Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Nijmegen Breakage Syndrome

  • Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD  more...
 
Updated: Sep 29, 2014
 

Background

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition of chromosomal instability that is clinically characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy. Mutations in the NBN (NBS1) gene located in band 8q21 are responsible for Nijmegen breakage syndrome. Nijmegen breakage syndrome is identified as entries 251260 in and 602667 in Online Mendelian Inheritance in Man. Note the images below.

A 6-month-old infant with Nijmegen breakage syndro A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
Lateral facial features with sloping forehead and Lateral facial features with sloping forehead and receding mandible are shown in a 6-month-old infant.

In 1981, Weemaes et al[1] first delineated the syndrome in 2 siblings with microcephaly, short stature, skin pigmentation abnormalities, mental retardation, immunologic defects, and a high prevalence of chromosome 7 and/or chromosome 14 rearrangements in cultured lymphocytes.

In 1985, Seemanova et al[2] described a group of patients with an apparently new genetic disorder characterized by microcephaly with normal intelligence, cellular and humoral immune defects, and a striking predisposition to lymphoreticular malignancies. These cases were subsequently studied and found to fit into the category of Nijmegen breakage syndrome.

Further investigations revealed that in vitro cells derived from patients with Nijmegen breakage syndrome display characteristic abnormalities similar to those observed in ataxia-telangiectasia (A-T), including spontaneous chromosomal instability, sensitivity to ionizing radiation (IR), and radioresistant DNA synthesis (RDS).[3, 4, 5] However, aside from immune deficiency and a predisposition for malignancies (particularly those of lymphoid origin), the clinical manifestations are distinct. Consequently, Nijmegen breakage syndrome has long been considered a variant of A-T.

In 1998, on the basis of cellular phenotypes and the results of somatic cell complementation studies suggesting genetic heterogeneity, Jaspers et al proposed the term A-T variants for diseases in this group of patients. The 2 distinct groups were designated as A-T variant 1 (V1) for Nijmegen breakage syndrome and A-T variant 2 (V2) for Berlin breakage syndrome.[6, 7]

Linkage studies allowed the exclusion of the gene responsible for Nijmegen breakage syndrome from the A-T locus on band 11q23[8] and from the translocation breakpoints in a Polish patient.[9] The gene, NBS1 (actually named NBN), was finally mapped to band 8q21[5, 10, 11] and cloned it in 1998,[12, 13] and mutations in this single gene were found to account for both A-T complementation groups V1 and V2.[11, 14]

Next

Pathophysiology

Nijmegen breakage syndrome is caused by mutations in the NBN(NBS1) gene located at 8q21. The NBN gene product, nibrin, has been found to interact with at least 2 other proteins, hMre11 and Rad50. Nibrin plays a key role in regulating the activity of the M/R/N protein complex, which is involved in end-processing of both physiological and mutagenic DNA double-strand breaks (DSBs). DNA DSBs occur as intermediates in physiological events, such as V(D)J recombination during early B- and T-cell development and immunoglobulin class switch in mature B cells, but most frequently are generated by mutagenic agents such as IR and radiomimetic chemicals.[15, 16]

DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally can lead to cancer.[17, 18] Nibrin has been shown to play a crucial role in immunoglobulin class switch recombination and maintenance of the integrity of chromosomal stability.[19, 20, 21]

Because these key regulatory processes are defective in the cells of patients with Nijmegen breakage syndrome, chromosomal aberrations accumulate and immunodeficiency and gonadal failure occur.[22, 23] However, expression study of the murine Nbn gene during mouse development provides evidence that apart from sites of physiologic DSBs in the testis, thymus, and spleen, Nbn expression is also evident in several tissues and organs in which rejoining of DSBs is not known to occur.[24]

Mutant murine models of Nijmegen breakage syndrome have recently been derived. A null mutation affecting both alleles of the homologous gene, Nbn, is embryonically lethal for knockout mice. It has also been demonstrated that the common human mutation is hypomorphic and that the expression of a truncated protein is sufficient for survival.[25] Using humanized mouse models, e.g. with introduced the 657Δ5 mutation into Nbn gene,[26] allowed to demonstrate pleiotropic effect of the defective protein at the cellular and organs levels.

