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Nijmegen Breakage Syndrome

[Ataxia-Telangiectasia Variant 1 , Berlin Breakage Syndrome]

Summary

Disease characteristics.  Nijmegen breakage syndrome (NBS) is characterized by short stature, progressive microcephaly with loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, and an increased risk for cancer, particularly lymphoma.

Diagnosis/testing.   NBS1 is the only gene known to be associated with Nijmegen breakage syndrome. Molecular genetic testing of the NBS1 gene detects disease-causing mutations in almost 100% of affected individuals. Such testing is available clinically.

Genetic counseling.  NBS is inherited in an autosomal recessive manner. Sibs of affected individuals have a 25% risk of having NBS. Prenatal testing is available.

Diagnosis

Clinical Diagnosis

The diagnosis of Nijmegen breakage syndrome (NBS) is suspected in individuals with the following characteristic findings:

• Microcephaly occurs in about 75% of affected individuals at birth, and in the remainder during the first months of life.
• Growth retardation is either present at birth or becomes manifest before two years of age. Thereafter, growth rate is appropriate, but individuals remain small for age.
• The characteristic facial features — a sloping forehead, receding mandible, prominent nasal root and nose, large ears, and upward slant of the palpebral fissures — become apparent at around three years of age.
• Recurrent sinopulmonary infections include pneumonia, bronchitis, otitis media, sinusitis, and mastoiditis.
• Malignancies, most commonly B-cell lymphoma, which develops in most individuals before the age of 15 years, occur in approximately 50% of individuals with NBS.
• In most individuals, decline in intellectual ability results in mental retardation in the borderline-to-moderate range by age ten years.

Testing

• Immunodeficiency involving the humoral and cellular system

  • Agammaglobulinemia has been found in 35% and IgA deficiency in 20% of affected individuals.
  • Deficiencies in IgG2 and IgG4 are frequent even when the IgG serum concentration is normal.
  • The most commonly reported defects in cellular immunity are reduced percentages of total CD3+ T cells and CD4+ cells.
  • An increased frequency of T cells with a memory phenotype (CD45RO+) and a concomitant decrease in naive T cells (CD45RA+) has been reported [Michalkiewicz et al 2003].

• Chromosomal 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.

• Immunoblotting.  This test is used to determine if the nibrin protein is present or absent.

  Note: This test requires that a lymphoblastoid cell line be established.

• Radiation sensitivity.  Cells from individuals with NBS have a decrease of colony-forming ability following exposure to ionizing radiation and radiomimetics in vitro. Such testing is available clinically.

  Note: This test requires that a lymphoblastoid cell line be established.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   NBS1 is the only gene known to be associated with Nijmegen breakage syndrome.

Other loci.  A number of reports suggest that mutations in at least one other gene, as yet unidentified, can lead to an almost identical disorder. Presently, distinction can only be made by excluding mutations in NBS1. Approximately 50% of individuals referred for diagnostic testing for NBS share significant clinical overlap and have pronounced radiosensitivity, but lack mutations in the NBS1 gene (author observation, unpublished).

Molecular genetic testing: Clinical uses

• Diagnosis. Definitive diagnosis of NBS requires the demonstration of disease-causing mutations in both alleles of the NBS1 gene.
• Carrier testing
• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Targeted mutation analysis

  • All affected individuals from Poland, the Czech Republic, and the Ukraine tested to date are homozygous for the common mutation 657del5.
  • In the US, about 70% of individuals tested to date are homozygous for the common allele, 15% are heterozygous for 657del5 and a second unique mutation, and 15% are homozygous for a unique mutation.

