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Nijmegen Breakage Syndrome

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

Author Information and Affiliations

Initial Posting: ; Last Update: August 18, 2022.

Estimated reading time: 25 minutes


Clinical characteristics.

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), 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. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).


The diagnosis of NBS is established in a proband with characteristic clinical features and biallelic pathogenic variants in NBN on molecular genetic testing and/or absent nibrin protein on immunoblotting assay.


Treatment of manifestations: Standard antimicrobial therapies for infections; immunoglobulin replacement therapy in individuals with severe hypogammaglobulinemia and frequent infections; acellular vaccines; standard treatment of bronchiectasis and pulmonary infections; chemotherapy protocols for lymphoid malignancies adapted to individual tolerance; treatment of solid tumors adapted 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 physical growth, infection frequency, and developmental progress; lifelong monitoring of immune biomarkers; monitor for malignancy and particularly in those with weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, and hepatosplenomegaly (assessment should be considered using ultrasonography, MRI, biopsy); monitor pubertal progression in both sexes and for premature ovarian insufficiency in females; monthly breast self-examination when hormone replacement therapy is administered; assess cognitive developmental and intellectual abilities before starting school and follow up periodically.
  • For heterozygous adults. Monitor 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. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given.

Genetic counseling.

NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial NBN pathogenic variants. Heterozygotes are not at risk for NBS. However, heterozygous NBN pathogenic variants may be associated with an increased risk for breast cancer in women and prostate cancer in men. Carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.


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 deficiency that is more pronounced from birth until age two 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 [Wolska-Kuśnierz et al 2015]:
    • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%.
    • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order).
    • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals.
    • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls.
  • 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 the 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 suggestive findings and biallelic pathogenic (or likely pathogenic) variants in NBN identified by molecular genetic testing (see Table 1) and/or absent nibrin protein on an immunoblotting assay.

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular Genetic Testing

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

  • Single-gene testing. Targeted analysis for the common founder variant c.657_661del5 can be performed first. The c.657_661del5 pathogenic variant accounts for:
    • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry;
    • More than 70% of pathogenic alleles in individuals from the US.
    If the common founder variant 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 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 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

See Molecular Genetics for information on 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 detect 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. Almost all affected individuals in the US 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. 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 a range of techniques such as 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 large exon or multiexon deletions or duplications involving this gene have been reported to cause NBS.


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

Note: Immunoblotting 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

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, growth deficiency that improves with age, recurrent sinopulmonary infections, an increased risk for lymphoma, 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. Secondary malignancies including solid tumors have been reported in several individuals.

Table 2.

Nijmegen Breakage Syndrome: Frequency of Select Features

Feature% of Persons w/FeatureComment
Microcephaly >99%
Growth deficiency Variable w/ageGrowth deficiency in newborns, infants, & toddlers; growth improves w/age.
Immunodeficiency ≥99%
Malignancy >60% by age 25 yrs
Infertility 100% of femalesData are limited for males.

Growth. Children with NBS are generally born with weight below normal for gestational age and microcephaly (i.e., head circumference >2 SD below the mean for age and sex). 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 et al 2012].

Growth deficiency in the first years 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 their 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. The spectrum and frequency of infections and autoimmune complications in a large group of individuals with NBS was reported by Wolska-Kuśnierz et al [2015]. Correlation of the severity of respiratory tract infections with some humoral and cellular immune parameters was also presented. Most respiratory tract infections were caused by community-acquired pathogens; only about 5% of individuals suffered from opportunistic infections [Wolska-Kuśnierz et al 2015]. Another study showed low frequency of protective IgG antibodies to HBsAg after vaccination with Engerix-B®, indicating a very weak specific response [Gregorek et al 2002].

Buchbinder et al [2019] reported the presence of rubella-positive cutaneous and visceral granulomas following rubella vaccination in individuals with NBS. One individual with NBS was found to have pulmonary granulomas with no evidence of an infectious pathogen or any manifestations of systemic granulomatosis of lymphoid malignancy [Marczak et al 2018].

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. 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].

Several children have developed solid tumors, including medulloblastomas, glioma, rhabdomyosarcomas, and bilateral ovarian germ cell tumor (in a female) [Chrzanowska et al 1997, Hiel et al 2001, Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004, Sharapova et al 2021, Krawczyk et al 2022]. Radiotherapy of central nervous system tumors (medulloblastoma) caused severe complications and death in three individuals with NBS [Chrzanowska et al 1997, Bakhshi et al 2003, Distel et al 2003].

