Nijmegen Breakage Syndrome 

Updated: Jun 19, 2018
Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD 



Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition of chromosomal instability that is clinically characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy.[1] Mutations in the NBN (NBS1) gene located in band 8q21 are responsible for Nijmegen breakage syndrome. Nijmegen breakage syndrome is identified as entries 251260 in and 602667 in Online Mendelian Inheritance in Man. Note the images below.

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

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

In 1985, Seemanova et al[3] described a group of patients with an apparently new genetic disorder characterized by microcephaly with normal intelligence, cellular and humoral immune defects, and a striking predisposition to lymphoreticular malignancies. These cases were subsequently studied and found to fit into the category of Nijmegen breakage syndrome.

Further investigations revealed that in vitro cells derived from patients with Nijmegen breakage syndrome display characteristic abnormalities similar to those observed in ataxia-telangiectasia (A-T), including spontaneous chromosomal instability, sensitivity to ionizing radiation (IR), and radioresistant DNA synthesis (RDS).[4, 5, 6] However, aside from immune deficiency and a predisposition for malignancies (particularly those of lymphoid origin), the clinical manifestations are distinct. Consequently, Nijmegen breakage syndrome has long been considered a variant of A-T.

In 1998, on the basis of cellular phenotypes and the results of somatic cell complementation studies suggesting genetic heterogeneity, Jaspers et al proposed the term A-T variants for diseases in this group of patients. The 2 distinct groups were designated as A-T variant 1 (V1) for Nijmegen breakage syndrome and A-T variant 2 (V2) for Berlin breakage syndrome.[7, 8]

Linkage studies allowed the exclusion of the gene responsible for Nijmegen breakage syndrome from the A-T locus on band 11q23[9] and from the translocation breakpoints in a Polish patient.[10] The gene, NBS1 (actually named NBN), was finally mapped to band 8q21[6, 11, 12] and cloned it in 1998,[13, 14] and mutations in this single gene were found to account for both A-T complementation groups V1 and V2.[12, 15]


Nijmegen breakage syndrome is caused by mutations in the NBN(NBS1) gene located at 8q21. The NBN gene product, nibrin, has been found to interact with at least two other proteins, hMre11 and Rad50. Nibrin plays a key role in regulating the activity of the M/R/N protein complex, which is involved in end-processing of both physiological and mutagenic DNA double-strand breaks (DSBs). DNA DSBs occur as intermediates in physiological events, such as V(D)J recombination during early B- and T-cell development and immunoglobulin class switch in mature B cells, but most frequently are generated by mutagenic agents such as IR and radiomimetic chemicals.[16, 17, 18]

DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally can lead to cancer.[19, 20] Nibrin has been shown to play a crucial role in immunoglobulin class switch recombination and maintenance of the integrity of chromosomal stability.[21, 22, 23]

Because these key regulatory processes are defective in the cells of patients with Nijmegen breakage syndrome, chromosomal aberrations accumulate and immunodeficiency and gonadal failure occur.[24, 25] However, expression study of the murine NBN gene during mouse development provides evidence that apart from sites of physiologic DSBs in the testis, thymus, and spleen, NBN expression is also evident in several tissues and organs in which rejoining of DSBs is not known to occur.[26]

Mutant murine models of Nijmegen breakage syndrome have been derived. A null mutation affecting both alleles of the homologous gene, NBN, is embryonically lethal for knockout mice. It has also been demonstrated that the common human mutation is hypomorphic and that the expression of a truncated protein is sufficient for survival.[27] Using humanized mouse models, for example with introduced the 657Δ5 mutation into the NBN gene,[28] allowed the demonstration of the pleiotropic effect of the defective protein at the cellular and organ levels.

In 2016, Seidel et al demonstrated a novel function of NBN in skin homeostasis using a mouse model with conditional postnatal inactivation of NBN in hair follicle progenitors.[29] Deficiency of NBN in hair follicle progenitors promoted a signaling DNA damage cascade and secretion of proinflammatory cytokines, leading to psoriasiform dermatitis during senescence and hair loss.