Of particular significance was the discovery of the functional link between a network of genes that play important roles in repairing DNA damage, regulating cellular proliferation and apoptosis, and maintaining telomeric function. Defects in this network, including defects in the genes encoding ATM, NBN (NBS1), BRCA1, FANCD2, BLM, TP53, CDS1/CHK2, and others, can cause cancer.[27, 28, 29]

Not all patients with the Nijmegen breakage syndrome–like phenotype and radiation sensitivity have a defect in the NBN gene. Some of these were found to have mutations in the gene encoding DNA ligase IV (LIG4)[30, 31] and, recently, in the RAD50 gene.[32] However, many have still-unknown defects.[33, 34, 35]

Previous
Next

Epidemiology

Frequency

United States

The number of Nijmegen breakage syndrome patients diagnosed and molecularly confirmed within North America cannot be estimated exactly.

International

The total number of patients identified worldwide is systematically increasing, probably because physicians are becoming more aware of the disorder. The largest groups of patients were diagnosed in Poland, the Czech Republic and Slovakia, Germany, and Ukraine. Nijmegen breakage syndrome has also been reported in Italy, France, Great Britain, The Netherlands, Spain, Bosnia, Croatia, Yugoslavia, Turkey, Russia, Morocco, Argentina, Chile, and New Zealand.

The relative frequency of the common c.657_661del5 mutation in the Czech Republic, Poland, and Ukraine was studied, and it was found to be unexpectedly high in these 3 Slavic populations (a mean estimated prevalence of 1 case per 177 newborns).[36] The highest estimated frequency was reported in Sorbs, a Slavic population isolate in Northeast Saxony, Germany (1 per 34 newborns).[37]

Mortality/Morbidity

Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.[23, 38, 39] Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency,[23] and bone marrow aplasia (aplastic anemia).[40]

Race

Nijmegen breakage syndrome seems to occur worldwide, with an increased prevalence among persons of Eastern European and Central European descent, particularly Czech and Polish people (founder effect).

Sex

No sex predilection is recognized for Nijmegen breakage syndrome.

Age

Microcephaly, the most striking symptom of the disease, is usually present at birth or develops soon thereafter.

Craniofacial characteristics become more obvious as patients age.

Growth is delayed from the very earliest stages of life, in comparison with age- and sex-matched controls, but improvement of the growth rate is usually observed after age 2 years.

Longitudinal studies of Polish patients indicate a decline in intellectual function with age. Most children tested during infancy and their preschool years have IQ scores indicative of normal or borderline intelligence. A shift toward a lower level of intellectual function is observed during their school-age years. This shift becomes more evident in patients older than 14 years; at this age, all tested patients had mild or moderate mental retardation.

Progression of humoral immunodeficiency with time is observed in some children.

Most malignancies develop before patients are aged 20 years (mean age, 9 y). The youngest patient recorded to have had acute lymphoblastic leukemia was a 1-year-old girl. Cancer appears prior to the diagnosis of Nijmegen breakage syndrome in approximately 20-30% of patients.

Skin pigmentation abnormalities in the form of café au lait spots and/or vitiligo are present in more than half of Nijmegen breakage syndrome patients. Progressive vitiligo has been observed in 3 teenage patients of Polish descent.

Gray hair, which reflects progeric changes, usually appears by adolescence or early adulthood.

The longest known survival is 53 years, in an Italian woman, and 33 and 31 years in 2 men, Polish and Dutch, respectively (the latter both died from malignancy.)

Previous
 
 
Contributor Information and Disclosures
Author

Krystyna H Chrzanowska, MD, PhD Head of Genetic Counseling Unit, Professor, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Noah S Scheinfeld, JD, MD, FAAD Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Abbvie<br/>Received income in an amount equal to or greater than $250 from: Optigenex<br/>Received salary from Optigenex for employment.

References
  1. Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand. 1981 Jul. 70(4):557-64. [Medline].

  2. Seemanova E, Passarge E, Beneskova D, Houstek J, Kasal P, Sevcikova M. Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet. 1985 Apr. 20(4):639-48. [Medline].