Molecular genetic testing: Research

• Sequence analysis/mutation scanning.  Full gene sequencing is only performed after prior testing has revealed that: 1) the 657del5 mutation is absent, 2) the nibrin protein is absent or truncated, and 3) the cells are radiosensitive.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic  Testing Used in NBS Test Methods Mutations Detected Mutation Detection Rate  1 Test Availability Slavic  2 North American  3 Targeted mutation analysis 657del5 in NBS1 Homozygous (657del5/657del5): 100% Homozygous (657del5/657del5): 70% Clinical Sequence analysis/mutation scanning NBS1 sequence alterations Heterozygous 657del5/unique mutation): 15% Research only Homozygous (unique mutation/unique mutation): 15%

1. Given the rarity of NBS it is likely that most of the mutations show some kind of founder effect, making reliable estimates of incidence difficult to establish. 2. Slavic = Poland, Czech Republic, Ukraine 3. Based on the small number of individuals observed

Testing Strategy

Diagnostic testing for NBS can be performed on a single sample of heparinized blood:

1. Targeted mutation analysis to determine if the 657del5 mutation is present

If the mutation is not present:

2. Immunoblotting to determine if the nibrin protein is present or absent
3. Colony survival assay to determine radiosensitivity

Interpretation of test results

• If all three tests are normal, a diagnosis of NBS is extremely unlikely.
• If nibrin is absent, the possibility of NBS remains, but sequence analysis of NBS1 to identify other mutations is available on a research basis only.
• If nibrin is present, but the cells are radiosensitive, evaluation for other disorders of DNA repair or immunodeficiency is warranted.

Genetically Related (Allelic) Disorders

No other distinct genetic disorders are associated with mutations in NBS1.

Clinical Description

Natural History

Growth.  Children with NBS generally have lower than normal birth weight and are small for gestational age. If not present from birth, microcephaly develops during the first months of life and progresses to severe microcephaly. Growth failure during the first two years of life results in height that is usually less than the third centile by two years of age. The linear growth rate tends to be normal after two years of age, but individuals remain small for age.

Facial features.  As microcephaly progresses, the facial features tend to become distinct, with sloping forehead, upslanting palpebral fissures, prominent midface, long nose, and small jaw. The ears may be large.

Psychomotor development.  Developmental milestones are attained at the usual time during the first year. Borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after the age of seven years have mild-to-moderate mental retardation. The children are described as having a cheerful, shy personality with good interpersonal skills.

Infections.  Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in pulmonary failure and early death. Chronic diarrhea and urinary tract infections may also occur.

Malignancy.  According to Wegner et al (1999), 25 of the 70 individuals (35%) reported to date have developed malignancies between the ages of one and 34 years. Twenty-two of the 25 were lymphomas, of which 19 occurred before the age of 15 years. Nine out of 19 were B-cell lymphomas; 1/19 was a T-cell lymphoma [Michallet et al 2003]. Several children have developed solid tumors, such as medulloblastomas, glioma, and rhabdomyosarcoma [Hiel et al 2001 , Bakhshi et al 2003 , Distel et al 2003 , Meyer et al 2004].

Premature ovarian failure (POF).  Wegner et al (1999) report a high incidence of premature ovarian failure in both prepubertal girls with NBS and adolescent and post-adolescent women with NBS, as evidenced by elevated serum concentration of gonadotrophins in both groups and primary amenorrhea and lack of secondary sexual development in the latter. Whether gonadal failure is part of the phenotype in males is not yet clear.

Other findings.  Irregular skin pigmentation, manifested as hyperpigmented or hypopigmented irregular spots, is seen in most individuals. Congenital malformations, usually observed in single cases, include hydrocephalus, preaxial polydactyly, occipital cyst, choanal atresia, cleft lip and palate, tracheal hypoplasia, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.

Genotype-Phenotype Correlations

There are no known phenotype-genotype correlations.

Heterozygotes.  Heterozygotes are asymptomatic. Epidemiologic studies are underway to investigate a possible increased susceptibility to malignancy in heterozygotes. These studies are ideally performed in Eastern European populations where the incidence of the 657del5 mutation is high, allowing direct screening for this single variant in individuals with cancer. Preliminary studies have provided suggestive evidence of an increased frequency of 657del5 carriers in several different cancers including breast cancer, prostate cancer, and melanoma [Cybulski et al 2004 , Steffen et al 2004]. There is also anecdotal evidence of increased frequencies of cancer in relatives of individuals with NBS.

Nomenclature

The NBS syndrome was described by Weemaes et al (1981).