Of particular significance was the discovery of the functional link between a network of genes that play important roles in repairing DNA damage, regulating cellular proliferation and apoptosis, and maintaining telomeric function. Defects in this network, including defects in the genes encoding ATM, NBN (NBS1), BRCA1, FANCD2, BLM, TP53, CDS1/CHK2, and others, can cause cancer.[30, 31, 32]

Not all patients with the Nijmegen breakage syndrome–like phenotype and radiation sensitivity have a defect in the NBN gene. Some of these were found to have mutations in the gene encoding DNA ligase IV (LIG4),[33, 34] in the RAD50 gene,[35] , in the NHEJ1 gene,[36, 37] or the XRCC4 gene.[38, 39]


Nijmegen breakage syndrome is a disease with an autosomal recessive pattern of inheritance.

Consanguineous matings have been reported.

The gene responsible for Nijmegen breakage syndrome, designated NBN (NBS1), is located on band 8q21.

The entire gene consists of 16 exons and spans a DNA region of more than 50 kilobases.

All disease-causing mutations identified to date have been found within exons 6-10 in the NBS1 gene and resulted in the production of a truncated protein.

More than 90% of all patients tested are homozygous for the common mutation of Slavic origin, a 5 base-pair deletion (c.657_661del5) in exon 6 of the NBN gene.[15]

The remaining patients tested to date are either heterozygous for c.657_661del5 and a second unique mutation (compound heterozygosity) or homozygous for a unique mutation. Ten unique mutations have been detected in various ethnic groups[12, 14, 15, 40, 41, 42] ; see the Table in Lab Studies.

The recent finding of the homozygous mutation c. 1089C>A in Pakistani Nijmegen breakage syndrome patients, initially diagnosed as having FA, has drawn attention to the clinical (microcephaly and congenital anomalies) and biological (increased sensitivity to both DNA cross-linking agents and IR) overlap of these 2 diseases.[43, 44]

Single case of Nijmegen breakage syndrome due to maternal isodisomy of chromosome 8 was reported.[45]



United States

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


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

The relative frequency of the common c.657_661del5 mutation in the Czech Republic, Poland, and Ukraine was studied, and it was found to be unexpectedly high in these 3 Slavic populations (a mean estimated prevalence of 1 case per 177 newborns).[46] The highest estimated frequency was reported in Sorbs, a Slavic population isolate in Northeast Saxony, Germany (1 per 34 newborns).[47]


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


No sex predilection is recognized for Nijmegen breakage syndrome.


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

Craniofacial characteristics become more obvious as patients age.

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

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

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

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

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

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

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


Currently, the long-term prognosis for patients with Nijmegen breakage syndrome appears to be more positive as a result of more effective prevention, control, and treatment of infections. Premature death occurs mainly from aggressive malignancy; however, experience gained in diagnostics and management of lymphoid malignancies over the last decade has led to reduced mortality.[48] Successful bone marrow transplantation (BMT)[43] has opened a new treatment opportunity.[49]

Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.[25, 50, 51] Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency,[25] and bone marrow aplasia (aplastic anemia).[40]

Survival the fifth decade has been recorded.[14]

Patient Education

Delayed speech development is observed in many children, and speech therapy is needed to correct articulation problems. Most patients with mental retardation require educational support. They may need to attend special education classes or schools. To find a genetics or prenatal diagnosis clinic, see GeneTests, Laboratory Directory.




The patient history may reveal clues to the diagnosis, such as the following:

  • Course of pregnancy and delivery: Most children with Nijmegen breakage syndrome are born at term, in vertical presentation.

  • Early somatic development: Birth weight, length, and head circumference are usually significantly lower in comparison with sex-matched controls; a slow growth rate and poor weight gain is observed in infancy and early childhood.

  • Psychomotor development: Usually, no gross delay of milestones is observed during the first year of life; toddlers and preschool children are frequently hyperactive; speech delay is common.

  • Mild complications after vaccinations (ie, against polio or measles) or in the course of childhood infectious diseases (eg, varicella) are reported in some patients.

  • Recurring infections: These are mainly of the respiratory tract, urinary tract, and gastrointestinal system, and they become a problem in approximately two thirds of patients.