A recent study of 241 individuals with NBS showed improved long-term survival in those treated with hematopoietic stem cell transplantation (HSCT) during first malignancy remission [Wolska-Kusnierz et al 2021]. In a second study of 136 individuals with NBS – 62 of whom developed malignancies – seven individuals were treated with HSCT due to leukemia/lymphoma; six, who were cancer-free, were transplanted due to immunodeficiency [Sharapova et al 2021].

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 / preschool age. Intellectual abilities tend to decline, with mild-to-moderate intellectual disability during childhood. Affected children are described as having a cheerful, shy personality with good interpersonal skills.

Fertility. Results of a longitudinal study demonstrated the presence of hypergonadotropic hypogonadism 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 sibs, 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.


An increased frequency of NBN pathogenic variant c.657_661del5 has been observed in individuals with several different cancers, including breast cancer, prostate cancer, medulloblastoma, and melanoma, suggesting that NBN pathogenic variants could 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 typical features of NBS. 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 woman age 53 years with NBS who was homozygous for the NBN truncating allele c.741_742dupGG. She had a somewhat milder phenotype, including microcephaly, chromosome instability, immunodeficiency, and primary amenorrhea. (Her sister, with similar clinical manifestations, had died at age 20 years of malignant lymphoma [Maraschio et al 1986]). However, analysis of transcripts from the woman's cells indicated a highly prevalent alternatively spliced form of NBN lacking exons 6 and 7 (where the pathogenic variant is located). This transcript codes for 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 brother, had biallelic truncating variants in NBN (p.Tyr110Ter and p.Trp375Ter). Neither sib had short stature, reduced head circumference, or dysmorphic facial features; however, both were referred for fertility defects (premature ovarian failure and oligo-terato-asthenozoospermia) 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 (NBS) was described by Weemaes et al [1981].

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


No reliable estimates of worldwide 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 Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations [Varon et al 2000, Seemanová et al 2004]. The highest reported prevalence is in the Sorbian population, an isolated Slavic group from southeastern Germany, in whom the carrier frequency is estimated at 1:34 [Maurer et al 2010]. In a cohort of 136 individuals with NBS from Belarus, Ukraine, Russia, and Latvia, the highest prevalence was found in Belarus and Ukraine (2.3 and 1.3 in 1 million, respectively), with the highest incidence in western Belarus and western Ukraine (>2:100,000) [Sharapova et al 2021].

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 3.

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 (e.g., 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 3.

Disorders to Consider in the Differential Diagnosis of Nijmegen Breakage Syndrome

Gene(s)Disease NameImmunodeficiency &/or Bone Marrow FailureMicrocephaly /
Craniofacial Features
Growth DelayCellular SensitivityChromosome InstabilityCancer PredispositionOther
NBN Nijmegen breakage syndrome (NBS; topic of this chapter)Immunodeficiency, combined; recurrent sinopulmonary infectionsProgressive disproportionate microcephaly; characteristic facial features 1Mild growth restriction↓ in colony-forming ability after exposure to ionizing radiation & radiomimeticsInversions & translocations involving chromosomes 7 & 14 in lymphocytes↑ risk, mainly of lymphoid originPrimary ovarian failure; mild-to-moderate ID
Fanconi anemia Progressive bone marrow failure (pancytopenia); myelodysplastic syndromeMicrocephaly (1/3 of persons)Growth restrictionCellular sensitivity to ionizing radiation & DNA cross-linking agents 2Chromosome breakage induced by mitomycin C & diepoxybutane 2Myeloblastic leukemia; solid tumorsLimited fertility
ATM A-TFresno (nonclassic form of ataxia-telangiectasia)No ↑ risk of infections reportedMicrocephalyGrowth restrictionHypersensitivity to ionizing radiationChromosome instability (incl 7;14 rearrangements) in lymphocytesLeukemia; Hodgkin & non-Hodgkin lymphomaScleral telangiectasia; progressive truncal ataxia; ID
Rubinstein-Taybi syndrome Recurrent infections; defect in polysaccharide antibody responseMicrocephaly; distinctive facial featuresMild growth restriction; short statureNo cellular sensitivityNot presentLeukemia; tumors that affect headID
LIG4 LIG4 syndrome 3 (OMIM 606593)Immunodeficiency, combined; pancytopenia & myelodysplastic syndromeMicrocephaly; facial features resembling NBS 1Short statureSevere radiosensitivitychromosome breakage ratePredisposition to malignancy (mainly lymphoma & leukemia)High intrafamilial clinical variability
NHEJ1 NHEJ1 syndrome (Cernunnos-XLF deficiency) (OMIM 611291)Mild immunodeficiency to severe combined immunodeficiencyMicrocephalySevere (typically) growth restrictionCellular sensitivity to ionizing radiationHigh chromosome breakage rate (w/o chromosome 7;14 rearrangements) 4Limited data; unknown
RAD50 Nijmegen breakage syndrome-like disorder (RAD50 deficiency) (OMIM 613078)No immunodeficiency reportedMicrocephaly; facial features resembling NBS 1Severe growth restrictionX-ray hypersensitivityChromosome instability (incl 7;14 rearrangements) in lymphocytes & fibroblastsLimited data; unknownNormal puberty; disturbed sensorimotor coordination; ID
Seckel syndrome (OMIM PS210600)PancytopeniaSevere microcephalySevere growth restrictionNot typically radiosensitive by colony survival assay 5sister chromatid exchangeLimited data, possible myelodysplasiaID
XRCC4 6Short stature, microcephaly, & endocrine dysfunction (OMIM 616541)No clinical manifestations of immunodeficiencyPrimary microcephalySevere growth restrictionPronounced cellular radiosensitivityNot reportedSolid tumorPrimary ovarian failure; early-onset metabolic syndrome

