BBS, INCLUDED
SEEMANOVA SYNDROME II
AT-V2, INCLUDED
ATAXIA-TELANGIECTASIA VARIANT V2, INCLUDED
IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY BERLIN BREAKAGE SYNDROME, INCLUDED
MICROCEPHALY WITH NORMAL INTELLIGENCE, IMMUNODEFICIENCY, AND LYMPHORETICULAR MALIGNANCIES
NONSYNDROMAL MICROCEPHALY, AUTOSOMAL RECESSIVE, WITH NORMAL INTELLIGENCE
ATAXIA-TELANGIECTASIA VARIANT V1
NBS
AT V1
AT-V1
Ataxia-telangiectasia, variant 1
Berlin breakage syndrome
Seemanova syndrome type 2
Microcephaly - immunodeficiency - lymphoreticuloma
Immunodeficiency - microcephaly - chromosomal instability
The Nijmegen breakage syndrome and the phenotypically indistinguishable Berlin breakage syndrome are autosomal recessive chromosomal instability syndromes characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome ... The Nijmegen breakage syndrome and the phenotypically indistinguishable Berlin breakage syndrome are autosomal recessive chromosomal instability syndromes characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome and AT variant-2 is the designation for the Berlin breakage syndrome, which differ only in complementation studies. Cells from NBS/BBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from those of ataxia-telangiectasia (AT; 208900), but NBS/BBS patients have a distinct clinical phenotype. The clinical features of LIG4 syndrome (606593), caused by mutation in the LIG4 gene (601837), resemble those of NBS.
Patients with AT variant-1 are clinically indistinguishable from those with AT variant-2. These patients share mitogenic features with AT, such as spontaneous chromosomal instability, clonal occurrence of rearrangements involving, in particular, chromosomes 7 and 14, chromosomal and cellular ... Patients with AT variant-1 are clinically indistinguishable from those with AT variant-2. These patients share mitogenic features with AT, such as spontaneous chromosomal instability, clonal occurrence of rearrangements involving, in particular, chromosomes 7 and 14, chromosomal and cellular hypersensitivity to irradiation, and radioresistant DNA synthesis. However, patients with AT-V have neither ataxia nor telangiectasia, and are characterized by pronounced microcephaly, microgenia, 'bird-like' facies, immunodeficiency, and normal serum levels of alpha-fetoprotein. V1 and V2 are distinguished from one another only by complementation analysis (Wegner et al., 1988; Saar et al., 1997). Weemaes et al. (1981) described 2 sons of second-cousin parents who had microcephaly, stunted growth, mental retardation, cafe-au-lait spots, and immunodeficiency. Cytogenetic studies showed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. A lower frequency of the same chromosome abnormalities was found in the father and 3 of the phenotypically normal sibs. Seemanova et al. (1985) described 9 patients in 6 families with a 'new' disorder characterized by low birth weight for dates, microcephaly with normal intelligence, receding mandibula, cellular and humoral immune defects, and increased risk of lymphoreticular malignancies. No evidence of chromosomal instability was found, but chromosome analysis was difficult because the rate of blastic transformation with phytohemagglutinin was low. Even sex ratio, consanguinity in 1 family and grandparental isonymy in a second, and the occurrence of 2 affected sibs in 3 families supported autosomal recessive inheritance. Bronchiectasis, pneumonia, otitis media, mastoiditis, and sinusitis occurred. Immunoglobulin levels were reduced. In 2 sibs, acute lymphoblastic leukemia developed at ages 9 years and 12 months, respectively. Generalized malignancies, apparently originating in the mediastinum and variously identified as malignant lymphogranuloma, acute undifferentiated hemoblastoma and mediastinal blastoma (probably neuroblastoma) was the cause of death in several. The oldest surviving patient of 4 was 12.5 years old. Conley et al. (1986) described