NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Nijmegen Breakage Syndrome

Synonyms: Berlin Breakage Syndrome, Ataxia-Telangiectasia Variant 1

, PhD, , PhD, and , PhD.

Author Information
, PhD
Institute of Medical and Human Genetics
Charité – Universitätsmedizin Berlin
Berlin, Germany
, PhD
Institute of Medical and Human Genetics
Charité – Universitätsmedizin Berlin
Berlin, Germany
, PhD
Institute of Medical and Human Genetics
Charité – Universitätsmedizin Berlin
Berlin, Germany

Initial Posting: ; Last Update: May 8, 2014.

Summary

Disease characteristics. Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild to moderate intellectual disability. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Approximately 40% of affected individuals have developed malignancies before age 20 years, with the risk being highest for T-cell (55%) and B-cell lymphomas (45%). Other tumors include T-cell lymphoma and solid tumors (e.g., medulloblastoma, glioma, and rhabdomyosarcoma). Note, however, that much of what is reported about NBS is based on individuals who are homozygous for the single most common Eastern European pathogenic variant, 657_661del5.

Diagnosis/testing. Diagnosis is based on molecular genetic testing of NBN, the only gene known to be associated with Nijmegen breakage syndrome. Pathogenic variants are identified in almost 100% of affected individuals. If the diagnosis is not established by molecular genetic testing, immunoblotting to determine if the nibrin protein is absent and colony survival assay to determine radiosensitivity can be used for diagnosis.

Management. Treatment of manifestations: Use of IVIg should be considered in individuals with severe humoral immunodeficiency and frequent infections.

Surveillance: Periodic follow up to monitor mental and physical growth and infection frequency. Monitoring for premature ovarian insufficiency should be considered in females.

Agents/circumstances to avoid: Because the cells from individuals with NBS are radiosensitive in vitro, doses of radiation used in radiotherapy need to be reduced.

Genetic counseling. NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing are possible if both if the pathogenic variants have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

The diagnosis of Nijmegen breakage syndrome (NBS) is suspected in individuals with the following findings:

  • Microcephaly, present in about 75% of affected individuals at birth, and in the remainder during the first months of life
  • Growth retardation, either present at birth or manifesting before age two years. Thereafter, growth rate is appropriate, but individuals remain small for age.
  • Characteristic facial features — a sloping forehead, retrognathia, prominent nasal bridge and nose, large ears, and upslanted palpebral fissures — which become apparent at about age three years
  • Recurrent sinopulmonary infections including pneumonia, bronchitis, otitis media, sinusitis, and mastoiditis
  • Malignancies. B-cell and T-cell lymphoma are approximately equally common, and occur in approximately 40% of individuals with NBS before age 20 years.
  • Decline in intellectual ability, which results in intellectual disability in the borderline-to-moderate range by age ten years in most affected children

Testing

Immunoblotting is used to determine if the nibrin protein is present or absent.

Note: This test requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically.

Radiation sensitivity. Cells from individuals with NBS have a decrease in colony-forming ability following exposure to ionizing radiation and radiomimetics in vitro.

Note: This test requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically.

Immunodeficiency involving the humoral and cellular system:

  • Agammaglobulinemia has been found in 35% of affected individuals and IgA deficiency in 20%.
  • Deficiencies in IgG2 and IgG4 are frequent even when the IgG serum concentration is normal.
  • The most commonly reported defects in cellular immunity are reduced percentages of total CD3+ T cells and CD4+ cells.
  • An increased frequency of T cells with a memory phenotype (CD45RO+) and a concomitant decrease in naive T cells (CD45RA+) has been reported [Michalkiewicz et al 2003].

Chromosomal instability. Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T cell-receptor genes.