ID = intellectual disability


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


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


XRCC4 is another component of the nonhomologous end joining (NHEJ) pathway.


No clinical practice guidelines for Nijmegen breakage syndrome (NBS) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NBS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Nijmegen Breakage Syndrome

Constitutional Assessment of growth & nutrition
  • Eval of immunologic profile at time of diagnosis
  • Assessment of types & frequency of infections
  • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells
  • Proliferative response of peripheral blood mononuclear cells to stimuli
  • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses
  • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV)
Pulmonary Assess pulmonary function in those w/recurrent/chronic pulmonary infections.
  • Assess for signs/symptoms of lymphoma & solid tumors.
  • Assess family history for malignancy.
  • Eval by gynecologist &/or endocrinologist
  • Pelvic ultrasound to evaluate for streak gonads
  • Plasma FSH, LH, & estrogen
In females of pubertal age
Neurodevelopment Assess cognitive development & intellectual abilities.
Genetic counseling By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of NBS to facilitate medical & personal decision making
Family support
& resources
Assess need for:

CMV = cytomegalovirus; EBV = Epstein-Barr virus; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; NBS = Nijmegen breakage syndrome


Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Nijmegen Breakage Syndrome

Immunodeficiency Antibiotics as needed for infections; selected for microorganism being treatedThe spectrum of recurrent infections in NBS is not opportunistic. Long-term antibiotic, antiviral, or antifungal prophylaxis is not recommended.
Consider Ig replacement, typically intravenously (IVIg) or subcutaneously (SCIg).In those w/severe hypogammaglobulinemia & frequent infections
Acellular vaccines are recommended.Live vaccines (against tuberculosis, measles, mumps, rubella, & varicella) should not be given.
Pulmonary infections
  • Standard treatments for bronchiectasis
  • Treatment of pulmonary infection is based on underlying pathogen.
  • Lymphoid malignancy
  • Chemotherapy protocols need to be adapted to individual tolerance. 1
  • Requires careful follow up by oncologist, as symptoms of lymphoid malignancies in immunodeficient persons can be misleading.
  • There are currently no dedicated protocols of cancer treatment for persons w/NBS or recommendations of chemotherapy reduction.
  • Notably, ↓ chemotherapy dosages were not assoc w/↓ side effects but contributed to ↑ risk of disease recurrence & poorer overall survival.
Treatment of solid tumors depends on type of malignancy.
  • Protocols should be adapted for NBS depending on treatment tolerance.
  • Radiotherapy & radiomimetic chemotherapeutics are avoided.
Consider HSCT.Recommended after 1st remission from malignancy of hematologic origin 2
  • Consider HRT.
  • Careful monitoring of secondary sexual characteristics & uterus development is needed.
HRT is recommended at appropriate age to induce secondary sexual characteristics & to prevent osteoporosis & metabolic, cardiovascular, & psychosocial sequelae.

