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Nijmegen Breakage Syndrome

, PhD, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: February 2, 2017.

Estimated reading time: 24 minutes


Clinical 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 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, c.657_661del5.


The diagnosis of NBS is established in a proband with the clinical findings listed above who has biallelic pathogenic variants in NBN on molecular genetic testing and/or absent nibrin protein on immunoblotting assay.


Treatment of manifestations: Vitamin E and folic acid supplementation; use of IVIg in individuals with severe humoral immunodeficiency and frequent infections; standard chemotherapy protocols for lymphoid malignancies (adopted to individual tolerance); consideration of hematopoietic stem cell transplantation; hormone replacement therapy for females who have hypergonadotropic hypogonadism.


  • For affected individuals: Periodic follow up to monitor developmental progress, physical growth and infection frequency; in those with weight loss, assessment for malignancy should be considered; lifelong monitoring of immune biomarkers; careful monitoring by an oncologist; monitoring for pubertal progression in both sexes and premature ovarian insufficiency in females; breast self-examination and ultrasonographic evaluation.
  • For carriers (heterozygotes): Parents should be monitored for malignancy, particularly breast cancer in women and prostate cancer in men.

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. Unnecessary exposure to imaging studies that use ionizing radiation (plain radiograph, CT scan) should be avoided and use of MRI and/or ultrasound considered.

Evaluation of relatives at risk: Molecular genetic testing for the NBN pathogenic variants identified in the proband should be offered to apparently asymptomatic sibs of a proband and young adult relatives at risk of being carriers (heterozygotes) in order to identify as early as possible those who would benefit from monitoring for malignancy and to inform treatment options if a malignancy is diagnosed.

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 of the pathogenic variants have been identified in an affected family member.


Suggestive Findings

Nijmegen breakage syndrome (NBS) should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical features

  • Disproportionate microcephaly that is progressive
  • Craniofacial features that include a sloping forehead, upward slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia
  • Growth retardation that is more pronounced from birth until the age of three years, with mild improvement thereafter
  • Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis
  • Malignancies, predominantly of lymphoid origin
  • Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals

Supportive laboratory findings

  • Immunodeficiency involving the humoral and cellular systems [Gregorek et al 2002, Michałkiewicz et al 2003, Wolska-Kuśnierz et al 2015]:
    • Severe hypogammaglobulinemia has been found in 20%-24% of affected individuals and IgA deficiency in 50%-57%.
    • Deficiencies of IgG2 and IgG4 are frequent even when the IgG serum concentration is normal.
    • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells, CD3+ T cells, and CD4+ cells; observed in 80%-89% of affected individuals.
    • An increased frequency of T cells with a memory phenotype (CD45RO+) and a concomitant decrease in naïve T cells (CD45RA+) has been reported.
    • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is greatly reduced in most affected individuals.
  • Chromosome 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.
  • 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.

Establishing the Diagnosis

The diagnosis of NBS is established in a proband with the clinical features above who has biallelic pathogenic variants in NBN on molecular genetic testing (see Table 1) and/or absent nibrin protein on an immunoblotting assay (see Immunoblotting; below Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel.

Single-gene testing

  • Targeted analysis for the pathogenic variant c.657_661del5 can be performed first. The c.657_661del5 pathogenic variant is detected in:
    • ~100% of alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry;
    • ~70% of alleles in individuals of North American ancestry.
  • If the common allele is not present in a homozygous form, sequence analysis of NBN can be pursued.

A multigene panel that includes NBN and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Nijmegen Breakage Syndrome

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
NBN Targeted analysis for c.657_661del5 variant 370%-100% 4
Sequence analysis 5~100%
Gene-targeted deletion/duplication analysis 6None reported 7
Unknown 8NA

See Molecular Genetics for information on allelic variants detected in this gene.


Methods that may be used to detect the c.657_661del5 pathogenic variant can include: allele-specific PCR, sequence analysis, and genotyping assays designed to this variant. Note that these assays may not detect variants other than the targeted variant.


