Sections

Workup

Laboratory Studies

Systematic screening for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, and hepatitis C virus is recommended (once a year or when infection is suspected).

Basis for diagnosis

The diagnosis is based on the characteristic phenotype and laboratory results. Laboratory studies helpful in diagnosing Nijmegen breakage syndrome include cytogenetic analysis, an evaluation of humoral and cellular immunity, and radiation-sensitivity testing. Molecular genetic analysis enables definite confirmation.

Cytogenetic analysis

Cytogenetic analysis allows detection of chromosomal instability, which is a characteristic feature of the disease, although the poor response of T lymphocytes to mitogens can often make diagnosis difficult.

In general, the constitutional karyotypes of patients with Nijmegen breakage syndrome are normal (46,XX or 46,XY). However, in a high proportion of phytohemagglutinin-stimulated lymphocytes (10-60%), spontaneous structural chromosomal rearrangements are observed (QFQ or GTG banding), as well as other aberrations such as chromatid and/or chromosome breaks and acentric fragments (after Giemsa-staining).

Most of these rearrangements specifically involve chromosomes 7 and 14, with breakpoints at bands 7p13, 7q35, 14q11, and 14q32, which are identical to those found in persons with ataxia-telangiectasia (A-T).

Immunoglobulin chain and T-cell receptor genes are located at these sites. The most frequently and constantly detected aberration is inv(7)(p13q35), followed by translocations 7/14, 7/7, and 14/14.

Immunologic testing

Diagnostic evaluation of the immunological profile is required at the time of diagnosis. Afterwards, the evolution of humoral (every 6 mo) and cellular immunity (once a year) needs to be systematically monitored (until immunoglobulin administration or immunomodulating therapy is started).

Evaluation of humoral immunity should include measurements of serum immunoglobulin levels (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM]) and IgG subclass levels. The most frequently observed defects are the combined deficit of IgG and IgA, followed by an isolated IgG deficiency. The most characteristic feature of humoral disturbances is a deficiency in one or more IgG subclasses, even with total IgG levels in the reference range; selective deficiency of IgG4 and IgG2 are the most common.^[56]

Evaluation of cell-mediated immunity should include measurements of T-cell lymphocyte subpopulations (CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD8⁺; CD4/CD45RA⁺, CD4/CD45RO⁺), B cells (CD19⁺), and natural killer cells (CD16⁺, CD56⁺) and an assessment of the proliferative response to mitogens or antigens (phytohemagglutinin, anti-CD3). T-cell immunity is impaired in most patients with Nijmegen breakage syndrome.^[84]The most commonly reported defects are mild-to-moderate lymphopenia, expressed as a low percentage of CD3⁺ T cells, a low proportion of CD4⁺ (helper) T cells, and a decreased CD4⁺/CD8⁺ ratio. A deficiency of CD4/CD45RA⁺ (naive) cells and an excess of CD4/CD45RO⁺ (memory) cells has been observed, and a high number of natural killer cells has been noted in a proportion of patients.^[85]

Alpha-fetoprotein determination

Serum alpha-fetoprotein levels are within the reference range in patients with Nijmegen breakage syndrome, in contrast to elevated concentrations in approximately 90% of patients with A-T.

IR and RDS sensitivity analysis

IR induces a variety of DNA lesions, including single-strand breaks and DSBs. Some laboratories use the increased sensitivity of different types of cells (eg, lymphoblastoid cell lines [LCLs], cultured skin fibroblasts) to IR or to the radiomimetic agent bleomycin to confirm the diagnosis of Nijmegen breakage syndrome.

The increased frequency of induced chromosomal breakage in lymphocytes and fibroblasts clearly differentiates Nijmegen breakage syndrome cells from healthy cells. In a colony survival assay, Nijmegen breakage syndrome cells are 3-5 times more radiosensitive than control cells.

Examination of DNA replication in irradiated Nijmegen breakage syndrome cells, as well as cells in A-T and A-T–like disorder, reveals the phenomenon of RDS, which reflects a defect in control of the S-phase progression until the repair of DNA damage is complete.^{[10, 12]}

Immunoblotting assay

Western blotting allows demonstration of the presence or absence of the p95/nibrin protein in LCLs.^{[18, 20]}

Molecular genetic analysis

The cloning of the NBN (NBS1) gene, which was accomplished in 1998, provides the basis for both postnatal and prenatal diagnosis by means of mutation analysis.

The demonstration of disease-causing mutations in both alleles of the NBN gene is required for definitive confirmation of Nijmegen breakage syndrome.

In more than 90% of patients tested so far, the common c.657_661del5 mutation is homozygous. The remaining patients have a heterozygous c.657_661del5 deletion and a second unique mutation or a homozygous unique mutation.

