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Nijmegen breakage syndrome
2002-10-01
Nancy Uhrhammer
,
Jacques-Olivier Bay
,
Richard A Gatti
Affiliation
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France
Identity
Name
Nijmegen breakage syndrome
Alias
Ataxia-telangiectasia, variant VI , Seemanova syndrome II , Microcephaly with normal intelligence, immunodeficiency, lymphoreticular malignancies , Immunodeficiency, microcephaly, chromosomal instability
Note
belongs to the group of inherited chromosomal instability syndromes including
Blooms syndrome,
Fanconis disease, and
ataxia telangiectasia(AT); see also, in Deep Insight section:
Ataxia-Telangiectasia and variants
Inheritance
autosomal recessive disease; since the recognition of the Nijmegen breakage syndrome (NBS) in 1981, about 70 patients are included in the NBS Registry in Nijmegen; the disease appears to have originated in central Europe, in the Slavic population, and to have spread through a founder effect.
Omim
251260 , 613078
Mesh
C531759;D049932
Orphanet
647 Nijmegen breakage syndrome
Umls
C0398791;C2930831
Clinics
Note
the condition is characterised by growth and mental retardation, craniofacial dysmorphy, ovarian failure, immunodeficiency, chromosome instability, predisposition to lymphoid malignancies, and radiosensitivity.
Phenotype and clinics
growth and mental development: 30 % of children have low birth weight and short stature, and 75% a head circumference at birth below the 3rd percentile; all patients develop a severe microcephaly during the first months of life; mental development is normal in 35% of the patients, moderately retarded in the others, though the mental retardation appears to be progressive; cerebellar ataxia is absent; alphafoetoprotein levels are normal, in contrast to AT patients.
craniofacial dysmorphy: progressive and severe microcephaly, \"bird-like\" face with prominent midface, long nose and receding mandible
immunodeficiency: severe combined deficiency with agammaglobulinemia, IgA, IgG2 and IgG4 deficiencies, decreased CD3+ and CD4+ lymphocytes, and decreased CD4+ \/ CD8+ ratio; these disturbances are responsible of frequent respiratory, garstrointestinal and urinary infections.
Neoplastic risk
high frequency and early development of lymphomas, more often involving B-cells, in contrast with those found in AT.
other forms of cancer may also be at higher risk
Cytogenetics
Inborn condition
lymphocyte cultures often show low mitotic index
structural chromosome aberrations are observed in 10-30% of metaphases; most of the rearrangements occur in or between chromosomes 7 and 14, at bands 7p13, 7q35, 14q11, and 14q32, as in AT; these bands contain immunoglobulin and T-cell receptor genes; the most frequent rearrangement is the inv(7)(p13q35)
Other Findings
Note
radiosensitivity: increased sensitivity of both lymphocytes and fibroblasts to ionising radiations and radiomimetics, radio-resistant DNA synthesis.
Genes involved and Proteins
Description
16 exons
Function
the product of NBS1, nibrin (p95), associates with Mre and Rad50 to control the repair of double-strand DNA breaks involved, for example, in VDJ joining in immunoglobulin and T-cell receptor genes recombination process, in meiotic recombination, and in radio-induced DNA lesions; this suggests that nibrin and the product of
ATM
could act in a common pathway of detection or repair of double-strand breaks, and indeed, ATM phosphorylates nibrin in response to DNA damage. Nibrin\/p95 is found associated with Rad50 and Mre11 at sites of DNA double-strand breaks and is essential for the nuclear localization of the complex.
Germinal
all NBS patients show truncating mutations. The common 657del5 allele has been shown to produce a short N-terminal protein of no detectable function, and also a C-terminal protein produced through an alternative translation initiation signal in the deleted mRNA. Data from knockout mice indicates that this C-terminal protein is partially functional, as Nbs1 null alleles are lethal.
Somatic
Missence mutations in NBS1 have been associated with childhood acute lymphoblastic leukemia.
To be noted
Hgmd
9598211
Bibliography
Pubmed ID
Last Year
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External Links
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ERN GENTURIS
OMIM
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