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


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


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


No deletions or duplications involving this gene have been reported to cause NBS.


NBN is the only gene associated with NBS; however, because NBS is clinically similar to other disorders (see Differential Diagnosis), many individuals referred for diagnostic testing for NBS based on clinical findings and radiosensitivity lack identified pathogenic variants in NBN [Author, unpublished observation]. Presently, distinction can only be made by excluding pathogenic variants in NBN.

Immunoblotting can be 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.

Clinical Characteristics

Clinical Description

Growth. Children with Nijmegen breakage syndrome (NBS) generally are born with weight below normal for gestational age and microcephaly (i.e., head circumference >2 SD below the mean for age and gender). Microcephaly progresses with age – in contrast to linear growth, which may improve with age, causing disproportionate head dimensions compared to the rest of the body. Microcephaly is occasionally masked by hydrocephaly or developmental abnormalities of the brain [Szczałuba 2012].

Growth failure in the early stages of life results in length/height that is usually below the third centile by age two years. Thereafter, linear growth velocity tends to normalize, however many individuals remain shorter than peers (i.e., affected individuals do not experience catch-up growth). Some adults, both females and males, can achieve height within lower normal ranges [Chrzanowska et al 2012].

Craniofacial features. The craniofacial features discussed in Suggestive Findings are found in the majority of affected individuals and become more pronounced with age as microcephaly progresses.

Infections. Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in bronchiectasis, and even 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 [Gładkowska-Dura et al 2008, Wolska-Kuśnierz et al 2015]. 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].

Psychomotor and intellectual development. Developmental milestones are attained at the usual time during the first year. Normal or borderline intellectual development and psychomotor hyperactivity may be observed in early childhood/pre-school age. Intellectual abilities tend to decline from mild to moderate intellectual disability during childhood. Affected children are described as having a cheerful, shy personality with good interpersonal skills.

Fertility. Two reports of gonadal dysfunction in affected females with chromosome instability disorder / syndrome appeared in 1986 [Maraschio et al 1986]. Twenty years later, Varon et al [2006] identified biallelic pathogenic c.741_742dup variants in exon 7 of NBN one of the original women reported by Maraschio and colleagues [1986].

Chrzanowska et al [2000] originally presented observations that strongly suggested an increased risk of premature ovarian failure in women with NBS. Results of a longitudinal study demonstrated that hypergonadotropic hypogonadism was present in a large cohort of affected females, all of whom were homozygous for the common c.657_661del5 pathogenic variant [Chrzanowska et al 2010a].

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 two adult siblings, a male with oligo-terato-asthenozoospermia and a female with premature ovarian failure, who had biallelic truncating variants in NBN but none of the other clinical features of NBS.

Other findings

  • Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [Yoo et al 2008, Pasic et al 2012].
  • Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.

Heterozygotes. Heterozygotes are asymptomatic, however, there is clear evidence of increased cancer occurrence among heterozygous relatives of individuals with NBS in the Czech Republic [Seemanová et al 2007]. Furthermore, an increased frequency of the pathogenic c.657_661del5 variant in NBN has been observed in several different cancers including breast cancer, prostate cancer, medulloblastoma, and melanoma, suggesting that pathogenic variants in NBN might play a role in the etiology of these types of cancer [Cybulski et al 2004, Steffen et al 2004, Ciara et al 2010].

Genotype-Phenotype Correlations

The common pathogenic variant, c.657_661del5, and most other loss-of-function variants result in a classic presentation. However, exceptions have been reported. There are two reports of families in which biallelic truncating variants in NBN occur in individuals with milder features:

  • Varon et al [2006] described a 53-year-old woman who was homozygous for the NBN truncating allele c.741_742dupGG. This affected woman had a somewhat milder phenotype including microcephaly, chromosome instability, immunodeficiency, and primary amenorrhea. Her sister, with similar clinical manifestations died at 20 years of malignant lymphoma [Maraschio et al 1986]. However, analysis of transcripts from the affected individual’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, a sister and a brother, had biallelic truncating variants in NBN (p.Tyr110Ter and p.Trp375Ter). Both were normal on clinical examination and did not have any evidence of short stature, reduced head circumference, or facial dysmorphic features; however, both were referred for fertility defects and were subsequently found to have the cellular phenotypes typical of NBS including chromosome instability, hypersensitivity to ionizing radiation, and impaired checkpoint responses.