The following information from the family history is also particularly important:

  • Occurrence of microcephaly or hydrocephaly in patient's siblings

  • Death of patient's siblings due to malignancy or severe infection

  • Malignancies among other family members

Physical Examination

The main clinical manifestations of Nijmegen breakage syndrome include progressive microcephaly with characteristic facies, growth retardation, and impaired sexual maturation in females; recurrent infections due to a combined immune deficiency; and a strongly increased risk of developing cancer, in particular leukemia and lymphoma. Other frequently observed manifestations include skin pigmentation defects (café au lait and/or vitiligo spots) and minor limb abnormalities.[25, 51, 52, 49]


Microcephaly (ie, head circumference below the third percentile) is the most striking and consistent symptom of Nijmegen breakage syndrome. In the great majority of children, it is observed at birth; in individuals who were born with a head circumference within the reference range, progressive and severe microcephaly develops during the first months of life. However, despite severe and progressive microcephaly, neuromotor development is not disturbed; epileptic seizures are not characteristic of the disease.

Among the 77 patients of Polish descent whom Chrzanowska observed, the deficiency of occipitofrontal circumference ranged from -4.4 to -9 standard deviation, but the proportions among the diminished head measurements (length and breadth) were retained.

Craniofacial characteristics

A sloping forehead and receding mandible, a prominent midface with a relatively long nose, upward slanting of the palpebral fissures (in most), and relatively large and dysplastic ears (in some) characterize the facial appearance in Nijmegen breakage syndrome, which is similar among all patients. The craniofacial characteristics of Nijmegen breakage syndrome become more obvious with patient age, probably because of progressive microcephaly. Note the images below.

Typical facial features in a 9-year-old girl with Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
Lateral profile. This view shows a relatively long Lateral profile. This view shows a relatively long nose and receding mandible.

Growth retardation

Children with Nijmegen breakage syndrome, in spite of being born at term, are characterized by a significantly lower birth weight and head circumference in comparison with sex-matched controls, as well as lower birth length and chest circumference.

The range of birth weight of Polish neonates was 1900-3600 g for females and 2170-3950 g for males.

After approximately a 2-year period of distinct postnatal growth retardation, a slight improvement in the growth rate (including those of body height and weight but not head circumference) is usually observed (Polish data).

Most patients' growth is around the third percentile for height and weight; in some teenage patients, growth is between the 10th and 25th percentiles for height and weight. Young adult individuals with Nijmegen breakage syndrome can reach a height of approximately 165 cm (ie, approximately 50th percentile for females and less than third percentile for males; Polish data).

Sexual maturation

Results of long-term follow-up in a large group of Polish patients drew attention to the poor development of secondary sex characteristics (ie, lack of development of genital organs and breasts, primary amenorrhea) in female patients with Nijmegen breakage syndrome who reached pubertal age.[53]

Endocrinologic evaluation indicates ovarian failure (see Lab Studies). Affected female patients fail to reach sexual maturity because of hypergonadotropic hypogonadism.[53, 54]

Immune deficiency and recurring infections

Because of defective humoral and cellular immunity, Nijmegen breakage syndrome patients are prone to developing infections. A considerable variability in immune deficiency is observed among different patients.[55]

The most common infections are respiratory tract infections (pneumonia, bronchitis) and sinusitis. Recurrent bronchopneumonia may result in bronchiectasis. Urinary and/or gastrointestinal tract infections and otitis media are also relatively common. Opportunistic infections are rare, as they are in patients with A-T.

Immunodeficiency in Nijmegen breakage syndrome is caused by reduced numbers of peripheral B and T lymphocytes, which can be explained as a precursor B-cell and, probably, also T-cell differentiation problem, due to a dysfunction of a truncated nibrin molecule.[56] A defect in humoral immunity in Nijmegen breakage syndrome patients is caused by reduced numbers of peripheral B lymphocytes and, simultaneously, by failure of their maturation, which results in an ineffective class-switch recombination.[57]


Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.

The prevalence of lymphoid malignancies in individuals with Nijmegen breakage syndrome is unprecedentedly high compared with healthy individuals and persons with other cancer-predisposing diseases such as A-T, Bloom syndrome, and FA. To date, 40-50% of Nijmegen breakage syndrome patients have developed a malignancy by age 20 years, of which 85-90% are leukemias or lymphomas. The most common of these are non-Hodgkin lymphomas (two morphological subtypes predominate: diffuse large B-cell lymphoma, DLBCL, and T-cell lymphoblastic lymphoma, T-LBL), lymphoblastic leukemia (acute lymphoblastic leukemia, with both precursor B cells and T cells), and Hodgkin disease.[58, 59, 60, 61] Two cases of acute myeloblastic leukemia[62] and a single case of acute monocytic leukemia[63] were also reported.