HRT = hormonal replacement therapy; HSCT = hematopoietic stem cell transplantation



Table 6.

Recommended Surveillance for Individuals with Individuals with Nijmegen Breakage Syndrome

Constitutional Monitor weight, length/height, & head circumference.Monthly until age 1 yr; every 3-6 mos until age 2-3 yrs; annually thereafter
  • Monitor types & frequency of infections.
  • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells
  • Proliferative response of peripheral blood mononuclear cells to stimuli
  • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses
  • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV)
  • Eval of cellular immunity & proliferative response to mitogens or antigens every 12 mos
  • Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started)
  • Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected
  • Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, &/or hepatosplenomegaly.
  • Assessment should be considered using ultrasonography, MRI, biopsy.
Breast self-examMonthly in females when HRT is administered.
  • Monitor pubertal progression in females & males.
  • Assess for premature ovarian insufficiency in females.
Neurodevelopment Assess cognitive development & intellectual abilities.Before starting school & repeated periodically to ensure educational support as needed

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HRT = hormonal replacement therapy

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 the risk associated with radiotherapy 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, MRI and/or ultrasound examination are strongly recommended.

Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given.

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 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

Nijmegen breakage syndrome (NBS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a NBN pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NBN pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Heterozygotes are not at risk for NBS; however, in some populations, there is clear evidence of increased cancer risk among individuals heterozygous for an NBN pathogenic variant (e.g., c.657_661del5) (see Clinical Description, Heterozygotes). Heterozygous parents should be monitored for malignancy, particularly breast cancer in women and prostate cancer in men (see Surveillance).

Sibs of a proband

  • If both parents are known to be heterozygous for an NBN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having NBS, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial NBN pathogenic variants.
  • Heterozygotes are not at risk for NBS; however, in some populations there is clear evidence of increased cancer risk among individuals heterozygous for an NBN pathogenic variant (e.g., c.657_661del5) (see Clinical Description, Heterozygotes). Adult heterozygous sibs should be monitored for malignancy, particularly breast cancer in women and prostate cancer in men (see Surveillance).

Offspring of a proband. To date, individuals with NBS are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an NBN pathogenic variant and at increased risk for malignancy (see Clinical Description, Heterozygotes).

Heterozygote Detection

Heterozygote 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 and discussion of the availability of prenatal/preimplantation genetic 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 heterozygotes or are at risk of being heterozygotes.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


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
    Engesserstrasse 4
    79106 Freiburg
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de

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)


Molecular Pathogenesis

NBN encodes nibrin, also known as p95. Nibrin 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, the associated proteins hMre11, hRad50, and nibrin form 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].

Most known NBN pathogenic variants are predicted to result in truncation of the nibrin protein. All known NBS-related 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 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.

Mechanism of disease causation. Loss of function

Table 7.

Notable NBN Pathogenic Variants

Reference SequencesDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeComment [References]
c.330T>Gp.Tyr110TerSee Genotype-Phenotype Correlations.
c.643C>Tp.Arg215TrpReported in MZ twins also heterozygous for c.657_661del5 w/more severe neurologic features but w/o cellular & radiation sensitivity [Seemanová et al 2006]
(c.657_661del5; 657del5)
p.Lys219AsnfsTer16Slavic founder variant [Varon et al 1998]
p.Glu248GlyfsTer5See Genotype-Phenotype Correlations.
c.1089C>Ap.Tyr363TerHomozygous in affected persons from 1 family w/features of atypical Fanconi anemia [Gennery et al 2005, New et al 2005]
c.1125G>Ap.Trp375TerSee Genotype-Phenotype Correlations.