a 21-year-old woman with growth failure, immunodeficiency, and chromosomal breakage syndrome involving chromosomes 7 and 14. Maraschio et al. (1986) described the case of a 31-year-old woman with primary amenorrhea, microcephaly and immunodeficiency. Her healthy parents were related as first cousins once removed. A younger sister, who also had primary amenorrhea, had died at age 20 years with a malignant lymphoma. Chromosome studies revealed a high proportion of metaphases with multiple chromosome aberrations. The same unbalanced translocation, t(8q;21q), was present in about 59% of metaphases. A few rearrangements involving chromosomes 7 and 14, similar to those described in patients with ataxia-telangiectasia, were found. Sister chromatid exchanges were not increased. Teebi et al. (1987) reported a large inbred Arab kindred in which 8 individuals in 5 sibships had microcephaly and normal intelligence. Two died of acute lymphoreticular malignancy or bronchial pneumonia. Immunologic and chromosomal studies carried out in 3 affected living sibs yielded normal results. Taalman et al. (1989) reported the findings in 5 families, 2 from the Netherlands and 3 from Czechoslovakia, containing a total of 8 patients with NBS. The patients had microcephaly, short stature, a 'bird-like' face, and immunologic defects. The basic karyotype in these patients was normal, but in a fifth or more of metaphases, rearrangements were found, preferentially involving chromosomes 7 and/or 14 at the sites 7p13, 7q34, and 14q11. The chromosomes of all 5 living patients were very sensitive to ionizing radiation. Chrzanowska et al. (1995) reported 11 patients with Nijmegen breakage syndrome from 8 independent Polish families, with a total of 3 pairs of affected sibs. The clinical pattern included microcephaly, particular 'bird-like' face, growth retardation, and, in some cases, mild to moderate mental deficiency. Most of the patients had recurrent respiratory tract infections. One girl developed B-cell lymphoma. Chromosome studies showed structural aberrations with multiple rearrangements, preferentially involving chromosomes 7 and 14, in a proportion of metaphase in all individuals. Profound humoral and cellular immune defects were observed. Serum AFP levels were within normal range. Radioresistant DNA synthesis was strongly increased in all 8 patients who were studied from this point of view. The clinical, immunologic, chromosomal, and cell-biologic findings in 42 patients in the NBS Registry in Nijmegen were reviewed by van der Burgt et al. (1996). Although the immunologic, chromosomal, and cell-biologic findings resembled those in AT, the clinical findings were quite different. The authors stated that NBS appears to be a separate entity that is not allelic to AT, as indicated by the fact that linkage studies exclude 11q22-q23, where the gene for ataxia-telangiectasia is located, as the site of the NBS gene. None of the patients had signs of cerebellar ataxia, apraxic eye movements, or other neurologic abnormalities except for twin girls described by Curry et al. (1989) who had clinical symptoms of both NBS and AT (see 607585.0014). Complementation studies assigned these cases to NBS complementation group V1. Subtle scleral telangiectasia was noted in 10 of 25 patients. The patients did not have raised serum AFP levels, as in ataxia-telangiectasia. Twelve patients varying in age from 1 to 22 years had developed lymphoma. One patient developed a glioma at the age of 12 years, 1 patient a medulloblastoma at 15 years, and 1 patient a rhabdomyosarcoma at 4 years. Der Kaloustian et al. (1996) described a boy who in addition to typical manifestations had penoscrotal hypospadias. He had lymphopenia with low percentage of B and T cells, absence of IgE, and low response to mitogen stimulation. At the age of 4 years he developed rhabdomyosarcoma. Cytogenetic study showed multiple chromatid and chromosome breaks, structural