Among solid tumors, 2 were observed relatively frequently: medulloblastoma in 5 patients[10, 64, 65] (further 2 cases unpublished) and rhabdomyosarcoma of the perianal region in 3 others.[66, 67, 68] The latter, rhabdomyosarcoma arising perianally, is extremely uncommon in children; therefore, taking into account the number of Nijmegen breakage syndrome patients with this type of cancer, a strong association with Nijmegen breakage syndrome is suggested.[68]

Other malignancies were present in single patients only. These included papillary thyroid carcinoma, gonadoblastoma, glioma, meningioma, neuroblastoma, and Ewing sarcoma.[25]

Cutaneous manifestations and hair characteristics

Skin pigmentation abnormalities include café au lait spots (usually 2-5 spots, irregular in shape) and/or depigmented spots, which are present in approximately half the patients.[25, 50, 51] In 3 Polish patients, vitiligo was observed by the time they became adolescents, with progression as they aged. Less frequently, sun sensitivity of the eyelids is observed, and, occasionally, cutaneous telangiectasia (particularly on the back) is seen. Multiple pigmented nevi and cavernous or flat hemangiomas can also occur.

Cutaneous, sarcoidlike granulomas were observed in two female Nijmegen breakage syndrome patients with accompanying ocular manifestations in one of them.[69] (Chrzanowska, unpublished data). Primary cutaneous tuberculosis and necrobiotic cutaneous granulomas were reported, respectively.[70, 71]

Usually, the hair is thin in infants and toddlers, but later, improvement is observed. Early graying of hair may be observed by adolescence.

Note the images below.

Cutaneous sarcoidosis in a patient with Nijmegen b Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
Vitiligo spots in a patient with Nijmegen breakage Vitiligo spots in a patient with Nijmegen breakage syndrome.
Progressive vitiligo in a patient with Nijmegen br Progressive vitiligo in a patient with Nijmegen breakage syndrome.
Café au lait–like spots in a patient with Nijmegen Café au lait–like spots in a patient with Nijmegen breakage syndrome.

Other developmental anomalies

CNS malformations are observed relatively frequently and may be more common than expected. Small frontal lobes and narrow frontal horns of the lateral ventricles were documented in all patients who underwent cranial MRI.[72] Small brain size may be associated with other CNS developmental abnormalities, including partial agenesis of the corpus callosum, hydrocephaly, arachnoid cysts, and neuronal migration disorder (in the form of schizencephaly or pachygyria).[66, 72, 73]

Minor skeletal anomalies, such as clinodactyly of the fifth fingers and/or partial syndactyly of the second and third toes, are encountered in approximately half the patients. Hip dysplasia, preaxial polydactyly, and sacral agenesis are less common. Note the image below.

Preaxial polydactyly of the hand in a patient with Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.

Urogenital defects noted in several patients with Nijmegen breakage syndrome have included kidney pathology (eg, agenesis or hypoplasia, ectopic single kidney or dystopic kidneys), hydronephrosis, hypospadias, and cryptorchidism.

Among other abnormalities, tracheal hypoplasia, cleft lip and/or palate, choanal atresia, anal atresia/stenosis, and cardiovascular defects (patent ductus arteriosus, ventricular septal defect) are reported. Polysplenia, a peculiarity with no clinical significance, is relatively frequently detected by ultrasonography.

Other complications

Two pediatric patients were reported to suffer from juvenile rheumatoid arthritis–like arthritis and chronic polyarthritis, respectively.[74, 75]


Recurrent pneumonia and bronchitis may result in bronchiectasis or respiratory insufficiency.

Recurrent otitis media may result in draining ear(s) or mastoiditis.

Malignancies occur frequently in patients with Nijmegen breakage syndrome.

An adverse reaction to radiation therapy, chemotherapy, or both in patients with unrecognized Nijmegen breakage syndrome may result in toxic death.

At least 3 patients who had medulloblastoma and received radiation before being diagnosed with Nijmegen breakage syndrome were fatally injured, and they eventually died from complications of the therapy.[10, 64, 65]

Alopecia was an adverse effect observed in a Polish patient with acute myeloblastic leukemia given an 18-Gy dose of cranial irradiation for CNS prophylaxis. However, another Polish patient manifested no complications after receiving an identical dose by prophylactic cranial irradiation for high-risk group T-cell acute lymphoblastic leukemia. Both patients were treated for the malignancy before the diagnosis of Nijmegen breakage syndrome was established (Chrzanowska, unpublished data).