MZ = monozygotic

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

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


Variant designation that does not conform to current naming conventions

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

  • 18 August 2022 (sw) Comprehensive update posted live
  • 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


Literature Cited

  • Altmann T, Gennery AR. DNA ligase IV syndrome; a review. Orphanet J Rare Dis. 2016;11:137. [PMC free article: PMC5055698] [PubMed: 27717373]
  • 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]
  • Bienemann K, Burkhardt B, Modlich S, Meyer U, Möricke A, Bienemann K, Mauz-Körholz C, Escherich G, Zimmermann M, Körholz D, Janka-Schaub G, Schrappe M, Reiter A, Borkhardt A. 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;155:468–76. [PubMed: 21923652]
  • Buchbinder D, Hauck F, Albert MH, Rack A, Bakhtiar S, Shcherbina A, Deripapa E, Sullivan KE, Perelygina L, Eloit M, Neven B, Pérot P, Moshous D, Suarez F, Bodemer C, Bonilla FA, Vaz LE, Krol AL, Klein C, Seppanen M, Nugent DJ, Singh J, Ochs HD. Rubella virus-associated cutaneous granulomatous disease: a unique complication in immune-deficient patients, not limited to DNA repair disorders. J Clin Immunol. 2019;39:81–9. [PMC free article: PMC7739844] [PubMed: 30607663]
  • Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, 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]
  • Chrzanowska K, Stumm M, Bialecka M, Saar K, Bernatowska-Matuszkiewicz E, Michalkiewicz J, Barszcz S, Reis A, Wegner RD. Linkage studies exclude the AT-V gene(s) from the translocation breakpoints in an AT-V patient. Clin Genet. 1997;51:309–13. [PubMed: 9212178]
  • 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]
  • 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]
  • 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. Abstract.
  • 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]
  • 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]
  • Dembowska-Baginska B, Perek D, Brozyna A, Wakulinska A, Olczak-Kowalczyk D, Gladkowska-Dura M, Grajkowska W, Chrzanowska KH. Non-Hodgkin lymphoma (NHL) in children with Nijmegen breakage syndrome (NBS). Pediatr Blood Cancer. 2009;52:186–90. [PubMed: 18937313]
  • 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]
  • Dutrannoy V, Demuth I, Baumann U, Schindler D, Konrat K, Neitzel H, Gillessen-Kaesbach G, Radszewski J, Rothe S, Schellenberger MT, Nürnberg G, Nürnberg P, Teik KW, Nallusamy R, Reis A, Sperling K, Digweed M, Varon R. Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype. Hum Mutat. 2010;31:1059–68. [PubMed: 20597108]
  • 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]
  • Felgentreff K, Baxi SN, Lee YN, Dobbs K, Henderson LA, Csomos K, Tsitsikov EN, Armanios M, Walter JE, Notarangelo LD. Ligase-4 deficiency causes distinctive immune abnormalities in asymptomatic individuals. J Clin Immunol. 2016;36:341–53. [PMC free article: PMC4842108] [PubMed: 27063650]
  • Gennery AR, Slatter MA, Bhattacharya A, Jeggo PA, Abinun M, Flood TJ, Cant AJ. Bone marrow transplantation for Nijmegen breakage syndrome. J Pediatr Hematol Oncol. 2005;27:239. [PubMed: 15838402]
  • Gładkowska-Dura M, Dzierzanowska-Fangrat K, Dura WT, van Krieken JH, Chrzanowska KH, van Dongen JJ, Langerak AW. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J Pathol. 2008;216:337–44. [PubMed: 18788073]
  • 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;130:319–24. [PMC free article: PMC1906518] [PubMed: 12390322]
  • Hiel JA, Weemaes CM, van Engelen BG, Smeets D, Ligtenberg M, van Der Burgt I, van Den Heuvel LP, Cerosaletti KM, Gabreëls 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]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Krawczyk MA, Styczewska M, Birkholz-Walerzak D, Iliszko M, Lipska-Zietkiewicz BS, Kosiak W, Irga-Jaworska N, Izycka-Swieszewska E, Bien E. Bilateral ovarian germ cell tumor in a 46,XX female with Nijmegen breakage syndrome and hypergonadotropic hypogonadism. J Clin Res Pediatr Endocrinol. 2022;14:251–7. [PMC free article: PMC9176082] [PubMed: 34544220]
  • Maraschio P, Peretti D, Lambiase S, Lo Curto F, Caufin D, Gargantini L, Minoli L, Zuffardi O. New chromosome instability disorder. Clin Genet. 1986;30:353–65. [PubMed: 3802554]