rearrangements involving mainly chromosomes 7 and 14, and different monosomies in 57 to 58% of cells. Nijmegen breakage syndrome was diagnosed, although hypospadias and a high percentage of monosomic cells led the authors to suggest he represented a specific variant of this syndrome. Der Kaloustian et al. (1996) suggested that the boy described by Woods et al. (1995) as a patient with Seckel syndrome might have the same variant of Nijmegen breakage syndrome. Meyer et al. (2004) described a 7-year-old girl with NBS who was homozygous for the NBS1 698del4 mutation (602667.0002). She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is exceedingly uncommon but had previously been described in 2 cases of NBS (Der Kaloustian et al., 1996; Tekin et al., 2002). Thus, association with NBS should be considered when a perianal RMS is encountered. Tupler et al. (1997) provided the first report of an Italian case of Nijmegen breakage syndrome. The proband was an immunodeficient, microcephalic, 11-year-old boy with a 'bird-like' face. He developed a T-cell-rich B-cell lymphoma. Spontaneous chromosomal instability was detected in T- and B-lymphocytes and in fibroblasts; chromosomes 7 and 14 were only sporadically involved in the rearrangements and no clonal abnormality was present. The patient appeared to be sensitive both to ionizing radiation and to bleomycin, although his sensitivity did not reach the level of ataxia-telangiectasia reference cells. Although the clinical evaluation suggested to Tupler et al. (1997) a diagnosis of NBS, differences in the cytogenetic and cell-biologic data suggested that the patient might have an allelic form of the disorder. To evaluate the possibility of carrier detection, Tanzarella et al. (2003) studied heterozygous individuals from 3 unrelated NBS families with distinct gene deletion mutations for the frequency of spontaneous chromosome abnormalities in blood lymphocytes, x-ray G2 sensitivity in lymphoblastoid cell lines, and the ability to detect nibrin variants by immunoprecipitation and immunoblotting. All 13 heterozygotes showed chromosomal instability (chromatid and chromosomal breaks as well as rearrangements), but 7 of 8 tested were similar to controls in radiosensitivity. Immunoprecipitation of nibrin detected the normal and variant proteins in carriers from all 3 families, but immunoblotting was not as discriminating. - Complementation Groups Jaspers et al. (1988) studied fibroblast cultures from 6 unrelated patients with immunodeficiency, developmental delay, microcephaly, and chromosomal instability; 1 of the patients had been described by Weemaes et al. (1981), 1 by Sperling (1983), 3 by Seemanova et al. (1985), and 1 by Conley et al. (1986). The cells showed radiosensitivity, clonogenic cell survival, and abnormal inhibition of DNA synthesis. Fibroblasts from all cases showed complementation with the 5 complementation groups of AT. Cross-complementation studies within the group indicated the existence of 2 separate complementation groups, designated V1 and V2, that were genetically distinct from AT. The case of Conley et al. (1986) and 1 case of Sperling (1983) showed complementation with the other cases, and were therefore classified as having V2. The patient of Sperling (1983) was further studied by Wegner et al. (1988). Wegner et al. (1988) reported 2 sibs with a syndrome identical to that in the patient reported by Conley et al. (1986), as shown by complementation studies. These patients had V2. Jaspers et al. (1988) performed complementation studies on fibroblast strains from 50 patients with either AT or NBS. Using the radioresistant DNA replication characteristic as a marker, they demonstrated 6 different genetic complementation groups, 2 of which, groups V1 and V2, involved patients with NBS. An individual with clinical symptoms of both AT and NBS was found in group V2, indicating that the 2 disorders are closely related.