Molecular Genetic Testing

Gene. NBN is the only gene in which pathogenic variants are known to cause Nijmegen breakage syndrome.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Nijmegen Breakage Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method 2
Slavic 3North American 4
NBNTargeted mutation analysis 5Homozygous c.[657_661del5];[657_661del5]: approx. 100% 6Homozygous c.[657_661del5];[657_661del5]: 70% 7, 8
Sequence analysis 9Not applicableSee footnote 10
Deletion/duplication analysis 11Unknown, none reported 12Unknown, none reported 12
Unknown 13NAUnknownUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Given the rarity of NBS it is likely that most of the pathogenic variants show some kind of founder effect, making reliable estimates of incidence difficult to establish.

3. Slavic = Poland, Czech Republic, Ukraine

4. Based on the small number of individuals observed

5. Note: Pathogenic variants included in a panel may vary by laboratory.

6. Nearly all affected individuals from Poland, the Czech Republic, and Ukraine tested to date are homozygous for the common pathogenic variant c.657_661del5. In a study of eight unrelated individuals with NBS from the Russian population, Resnick et al [2002] found that all but one of the 16 alleles were c.657_661del5.7. In the US, about 70% of individuals tested to date are homozygous for the common allele, 15% are heterozygous for c.657_661del5 and a second unique pathogenic variant, and 15% are homozygous for a unique pathogenic variant.

8. In the US patient population, almost all affected individuals who have the c.657_661del5 pathogenic variant are of known Eastern European ancestry.

9. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

10. Of individuals tested to date in the US, 15% are heterozygous for the common allele (c.657_661del5) and a second unique pathogenic variant; 15% are homozygous for a unique pathogenic variant.

11. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

12. No deletions or duplications involving this gene as causative of this disease have been reported.

13. Many individuals referred for diagnostic testing for NBS have clinical findings of NBS and radiosensitivity but lack identified pathogenic variants in NBN [Author, unpublished observation]. A number of reports suggest that pathogenic variants in other genes including LIG4, RAD50, XLF, and FANC can lead to disorders with similar clinical presentations [O’Driscoll et al 2001, Gennery et al 2004, New et al 2005, Enders et al 2006, Waltes et al 2009]. However, pathogenic variants in these genes are very rare and do not account for the incidence of NBS-like clinical presentation in persons lacking NBN pathogenic variants. Presently, distinction can only be made by excluding pathogenic variants in NBN.

Testing Strategy

To confirm/establish the diagnosis in a proband

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having NBS is analysis of only NBN.

If the common allele is not present:

  • Perform sequencing of the entire NBN gene

If sequencing fails to identify biallelic mutations, the diagnosis of NBS is very unlikely. Further tests (available in certain laboratories) include:

  • Immunoblotting to determine if the nibrin protein is present or absent;
  • Colony survival assay to determine radiosensitivity.

These tests require the establishment of a lymphoblastoid cell line. If results are normal, a diagnosis of NBS is extremely unlikely. If nibrin is present, but the cells are radiosensitive, evaluation for other disorders of DNA repair or immunodeficiency is warranted. (See Differential Diagnosis.)

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having NBS is use of a multi-gene panel that includes NBN and other genes of interest. See Differential Diagnosis.

Clinical Description

Natural History

Growth. Children with Nijmegen breakage syndrome (NBS) generally have lower than normal birth weight and are small for gestational age. If not present from birth, microcephaly develops during the first months of life and progresses to severe microcephaly. Growth failure during the first two years of life results in height that is usually less than the third centile by age two years. The linear growth rate tends to be normal after age two years, but individuals remain small for age.

Facial features. As microcephaly progresses, the facial features tend to become distinct, with sloping forehead, upslanted palpebral fissures, midface prominence, long nose, and retrognathia. The ears may be large.

Psychomotor development. Developmental milestones are attained at the usual time during the first year. Borderline delays in development and psychomotor hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild-to-moderate intellectual disability. The children are described as having a cheerful, shy personality with good interpersonal skills.

Infections. Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in pulmonary failure and early death. Chronic diarrhea and urinary tract infections may also occur.