  3. Taalman RD, Hustinx TW, Weemaes CM, et al. Further delineation of the Nijmegen breakage syndrome. Am J Med Genet. 1989 Mar. 32(3):425-31. [Medline].

  4. 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 Jul 3. 57(3):462-71. [Medline].

  5. Matsuura S, Weemaes C, Smeets D, et al. Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24. Am J Hum Genet. 1997 Jun. 60(6):1487-94. [Medline].

  6. Jaspers NG, Taalman RD, Baan C. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet. 1988 Jan. 42(1):66-73. [Medline].

  7. Wegner RD, Metzger M, Hanefeld F, et al. A new chromosomal instability disorder confirmed by complementation studies. Clin Genet. 1988 Jan. 33(1):20-32. [Medline].

  8. Stumm M, Gatti RA, Reis A, et al. The ataxia-telangiectasia-variant genes 1 and 2 are distinct from the ataxia-telangiectasia gene on chromosome 11q23.1. Am J Hum Genet. 1995 Oct. 57(4):960-2. [Medline].

  9. Chrzanowska K, Stumm M, Bialecka M, et al. Linkage studies exclude the AT-V gene(s) from the translocation breakpoints in an AT-V patient. Clin Genet. 1997 May. 51(5):309-13. [Medline].

  10. Saar K, Chrzanowska KH, Stumm M, et al. The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet. 1997 Mar. 60(3):605-10. [Medline].

  11. Cerosaletti KM, Lange E, Stringham HM, et al. Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype. Am J Hum Genet. 1998 Jul. 63(1):125-34. [Medline].

  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 May 1. 93(3):477-86. [Medline].

  13. Varon R, Dutrannoy V, Weikert G, et al. Mild Nijmegen breakage syndrome phenotype due to alternative splicing. Hum Mol Genet. 2006 Mar 1. 15(5):679-89. [Medline].

  14. Varon R, Vissinga C, Platzer M, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998 May 1. 93(3):467-76. [Medline].

  15. Kanaar R, Wyman C. DNA repair by the MRN complex: break it to make it. Cell. 2008 Oct 3. 135(1):14-6. [Medline].

  16. Matsumoto Y, Miyamoto T, Sakamoto H, Izumi H, Nakazawa Y, Ogi T, et al. Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. DNA Repair (Amst). 2011 Mar 7. 10(3):314-21. [Medline].

  17. Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res. 2006 Jan. 16(1):45-54. [Medline].

  18. Pluth JM, Yamazaki V, Cooper BA, Rydberg BE, Kirchgessner CU, Cooper PK. DNA double-strand break and chromosomal rejoining defects with misrejoining in Nijmegen breakage syndrome cells. DNA Repair (Amst). 2008 Jan 1. 7(1):108-18. [Medline].

  19. Lähdesmäki A, Taylor AM, Chrzanowska KH, Pan-Hammarström Q. Delineation of the role of the Mre11 complex in class switch recombination. J Biol Chem. 2004 Apr 16. 279(16):16479-87. [Medline].

  20. Kracker S, Bergmann Y, Demuth I, et al. Nibrin functions in Ig class-switch recombination. Proc Natl Acad Sci U S A. 2005 Feb 1. 102(5):1584-9. [Medline]. [Full Text].

  21. Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci U S A. 2005 Feb 1. 102(5):1590-5. [Medline]. [Full Text].

  22. Demuth I, Digweed M. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome. Oncogene. 2007 Dec 10. 26(56):7792-8. [Medline].

  23. Wegner RD, German JJ, Chrzanowska KH, Digweed M, Stumm M. Chromosomal instability syndromes other than ataxia-telangiectasia. HD Ochs, CIE Smith, JM Puck. Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. Second. New York, NY: Oxford University Press; 2007. 427-453.

  24. Wilda M, Demuth I, Concannon P, Sperling K, Hameister H. Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. Hum Mol Genet. 2000 Jul 22. 9(12):1739-44. [Medline].

  25. Demuth I, Frappart PO, Hildebrand G, et al. An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. Hum Mol Genet. 2004 Oct 15. 13(20):2385-97. [Medline].