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

Three Czech families with Seemanová syndrome [Seemanová 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.


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

Microcephaly, growth delay, immunodeficiency, and/or bone marrow failure are common manifestations of several inherited disorders, mainly related to defective sensing, processing, and repair of double-strand DNA breaks. Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. See Table 2.

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

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

Table 2.

Disorders to Consider in the Differential Diagnosis of Nijmegen Breakage Syndrome

Disease NameGene(s)Immunodeficiency and/or
Bone Marrow Failure
Microcephaly /
Craniofacial Features
Growth DelayCellular SensitivityChromosome InstabilityCancer PredispositionOther
Nijmegen breakage syndrome NBN Immunodeficiency, combined; recurrent sinopulmonary infectionsProgressive disproportionate microcephaly 1; characteristic facial features 2Mild growth restrictionDecrease in colony-forming ability after exposure to ionizing radiation & radiomimeticsInversions & translocations involving chromosomes 7 & 14 in lymphocytesIncreased risk, mainly of lymphoid originPrimary ovarian failure; mild-to-moderate intellectual disability
LIG4 syndrome 3
OMIM 606593
LIG4 Immunodeficiency combined; pancytopenia & myelodysplastic syndromeMicrocephaly; facial features resembling NBS 2Short statureSevere radiosensitivityIncreased chromosome breakage ratePredisposition to malignancy (mainly lymphoma & leukemia)High intrafamilial clinical variability
NHEJ1 syndrome
OMIM 611291
NHEJ1 Mild immunodeficiency to severe combined immunodeficiencyMicrocephalySevere (typically) growth restrictionCellular sensitivity to ionizing radiationHigh chromosome breakage rate (w/out chromosome 7;14 rearrangements) 4Limited data; unknown
Short stature, microcephaly, and endocrine dysfunction 5
OMIM 616541
XRCC4 6No clinical manifestations of immunodeficiencyPrimary microcephalySevere growth restrictionPronounced cellular radiosensitivityNot reportedSolid tumorPrimary ovarian failure; early-onset metabolic syndrome
Nijmegen breakage syndrome-like disorder
(RAD50 deficiency) 7, 8
OMIM 613078
RAD50 No immunodeficiencyMicrocephaly; facial features resembling NBS 2Severe growth restrictionX-ray hypersensitivityChromosome instability (incl. 7;14 rearrangements) in lymphocytes & fibroblastsLimited data; unknownNormal puberty; disturbed sensorimotor coordination; intellectual disability
Fanconi anemia  9 18 genes 10Progressive bone marrow failure (pancytopenia); myelodysplastic syndromeMicrocephaly (1/3 of individuals)Growth restrictionCellular sensitivity to ionizing radiation & DNA cross-linking agents 11Chromosome breakage induced by mitomycin C & diepoxybutaneMyeloblastic leukemia; solid tumorsLimited fertility
Ataxia-telangiectasia ATM (A-TFresno12No increased risk of infectionsMicrocephalyGrowth restrictionHypersensitivity to ionizing radiationChromosome instability (incl. 7;14 rearrangements) in lymphocytesLeukemia; Hodgkin & non-Hodgkin lymphomaScleral telangiectasia; progressive truncal ataxia; intellectual disability
Seckel syndrome 13
OMIM PS210600
See footnote 14PancytopeniaSevere microcephalySevere growth restrictionNot typically radiosensitive by colony survival assay 13Increased sister chromatid exchangeLimited data, possible myelodyplasiaIntellectual disability
Rubinstein-Taybi syndrome CREBBP
Recurrent infections; defect in polysaccharide antibody responseMicrocephaly; distinctive facial featuresMild growth restriction; short statureNo cellular sensitivityNot presentLeukemia; tumors that affect the headIntellectual disability

Seeman et al [2004] suggest that NBN pathogenic variants account for a significant number of children with primary microcephaly in the Czech Republic.