Malignancy. According to Chrzanowska et al [2012], 40% of affected individuals reported to date have developed malignancies before age 20 years. Malignancies are primarily lymphomas. Approximately 45% of lymphomas are of B cell origin and 55% are T cell lymphomas. Several children have developed solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma [Hiel et al 2001, Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].

Fertility. Wegner et al [1999] report a high incidence of premature ovarian insufficiency in both prepubertal girls with NBS and adolescent and post-adolescent women with NBS, as evidenced by elevated serum concentration of gonadotropins in both groups and primary amenorrhea and lack of secondary sexual development in the latter. Chrzanowska et al [2010a] provide further support for these findings in a larger study of females with NBS, all homozygous for the common c.657_661del5 pathogenic variant.

No detailed studies of fertility in males with NBS have been published; however, puberty initiation and progress are comparable to healthy boys [Chrzanowska et al 2010b]. Warcoin et al [2009] described an atypical male with oligo-terato-asthenozoospermia who had biallelic truncating mutations in NBN but none of the clinical features of NBS.

Other findings

  • Irregular skin pigmentation, manifest as hyperpigmented or hypopigmented irregular spots, is seen in most individuals.
  • Congenital malformations, usually observed in single cases, include hydrocephalus, preaxial polydactyly, occipital cyst, choanal atresia, cleft lip and palate, tracheal hypoplasia, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.

Genotype-Phenotype Correlations

There are two reports of families in whom biallelic truncating mutations in NBN occur in healthy adult individuals:

  • Varon et al [2006] described a 53-year-old woman who was homozygous for the NBN truncating allele c.741_742dup, but had no clinical features of NBS other than primary amenorrhea. However, analysis of transcripts from the patient’s cells indicated a highly prevalent alternatively spliced form of NBN lacking exons 6 and 7 (where the pathogenic variant is located). This transcript produces a 73-kd form of NBN with an internal deletion.
  • Warcoin et al [2009] described a family in which two healthy adult sibs had biallelic truncating mutations in NBN (c.330T>G and c.1125G>A). Both were normal on clinical examination and did not have any evidence of short stature, reduced head circumference, or facial dysmorphology; however, both were referred for fertility defects and were subsequently found to have the cellular phenotypes typical of NBS including chromosomal instability, hypersensitivity to ionizing radiation, and impaired checkpoint responses.

While the clinical findings in these individuals would not suggest a diagnosis of NBS, the testing strategy would have identified these individuals based on the presence of two truncating mutations and radiation hypersensitivity.

Heterozygotes. Heterozygotes are asymptomatic, however, there is clear evidence of increased cancer occurrence among heterozygous relatives of individuals with NBS in the Czech Republic [Seemanova et al 2007]. Furthermore, preliminary studies have provided suggestive evidence of an increased frequency of c.657_661del5 carriers in several different cancers including breast cancer, prostate cancer, medulloblastoma, and melanoma [Cybulski et al 2004, Steffen et al 2004, Ciara et al 2010].

Nomenclature

The Nijmegen breakage syndrome was described by Weemaes et al [1981].

Three Czech families with Seemanova syndrome [Seemanova et al 1985] were later identified as having NBS.

Genetic complementation studies are no longer of clinical importance. The report of Jaspers et al [1988] noted a strong similarity between NBS cells and ataxia-telangiectasia (A-T) cells; however, they also described the NBS cells as genetically distinct from A-T, grouping individuals with either Nijmegen breakage syndrome or Czech breakage syndrome into A-T variant group V1 and Germans with 'Berlin breakage syndrome' [Wegner et al 1999] into A-T variant group V2 [Jaspers et al 1988]. Subsequently, NBN pathogenic variants were found in all individuals studied from the A-T variant groups V1 and V2, indicating that these individuals had NBS, not ataxia-telangiectasia.

Prevalence

No reliable estimates of world-wide prevalence exist, but it is likely to approximate 1:100,000 live births.

