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Nijmegen Breakage Syndrome

  • Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD  more...
Updated: Sep 29, 2014


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. 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[1] first delineated the syndrome in 2 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[2] 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).[3, 4, 5] 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.[6, 7]

Linkage studies allowed the exclusion of the gene responsible for Nijmegen breakage syndrome from the A-T locus on band 11q23[8] and from the translocation breakpoints in a Polish patient.[9] The gene, NBS1 (actually named NBN), was finally mapped to band 8q21[5, 10, 11] and cloned it in 1998,[12, 13] and mutations in this single gene were found to account for both A-T complementation groups V1 and V2.[11, 14]



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 2 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.[15, 16]

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.[17, 18] Nibrin has been shown to play a crucial role in immunoglobulin class switch recombination and maintenance of the integrity of chromosomal stability.[19, 20, 21]

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.[22, 23] 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.[24]

Mutant murine models of Nijmegen breakage syndrome have recently 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.[25] Using humanized mouse models, e.g. with introduced the 657Δ5 mutation into Nbn gene,[26] allowed to demonstrate pleiotropic effect of the defective protein at the cellular and organs levels.

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.[27, 28, 29]

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)[30, 31] and, recently, in the RAD50 gene.[32] However, many have still-unknown defects.[33, 34, 35]




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).[36] The highest estimated frequency was reported in Sorbs, a Slavic population isolate in Northeast Saxony, Germany (1 per 34 newborns).[37]


Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.[23, 38, 39] Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency,[23] and bone marrow aplasia (aplastic anemia).[40]


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.)

Contributor Information and Disclosures

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

Disclosure: Nothing to disclose.


Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Noah S Scheinfeld, JD, MD, FAAD Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Abbvie<br/>Received income in an amount equal to or greater than $250 from: Optigenex<br/>Received salary from Optigenex for employment.

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A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
Lateral facial features with sloping forehead and receding mandible are shown in a 6-month-old infant.
Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
Lateral profile. This view shows a relatively long nose and receding mandible.
Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
Vitiligo spots in a patient with Nijmegen breakage syndrome.
Progressive vitiligo in a patient with Nijmegen breakage syndrome.
Café au lait–like spots in a patient with Nijmegen breakage syndrome.
Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.
MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
Table. NBS1 Gene Pathogenic Molecular Variants
Mutation Exon Mutation Type Change in Protein Number of Families and Origin Allelic Status
c.643C>T 6 Missense R215W 1†




6 Frameshift Truncated

protein (233 aa)



founder mutation



c.681delT 6 Frameshift Truncated

protein (229 aa)





6 Frameshift Truncated

protein (236 aa)







7 Frameshift Truncated

protein (251 aa)





7 Frameshift Truncated

protein (279 aa)





7 Frameshift Truncated

protein (283 aa)





8 Frameshift Truncated

protein (305 aa)



c.976C>T 8 Nonsense Q326X 1


c.1089C>A 9 Nonsense Y363X 3



c.1142delC 10 Frameshift Truncated

protein (402 aa)



*He - Heterozygous (compound with 657del5).

†Monozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.[71]

‡Ho - Homozygous.

§Three nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).[67, 68]

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