Testing for the c.657_661del5 mutation is available on a clinical basis (and is always performed first); tests for other mutations are used in research studies.

In the United States, approximately 70% of individuals tested to date are homozygous for the common allele c.657_661del5, a further 15% are heterozygous for c.657_661del5 and a second unique mutation, and the remaining 15% are homozygous for a unique mutation. See GeneReviews, Nijmegen Breakage Syndrome .

If further testing is requested, an LCL is established and the nuclear lysate is analyzed by means of Western blot for nibrin and by colony survival assay for radiosensitivity. If nibrin is absent or truncated and the cells are sensitive to IR, DNA is analyzed by direct sequencing for NBS1 mutations.

Table 2. Selected NBN Gene Pathogenic Molecular Variants (Open Table in a new window)

Mutation	Exon	Mutation Type	Change in Protein	Number of Families and Origin	Allelic Status
c.643C>T	6	Missense	R215W	1^a Czech	He^b
c.657_661del5 (657del5)	6	Frameshift	Truncated protein (233 aa)	>90% Slavic founder mutation	Ho^c (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^d Pakistani	Ho
c.1142delC	10	Frameshift	Truncated protein (402 aa)	2 Canadian	He
^aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.^[86] ^bHe - Heterozygous (compound with 657del5). ^cHo - Homozygous. ^dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).^{[47, 48]}

Endocrinologic evaluation

Ovarian failure is expected in most female patients with Nijmegen breakage syndrome.^{[13, 54]} A study of the pituitary-gonadal axis (ie, plasma concentrations of follicle-stimulating hormone [FSH], luteinizing hormone, and estradiol [E2]) in females reaching pubertal age is recommended. A serum FSH level exceeding 40 IU/L and a low E2 level indicate ovarian failure (hypergonadotropic hypogonadism).

Imaging Studies

Because patients with Nijmegen breakage syndrome have an inherited hypersensitivity to IR, CT scanning is contraindicated; therefore, MRI and ultrasonography are the methods of choice when imaging studies are necessary.

Cranial MRI may reveal CNS developmental abnormalities or solid tumor.

MRI of chest or abdomen/pelvis allows demonstration/detection of a tumor mass.

Ultrasonography of the abdomen depicts urinary tract abnormalities, multiple or accessory spleens, and enlarged lymph nodes

In general, pelvic ultrasonograms in females show small homoechoic ovaries resembling streaks and an infantile uterus.

Note the images below.

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.

View Media Gallery

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.

View Media Gallery

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.

View Media Gallery

Histologic Findings

Data yielded from histopathologic analysis of tissue biopsy and autopsy specimens from patients with Nijmegen breakage syndrome are limited. Findings suggestive of a lymphoproliferative disorder are the most common indications for lymph node biopsy, but only a few reports on the histologic and immunophenotypic features of lymphomas are available. In 2000, Gladkowska-Dura et al reported a detailed study of lymphomas in 11 Nijmegen breakage syndrome patients.^[59]

Although at least 50 patients with Nijmegen breakage syndrome are known to have died, extensive autopsy findings are well documented in only 1 patient, and limited information is available in a few others. Markedly reduced brain weight and thymus dysplasia or aplasia were consistent findings in all cases. No cerebellar degeneration was confirmed, which is in contrast to persons with A-T. A detailed neuropathological study of the first-recognized Nijmegen breakage syndrome case was reported by Lammens et al^[87]in 2003.