  26. Difilippantonio S, Celeste A, Fernandez-Capetillo O, et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat Cell Biol. 2005 Jul. 7(7):675-85. [Medline].

  27. Wang JY. Cancer. New link in a web of human genes. Nature. 2000 May 25. 405(6785):404-5. [Medline].

  28. Williams RS, Williams JS, Tainer JA. Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol. 2007 Aug. 85(4):509-20. [Medline].

  29. Czornak K, Chughtai S, Chrzanowska KH. Mystery of DNA repair: the role of the MRN complex and ATM kinase in DNA damage repair. J Appl Genet. 2008. 49(4):383-96. [Medline].

  30. O'Driscoll M, Cerosaletti KM, Girard PM, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec. 8(6):1175-85. [Medline].

  31. Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A. 2005 Sep 1. 137A(3):283-7. [Medline].

  32. Waltes R, Kalb R, Gatei M, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009 May. 84(5):605-16. [Medline]. [Full Text].

  33. Hiel JA, Weemaes CM, van Engelen BG, et al. Nijmegen breakage syndrome in a Dutch patient not resulting from a defect in NBS1. J Med Genet. 2001 Jun. 38(6):E19. [Medline].

  34. Maraschio P, Spadoni E, Tanzarella C, et al. Genetic heterogeneity for a Nijmegen breakage-like syndrome. Clin Genet. 2003 Apr. 63(4):283-90. [Medline].

  35. Berardinelli F, di Masi A, Salvatore M, et al. A case report of a patient with microcephaly, facial dysmorphism, chromosomal radiosensitivity and telomere length alterations closely resembling "Nijmegen breakage syndrome" phenotype. Eur J Med Genet. 2007 May-Jun. 50(3):176-87. [Medline].

  36. 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 Nov. 8(11):900-2. [Medline].

  37. Maurer MH, Hoffmann K, Sperling K, Varon R. High prevalence of the NBN gene mutation c.657-661del5 in Southeast Germany. J Appl Genet. 2010. 51(2):211-4. [Medline].

  38. van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C. Nijmegen breakage syndrome. J Med Genet. 1996 Feb. 33(2):153-6. [Medline].

  39. Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child. 2000 May. 82(5):400-6. [Medline].

  40. Resnick IB, Kondratenko I, Togoev O, et al. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr. 2002 Mar. 140(3):355-61. [Medline].

  41. Van de Kaa CA, Weemaes CM, Wesseling P, Schaafsma HE, Haraldsson A, De Weger RA. Postmortem findings in the Nijmegen breakage syndrome. Pediatr Pathol. 1994 Sep-Oct. 14(5):787-96. [Medline].

  42. Chrzanowska KH, Romer T, Krajewska-Walasek M. Evidence for a high rate of gonadal failure in female patients with Nijmegen breakage syndrome. Eur J Hum Genet. 2000. 8 (Suppl. 1):73.

  43. Chrzanowska KH, Szarras-Czapnik M, Gajdulewicz M, Kalina MA, Gajtko-Metera M, Walewska-Wolf 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 Jul. 95(7):3133-40. [Medline].

  44. Gregorek H, Chrzanowska KH, Michalkiewicz J, Syczewska M, Madalinski K. 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 Nov. 130(2):319-24. [Medline].

  45. 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 Jun 10. 115(23):4770-7. [Medline].

  46. Piatosa 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 Oct. 81(10):835-42. [Medline].

  47. Gladkowska-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 Nov. 216(3):337-44. [Medline].

  48. Chrzanowska KH, Digweed M, Sperling K, Seemanova E. DNA-repair deficiency and cancer: Lessons from lymphoma. H. Allgayer, H. Rehder, S. Fulda. Hereditary tumors. From genes to clinical consequences. Weinheim Germany: WILEY-VH; 2009. 377-391.

  49. Pastorczak A, Stolarska M, Trelinska J, Zawitkowska J, Kowalczyk J, Mlynarski W. Nijmegen breakage syndrome (NBS) as a risk factor for CNS involvement in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011 Jul 15. 57(1):160-2. [Medline].

  50. Engel K, Rudelius M, Meinel FG, Peschel C, Keller U. An adult patient with Nijmegen Breakage Syndrome and Hodgkin's Lymphoma. BMC Hematol. 2014 Jan 16. 14(1):2. [Medline]. [Full Text].