Varon et al. (1998) and Carney et al. (1998) isolated the gene responsible for the Nijmegen breakage syndrome. In patients with NBS, Varon et al. (1998) identified mutations in the nibrin/p95 gene (see, e.g., 657del5; 602667.0001). In the ... Varon et al. (1998) and Carney et al. (1998) isolated the gene responsible for the Nijmegen breakage syndrome. In patients with NBS, Varon et al. (1998) identified mutations in the nibrin/p95 gene (see, e.g., 657del5; 602667.0001). In the patient reported by Maraschio et al. (1986), Varon et al. (2006) identified a homozygous hypomorphic mutation in the NBN gene (602667.0010). In monozygotic twin brothers with a severe form of NBS without chromosomal instability, Seemanova et al. (2006) identified compound heterozygosity for the major 657del5 mutation and a missense mutation (R215W; 602667.0009) in the NBS1 gene. The infants were small for gestational age and microcephalic; ultrasound revealed enlarged, mildly asymmetric lateral ventricles, enlarged subarachnoid areas, and poor gyrification of the brain. Psychomotor development was severely retarded in both boys. Seemanova et al. (2006) postulated that the severity of the phenotype was due to the R215W mutation. - Genetic Heterogeneity Maraschio et al. (2003) confirmed genetic heterogeneity for NBS by demonstrating lack of mutation in either the NBS1 or the LIG4 gene in a patient with a typical NBS phenotype. The patient showed intrauterine growth retardation and was born with bilateral inguinal hernia, right cryptorchidism, and curved penis with hypospadias, all of which required surgical treatment. He was seen at the age of 9 months for growth and developmental delay and facial dysmorphism. Facial features included upslanted palpebral fissures, prominent nasal bridge, large mouth with thin upper lip and everted lower lip, and micrognathia. In the proband's blood samples, the frequency of abnormal metaphases was found to vary between 5% and 22%, with a mean value of 10.4%, on a total of 501 observed metaphases. Aberrations consisted mainly of chromatid breaks and chromosome breaks. A slightly increased frequency of chromatid breaks was observed in both parents. - Heterozygosity Cheung and Ewens (2006) found 520 genes with expression levels that differed significantly (p less than 0.001) between heterozygous NBS mutation carriers and controls. By linear discrimination analysis, they identified a combination of 16 genes that allowed 100% correct classification of individuals as either carriers or noncarriers. Cheung and Ewens (2006) concluded that NBS carriers have a specific gene expression phenotype, and suggested that heterozygous mutations can contribute significantly to natural variation in gene expression.
Some of the patients studied by Saar et al. (1997) were Germans in whom the Berlin breakage syndrome had been described and others were Slavic patients in whom the Seemanova syndrome (a synonym for NBS) had been described. ... Some of the patients studied by Saar et al. (1997) were Germans in whom the Berlin breakage syndrome had been described and others were Slavic patients in whom the Seemanova syndrome (a synonym for NBS) had been described. Saar et al. (1997) noted that it would be interesting to investigate whether Dutch patients also showed an allelic association at D8S1811, similar to what they had found in Slavic and German patients. In the first half of the 17th century, after the battle of Weissenberg in the Thirty Years War, a considerable number of Bohemian Protestants emigrated to the Netherlands from an area presently part of Poland and the Czech Republic. A major NBS mutation may have found its way to the Netherlands by migration.
The diagnosis of Nijmegen breakage syndrome (NBS) is suspected in individuals with the following findings:...
DiagnosisClinical DiagnosisThe diagnosis of Nijmegen breakage syndrome (NBS) is suspected in individuals with the following findings:Microcephaly is present 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 manifests before age two years. Thereafter, growth rate is appropriate, but individuals remain small for age. 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 about age three years. Recurrent sinopulmonary infections include pneumonia, bronchitis, otitis media, sinusitis, and mastoiditis. Malignancies, most commonly B-cell lymphoma, which develops in most individuals before age 15 years, occur in approximately 50% of individuals with NBS. Decline in intellectual ability results in intellectual disability in the borderline-to-moderate range by age ten years in most affected children TestingImmunoblotting 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. S Note: This test requires that a lymphoblastoid cell line be established.