Nijmegen Breakage Syndrome

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The Nijmegen breakage syndrome (abbreviation: NBS ; English: Nijmegen breakage syndrome ) is a syndromic , rare, congenital disease in humans with a disruption of the repair mechanism of the genetic material ( DNA ) in all cells and organs with increased chromosome fragility . This results in symptoms such as delayed growth and development (also during pregnancy ), head that is too small ( microcephaly ), mental development disorders , immune deficiencies and an increased susceptibility to malignant diseases such as leukemia , lymphomas and other malignant tumors . There is currently no known cure for Nijmegen Breakage Syndrome. Treatment is exclusively symptomatic: for example, psychological and physical support measures and measures to prevent or combat infections. If cancer develops , it will be treated like any other patient. However, it is problematic that patients with Nijmegen Breakage Syndrome have a significantly increased sensitivity to ionizing radiation and cytostatics due to the increased chromosome fragility . The Nijmegen Breakage Syndrome was first described in 1981 in the Dutch city of Nijmegen .

Cause and pathomechanism

The Nijmegen breakage syndrome is an autosomal - recessive inherited disease caused by a change in the Nibrin gene (NBS1) on chromosome 8 portion is caused q21-24. The nibrin gene codes for the protein nibrin. This is part of a protein complex that is involved in the DNA repair of double-strand breaks (damage to both DNA strands). In addition, nibrin is also a factor in the ATM signaling pathway (compare ATM protein and Louis-Bar syndrome ). Cells that show damage to their DNA are no longer sent into programmed cell death ( apoptosis ) due to the changed nibrin .

The autosomal - recessive inheritance means that people with only one altered (mutated) Nibrin gene usually do not become ill. People who have two mutated nibrin genes develop NBS.

Symptoms of illness

There are no symptoms for Nijmegen Breakage Syndrome that only occur with this disease. All reported and described symptoms can also occur with other diseases such as ataxia telangietactica ( Louis-Bar syndrome , AT) or Fanconi anemia (FA).

The following symptoms and signs of Nijmegen Breakage Syndrome have been reported and described:

Another sign of Nijmegen Breakage Syndrome is the occurrence of malignant diseases (cancer) in childhood and adolescence.

forecast

Only a few people with Nijmegen Breakage Syndrome reach adulthood. Usually by puberty at the latest, the increased chromosome fragility leads to cancer, often to lymphoma . The treatment of lymphomas and other cancers is made more difficult by this fragility, as the patients cannot be irradiated. The use of cytostatics is also associated with a higher risk than in people without increased chromosome fragility. X-rays or CT scans should be avoided as often as possible in people with Nijmegen breakage syndrome, as any use of ionizing radiation in NBS patients increases the risk of permanent damage, including cancer.

Individual evidence

  1. ↑ RD Taalman, NG Jaspers include: Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome. In: Mutation Research . Volume 112, Number 1, February 1983, pp. 23-32, ISSN  0027-5107 . PMID 6828038 .
  2. ↑ CM Weemaes, TW Hustinx et al.: A new chromosomal instability disorder: the Nijmegen breakage syndrome. In: Acta paediatrica Scandinavica. Volume 70, Number 4, July 1981, pp. 557-564, ISSN  0001-656X . PMID 7315300 .
  3. ↑ S. Matsuura, C. Weemaes et al. a .: Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24. In: American Journal of Human Genetics . Volume 60, Number 6, June 1997, pp. 1487-1494, ISSN  0002-9297 . doi : 10.1086 / 515461 . PMID 9199571 . PMC 1716114 (free full text).
  4. ↑ R. Varon, C. Vissinga et al .: Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. In: Cell . Volume 93, Number 3, May 1998, pp. 467-476, ISSN  0092-8674 . PMID 9590180 .
  5. ↑ A. Ito, H. Tauchi et al: Expression of full-length NBS1 protein restores normal radiation responses in cells from Nijmegen breakage syndrome patients. In: Biochemical and biophysical research communications . Volume 265, Number 3, November 1999, pp. 716-721, ISSN  0006-291X . doi : 10.1006 / bbrc.1999.1737 . PMID 10600486 .
  6. ↑ KH Chrzanowska, WJ Kleijer et al: Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. In: American journal of medical genetics. Volume 57, Number 3, July 1995, pp. 462-471, ISSN  0148-7299 . doi : 10.1002 / ajmg.1320570321 . PMID 7545870 . (Review).
  7. ↑ S. Kleier, M. Herrmann et al .: Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome. In: Clinical genetics. Volume 57, Number 5, May 2000, pp. 384-387, ISSN  0009-9163 . PMID 10852373 .
  8. ↑ KH Chrzanowska, M. Bekiesinska-Figatowska, S. Józwiak: Corpus callosum hypoplasia and associated brain anomalies in Nijmegen breakage syndrome. In: Journal of medical genetics. Volume 39, Number 5, May 2002, pp. E25, ISSN  1468-6244 . PMID 12011166 . PMC 1735117 (free full text).
  9. ↑ VM Der Kaloustian, AM Elliott, P. Eydoux: Severe intrauterine growth retardation with increased mitomycin C sensitivity, or Nijmegen breakage syndrome? In: Journal of medical genetics. Volume 32, Number 12, December 1995, pp. 998, ISSN  0022-2593 . PMID 8825936 . PMC 1051794 (free full text).
  10. ↑ BG van Engelen, JA Hiel et al: Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect. In: Human immunology. Volume 62, Number 12, December 2001, pp. 1324-1327, ISSN  0198-8859 . PMID 11756000 .
  11. ↑ K. Seidemann, M. Tiemann et al: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. In: Medical and pediatric oncology. Volume 33, Number 6, December 1999, pp. 536-544, ISSN  0098-1532 . PMID 10573576 .
  12. ↑ K. Seidemann, G. Henze et al .: Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials. In: Annals of Oncology Volume 11 Suppl 1, 2000, pp. 141-145, ISSN  0923-7534 . PMID 10707797 .
  13. ↑ E. Barth, E. Demori et al.: Anthracyclines in Nijmegen breakage syndrome. In: Medical and pediatric oncology. Volume 40, Number 2, February 2003, pp. 122-124, ISSN  0098-1532 . doi : 10.1002 / mpo.10079 . PMID 12461799 .
  14. ↑ L. Distel, S. Neubauer et al: Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. In: Medical and pediatric oncology. Volume 41, Number 1, July 2003, pp. 44-48, ISSN  0098-1532 . doi : 10.1002 / mpo.10275 . PMID 12764742 .