  • Marczak H, Heropolitańska-Pliszka E, Langfort R, Roik D, Grzela K. Nijmegen breakage syndrome complicated with primary pulmonary granulomas. Pediatrics. 2018;142:e20180122. [PubMed: 30209074]
  • 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]
  • Matsuura S, Kobayashi J, Tauchi H, Komatsu K. Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys. 2004;38:65–80. [PubMed: 15476893]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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;22:138–40. [PubMed: 22533239]
  • Pastorczak A, Szczepanski T, Mlynarski W. Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome. Eur J Med Genet. 2016;59:126–32. [PubMed: 26826318]
  • 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]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Seemanová 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]
  • Seemanová E, Pohanka V, Seeman P, Misovicová N, Behunová J, Kvasnicová M, Dlholucký S, Valachová A, Cisarik F, Veghová E, Varon R, Sperling K. Nijmegen breakage syndrome in Slovakia. Cas Lek Cesk. 2004;143:538–41. [PubMed: 15446459]
  • Seemanová 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]
  • Sharapova SO, Pashchenko OE, Bondarenko AV, Vakhlyarskaya SS, Prokofjeva T, Fedorova AS, Savchak I, Mareika Y, Valiev TT, Popa A, Tuzankina IA, Vlasova EV, Sakovich IS, Polyakova EA, Rumiantseva NV, Naumchik IV, Kulyova SA, Aleshkevich SN, Golovataya EI, Minakovskaya NV, Belevtsev MV, Latysheva EA, Latysheva TV, Beznoshchenko AG, Akopyan H, Makukh H, Kozlova O, Varabyou DS, Ballow M, Ong MS, Walter JE, Kondratenko IV, Kostyuchenko LV, Aleinikova OV. Geographical distribution, incidence, malignancies, and outcome of 136 eastern Slavic patients with Nijmegen breakage syndrome and NBN founder variant c.657_661del5. Front Immunol. 2021;11:602482. [PMC free article: PMC7819964] [PubMed: 33488600]
  • 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]
  • Szczałuba K, Mierzewska H, Obersztyn E, Tryfon J, Bekiesińska-Figatowska M, Szczepanik E, Chrzanowska K, Bocian E. Nijmegen breakage syndrome with macrocephaly, schizencephaly and large CSF spaces—extended spectrum of the condition. J Appl Genet. 2012;53:189–91. [PubMed: 22293976]
  • 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]
  • Varon R, Seemanova E, Chrzanowska K, Hnateyko O, Piekutowska-Abramczuk D, Krajewska-Walasek M, Sykut-Cegielska J, Sperling K, Reis A. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet. 2000;8:900–2. [PubMed: 11093281]
  • Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998;93:467–76. [PubMed: 9590180]
  • 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]
  • 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]
  • Wolska-Kuśnierz B, Gregorek H, Chrzanowska K, Piątosa B, Pietrucha B, Heropolitańska-Pliszka E, Pac M, Klaudel-Dreszler M, Kostyuchenko L, Pasic S, Marodi L, Belohradsky BH, Čižnár P, Shcherbina A, Kilic SS, Baumann U, Seidel MG, Gennery AR, Syczewska M, Mikołuć B, Kałwak K, Styczyński J, Pieczonka A, Drabko K, Wakulińska A, Gathmann B, Albert MH, Skarżyńska U, Bernatowska E. Nijmegen breakage syndrome: clinical and immunological features, long-term outcome and treatment options - a retrospective analysis. J Clin Immunol. 2015;35:538–49. [PubMed: 26271390]
  • Wolska-Kusnierz B, Pastorczak A, Fendler W, Wakulinska A, Dembowska-Baginska B, Heropolitanska-Pliszka E, Piątosa B, Pietrucha B, Kałwak K, Ussowicz M, Pieczonka A, Drabko K, Lejman M, Koltan S, Gozdzik J, Styczynski J, Fedorova A, Miakova N, Deripapa E, Kostyuchenko L, Krenova Z, Hlavackova E, Gennery AR, Sykora KW, Ghosh S, Albert MH, Balashov D, Eapen M, Svec P, Seidel MG, Kilic SS, Tomaszewska A, Wiesik-Szewczyk E, Kreins A, Greil J, Buechner J, Lund B, Gregorek H, Chrzanowska K, Mlynarski W. Hematopoietic stem cell transplantation positively affects the natural history of cancer in Nijmegen breakage syndrome. Clin Cancer Res. 2021;27:575–84. [PubMed: 33082212]
  • Yoo J, Wolgamot G, Torgerson TR, Sidbury R. Cutaneous noncaseating granulomas associated with Nijmegen breakage syndrome. Arch Dermatol. 2008;144:418–9. [PubMed: 18347309]
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