Facial features characteristic of Nijmegen breakage syndrome are: a sloping forehead, retrognathia, prominent nasal bridge and nose, large ears, and upslanted palpebral fissures.


XRCC4 is another component of the non-homologous end joining (NHEJ) pathway.


As only one individual with RAD50 pathogenic variants has been described, it is unclear how consistent the clinical features of RAD50 deficiency appear to overlap with NBS.


Overlap of some clinical features and cellular sensitivity to ionizing radiation and DNA cross-linking agents could lead to misdiagnosis of NBS as Fanconi anemia [Gennery et al 2004, New et al 2005].


Fanconi anemia is associated with mutation of BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51, RAD51C, SLX4, or UBE2T.


Increased sensitivity of lymphocytes to alkylating agents like mitomycin C and/or diepoxybutane is the cellular marker of Fanconi anemia and is used as a diagnostic aid.


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



Evaluations 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 (if they were not performed as part of the diagnostic evaluation):

  • Assessment of growth
  • Evaluation of immunologic status to include:
    • Complete blood count;
    • Absolute number of B-cells, T-cells, and T-cell subsets, with special attention to naïve CD4+CD45RA cells;
    • Proliferative response of peripheral blood mononuclear cells to stimuli;
    • Concentration of total serum immunoglobulins (IgG, IgA, IgM) and IgG subclasses;
    • Evaluation for viruses with lymphotrotropic capacity (i.e., EBV and CMV).
  • Evaluation for malignancy, including a focused family history of other individuals with cancer
  • Evaluation of the endocrinologic status in females who are of pubertal age to include pelvic ultrasound to evaluate for streak gonads and plasma levels of FSH, LH, and estrogen [Chrzanowska et al 2010a]
  • Assessment of cognitive development and intellectual abilities
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

Infections. In individuals with severe humoral immunodeficiency and frequent infections, Ig replacement therapy should be considered.

  • Ig replacement is typically administered either intravenously (IVIg) or subcutaneously (SCIg).
  • The spectrum of recurrent infections in NBS is not opportunistic; therefore, the antibiotic selected should be appropriate for the microorganism being treated.

Malignancy. Standard treatment chemotherapy protocols for lymphoid malignancies in NBS need to be adopted according to individual tolerance [Dembowska-Baginska et al 2009, Pastorczak et al 2016]. Treatment of affected individuals with solid tumors is also challenging. Radiotherapy of CNS tumors (medulloblastoma) caused severe complications and death in three individuals with NBS [Chrzanowska et al 1997, Bakhshi et al 2003, Distel et al 2003].

  • Although complete clinical remission (for >5 years) can be successfully achieved, in a proportion of affected individuals outcome is complicated by relapse or the development of a second malignancy [Dembowska-Baginska et al 2009, Bienemann et al 2011].
  • For individuals who achieve first remission, hematopoietic stem cell transplantation (HSCT) may be considered:

Puberty and fertility. Females with NBS who are of pubertal age should be referred for evaluation by a gynecologist and/or endocrinologist to evaluate for hypergonadotropic hypogonadism.

  • Hormonal replacement therapy should be considered with careful monitoring of secondary sexual characteristics and uterus development.
  • Females are infertile; similarly, no male paternity has been reported.