NBS is most common in Eastern European/Slavic populations. Studies in Poland, the Czech Republic, and the Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations. The highest reported prevalence is in Sorbians, a Slavic population isolate from southeastern Germany, in whom the carrier frequency is estimated at 1:34 [Maurer et al 2010].

Differential Diagnosis

Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. Some inherited immunodeficiencies (e.g., X-linked agammaglobulinemia [Bruton's agammaglobulinemia] and X-linked severe combined immunodeficiency) also demonstrate radiosensitivity (in colony survival assays).

Individuals homozygous for the NBN c.1089C>A pathogenic variant have features of Fanconi anemia [Gennery et al 2004].

Occasionally individuals with the ATM pathogenic variant A-TFresno have symptoms of both Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (A-T) [Curry et al 1989, Gilad et al 1998].

Microcephaly, midface prominence, and intellectual disability suggest syndromes such as Seckel syndrome [O'Driscoll et al 2003] and Rubinstein-Taybi syndrome; however, cells from these individuals are not typically radiosensitive by colony survival assay [O’Driscoll et al 2003]. Seeman et al [2004] suggest that NBN pathogenic variants account for a significant number of children with primary microcephaly in the Czech Republic. See also Primary Autosomal Recessive Microcephaly.

Individuals with ligase IV syndrome [O'Driscoll et al 2001] may present with features of NBS, including microcephaly, short stature, midface prominence, immunodeficiency, and radiosensitivity. However, the immunodeficiency (pancytopenia) in individuals with ligase IV syndrome is typically more severe than that in individuals with NBS and may present in infancy as severe combined immunodeficiency [Enders et al 2006]. Ligase IV syndrome, caused by pathogenic variants in LIG4, is not associated with an increase in chromosomal instability or t(7;14). The two disorders can be differentiated by molecular genetic testing of LIG4 and NBN.

Waltes et al [2009] described a single individual with biallelic pathogenic variants in RAD50 resulting in reduced production of an unstable RAD50 protein. This person had microcephaly, intellectual disability, short stature and facial dysmorphology typical of NBS, but had normal immunoglobulin levels and did not have recurrent sinopulmonary infections. As only one individual with RAD50 pathogenic variants has been described, it is unclear how consistent the clinical features of RAD50 deficiency will be — hence, the overlap with NBS.

The early growth failure in NBS may suggest other disorders of growth, such as thyroid hormone or growth hormone deficiency, or primary disorders of bone growth (i.e., a skeletal dysplasia).

Because lymphoma may be the presenting finding in NBS, the diagnosis of NBS should be considered before radiotherapy is initiated in individuals with lymphoma who are younger than age three years [Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Nijmegen breakage syndrome (NBS), the following evaluations are recommended:

  • Baseline evaluation of immune and endocrinologic status, degree of mental impairment, and head circumference
  • History of radiation exposure
  • Familial history of cancer
  • Medical genetics consultation

Treatment of Manifestations

In individuals with severe humoral immunodeficiency and frequent infections, IVIg should be considered. The spectrum of recurrent infections in NBS is not opportunistic; therefore, the antibiotic selected should be appropriate for the microorganism being treated.

Because of chromosomal instability, vitamin E and folic acid supplementation in doses appropriate for body weight is recommended.

Children with developmental delay should be referred to special services for treatment options.

Surveillance

Affected individuals

  • Periodic follow-up to monitor mental and physical growth and frequency of infections
  • For females with NBS, periodic monitoring for premature ovarian insufficiency [Chrzanowska et al 2010a]
  • Monitoring for weight loss, which may signal the presence of a malignancy

Carriers (heterozygotes)

  • Parents. As obligate carriers, parents should be monitored for malignancy.
  • At-risk sibs. Evidence of cancer risk in young carriers is insufficient to warrant testing in childhood.