Physicians should be aware of the possibility that Nijmegen breakage syndrome is underdiagnosed in children with malignant diseases in geographical areas where the disease is less frequent.

A high index of suspicion is necessary for patients who (1) develop any type of malignancy and have congenital defects (eg, microcephaly) and (2) develop lymphoid malignancy at a very young age (younger than 3 y).



Diagnostic Considerations

Table 1.Syndromes to be Considered in the Differential Diagnosis of Nijmegen Breakage Syndrome (Open Table in a new window)

Clinical and Cellular Phenotype

Nijmegen Breakage Syndrome

Nijmegen Breakage Syndrome‒Like Disorder[35, 76]

DNA LIG4 Deficiency[33, 34, 77]

NHEJ1 Syndrome[36, 37]

XRCC4 Deficiency[38, 39]

Fanconi Anemia[43, 44, 78]

Warsaw Breakage Syndrome[79, 80]

Bloom Syndrome[81, 82]

Online Mendelian Inheritance in Man (OMIM)



















Severe, disproportionate





In ~30%

Severe, disproportionate

Severe, proportionate

Growth Deficiency

Mild to moderate


Moderate to severe


Severe, disproportionate

Mild to moderate



Congenital Malformations

Heart, kidney, polydactyly

Not reported

Polydactyly, syndactyly


Not reported

Heart, kidney radial bone defects (~50%)


Kidney, polydactyly

Puberty and Fertility

Primary amenorrhea (hypergonadotropic hypogonadism)

Normal puberty


Not reported

Primary amenorrhea

Males, infertility; females, early menopause

Normal puberty

Males, infertility; females, early menopause

Other Endocrinologic Problems

Not reported

Not reported

Hypothyroidism, type 2 diabetes

Not reported

Early-onset metabolic syndrome

Type 2 diabetes mellitus

Not reported

Type 2 diabetes mellitus

Recurrent Infections










Combined (B- and T-cell)


Combined (B- and T-cell)

Combined (B- and T-cell)




B-cell type

Hematologic Findings

Myelodysplastic syndrome (incidentally)

Not reported

Pancytopenia, myelodysplastic syndrome

Pancytopenia, myelodysplastic syndrome

Thrombocytopenia, pancytopenia

Progressive bone marrow failure, myelodysplastic syndrome

Not reported

Myelodysplastic syndrome

Malignancy Type

Predominantly lymphoid origin

Not reported

Predominantly lymphoid origin

Not reported


Acute myeloid leukemia, solid tumors (early onset)

Not reported

Lymphoid origin, acute myeloid leukemia, solid tumors

Chromosomal Instability

Breakages, including 7/14 rearrangements

Breakages, 7/14 rearrangements

Breakages, no 7/14 rearrangements

Breakages, not specified

Not reported

Breakages, figures (asymmetric)

Breakages and cohesinopathy

Breakages, figures (symmetric), high sister chromatid exchange rate

Sensitivity to Damaging Agents (in vitro)

Ionizing radiation, bleomycin; mitomycin C and diepoxybutane, mild

Ionizing radiation, bleomycin

Ionizing radiation, bleomycin

Ionizing radiation (variable)

Ionizing radiation (extreme)

Mitomycin C and diepoxybutane; ionizing radiation, mild

Mitomycin C, camptothecin


Mental Retardation

Mild to moderate


Mild to moderate

Yes, not defined

Moderate to severe

Moderate to severe

Moderate to severe

Normal to mild

aFANC: Genetic and phenotypic heterogeneity; 19 genes known (OMIM).

Also consider the following:

  • Autosomal recessive primary microcephaly (MCPH), genetic and phenotypic heterogeneity (OMIM 17 entries): Defined by primary microcephaly over -3 standard deviations below the mean and various neurological problems (eg, spasticity, motor disability, mental retardation)
  • Seckel syndrome spectrum disorders (SCKS), genetic and phenotypic heterogeneity (OMIM 10 entries): Defined by severe primary microcephaly, severe prenatal and postnatal growth restriction, multiple various congenital malformations, and/or metabolic/biochemical features