Treatment & Management

Pastorczak A, Szczepanski T, Mlynarski W, International Berlin-Frankfurt-Munster (I-BFM) ALL host genetic variation working group. Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome. Eur J Med Genet. 2016 Mar. 59 (3):126-32. [QxMD MEDLINE Link].
[Guideline] Pastorczak A, Attarbaschi A, Bomken S, Borkhardt A, van der Werff Ten Bosch J, Elitzur S, et al. Consensus Recommendations for the Clinical Management of Hematological Malignancies in Patients with DNA Double Stranded Break Disorders. Cancers (Basel). 2022 Apr 14. 14 (8):[QxMD MEDLINE Link]. [Full Text].
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.
Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child. 2000 May. 82(5):400-6. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Wolska-Kuśnierz B, Gregorek H, Chrzanowska K, et al. Nijmegen Breakage Syndrome: Clinical and Immunological Features, Long-Term Outcome and Treatment Options - a Retrospective Analysis. J Clin Immunol. 2015 Aug. 35 (6):538-49. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Kanaar R, Wyman C. DNA repair by the MRN complex: break it to make it. Cell. 2008 Oct 3. 135(1):14-6. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Kuo YC, Wu HT, Hung JJ, Chou TY, Teng SC, Wu KJ. Nijmegen breakage syndrome protein 1 (NBS1) modulates hypoxia inducible factor-1α (HIF-1α) stability and promotes in vitro migration and invasion under ionizing radiation. Int J Biochem Cell Biol. 2015 Jul. 64:229-38. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Seidel P, Remus M, Delacher M, Grigaravicius P, Reuss DE, Frappart L, et al. Epidermal Nbn deletion causes premature hair loss and a phenotype resembling psoriasiform dermatitis. Oncotarget. 2016 Apr 26. 7 (17):23006-18. [QxMD MEDLINE Link].
Wang JY. Cancer. New link in a web of human genes. Nature. 2000 May 25. 405(6785):404-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Buck D, Malivert L, de Chasseval R, Barraud A, Fondanèche MC, Sanal O, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006 Jan 27. 124 (2):287-99. [QxMD MEDLINE Link].
Dutrannoy V, Demuth I, Baumann U, Schindler D, Konrat K, Neitzel H, et al. Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype. Hum Mutat. 2010 Sep. 31 (9):1059-68. [QxMD MEDLINE Link].
Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q, Ochi T, et al. Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet. 2015 Mar 5. 96 (3):412-24. [QxMD MEDLINE Link].
Rosin N, Elcioglu NH, Beleggia F, Isgüven P, Altmüller J, Thiele H, et al. Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability. Hum Mol Genet. 2015 Jul 1. 24 (13):3708-17. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
New HV, Cale CM, Tischkowitz M, et al. Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer. 2005 May. 44(5):494-9. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Bienemann K, Burkhardt B, Modlich S, Meyer U, Möricke A, Bienemann K, et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011 Nov. 155 (4):468-76. [QxMD MEDLINE Link].
van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C. Nijmegen breakage syndrome. J Med Genet. 1996 Feb. 33(2):153-6. [QxMD MEDLINE Link].
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.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Yoo J, Wolgamot G, Torgerson TR, Sidbury R. Cutaneous noncaseating granulomas associated with Nijmegen breakage syndrome. Arch Dermatol. 2008 Mar. 144(3):418-9. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, et al. Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology. 2000 Jan. 42(1):43-7. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Barbi G, Scheres JM, Schindler D, Taalman RD, Rodens K, Mehnert K, et al. Chromosome instability and X-ray hypersensitivity in a microcephalic and growth-retarded child. Am J Med Genet. 1991 Jul 1. 40 (1):44-50. [QxMD MEDLINE Link].
Altmann T, Gennery AR. DNA ligase IV syndrome; a review. Orphanet J Rare Dis. 2016 Oct 7. 11 (1):137. [QxMD MEDLINE Link].
Mehta PA, Tolar J. Fanconi Anemia. GeneReviews. National Center for Biotechnology Information. Available at https://www.ncbi.nlm.nih.gov/books/NBK1401/. September 22, 2016; Accessed: January 13, 2017.
van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, et al. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet. 2010 Feb 12. 86 (2):262-6. [QxMD MEDLINE Link].
Capo-Chichi JM, Bharti SK, Sommers JA, Yammine T, Chouery E, Patry L, et al. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum Mutat. 2013 Jan. 34 (1):103-7. [QxMD MEDLINE Link].
Sanz MM, German J, Cunniff C. Bloom's Syndrome. GeneReviews. National Center for Biotechnology Information. Available at https://www.ncbi.nlm.nih.gov/books/NBK1398/. April 7, 2016; Accessed: January 13, 2017.
Elbendary AM, Elston DE. Bloom Syndrome (Congenital Telangiectatic Erythema). Medscape Drugs & Diseases by WebMD. Available at http://emedicine.medscape.com/article/1110271-overview. December 14, 2015; Accessed: January 13, 2017.
Meijers RW, Dzierzanowska-Fangrat K, Zborowska M, Solarska I, Tielemans D, van Turnhout BA, et al. Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence. J Clin Immunol. 2017 Feb. 37 (2):133-142. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Lohynská R, Pechačová Z, Mazaná E, et al. Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations. Klin Onkol. 2022 Spring. 35 (2):119-127. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Deripapa E, Balashov D, Rodina Y, Laberko A, Myakova N, Davydova NV, et al. Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT). Front Immunol. 2017. 8:807. [QxMD MEDLINE Link]. [Full Text].
Albert MH, Gennery AR, Greil J, et al. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant. 2010 Apr. 45(4):622-6. [QxMD MEDLINE Link].
Woźniak M, Krzywoń M, Hołda MK, Goździk J. Reduced-intensity conditioning umbilical cord blood transplantation in Nijmegen breakage syndrome. Pediatr Transplant. 2015 Mar. 19 (2):E51-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
di Masi A, Antoccia A. NBS1 Heterozygosity and Cancer Risk. Curr Genomics. 2008 Jun. 9(4):275-81. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

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.

of 13

Table 1.Syndromes to be Considered in the Differential Diagnosis of Nijmegen Breakage Syndrome