  51. Michallet AS, Lesca G, Radford-Weiss I, Delarue R, Varet B, Buzyn A. T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome. Ann Hematol. 2003 Aug. 82(8):515-7. [Medline].

  52. Pastorczak A, Szczepanski T, Trelinska J, et al. Secondary acute monocytic leukemia positive for 11q23 rearrangement in Nijmegen breakage syndrome. Pediatr Blood Cancer. 2014 Aug. 61(8):1469-71. [Medline].

  53. Bakhshi S, Cerosaletti KM, Concannon P, et al. Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. J Pediatr Hematol Oncol. 2003 Mar. 25(3):248-51. [Medline].

  54. Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol. 2003 Jul. 41(1):44-8. [Medline].

  55. Der Kaloustian VM, Kleijer W, Booth A, et al. Possible new variant of Nijmegen breakage syndrome. Am J Med Genet. 1996 Oct 2. 65(1):21-6. [Medline].

  56. Tekin M, Akcayoz D, Ucar C, Gulen H, Akar N. 657del5 mutation of the Nijmegen breakage syndrome gene (NBS1) in the Turkish population. Hum Biol. 2005 Jun. 77(3):393-7. [Medline].

  57. Meyer S, Kingston H, Taylor AM, et al. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet. 2004 Oct 15. 154(2):169-74. [Medline].

  58. Yoo J, Wolgamot G, Torgerson TR, Sidbury R. Cutaneous noncaseating granulomas associated with Nijmegen breakage syndrome. Arch Dermatol. 2008 Mar. 144(3):418-9. [Medline].

  59. Erdös M, Tóth B, Veres I, Kiss M, Remenyik E, Maródi L. Nijmegen breakage syndrome complicated with primary cutaneous tuberculosis. Pediatr Infect Dis J. 2011 Apr. 30(4):359-60. [Medline].

  60. Pasic S, Kandolf-Sekulovic L, Djuricic S, Zolotarevski L, Simic R, Abinun M. Necrobiotic cutaneous granulomas in Nijmegen breakage syndrome. J Investig Allergol Clin Immunol. 2012. 22(2):138-40. [Medline].

  61. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, et al. Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology. 2000 Jan. 42(1):43-7. [Medline].

  62. Chrzanowska KH, Stumm M, Bekiesiska-Figatowska M, et al. Atypical clinical picture of the Nijmegen breakage syndrome associated with developmental abnormalities of the brain. J Med Genet. 2001 Jan. 38(1):E3. [Medline].

  63. Rosenzweig SD, Russo RA, Gallego M, Zelazko M. Juvenile rheumatoid arthritis-like polyarthritis in Nijmegen breakage syndrome. J Rheumatol. 2001 Nov. 28(11):2548-50. [Medline].

  64. Pasic S, Cupic M, Jovanovic T, Djukic S, Kavaric M, Lazarevic I. Nijmegen breakage syndrome and chronic polyarthritis. Ital J Pediatr. 2013 Sep 17. 39:59. [Medline]. [Full Text].

  65. Maraschio P, Danesino C, Antoccia A, et al. A novel mutation and novel features in Nijmegen breakage syndrome. J Med Genet. 2001 Feb. 38(2):113-7. [Medline].

  66. Seemanova E, Sperling K, Neitzel H, et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. 2006 Mar. 43(3):218-24. [Medline]. [Full Text].

  67. Gennery AR, Slatter MA, Bhattacharya A, et al. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol. 2004 Nov. 113(2):214-9. [Medline].

  68. New HV, Cale CM, Tischkowitz M, et al. Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer. 2005 May. 44(5):494-9. [Medline].

  69. Varon R, Muer A, Wagner K, et al. Nijmegen breakage syndrome (NBS) due to maternal isodisomy of chromosome 8. Am J Med Genet A. 2007 Jan 1. 143(1):92-4. [Medline].

  70. Michalkiewicz J, Barth C, Chrzanowska K, et al. Abnormalities in the T and NK lymphocyte phenotype in patients with Nijmegen breakage syndrome. Clin Exp Immunol. 2003 Dec. 134(3):482-90. [Medline].