Agents/Circumstances to Avoid

Because the cells from individuals with NBS are as radiosensitive in vitro as those from individuals with ataxia-telangiectasia (another chromosomal instability syndrome), conventional doses of radiation used in radiotherapy could be lethal in individuals with NBS. Family members should be made aware of this risk so that they can discuss appropriate treatment options if a malignancy is diagnosed.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NBS is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry a single copy of an NBN pathogenic variant.
  • Heterozygotes are asymptomatic; however, in some populations, there is evidence of increased cancer risk for heterozygotes [Seemanova et al 2007].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an NBN pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic; however, in some populations, there is evidence of an increased cancer risk for heterozygotes [Seemanova et al 2007].

Offspring of a proband. No affected individuals have been reported to reproduce.

Other family members of a proband. Sibs of the proband's parents are at a 50% risk of also being carriers of an NBN pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the NBN pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Nijmegen Breakage Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Nijmegen Breakage Syndrome (View All in OMIM)

251260NIJMEGEN BREAKAGE SYNDROME
602667NIBRIN; NBN

Gene structure. NBN is encoded in 16 exons and spans approximately 51 kb of DNA. The entire gene has been sequenced. The gene encodes two transcripts of 4.6 (NM_002485.4) and 2.4 kb [Carney et al 1998] that are expressed in all tissues examined and differ only in their site of polyadenylation. Transcript NM_002485.4 has 16 exons and encodes a protein of 754 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A number of benign and rare allelic variants in NBN have been described. Table 2 lists examples for which unaffected homozygous individuals have been identified, verifying that they are not pathogenic allelic variants. Alleles at these sites are all in very strong linkage disequilibrium in the general population.

Table 2. Selected NBN Benign Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.102G>ANo changeNM_002485​.4
NP_002476​.2
c.553G>Cp.Glu185Gln
c.1197T>CNo change
c.2016A>GNo change

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Variants of unknown significance. Additional germline variants such as c.283G>A (p.Asp95Asn), c.628G>T (p.Val210Phe), c.643C>T (p.Arg215Trp), and c.797C>T (p.Pro266Leu) have been reported in various cancer cases and controls (reference sequence NM_002485.4). Of these, so far only c.643C>T has been found in NBS (in combination with c.657_661del5).

Pathogenic allelic variants. Most disease-causing NBN alleles identified to date are predicted to result in truncation of the nibrin protein (see Table 3). The c.657_661del5 pathogenic variant predominates in affected persons from Eastern Europe, accounting for more than 90% of all mutant alleles in NBN. Each of the other pathogenic variants listed in Table 3 occurs in one or a small number of families. NBN mRNA is always detectable in cell lines from individuals with NBS, but full-length nibrin protein is not detectable by Western blotting. Although some, and possibly all, NBN alleles produce one or more partial proteins, their abundance is generally low and varies in different cell types, making them a poor diagnostic marker.

One pathogenic variant, c.1089C>A is particularly noteworthy. It was originally described in a person diagnosed with atypical Fanconi anemia. Subsequent testing revealed homozygosity for an NBN mutation. Several additional families with this pathogenic variant have been identified and all display overlapping clinical features with Fanconi anemia syndrome [Gennery et al 2004, New et al 2005]. These findings highlight the lack of disease specificity in assays that test for sensitivity to DNA crosslinking agents.

While the overwhelming majority of persons with NBS have biallelic truncating alleles at NBN, Seemanova et al [2006] have described a unique set of monozygotic twins who are compound heterozygotes for the common c.657_661del5 pathogenic variant and a missense mutation, c.643C>T resulting in p.Arg215Trp. These twins had a more severe clinical course than typical for NBS (particularly with respect to neurologic features) but lacked the cellular chromosomal instability and radiation sensitivity characteristic of the disorder.