Differential Diagnoses



Laboratory Studies

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

Basis for diagnosis

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

Cytogenetic analysis

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

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

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

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

Immunologic testing

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

Evaluation of humoral immunity should include measurements of serum immunoglobulin levels (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM]) and IgG subclass levels. The most frequently observed defects are the combined deficit of IgG and IgA, followed by an isolated IgG deficiency. The most characteristic feature of humoral disturbances is a deficiency in one or more IgG subclasses, even with total IgG levels in the reference range; selective deficiency of IgG4 and IgG2 are the most common.[55]

Evaluation of cell-mediated immunity should include measurements of T-cell lymphocyte subpopulations (CD3+, CD4+, CD8+, CD4+/CD8+; CD4/CD45RA+, CD4/CD45RO+), B cells (CD19+), and natural killer cells (CD16+, CD56+) and an assessment of the proliferative response to mitogens or antigens (phytohemagglutinin, anti-CD3). T-cell immunity is impaired in most patients with Nijmegen breakage syndrome.[83] The most commonly reported defects are mild-to-moderate lymphopenia, expressed as a low percentage of CD3+ T cells, a low proportion of CD4+ (helper) T cells, and a decreased CD4+/CD8+ ratio. A deficiency of CD4/CD45RA+ (naive) cells and an excess of CD4/CD45RO+ (memory) cells has been observed, and a high number of natural killer cells has been noted in a proportion of patients.[84]

Alpha-fetoprotein determination

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

IR and RDS sensitivity analysis

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

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

Examination of DNA replication in irradiated Nijmegen breakage syndrome cells, as well as cells in A-T and A-T–like disorder, reveals the phenomenon of RDS, which reflects a defect in control of the S-phase progression until the repair of DNA damage is complete.[5, 7]

Immunoblotting assay

Western blotting allows demonstration of the presence or absence of the p95/nibrin protein in LCLs.[13, 15]

Molecular genetic analysis

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

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

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

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

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

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

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



Mutation Type

Change in Protein

Number of Families and Origin

Allelic Status













protein (233 aa)



founder mutation







protein (229 aa)









protein (236 aa)










protein (251 aa)









protein (279 aa)









protein (283 aa)









protein (305 aa)






















protein (402 aa)




aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.[85]

bHe - Heterozygous (compound with 657del5).

cHo - Homozygous.

dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).[43, 44]

Endocrinologic evaluation

Ovarian failure is expected in most female patients with Nijmegen breakage syndrome.[8, 53]  A study of the pituitary-gonadal axis (ie, plasma concentrations of follicle-stimulating hormone [FSH], luteinizing hormone, and estradiol [E2]) in females reaching pubertal age is recommended. A serum FSH level exceeding 40 IU/L and a low E2 level indicate ovarian failure (hypergonadotropic hypogonadism).

Imaging Studies

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

Cranial MRI may reveal CNS developmental abnormalities or solid tumor.

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

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

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

Note the images below.

MRI in a patient with Nijmegen breakage syndrome s MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

Histologic Findings

Data yielded from histopathologic analysis of tissue biopsy and autopsy specimens from patients with Nijmegen breakage syndrome are limited. Findings suggestive of a lymphoproliferative disorder are the most common indications for lymph node biopsy, but only a few reports on the histologic and immunophenotypic features of lymphomas are available. In 2000, Gladkowska-Dura et al reported a detailed study of lymphomas in 11 Nijmegen breakage syndrome patients.[58]

Although at least 50 patients with Nijmegen breakage syndrome are known to have died, extensive autopsy findings are well documented in only 1 patient, and limited information is available in a few others. Markedly reduced brain weight and thymus dysplasia or aplasia were consistent findings in all cases. No cerebellar degeneration was confirmed, which is in contrast to persons with A-T. A detailed neuropathological study of the first-recognized Nijmegen breakage syndrome case was reported by Lammens et al[86] in 2003.



Medical Care

No specific therapy is available for Nijmegen breakage syndrome (NBS).

Substitution with immunoglobulins (ie, intravenous immunoglobulin [IVIG] therapy) is indicated in patients with agammaglobulinemia (serum concentration of IgG <2.5-3 g/L, depending on patient age) and in children with IgG2 deficiency (<0.48 g/L in patients aged 2-5 y and <0.72 g/L in patients >5 y). Before IVIG is started, the presence of anti-IgA antibodies must be determined in patients with IgA deficiency. In such cases, the subcutaneous administration of immunoglobulins is advocated to prevent shock, which can occur in patients with anti-IgA antibodies. A pediatric immunologist must make the decision to start substitution therapy.