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. Molecular Genetic Testing Gene. NBN is the only gene in which mutations are known to cause Nijmegen breakage syndrome. Other loci. Approximately 50% of individuals referred for diagnostic testing for NBS share significant clinical overlap and have pronounced radiosensitivity, but lack mutations in NBN [Author, unpublished observation]. A number of reports suggest that mutations in other genes such as LIG4 and RAD50 can lead to disorders with similar clinical presentations. However, mutations in these genes are very rare and do not account for the incidence of NBS-like clinical presentation in persons lacking NBN mutations. Presently, distinction can only be made by excluding mutations in NBN. Clinical testing Targeted mutation analysis All affected individuals from Poland, the Czech Republic, and the Ukraine tested to date are homozygous for the common mutation c.657_661del5. In a study of eight unrelated individuals with NBS from the Russian population, Resnick et al [2002] found that all but one of the 16 alleles were 657_657del5.In the US, about 70% of individuals tested to date are homozygous for the common allele, 15% are heterozygous for c.657_661del5 and a second unique mutation, and 15% are homozygous for a unique mutation. Note: (1) Unique mutations are identified by sequence analysis. (2) In the US patient population, almost all affected individuals who have the p.657_661del5 mutation are of known Eastern European ancestry. Sequence analysis can detect the common allele and other mutations including small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Of individuals with NBS tested to date in the US, 15% are heterozygous for the common allele (c.657_661del5) and a second unique mutation, and 15% are homozygous for a unique mutation. Note: Unique mutations are identified by sequence analysis. Table 1. Summary of Molecular Genetic Testing Used in Nijmegen Breakage SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method and Population 1, 2Test AvailabilitySlavic 3North American 4NBNTargeted mutation analysisc.657_661del5Homozygous (c.657_661del5/ c.657_661del5): 100%Homozygous (c.657_661del5/ c.657_661del5): 70%Clinical Sequence analysisSequence variants 5Not applicableSee footnote 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Given the rarity of NBS it is likely that most of the mutations show some kind of founder effect, makingreliable estimates of incidence difficult to establish.3. Slavic = Poland, Czech Republic, Ukraine4. Based on the small number of individuals observed5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.6. Of individuals tested to date in the US, 15% are heterozygous for the common allele (c.657_661del5) and a second unique mutation; 15% are homozygous for a unique mutation.Testing Strategy To confirm/establish the diagnosis in a proband. Diagnostic testing for NBS can be performed on a single sample of heparinized blood: Targeted mutation analysis to determine if the c.657_661del5 common allele is present If the common allele is not present:Perform immunoblotting to determine if the nibrin protein is present or absent Perform colony survival assay to determine radiosensitivityIf all three tests (targeted mutation analysis, immunoblotting, colony survival assay) are normal, a diagnosis of NBS is extremely unlikely. Full gene sequencing is performed only after prior testing has revealed that: The c.657_661del5 mutation is not present, The nibrin protein is absent or truncated, and The cells are radiosensitive. If nibrin is present, but the cells are radiosensitive, evaluation for other disorders of DNA repair or immunodeficiency is warranted. (See Differential Diagnosis.)Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are at some increased risk of developing malignancy related to Nijmegen breakage syndrome.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
Growth. Children with Nijmegen breakage syndrome (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 age two years. The linear growth rate tends to be normal after age two years, but individuals remain small for age. ...
Natural HistoryGrowth. Children with Nijmegen breakage syndrome (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 age two years. The linear growth rate tends to be normal after age two years, 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 psychomotor hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild-to-moderate intellectual disability. 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 ages one and 34 years. Twenty-two of the 25 were lymphomas, of which 19 occurred before age 15 years. Nine out of 19 were B-cell lymphomas; 1/19 was a T-cell lymphoma [Michallet et al 2003]. Several children developed solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma [Hiel et al 2001, Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004]. Fertility. Wegner et al [1999] report a high incidence of premature ovarian insufficiency in both prepubertal girls with NBS and adolescent and post-adolescent women with NBS, as evidenced by elevated serum concentration of gonadotropins in both groups and primary amenorrhea and lack of secondary sexual development in the latter. Chrzanowska et al [2010] provide further support for these findings in a larger study of females with NBS, all homozygous for the common c.657_661del5 mutation. No detailed studies of fertility in males with NBS have been published. However, Warcoin et al [2009] did describe an atypical male with oligo-terato-asthenozoospermia who had biallelic truncating mutations in NBN but none of the clinical features of NBS. Whether gonadal failure is part of the NBS phenotype in males is not yet clear. Other findingsIrregular 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.