Table 3. Selected NBN Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference SequenceOriginNumber of Families in Whom Pathogenic Variant is Observed
c.330T>Gp.Tyr110TerNM_002485​.4
NP_002476​.2
1
c.643C>Tp.Arg215TrpSlavic1
c.657_661del5
(657del5)
p.Lys219AsnfsTer15 SlavicN/A
c.681delTp.Phe228LeufsTer3 Russian1
c.698_701del4p.Lys233SerfsTer4English2
c.741_742dup
(742insGG)
p.Glu248GlyfsTer5Italian1
c.835_838del4p.Gln279ProfsTer1 Italian1
c.842insTp.Leu281PhefsTer3 Mexican1
c.900del25p.Gly301LysfsTer5Moroccan1
c.976C>Tp.Gln326TerDutch1
c.1089C>Ap.Tyr363TerPakistani 23
c.1125G>Ap.Trp375Ter1
c.1142delCp.Pro381GlnfsTer22Canadian2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Individual originally diagnosed as having Fanconi anemia with atypical clinical features. See Differential Diagnosis

Normal gene product. The NBN protein product is nibrin. Nibrin is a protein of 85 kd in mass that is ubiquitously expressed. The electrophoretic mobility of nibrin has led to its also being referred to by some as p95. There are no global sequence similarities between nibrin and any other known proteins. However, nibrin contains recognizable protein domains (a forkhead-associated domain and two breast cancer carboxy-terminal domains), which are found in other proteins involved in cellular responses to DNA damage. In normal fibroblasts, nibrin is associated with two other proteins involved in DNA repair, hMre11 and hRad50. On exposure to ionizing radiation, this complex of proteins, including nibrin, forms nuclear foci at sites where DNA repair has taken place. Nibrin targets the NBN/Mre11/Rad50 complex to sites of double-strand breaks and interacts with ATM kinase to coordinate cell cycle arrest with DNA repair [Carney et al 1998, Matsuura et al 2004, Falck et al 2005].

Abnormal gene product. Most known NBN pathogenic variants are predicted to result in truncation of the nibrin protein (often termed p70). All known NBS pathogenic variants occur in exons 6-10; this is thought to reflect a requirement for production of a C-terminal protein fragment of nibrin that occurs by translational reinitiation mechanism [Maser et al 2001]. The requirement that protein termination and reinitiation occur in the same reading frame potentially limits the pathogenic variants that can give rise to NBS. Knockout mice homozygous for null alleles of NBN are embryonic lethal, suggesting that the partial protein produced from NBN alleles in humans is necessary for survival.

