eMedicine Specialties > Dermatology > Pediatric Diseases

Nijmegen Breakage Syndrome

Author: Krystyna H Chrzanowska, MD, PhD, Head of Genetic Counseling Unit, Associate Professor, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
Coauthor(s): Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Contributor Information and Disclosures

Updated: Oct 23, 2009

Introduction

Background

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 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.

A 6-month-old infant with Nijmegen breakage syndr...

A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.

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A 6-month-old infant with Nijmegen breakage syndr...

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 the same 6-month-old infant as in Media File 1.

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Lateral facial features with sloping forehead and...

Lateral facial features with sloping forehead and receding mandible are shown in the same 6-month-old infant as in Media File 1.


In 1981, Weemaes et al1 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 al2 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 11q238 and from the translocation breakpoints in a Polish patient.9 The gene, NBS1 (actually named NBN), was finally mapped to band 8q215,10,11 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

Pathophysiology

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

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.16,17 Nibrin has been shown to play a crucial role in immunoglobulin class switch recombination and maintenance of the integrity of chromosomal stability.18,19,20

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.21,22 However, expression study of the murine NBS1 gene during mouse development provides evidence that apart from sites of physiologic DSBs in the testis, thymus, and spleen, NBS1 expression is also evident in several tissues and organs in which rejoining of DSBs is not known to occur.23

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.24 Using humanized mouse models, e.g. with introduced the 657Δ5 mutation into Nbn gene,25 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.26,27,28

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)29,30 and, recently, in the RAD50 gene.31 However, many have still-unknown defects.32,33,34

Frequency

United States

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

International

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 657del5 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).35

Mortality/Morbidity

Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.22,36,37 Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency,22 and bone marrow aplasia (aplastic anemia).38

Race

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).

Sex

No sex predilection is recognized for Nijmegen breakage syndrome.

Age

  • 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.)

Clinical

History

  • 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

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.22,37,39

  • Microcephaly
    • 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.

      • 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.

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        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 of the same 9-year-old girl as in...

        Lateral profile of the same 9-year-old girl as in Media File 3. This view shows a relatively long nose and receding mandible.

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        Lateral profile of the same 9-year-old girl as in...

        Lateral profile of the same 9-year-old girl as in Media File 3. 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.40
    • Endocrinologic evaluation indicates ovarian failure (see Lab Studies).
    • Affected female patients fail to reach sexual maturity because of hypergonadotropic hypogonadism.40
  • 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.41
    • 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.
  • Malignancies
    • 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.42,43 Two cases of acute myeloblastic leukemia1 (Chrzanowska, unpublished data) and a single case of T-cell prolymphocytic leukemia were also noted.44
    • Among solid tumors, 2 were observed relatively frequently: medulloblastoma in 5 patients9,45,46 (further 2 cases unpublished) and rhabdomyosarcoma of the perianal region in 3 others.47,48,49 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.49
    • Other malignancies were present in single patients only. These included papillary thyroid carcinoma, gonadoblastoma, glioma, meningioma, neuroblastoma, and Ewing sarcoma.22
  • 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.22,36,37
    • 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 2 female Nijmegen breakage syndrome patients with accompanying ocular manifestations in one of them.50 (Chrzanowska, unpublished data)
    • Usually, the hair is thin in infants and toddlers, but later, improvement is observed. Early graying of hair may be observed by adolescence.

      • Cutaneous sarcoidosis in a patient with Nijmegen ...

        Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.

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        Cutaneous sarcoidosis in a patient with Nijmegen ...

        Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.


      • Vitiligo spots in a patient with Nijmegen breakag...

        Vitiligo spots in a patient with Nijmegen breakage syndrome.

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        Vitiligo spots in a patient with Nijmegen breakag...

        Vitiligo spots in a patient with Nijmegen breakage syndrome.


      • Progressive vitiligo in a patient with Nijmegen b...

        Progressive vitiligo in a patient with Nijmegen breakage syndrome.

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        Progressive vitiligo in a patient with Nijmegen b...

        Progressive vitiligo in a patient with Nijmegen breakage syndrome.


      • Café au lait–like spots in a patient w...

        Café au lait–like spots in a patient with Nijmegen breakage syndrome.

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        Café au lait–like spots in a patient w...

        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.51 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).47,51,52
    • 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.

      • Preaxial polydactyly of the hand in a patient wit...

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

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        Preaxial polydactyly of the hand in a patient wit...

        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.

Causes

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 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 (657del5) in exon 6 of the NBS1 gene.14
  • The remaining patients tested to date are either heterozygous for 657del5 and a second unique mutation (compound heterozygosity) or homozygous for a unique mutation. Ten unique mutations have been detected in various ethnic groups11,13,14,38,53,54 ; see the Table in Lab Studies.
  • The recent finding of the homozygous mutation 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.55,56
  • Single case of Nijmegen breakage syndrome due to maternal isodisomy of chromosome 8 was reported.57

More on Nijmegen Breakage Syndrome

Overview: Nijmegen Breakage Syndrome
Differential Diagnoses & Workup: Nijmegen Breakage Syndrome
Treatment & Medication: Nijmegen Breakage Syndrome
Follow-up: Nijmegen Breakage Syndrome
Multimedia: Nijmegen Breakage Syndrome
References
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References

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Further Reading

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Keywords

Nijmegen breakage syndrome, Nijmegen's breakage syndrome, NBS, Berlin breakage syndrome, BBS, Seemanova syndrome, ataxia-telangiectasia, AT-V1, AT-V2, A-T, congenital microcephaly, congenital immunodeficiency, chromosomal instability, microcephaly, microcephaly with normal intelligence, lymphoreticular malignancy, MIM 251260, OMIM 251260, MIM 602667, OMIM 602667

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Contributor Information and Disclosures

Author

Krystyna H Chrzanowska, MD, PhD, Head of Genetic Counseling Unit, Associate Professor, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Optigenex Consulting fee Independent contractor

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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