Affected individuals

  • Periodic follow-up to monitor developmental progress, physical growth (including weight, length/height, and head circumference) and frequency of infections; monitoring for weight loss, which may signal the presence of a malignancy
  • Lifelong monitoring of immune biomarkers to include the parameters listed in Evaluations Following Initial Diagnosis
  • Careful follow up by oncologist: in individuals with NBS who are immunodeficient symptoms of lymphoid malignancies can be misleading.
  • Monitoring for pubertal progression in both females and males and for premature ovarian insufficiency in females [Chrzanowska et al 2010b]
  • Breast self-examination and ultrasonographic evaluation recommended in affected females

Carriers (heterozygotes)

  • Parents. As obligate carriers, parents should be monitored for malignancy, in particular breast cancer in women and prostate cancer in men. No consensus tumor screening protocols for carriers have been published.
  • At-risk sibs. Evidence of cancer risk in young carriers is insufficient to warrant screening 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 chromosome 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.

Similarly, unnecessary exposure to ionizing radiation should be avoided; instead of radiograph or CT scan, MR imaging and ultrasound examination are strongly recommended.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing for the NBN pathogenic variants identified in the proband to apparently asymptomatic sibs of a proband and young adult relatives at risk of being carriers (heterozygotes) in order to identify as early as possible those who would benefit from monitoring for malignancy (see Surveillance) and to inform treatment options if a malignancy is diagnosed (see Agents/Circumstances to Avoid).

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

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 (i.e., carriers of one NBN pathogenic variant).
  • Heterozygotes are asymptomatic; however, in some populations, there is evidence of increased cancer risk for heterozygotes [Seemanová 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.
  • Heterozygotes (carriers) are asymptomatic; however, in some populations, there is evidence of an increased cancer risk for heterozygotes [Seemanová et al 2007].

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

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a NBN pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the NBN pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 and Preimplantation Genetic Diagnosis

Once the NBN pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for NBS are possible.


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.

  • MedlinePlus
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Phone: 49-761-270-34450

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
NBN 8q21​.3 Nibrin NBN @ LOVD NBN NBN

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Nijmegen Breakage Syndrome (View All in OMIM)

602667 NIBRIN; 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 kb (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.

Pathogenic 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 is most common, accounting for the majority of all disease alleles in NBN. Other pathogenic variants (Table 3) occur 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.

One pathogenic variant, p.Tyr363Ter, was detected homozygous in an individual diagnosed with atypical Fanconi anemia, as well as several affected family members with similar clinical features [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 NBN biallelic truncating alleles, Seemanová et al [2006] have described a unique set of monozygotic twins who are compound heterozygous for the common c.657_661del5 pathogenic variant and a missense variant, 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 chromosome instability and radiation sensitivity characteristic of the disorder.

Table 3.

Selected NBN Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference SequenceOrigin# of Families in Whom Pathogenic Variant is Seen
c.330T>Gp.Tyr110Ter NM_002485​.4
c.1089C>Ap.Tyr363TerPakistani 23

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 (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


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

Normal gene product. The NBN protein product is nibrin, also known as p95. Nibrin is a protein of 85 kd in mass that is ubiquitously expressed. There is no sequence homology between nibrin and other known proteins. However, nibrin contains a forkhead-associated domain and two breast cancer carboxy-terminal domains, which are 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; presumably reflecting a requirement for production of a C-terminal protein fragment of nibrin that occurs by translational re-initiation mechanism [Maser et al 2001]. The requirement that protein termination and re-initiation 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.


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Chapter Notes

Author History

Krystyna H Chrzanowska, MD, PhD (2017-present)
Patrick Concannon, PhD; University of Florida Genetics Institute (1999-2014)
Ilja Demuth, PhD (2014-present)
Martin Digweed, PhD; Universitätsmedizin Berlin (2014-2017)
Richard Gatti, MD; University of California Los Angeles (1999-2014)
Raymonda Varon, PhD (2014-present)

Revision History

  • 2 February 2017 (ma) Comprehensive update posted live
  • 8 May 2014 (me) Comprehensive update posted live
  • 1 March 2011 (me) Comprehensive update posted live
  • 14 June 2005 (me) Comprehensive update posted live
  • 14 March 2003 (me) Comprehensive update posted live
  • 17 May 1999 (me) Review posted live
  • 5 January 1999 (pc) Original submission
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