Figure 6. Pathophysiological concept. The patients’ cells in Nijmegen Breakage Syndrome have markedly reduced telomere lengths. Telomere attrition may induce genetic instability and alternative telomere elongation and thus enhance the cancerogenic effect (that is induced by defective repair of DNA double-strand breaks by non-homologous end joining) and also contribute to a progeroid phenotype. Telomere attrition may, however, also mitigate the clinical phenotype by inducing stable replicative senescence and cell cycle arrest. The latter is indicated by cells from patients with long tumor survival times with very short telomeres and little apoptosis.