Consider antibiotic prophylaxis in patients with recurrent respiratory tract infections. Urinary tract infections due to congenital malformations of the kidneys occur in some children; antibiotic prophylaxis is indicated in these patients.

Cancer treatment must be modified in Nijmegen breakage syndrome patients with malignancy because conventional doses of radiotherapy and chemotherapy may lead to severe (even lethal/ life-threatening) toxic complications. Curative therapy, however, is possible and should be attempted. The intensity of therapy must be adapted to individual risk factors and tolerance. The use of radiomimetics, alkylating agents, and epipodophyllotoxins should be avoided, and the dose of methotrexate should be limited.[87, 88, 89, 90] Anthracycline-induced cardiomyopathy was reported in one patient, and, therefore, echocardiographic monitoring is strongly recommended.[91]

Bone marrow transplantation (BMT) or hematopoietic stem cells transplantation (HSCT) is an option that can be considered in some patients with Nijmegen breakage syndrome.[92] HSCT experience in six Nijmegen breakage syndrome patients in Europe was reported, of whom two, initially diagnosed as atypical Fanconi anemia, were transplanted in order to correct severe immunodeficiency,[44] and the reminding four underwent HSCT for refractory, recurring, or secondary malignancy.[93] In five patients, a reduced-intensity conditioning regimen was implemented. In 2015, Wolska-Kuśnierz et al analyzed data on14 transplanted Nijmegen breakage syndrome patients to date and nine of them survived from 1.4-11 years.[49] Shortly after, Woźniak et al presented successful nonmyeloablative umbilical cord blood transplantation in a 19-month-old child with Nijmegen breakage syndrome presenting with severe combined immune deficiency (SCID).[94] Further follow-up is needed to monitor long-term effects, including the development of malignancies.

Prepubertal female patients with delayed or absent sexual maturation require the systematic care of a (pediatric) endocrinologist, gynecologist, or both. When hypergonadotropic hypogonadism is confirmed (serum FSH level >40 IU/L, low E2 level), substitution hormone therapy to support the development of secondary sex characteristics and to prevent osteoporosis must be considered when the patient reaches the appropriate age.

Vitamin E supplementation in doses appropriate for age and body weight is recommended, as in individuals with other chromosome instability disorders.

Surgical Care

Neurosurgical treatment with a ventriculoperitoneal shunt may be necessary for patients with hydrocephaly. Surgical repair may also be required in cases of inherited malformations (eg, anal atresia, polydactyly).


Consultations with the following various specialists may be required:

  • Pediatric immunologist

  • Oncologist

  • Pulmonologist

  • Neurologist

  • Endocrinologist

  • Gynecologist

  • Others, as determined by history and physical examination findings

Offer genetic counseling to provide families with information about the high recurrence risk and the possibility of prenatal diagnosis. Nijmegen breakage syndrome is inherited in an autosomal recessive manner. Parents of an affected child are obligate carriers of a single copy of a disease-causing mutation in the NBS1 gene and have a 25% likelihood (1:4) of giving birth to an affected child. Heterozygotes are asymptomatic. However, some reports have suggested an increased risk of malignancy in carriers of the common Slavic mutation, 657del5.[95, 96] Therefore, monitoring parents for malignancy is recommended.

Delayed speech development is observed in many children, and speech therapy is needed to correct articulation problems.

Most patients with mental retardation require educational support. They may need to attend special education classes or schools.


Infants and young children with Nijmegen breakage syndrome demonstrate striking psychomotor hyperactivity and have a short attention span. Generally, all children with Nijmegen breakage syndrome have a gentle personality and, despite being shy, they are usually capable of good social interactions.


Prenatal diagnosis is possible for families with a 25% risk of having an affected child. Molecular genetic analysis is the method of choice. However, the identification of disease-causing mutations in both alleles of the NBS1 gene is necessary before prenatal testing can be performed.

Fetal DNA is obtained either by chorionic villous sampling at 10-12 weeks' gestation or by early amniocentesis at 13-15 weeks' gestation.

Long-Term Monitoring

Further outpatient care (eg, IVIG therapy, infection treatment) is determined by the degree of immune deficiency and clinical course.

Periodic follow-up is indicated to monitor immune status, physical growth, and intellectual development.

Systematic periodic monitoring for malignancy development is mandatory.