basal state (spontaneously) or in response to DNA-damaging agents (table 1). These disorders cause defects in the recognition and/or repair of damage to DNA inflicted by different agents. In most cases, the genome instability is associated with immunodeficiency, a predisposition to develop cancer, and premature aging .
This topic review will discuss Nijmegen breakage syndrome (NBS; MIM #251260), which is a chromosomal breakage syndrome associated with immunodeficiency [2,3]. Discussions relating to similar disorders are presented separately. (See "Ataxia-telangiectasia" and "Bloom syndrome".)
Nijmegen breakage syndrome (NBS) is a rare disorder. The exact incidence is unknown. Most NBS patients have an ethnic origin from Eastern Europe, notably Poland and Czechoslovakia [4,5]. One study analyzed newborn screening cards for the most common NBS mutation (657del5) . The prevalence of this mutation ranged from 1 in 154 to 1 in 190 in three Slavic populations, compared with 1 in 866 in a German population reported in a separate study . The incidence of NBS was estimated to be 1 in 95,000 livebirths in Czechoslovakia .
Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder that is caused by mutations in the nibrin (NBN) gene on 8q21 that encodes the protein nibrin (MIM #602667) . The most common mutation in patients of Eastern European descent is hypomorphic, leading to a partially functional protein . Other mutations are more common in different populations .
Nibrin forms a complex with MRE11 (meiotic recombination 11, the protein mutated in ataxia-telangiectasia-like disorder) and RAD50 (a protein involved in deoxyribonucleic acid [DNA] double-strand break repair) and then rapidly localizes to the site of DNA double-strand breaks. DNA breaks are not efficiently repaired in the absence of nibrin [9-11]. This protein complex is also involved in meiotic recombination and telomere maintenance [12-14]. In addition, nibrin plays a role in the initiation of base excision repair after oxidative or alkylating stress .
- Kamenisch Y, Berneburg M. Progeroid syndromes and UV-induced oxidative DNA damage. J Investig Dermatol Symp Proc 2009; 14:8.
- Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, et al. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis 2012; 7:13.
- Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1176/ (Accessed on March 21, 2012).
- Weemaes CM, Hustinx TW, Scheres JM, et al. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 1981; 70:557.
- Varon R, Seemanova E, Chrzanowska K, et al. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 2000; 8:900.
- Carlomagno F, Chang-Claude J, Dunning AM, Ponder BA. Determination of the frequency of the common 657Del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer. Genes Chromosomes Cancer 1999; 25:393.
- Antoccia A, Kobayashi J, Tauchi H, et al. Nijmegen breakage syndrome and functions of the responsible protein, NBS1. Genome Dyn 2006; 1:191.
- Lins S, Kim R, Krüger L, et al. Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. Gene 2009; 447:12.
- Carney JP, Maser RS, Olivares H, et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 1998; 93:477.
- Yuan J, Chen J. MRE11-RAD50-NBS1 complex dictates DNA repair independent of H2AX. J Biol Chem 2010; 285:1097.
- Williams RS, Dodson GE, Limbo O, et al. Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair. Cell 2009; 139:87.
- Brugmans L, Verkaik NS, Kunen M, et al. NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication. DNA Repair (Amst) 2009; 8:1363.
- Attwooll CL, Akpinar M, Petrini JH. The mre11 complex and the response to dysfunctional telomeres. Mol Cell Biol 2009; 29:5540.
- Deng Y, Guo X, Ferguson DO, Chang S. Multiple roles for MRE11 at uncapped telomeres. Nature 2009; 460:914.
- Sagan D, Müller R, Kröger C, et al. The DNA repair protein NBS1 influences the base excision repair pathway. Carcinogenesis 2009; 30:408.
- Digweed M, Sperling K. Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amst) 2004; 3:1207.
- Van de Kaa CA, Weemaes CM, Wesseling P, et al. Postmortem findings in the Nijmegen breakage syndrome. Pediatr Pathol 1994; 14:787.
- Bekiesińska-Figatowska M, Chrzanowska KH, Sikorska J, et al. Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology 2000; 42:43.
- Warcoin M, Lespinasse J, Despouy G, et al. Fertility defects revealing germline biallelic nonsense NBN mutations. Hum Mutat 2009; 30:424.
- Chrzanowska KH, Szarras-Czapnik M, Gajdulewicz M, et al. High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study. J Clin Endocrinol Metab 2010; 95:3133.