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

Genetic complementation studies of Jaspers et al (1988) noted a strong similarity between NBS cells and ataxia-telangiectasia (A-T) cells; however, they also described the NBS cells as genetically distinct from A-T, grouping individuals with either Nijmegen breakage syndrome or Czech breakage syndrome into A-T variant group 1 (V1). Germans with 'Berlin breakage syndrome' [Wegner et al 1999] were grouped into A-T complementation group V2 [Jaspers et al 1988]. Subsequently, NBS1 mutations were found in all individuals studied from the V1 and V2 groups, indicating that these individuals had NBS, not ataxia-telangiectasia.

Prevalence

No reliable estimates of prevalence exist, but it is likely approximately 1:100,000 live births. NBS is most common in Eastern European/Slavic populations. Studies in Poland, the Czech Republic, and the Ukraine have suggested that the carrier frequency of the common allele approaches 1/155 in these populations.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. Some inherited immunodeficiencies (e.g., X-linked agammaglobulinemia (Bruton's agammaglobulinemia) and X-linked severe combined immunodeficiency) also demonstrate radiosensitivity (in colony survival assays).

Individuals homozygous for the 1089CA mutation in the NBS1 gene share features of Fanconi anemia [Gennery et al 2004].

Occasionally individuals with the ATM gene mutation A-T_Fresno have symptoms of both NBS and ataxia-telangiectasia (A-T) [Curry et al 1989 , Gilad et al 1998].

Microcephaly, midface prominence, and mental retardation suggest syndromes such as Seckel syndrome [O'Driscoll et al 2003] and Rubinstein-Taybi syndrome ; however, cells from these individuals are not typically radiosensitive by colony survival assay (unpublished). Seeman et al (2004) suggest that NBS1 mutations account for a significant number of children with primary microcephaly in the Czech Republic. Other forms of autosomal  recessive microcephaly have been linked chromosomes 9q, 8p, and 19q [Moynihan et al 2000].

Individuals with ligase IV syndrome [O'Driscoll et al 2001] may present with features of NBS, including microcephaly, short stature, midface prominence, immunodeficiency, and radiosensitivity. However, the immunodeficiency (pancytopenia) in individuals with ligase IV syndrome is typically more severe than in individuals with NBS. Ligase IV syndrome, caused by mutations in LIG4, is not associated with an increase in chromosomal instability or t(7; 14). The two disorders can be differentiated by molecular genetic testing of the LIG4 and NBS1 genes.

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

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

Management

Evaluation at Initial Diagnosis

• Baseline evaluation of immune and endocrinologic status, degree of mental impairment, and head circumference
• History of radiation exposure
• Familial history of cancer

Treatment of Manifestations

Because of chromosomal instability, Vitamin E and folic acid supplementation in doses appropriate for body weight is recommended.

Prevention of Primary Manifestations

No treatment for NBS is known.

Prevention of Secondary Complications

In individuals with severe humoral immunodeficiency and frequent infections, IVIg should be considered.

Surveillance

• Periodic follow-up to monitor mental and physical growth and frequent infections is indicated.
• Weight loss may signal the presence of a malignancy.

Testing of Relatives at Risk

• Parents, as obligate carriers, should be monitored for malignancy.
• Evidence of cancer risk in young carriers is insufficient to warrant testing of at-risk sibs 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 chromosomal instability syndrome), conventional doses of radiation used in radiotherapy could be lethal in individuals with NBS.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

NBS is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in the NBS1 gene.
• Heterozygotes are asymptomatic; however, anecdotal reports suggest an increased risk of malignancy in NBS heterozygotes for the common Slavic mutation, 657del5.

Sibs of a proband

• At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic; however, anecdotal reports suggest an increased risk of malignancy in NBS heterozygotes.

Offspring of a proband.  No affected individuals with offspring have been reported.

Other family members of a proband.  Sibs of the proband's parents are at 50% risk of also being carriers.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the proband.