Clinical and Cellular Phenotype	Nijmegen Breakage Syndrome	Nijmegen Breakage Syndrome‒Like Disorder ^{[39, 77]}	DNA LIG4 Deficiency ^{[37, 38, 78]}	NHEJ1 Syndrome ^{[40, 41]}	XRCC4 Deficiency ^{[42, 43]}	Fanconi Anemia ^{[47, 48, 79]}	Warsaw Breakage Syndrome ^{[80, 81]}	Bloom Syndrome ^{[82, 83]}
Online Mendelian Inheritance in Man (OMIM)	251260	604040	606593	611291	616541	227650	613398	210900
Gene	NBN	RAD50	DNA LIG4	NHEJ1	XRCC4	FANC^a	DDX11	RECQL3
Microcephaly	Severe, disproportionate	Severe	Severe	Severe	Severe	In ~30%	Severe, disproportionate	Severe, proportionate
Growth Deficiency	Mild to moderate	Severe	Moderate to severe	Severe	Severe, disproportionate	Mild to moderate	Severe	Severe
Congenital Malformations	Heart, kidney, polydactyly	Not reported	Polydactyly, syndactyly	Polydactyly	Not reported	Heart, kidney radial bone defects (~50%)	Heart	Kidney, polydactyly
Puberty and Fertility	Primary amenorrhea (hypergonadotropic hypogonadism)	Normal puberty	Amenorrhea	Not reported	Primary amenorrhea	Males, infertility; females, early menopause	Normal puberty	Males, infertility; females, early menopause
Other Endocrinologic Problems	Not reported	Not reported	Hypothyroidism, type 2 diabetes	Not reported	Early-onset metabolic syndrome	Type 2 diabetes mellitus	Not reported	Type 2 diabetes mellitus
Recurrent Infections	Yes	No	Rare	Yes	No	No	No	Yes
Immunodeficiency	Combined (B- and T-cell)	No	Combined (B- and T-cell)	Combined (B- and T-cell)	No	No	No	B-cell type
Hematologic Findings	Myelodysplastic syndrome (incidentally)	Not reported	Pancytopenia, myelodysplastic syndrome	Pancytopenia, myelodysplastic syndrome	Thrombocytopenia, pancytopenia	Progressive bone marrow failure, myelodysplastic syndrome	Not reported	Myelodysplastic syndrome
Malignancy Type	Predominantly lymphoid origin	Not reported	Predominantly lymphoid origin	Not reported	Tumor	Acute myeloid leukemia, solid tumors (early onset)	Not reported	Lymphoid origin, acute myeloid leukemia, solid tumors
Chromosomal Instability	Breakages, including 7/14 rearrangements	Breakages, 7/14 rearrangements	Breakages, no 7/14 rearrangements	Breakages, not specified	Not reported	Breakages, figures (asymmetric)	Breakages and cohesinopathy	Breakages, figures (symmetric), high sister chromatid exchange rate
Sensitivity to Damaging Agents (in vitro)	Ionizing radiation, bleomycin; mitomycin C and diepoxybutane, mild	Ionizing radiation, bleomycin	Ionizing radiation, bleomycin	Ionizing radiation (variable)	Ionizing radiation (extreme)	Mitomycin C and diepoxybutane; ionizing radiation, mild	Mitomycin C, camptothecin	Ultraviolet
Mental Retardation	Mild to moderate	Moderate	Mild to moderate	Yes, not defined	Moderate to severe	Moderate to severe	Moderate to severe	Normal to mild
^aFANC: Genetic and phenotypic heterogeneity; 19 genes known (OMIM).

Table 2. Selected NBN 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^a Czech	He^b
c.657_661del5 (657del5)	6	Frameshift	Truncated protein (233 aa)	>90% Slavic founder mutation	Ho^c (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^d Pakistani	Ho
c.1142delC	10	Frameshift	Truncated protein (402 aa)	2 Canadian	He
^aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.^[86] ^bHe - Heterozygous (compound with 657del5). ^cHo - Homozygous. ^dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).^{[47, 48]}

Back to List

Author

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

Krystyna H Chrzanowska, MD, PhD is a member of the following medical societies: European Association for Cancer Research, European Society of Human Genetics, Polish Academy of Sciences, Polish Genetics Society, Polish Pediatric Society, Polish Society of Human Genetics

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 Former 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: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

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: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

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: Nothing to disclose.

Nijmegen Breakage Syndrome Workup

Laboratory Studies

Basis for diagnosis

Cytogenetic analysis

Immunologic testing

Alpha-fetoprotein determination

IR and RDS sensitivity analysis

Immunoblotting assay

Molecular genetic analysis

Endocrinologic evaluation

Imaging Studies

Histologic Findings

References

Tables

Contributor Information and Disclosures

What would you like to print?