- Wolf EK, Shwayder TA. Nijmegen breakage syndrome associated with porokeratosis. Pediatr Dermatol 2009; 26:106.
- Yoo J, Wolgamot G, Torgerson TR, Sidbury R. Cutaneous noncaseating granulomas associated with Nijmegen breakage syndrome. Arch Dermatol 2008; 144:418.
- Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000; 82:400.
- Gładkowska-Dura M, Dzierzanowska-Fangrat K, Dura WT, et al. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J Pathol 2008; 216:337.
- Ciara E, Piekutowska-Abramczuk D, Popowska E, et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol 2010; 119:325.
- Huang J, Grotzer MA, Watanabe T, et al. Mutations in the Nijmegen breakage syndrome gene in medulloblastomas. Clin Cancer Res 2008; 14:4053.
- Pollard JM, Gatti RA. Clinical radiation sensitivity with DNA repair disorders: an overview. Int J Radiat Oncol Biol Phys 2009; 74:1323.
- Seemanová E. An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. Mutat Res 1990; 238:321.
- Seemanová E, Jarolim P, Seeman P, et al. Cancer risk of heterozygotes with the NBN founder mutation. J Natl Cancer Inst 2007; 99:1875.
- di Masi A, Antoccia A. NBS1 Heterozygosity and Cancer Risk. Curr Genomics 2008; 9:275.
- Gregorek H, Olczak-Kowalczyk D, Dembowska-Bagińska B, et al. Oral findings in patients with Nijmegen breakage syndrome: a preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 108:e39.
- Wegner RF, German JJ, Chrzanpwska KH, et al. Chromosomal instability syndromes other than ataxia-telangiectasia. In: Primary immunodeficiency syndromes: A molecular and genetic approach, Ochs HD, Smith CIE, Puck JM (Eds), Oxford University Press, Oxford 2007. p.432.
- Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M, et al. Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 1995; 57:462.
- Gregorek H, Chrzanowska KH, Michałkiewicz J, et al. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin Exp Immunol 2002; 130:319.
- van der Burg M, Pac M, Berkowska MA, et al. Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients. Blood 2010; 115:4770.
- Piątosa B, van der Burg M, Siewiera K, et al. The defect in humoral immunity in patients with Nijmegen breakage syndrome is explained by defects in peripheral B lymphocyte maturation. Cytometry A 2012; 81:835.
- Taalman RD, Hustinx TW, Weemaes CM, et al. Further delineation of the Nijmegen breakage syndrome. Am J Med Genet 1989; 32:425.
- Taalman RD, Jaspers NG, Scheres JM, et al. Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome. Mutat Res 1983; 112:23.
- Patel JP, Puck JM, Srinivasan R, et al. Nijmegen breakage syndrome detected by newborn screening for T cell receptor excision circles (TRECs). J Clin Immunol 2015; 35:227.
- Gennery AR, Slatter MA, Bhattacharya A, et al. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol 2004; 113:214.
- Waltes R, Kalb R, Gatei M, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet 2009; 84:605.
- Webster AD, Barnes DE, Arlett CF, et al. Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet 1992; 339:1508.
- Chistiakov DA, Voronova NV, Chistiakov AP. Ligase IV syndrome. Eur J Med Genet 2009; 52:373.
- Buck D, Malivert L, de Chasseval R, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 2006; 124:287.
- Griffith E, Walker S, Martin CA, et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 2008; 40:232.
- Albert MH, Gennery AR, Greil J, et al. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant 2010; 45:622.
- Gregorek H, Chrzanowska KH, Dzierzanowska-Fangrat K, et al. Nijmegen breakage syndrome: Long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin Immunol 2010; 135:440.
- Chistiakov DA, Voronova NV, Chistiakov PA. Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients. Acta Oncol 2008; 47:809.
- Jovanovic A, Minic P, Scekic-Guc M, et al. Successful treatment of hodgkin lymphoma in nijmegen breakage syndrome. J Pediatr Hematol Oncol 2009; 31:49.
- Dembowska-Baginska B, Perek D, Brozyna A, et al. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 2009; 52:186.
- Dumic M, Radman I, Krnic N, et al. Successful treatment of diffuse large B-cell non-hodgkin lymphoma with modified CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy and rituximab in a patient with Nijmegen syndrome. Clin Lymphoma Myeloma 2007; 7:590.