Nijmegen breakage syndrome (OMIM #251260) is a rare hereditary disease associated with an increased risk of cancer. It is caused by a defect in the DNA double strand break repair mechanism and increased chromosome breakage. Symptoms are striking facies due to microcephaly and retrognathia, immunodeficiency, and an increased susceptibility to infections. The most commonly associated tumors are malignant lymphomas.
Part of the MRE11/RAD50 double strand break repair complex
1:100.000 worldwide, more common in the Slavic population of Eastern Europe
The most commonly detected pathogenic variant in Eastern Europe is c.657_661del5 as well as the other most commonly identified loss of function mutations give rise to conventional disease presentations.
IgG2 and IgG4 deficiency (in conjunction with normal serum IgG levels)
Increase in CD45RO+ memory T cells with a simultaneous reduction in naive CD45RA+ T cells (rare)
Stimulation of B and T cell proliferation reduced in vitro
Structural aberrations in chromosomes 7 and 14 (as in A-T)
Frequent breakpoints 7p13, 7q35, 14q11, and 14q32 (loci for immunoglobulins and T-cell receptor genes)
Sensitivity to Radiation
Increased sensitivity to ionizing radiation (as in A-T)
Typical clinical symptoms combined with a molecular-genetically proven biallelic/homozygous, pathogenic variant in the NBN gene and/or an absence of nibrin in the immunoblot.
Analysis of the NBN gene
Specific analysis of the c.657_661del5 pathogenic variant (evident in around 100% of individuals of Slavic descent (Poland, Czech Republic, Ukraine) and approximately 70% of individuals of North American descent)
NBN sequence analysis is recommended in cases where a homozygous mutation was not identified.