Related Genetic Counseling Issues

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Molecular genetic testing.  Prenatal diagnosis for pregnancies at increased risk is possible. DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation is analyzed. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The NBS1 gene is encoded in 16 exons and spans approximately 51 kb of DNA. The entire gene and flanking genomic regions have been sequenced. The gene encodes two transcripts of 4.4 and 2.4 kb that are expressed in all tissues examined and differ only in their site of polyadenylation. Both transcripts contain a single open reading frame coding for a protein of 754 amino acids with a predicted molecular weight of 85 kd. A number of polymorphisms and rare variants in the NBS1 gene have been described. Table 2 summarizes those for which unaffected homozygous individuals have been identified, verifying that they are not disease alleles. Alleles at these sites are all in very strong linkage disequilibrium in the general population. Additional variants such as 283G/A (D95N), 628G/T (V210F), 643C/T (R215W), and 797C/T (P266L) have been reported in various cancer cases and controls. Their role in NBS, if any, is unclear as they are too rare to have been observed in homozygotes or in conjunction with a confirmed NBS mutation.

Pathologic allelic variants: All disease-causing alleles of the NBS1 gene identified to date are predicted to result in truncation of the nibrin protein (see Table 3). The 657del5 mutation predominates, accounting for more than 90% of all mutant alleles in NBS. Each of the other mutations listed in Table 3 occurs in one or a small number of families. NBS1 mRNA is always detectable in cell lines from individuals with NBS, but full-length NIBRIN protein is not detectable by Western blotting. Although some, and possibly all, NBS1 alleles produce one or more partial proteins, their abundance is generally low and varies in different cell types, making them a poor diagnostic marker.

One mutation, 1089CA is particularly noteworthy. This mutation was originally described in a person diagnosed with atypical Fanconi anemia . Subsequent testing revealed homozygosity for an NBS1 mutation. Several additional families with this mutation have been identified and all display overlapping clinical features with Fanconi anemia syndrome [Gennery et al 2004 , New et al 2005]. These findings highlight the lack of disease specificity in assays that test for sensitivity to DNA crosslinking agents.

Table 3: Pathologic Allelic Variants of the NBS1 Gene Mutation Nucleotide Change Exon Consequence Origin Mutation Observed Number of Families 657del5 657-661delACAAA 6 Frameshift Slavic N/A 681delT 681-682delT 6 Frameshift Russian 1 698del4 698-701delAACA 6 Frameshift English 2 835del4 835-838delCAGA 7 Frameshift Italian 1 842insT 842-842insT 7 Frameshift Mexican 1 900del25 900-924del25 8 Frameshift Moroccan 1 976CT CT at 976 8 Q326X Dutch 1 1089CA CA at 1089 9 Y363X Pakistani  1 3 1142delC 1142-1143delC 10 Frameshift Canadian 2

1. Individual originally diagnosed as having Fanconi anemia with atypical clinical features

Normal gene product: The protein product of the NBS1 gene is NIBRIN (also referred to as p95). NIBRIN is a protein of 85 kd in mass that is ubiquitously expressed. There are no global sequence similarities between NIBRIN and any other known proteins. However, NIBRIN contains two recognizable protein domains — a forkhead-associated domain and a breast cancer carboxy-terminal domain — that are found in other proteins involved in cellular responses to DNA damage. In normal fibroblasts, NIBRIN is associated with two other proteins putatively involved in DNA repair, hMre11 and hRad50. Upon exposure to ionizing radiation, this complex of proteins, including NIBRIN, forms nuclear foci at sites where DNA repair has taken place. Nibrin targets the NBS1/Mre11/Rad50 complex to sites of double-strand breaks and interacts with ATM kinase to coordinate cell cycle arrest with DNA repair [Carney et al 1998 , Matsuura et al 2004 , Falck et al 2005].

Abnormal gene product: All known NBS1 mutations are predicted to result in truncation of the NIBRIN protein. All known NBS1 mutations occur in exons 6-10 and this is thought to reflect a requirement for production of a C-terminal protein fragment of nibrin that occurs by translational re-initiation mechanism [Maser et al 2001]. The requirement that protein termination and re-initiation occur in the same reading frame potentially limits the mutations that can give rise to NBS. Knockout mice homozygous for null alleles of Nbs1 are embryonic lethal, suggesting that the partial protein produced from NBS1 alleles in humans is necessary for survival.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Literature Cited

• Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, Bhambhani K (2003) Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. J Pediatr Hematol Oncol 25:248-51 [Medline]
  
  
• Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477-86 [Medline]
  