References

Literature Cited

  1. Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, Bhambhani K. Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. J Pediatr Hematol Oncol. 2003;25:248–51. [PubMed: 12621246]
  2. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR, Hays L, Morgan WF, Petrini JH. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. 1998;93:477–86. [PubMed: 9590181]
  3. Chrzanowska KH, Szarras-Czapnik M, Gajdulewicz M, Kalina MA, Gajtko-Metera M, Walewska-Wolf M, Szufladowicz-Wozniak J, Rysiewski H, Gregorek H, Cukrowska B, Syczewska M, Piekutowska-Abramczuk D, Janas R, Krajewska-Walasek M. High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study. J Clin Endocrinol Metab. 2010a;95:3133–40. [PubMed: 20444919]
  4. Chrzanowska KH, Szarras-Czapnik M, Kalina M, Gajdulewicz M, Gajtko-Metera M, Rysiewski H, Dembowska-Bagińska B, Gregorek H, Piekutowska-Abramczuk D, Ciara E, Syczewska M, Janas R, Krajewska-Walasek M. Gonadal function in male patients with Nijmegen breakage syndrome, a cancer-prone disease with the DNA repair defect. Eur J Hum Genet. 2010b;18:88–9.
  5. Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012;7:13. [PMC free article: PMC3314554] [PubMed: 22373003]
  6. Ciara E, Piekutowska-Abramczuk D, Popowska E, Grajkowska W, Barszcz S, Perek D, Dembowska-Bagińska B, Perek-Polnik M, Kowalewska E, Czajńska A, Syczewska M, Czornak K, Krajewska-Walasek M, Roszkowski M, Chrzanowska KH. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010;119:325–34. [PubMed: 19908051]
  7. Curry CJ, O'Lague P, Tsai J, Hutchison HT, Jaspers NG, Wara D, Gatti RA. ATFresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am J Hum Genet. 1989;45:270–5. [PMC free article: PMC1683342] [PubMed: 2491181]
  8. Cybulski C, Gorski B, Debniak T, Gliniewicz B, Mierzejewski M, Masojc B, Jakubowska A, Matyjasik J, Zlowocka E, Sikorski A, Narod SA, Lubinski J. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 2004;64:1215–9. [PubMed: 14973119]
  9. 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;41:44–8. [PubMed: 12764742]
  10. Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, Peters A, Orlowska-Volk M, Schindler D, Friedrich W, Selle B, Niemeyer C, Ehl S. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol. 2006;176:5060–8. [PubMed: 16585603]
  11. Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005;434:605–11. [PubMed: 15758953]
  12. Gennery AR, Slatter MA, Bhattacharya A, Barge D, Haigh S, O'Driscoll M, Coleman R, Abinun M, Flood TJ, Cant AJ, Jeggo PA. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol. 2004;113:214–9. [PubMed: 15451479]
  13. Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y, Bar-Shira A. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 1998;62:551–61. [PMC free article: PMC1376949] [PubMed: 9497252]
  14. Hiel JA, Weemaes CM, van Engelen BG, Smeets D, Ligtenberg M, van Der Burgt I, van Den Heuvel LP, Cerosaletti KM, Gabreels FJ, Concannon P. Nijmegen breakage syndrome in a Dutch patient not resulting from a defect in NBS1. J Med Genet. 2001;38:E19. [PMC free article: PMC1734895] [PubMed: 11389166]
  15. Jaspers NG, Gatti RA, Baan C, Linssen PC, Bootsma D. Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet. 1988;49:259–63. [PubMed: 3248383]
  16. Maser RS, Zinkel R, Petrini JH. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet. 2001;27:417–21. [PubMed: 11279524]
  17. Matsuura S, Kobayashi J, Tauchi H, Komatsu K. Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys. 2004;38(Complete):65-80. [PubMed: 15476893]
  18. 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;51:211–4. [PubMed: 20453309]
  19. Meyer S, Kingston H, Taylor AM, Byrd PJ, Last JI, Brennan BM, Trueman S, Kelsey A, Taylor GM, Eden OB. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet. 2004;154:169–74. [PubMed: 15474156]
  20. Michalkiewicz J, Barth C, Chrzanowska K, Gregorek H, Syczewska M, Weemaes CM, Madalinski K, Stachowski J. Abnormalities in the T and NK lymphocyte phenotype in patients with Nijmegen breakage syndrome. Clin Exp Immunol. 2003;134:482–90. [PMC free article: PMC1808880] [PubMed: 14632755]
  21. New HV, Cale CM, Tischkowitz M, Jones A, Telfer P, Veys P, D'Andrea A, Mathew CG, Hann I. Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer. 2005;44:494–9. [PubMed: 15593232]
  22. O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001;8:1175–85. [PubMed: 11779494]
  23. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33:497–501. [PubMed: 12640452]
  24. Resnick IB, Kondratenko I, Togoev O, Vasserman N, Shagina I, Evgrafov O, Tverskaya S, Cerosaletti KM, Gatti RA, Concannon P. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr. 2002;140:355–61. [PubMed: 11953735]
  25. Seeman P, Gebertova K, Paderova K, Sperling K, Seemanova E. Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly. Pediatr Neurol. 2004;30:195–200. [PubMed: 15033202]
  26. Seemanova E, Sperling K, Neitzel H, Varon R, Hadac J, Butova O, Schröck E, Seeman P, Digweed M. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet. 2006;43:218–24. [PMC free article: PMC2563240] [PubMed: 16033915]
  27. Seemanova E, Jarolim P, Seeman P, Varon R, Digweed M, Swift M, Sperling K. Cancer risk of heterozygotes with the NBN founder mutation. J Natl Cancer Inst. 2007;99(24):1875–80. [PubMed: 18073374]
  28. 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;20:639–48. [PubMed: 3857858]
  29. Steffen J, Varon R, Mosor M, Maneva G, Maurer M, Stumm M, Nowakowska D, Rubach M, Kosakowska E, Ruka W, Nowecki Z, Rutkowski P, Demkow T, Sadowska M, Bidzinski M, Gawrychowski K, Sperling K. Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer. 2004;111:67–71. [PubMed: 15185344]
  30. Varon R, Dutrannoy V, Weikert G, Tanzarella C, Antoccia A, Stöckl L, Spadoni E, Krüger LA, di Masi A, Sperling K, Digweed M, Maraschio P. Mild Nijmegen breakage syndrome phenotype due to alternative splicing. Hum Mol Genet. 2006;15:679–89. [PubMed: 16415040]
  31. Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dork T. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009;84:605–16. [PMC free article: PMC2681000] [PubMed: 19409520]
  32. Warcoin M, Lespinasse J, Despouy G, Dubois d'Enghien C, Laugé A, Portnoï MF, Christin-Maitre S, Stoppa-Lyonnet D, Stern MH. Fertility defects revealing germline biallelic nonsense NBN mutations. Hum Mutat. 2009;30:424–30. [PubMed: 19105185]
  33. 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;70:557–64. [PubMed: 7315300]
  34. Wegner RD, Chrzanowska KH, Sperling K, Stumm M. Ataxia-telangiectasia variants (Nijmegen breakage syndrome). In: Ochs HD, Smith CIE, Puck JM, eds. Primary Immunodeficiency Diseases, a Molecular and Genetic Approach. Oxford, UK: Oxford University Press; 1999:324-34.