There are two reports of families in which biallelic truncating mutations in NBN occur in healthy adult individuals:...
Genotype-Phenotype CorrelationsThere are two reports of families in which biallelic truncating mutations in NBN occur in healthy adult individuals:Varon et al [2006] described a 53-year-old woman who was homozygous for the NBN truncating allele c.742insGG, but had no clinical features of NBS other than primary amenorrhea. However, analysis of transcripts from the patient’s cells indicated a highly prevalent alternatively spliced form of NBN lacking exons 6 and 7 (where the mutation is located). This transcript produces a 73-kd form of NBN with an internal deletion. Warcoin et al [2009] described a family in which two healthy adult sibs had biallelic truncating mutations in NBN (c.330T>G and c.1125G>A). Both were normal on clinical examination and did not have any evidence of short stature, reduced head circumference, or facial dysmorphology; however, both were referred for fertility defects and were subsequently found to have the cellular phenotypes typical of NBS including chromosomal instability, hypersensitivity to ionizing radiation, and impaired checkpoint responses. While the clinical findings in these individuals would not suggest a diagnosis of NBS, the testing strategy would have identified these individuals based on the presence of two truncating mutations and radiation hypersensitivity.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 c.657_661del5 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 c.657_661del5 carriers in several different cancers including breast cancer, prostate cancer, medulloblastoma, and melanoma [Cybulski et al 2004, Steffen et al 2004, Ciara et al 2010]. There is also anecdotal evidence of increased frequencies of cancer in relatives of individuals with NBS.
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). ...
Differential DiagnosisRecurrent 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 NBN c.1089C>A mutation have features of Fanconi anemia [Gennery et al 2004]. Occasionally individuals with the ATM mutation A-TFresno have symptoms of both Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (A-T) [Curry et al 1989, Gilad et al 1998]. Microcephaly, midface prominence, and intellectual disability 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 [O’Driscoll et al 2003]. Seeman et al [2004] suggest that NBN mutations account for a significant number of children with primary microcephaly in the Czech Republic. See also Primary Autosomal Recessive Microcephaly.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 and may present in infancy as severe combined immunodeficiency [Enders et al 2006]. 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 LIG4 and NBN.Waltes et al [2009] described a single individual with biallelic mutations in RAD50 resulting in production of reduced levels of an unstable RAD50 protein. This person had microcephaly, intellectual disability, short stature and facial dysmorphology typical of NBS, but had normal immunoglobulin levels and did not have recurrent sinopulmonary infections. As only one individual with RAD50 mutations has been described, it is unclear how consistent the clinical features of RAD50 deficiency will be; hence, the overlap with NBS.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 age three years [Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Nijmegen breakage syndrome (NBS), the following evaluations are recommended:...