  
• Curry CJ, O'Lague P, Tsai J, Hutchison HT, Jaspers NG, Wara D, Gatti RA (1989) ATFresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am J Hum Genet 45:270-5 [Medline]
  
  
• Cybulski C, Gorski B, Debniak T, Gliniewicz B, Mierzejewski M, Masojc B, Jakubowska A, Matyjasik J, Zlowocka E, Sikorski A, Narod SA, Lubinski J (2004) NBS1 is a prostate cancer susceptibility gene. Cancer Res 64:1215-9 [Medline]
  
  
• Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G (2003) Fatal toxicity following r Med Pediatr Oncol 41:44-8 [Medline]
  
  
• Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605-11 [Medline]
  
  
• Gennery AR, Slatter MA, Bhattacharya A, Barge D, Haigh S, O'Driscoll M, Coleman R, Abinun M, Flood TJ, Cant AJ, Jeggo PA (2004) The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol 113:214-9 [Medline]
  
  
• Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y, Bar-Shira A (1998) Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62:551-61 [Medline]
  
  
• Hiel JA, Weemaes CM, van Engelen BG, Smeets D, Ligtenberg M, van Der Burgt I, van Den Heuvel LP, Cerosaletti KM, Gabreels FJ, Concannon P (2001) Nijmegen breakage syndrome in a Dutch patient not resulting from a defect in NBS1. J Med Genet 38:E19 [Medline]
  
  
• Jaspers NG, Gatti RA, Baan C, Linssen PC, Bootsma D (1988) Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet 49:259-63 [Medline]
  
  
• Maser RS, Zinkel R, Petrini JH (2001) An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet 27:417-21 [Medline]
  
  
• Matsuura S, Kobayashi J, Tauchi H, Komatsu K (2004) Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys 38:65-80 [Medline]
  
  
• Meyer S, Kingston H, Taylor AM, Byrd PJ, Last JI, Brennan BM, Trueman S, Kelsey A, Taylor GM, Eden OB (2004) Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet 154:169-74 [Medline]
  
  
• Michalkiewicz J, Barth C, Chrzanowska K, Gregorek H, Syczewska M, Weemaes CM, Madalinski K, Stachowski J (2003) Abnormalities in the T and NK lymphocyte phenotype in patients with Nijmegen breakage syndrome. Clin Exp Immunol 134:482-90 [Medline]
  
  
• Michallet AS, Lesca G, Radford-Weiss I, Delarue R, Varet B, Buzyn A (2003) T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome. Ann Hematol 82:515-7 [Medline]
  
  
• Moynihan L, Jackson AP, Roberts E, Karbani G, Lewis I, Corry P, Turner G, Mueller RF, Lench NJ, Woods CG (2000) A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Am J Hum Genet 66:724-7 [Medline]
  
  
• New HV, Cale CM, Tischkowitz M, Jones A, Telfer P, Veys P, D'Andrea A, Mathew CG, Hann I (2005) Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer 44:494-9 [Medline]
  
  
• O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8:1175-85 [Medline]
  
  
• O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497-501 [Medline]
  
  
• Seeman P, Gebertova K, Paderova K, Sperling K, Seemanova E (2004) Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly. Pediatr Neurol 30:195-200 [Medline]
  
  
• Seemanova E, Passarge E, Beneskova D, Houstek J, Kasal P, Sevcikova M (1985) Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639-48 [Medline]
  
  
• 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 (2004) Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer 111:67-71 [Medline]
  
  
• Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD (1981) A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 70:557-64 [Medline]
  
  
• Wegner RD, Chrzanowska KH, Sperling K, Stumm M (1999) Ataxia-Telangiectasia variants (Nijmegen breakage syndrome). In: Ochs HD, Smith CIE, Puck JM (eds) Primary Immunodeficiency Diseases, a Molecular and Genetic Approach. Oxford University Press, Oxford, UK, pp 324-34
  
  

Suggested Readings

• Couturier J, Uhrhammer N, Bay JO, Gatti RA (updated 2002) Nijmegen breakage syndrome. Atlas of Genetics and Cytogenetics Oncology and Haematology. atlasgeneticsoncology.org
  
  

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