Suggested Reading

  1. Demuth I, Digweed M. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome. Oncogene. 2007;26:7792–98. [PubMed: 18066092]

Chapter Notes

Author History

Patrick Concannon, PhD; University of Florida Genetics Institute (1999-2014)
Richard Gatti, MD; University of California Los Angeles (1999-2014)
Martin Digweed, PhD (2014-present)
Raymonda Varon, PhD (2014-present)
Ilja Demuth, PhD (2014-present)

Revision History

  • 8 May 2014 (me) Comprehensive update posted live
  • 1 March 2011 (me) Comprehensive update posted live
  • 14 June 2005 (me) Comprehensive update posted to live Web site
  • 14 March 2003 (me) Comprehensive update posted to live Web site
  • 17 May 1999 (me) Review posted to live Web site
  • 5 January 1999 (pc) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1176PMID: 20301355
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • Review Nijmegen breakage syndrome (NBS).[Orphanet J Rare Dis. 2012]
    Review Nijmegen breakage syndrome (NBS).
    Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Orphanet J Rare Dis. 2012 Feb 28; 7:13. Epub 2012 Feb 28.
  • Perrault Syndrome[GeneReviews<sup>®</sup>. 1993]
    Perrault Syndrome
    Newman WG, Friedman TB, Conway GS. GeneReviews<sup>®</sup>. 1993
  • Congenital Insensitivity to Pain with Anhidrosis[GeneReviews<sup>®</sup>. 1993]
    Congenital Insensitivity to Pain with Anhidrosis
    Indo Y. GeneReviews<sup>®</sup>. 1993
  • Common Variable Immune Deficiency Overview[GeneReviews<sup>®</sup>. 1993]
    Common Variable Immune Deficiency Overview
    Scharenberg AM, Hannibal MC, Torgerson T, Ochs HD, Rawlings DJ. GeneReviews<sup>®</sup>. 1993
  • Fanconi Anemia[GeneReviews<sup>®</sup>. 1993]
    Fanconi Anemia
    Alter BP, Kupfer G. GeneReviews<sup>®</sup>. 1993
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...