ManagementEvaluation Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Nijmegen breakage syndrome (NBS), the following evaluations are recommended:Baseline evaluation of immune and endocrinologic status, degree of mental impairment, and head circumference History of radiation exposure Familial history of cancer Treatment of ManifestationsIn individuals with severe humoral immunodeficiency and frequent infections, IVIg should be considered. The spectrum of recurrent infections in NBS is not opportunistic; therefore, the antibiotic selected should be appropriate for the microorganism being treated.Because of chromosomal instability, vitamin E and folic acid supplementation in doses appropriate for body weight is recommended.Children with developmental delay should be referred to special services for treatment options.SurveillanceAffected individualsPeriodic follow-up to monitor mental and physical growth and frequency of infections For females with NBS, periodic monitoring for premature ovarian insufficiency [Chrzanowska et al 2010]Monitoring for weight loss, which may signal the presence of a malignancy Carriers (heterozygotes)Parents. As obligate carriers, parents should be monitored for malignancy. At-risk sibs. Evidence of cancer risk in young carriers is insufficient to warrant testing in childhood. Agents/Circumstances to AvoidBecause 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. Family members should be made aware of this risk so that they can discuss appropriate treatment options should a malignancy be diagnosed.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nijmegen Breakage Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNBN8q21.3NibrinNBN @ LOVDNBNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nijmegen Breakage Syndrome (View All in OMIM) View in own window 251260NIJMEGEN BREAKAGE SYNDROME 602667NIBRIN; NBNNormal allelic variants. NBN 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 normal and rare allelic variants in NBN have been described. Table 2 lists examples for which unaffected homozygous individuals have been identified, verifying that they are not disease-causing alleles. Alleles at these sites are all in very strong linkage disequilibrium in the general population. Additional variants such as c.283G>A (p.Asp95Asn), c.628G>T (p.Val210Phe), c.643C>T (p.Arg215Trp), and c.797C>T (p.Pro266Leu) 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 NBN mutation. Table 2. Selected NBN Normal Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.102G>ANo changeNM_002485.4 NP_002476.2c.553G>Cp.Glu185Glnc.1197T>CNo changec.2016A>GNo changeSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Pathologic allelic variants. Most disease-causing NBN alleles identified to date are predicted to result in truncation of the nibrin protein (see Table 3). The c.657_661del5 mutation predominates in affected persons from Eastern Europe, accounting for more than 90% of all mutant alleles in NBN. Each of the other mutations listed in Table 3 occurs in one or a small number of families. NBN 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, NBN 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, c.1089C>A is particularly noteworthy. It was originally described in a person diagnosed with atypical Fanconi anemia. Subsequent testing revealed homozygosity for an NBN 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. While the overwhelming majority of persons with NBS have biallelic truncating alleles at NBN, Seemanová et al [2006] have described a unique set of monozygotic twins who are compound heterozygotes for the common c.657_661del5 mutation and a missense mutation, c.643C>T resulting in p.Arg215Trp. These twins had a more severe clinical course than typical for NBS, particularly with respect to neurologic features, but lacked the cellular chromosomal instability and radiation sensitivity characteristic of the disorder.Table 3. Selected NBN Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequence OriginNumber of Families in Which Mutation is Observedc.330T>Gp.Tyr110*NM_002485.4 NP_002476.21c.643C>Tp.Arg215TrpSlavic1c.657_661del5 (657del5)p.Lys219Asnfs*15 SlavicN/Ac.681delTp.Phe228Leufs*3 Russian1c.698_701del4p.Lys233Serfs*4English2c.741_742dup (742insGG)p.Glu248Glyfs*5Italian1c.835_838del4p.Gln279Profs*1 Italian1c.842insTp.Leu281Phefs*3 Mexican1c.900del25p.Gly301Lysfs*5Moroccan1c.976C>Tp.Gln326*Dutch1c.1089C>Ap.Tyr363*Pakistani 23c.1125G>Ap.Trp375*1c.1142delCp.Pro381Glnfs*22Canadian2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Individual originally diagnosed as having Fanconi anemia with atypical clinical featuresNormal gene product. The NBN protein product 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, which are found in other proteins involved in cellular responses to DNA damage. In normal fibroblasts, nibrin is associated with two other proteins 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 NBN/Mre11/Rad50 complex to sites of double-strand breaks and interacts with ATM kinase to coordinate cell cycle arrest with DNA repair [Carney et al 1998, Matsuura et al 2004, Falck et al 2005]. Abnormal gene product. Most known NBN mutations are predicted to result in truncation of the nibrin protein. All known NBS mutations occur in exons 6-10; this is thought to reflect a requirement for production of a C-terminal protein fragment of nibrin that occurs by translational reinitiation mechanism [Maser et al 2001]. The requirement that protein termination and reinitiation occur in the same reading frame potentially limits the mutations that can give rise to NBS. Knockout mice homozygous for null alleles of NBN are embryonic lethal, suggesting that the partial protein produced from NBN alleles in humans is necessary for survival.