  71. Seemanova E, Sperling K, Neitzel H, et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. 2006 Mar. 43(3):218-24. [Medline]. [Full Text].

  72. Lammens M, Hiel JA, Gabreels FJ, van Engelen BG, van den Heuvel LP, Weemaes CM. Nijmegen breakage syndrome: a neuropathological study. Neuropediatrics. 2003 Aug. 34(4):189-93. [Medline].

  73. Seidemann K, Henze G, Beck JD, et al. Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials. Ann Oncol. 2000. 11 Suppl 1:141-5. [Medline].

  74. 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 Nov. 7(9):590-3. [Medline].

  75. Dembowska-Baginska B, Perek D, Brozyna A, et al. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer. 2009 Feb. 52(2):186-90. [Medline].

  76. Jovanovic A, Minic P, Scekic-Guc M, et al. Successful treatment of hodgkin lymphoma in nijmegen breakage syndrome. J Pediatr Hematol Oncol. 2009 Jan. 31(1):49-52. [Medline].

  77. Barth E, Demori E, Pecile V, Zanazzo GA, Malorgio C, Tamaro P. Anthracyclines in Nijmegen breakage syndrome. Med Pediatr Oncol. 2003 Feb. 40(2):122-4. [Medline].

  78. Albert MH, Gennery AR, Greil J, et al. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant. 2010 Apr. 45(4):622-6. [Medline].

  79. Seemanova E, Jarolim P, Seeman P, et al. Cancer risk of heterozygotes with the NBN founder mutation. J Natl Cancer Inst. 2007 Dec 19. 99(24):1875-80. [Medline].

  80. di Masi A, Antoccia A. NBS1 Heterozygosity and Cancer Risk. Curr Genomics. 2008 Jun. 9(4):275-81. [Medline]. [Full Text].

  81. Howlett NG, Scuric Z, D'Andrea AD, Schiestl RH. Impaired DNA double strand break repair in cells from Nijmegen breakage syndrome patients. DNA Repair (Amst). 2006 Feb 3. 5(2):251-7. [Medline].

  82. Kruger L, Demuth I, Neitzel H, et al. Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. Carcinogenesis. 2007 Jan. 28(1):107-11. [Medline].

 
Previous
Next
 
A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
Lateral facial features with sloping forehead and receding mandible are shown in a 6-month-old infant.
Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
Lateral profile. This view shows a relatively long nose and receding mandible.
Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
Vitiligo spots in a patient with Nijmegen breakage syndrome.
Progressive vitiligo in a patient with Nijmegen breakage syndrome.
Café au lait–like spots in a patient with Nijmegen breakage syndrome.
Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.
MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
Table. NBS1 Gene Pathogenic Molecular Variants
Mutation Exon Mutation Type Change in Protein Number of Families and Origin Allelic Status
c.643C>T 6 Missense R215W 1†



Czech



He*
c.657_661del5



(657del5)



6 Frameshift Truncated



protein (233 aa)



>90%



Slavic



founder mutation



Ho‡



(He)



c.681delT 6 Frameshift Truncated



protein (229 aa)



1



Russian



He
c.698_701del4



(698del4)



6 Frameshift Truncated



protein (236 aa)



2



English



Ho



He



c.742_743insGG



(742insGG)



7 Frameshift Truncated



protein (251 aa)



1



Italian



Ho
c.835_838del4



(835del4)



7 Frameshift Truncated



protein (279 aa)



1



Italian



Ho
c.842_843insT



(842insT)



7 Frameshift Truncated



protein (283 aa)



1



Mexican



Ho
c.900_924del25



(900del25)



8 Frameshift Truncated



protein (305 aa)



1



Moroccan



Ho
c.976C>T 8 Nonsense Q326X 1



Dutch



Ho
c.1089C>A 9 Nonsense Y363X 3



§



Pakistani



Ho
c.1142delC 10 Frameshift Truncated



protein (402 aa)



2



Canadian



He
*He - Heterozygous (compound with 657del5).



†Monozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.[71]



‡Ho - Homozygous.



§Three nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).[67, 68]



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.