Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome or ataxia-telangiectasia variant 1 (AT-V1), is a rare autosomal recessive chromosomal instability disorder caused by biallelic pathogenic variants in the NBN gene (formerly NBS1) on chromosome 8q21.3. This gene encodes nibrin, a protein essential for DNA double-strand break repair. The condition is characterized by severe microcephaly present at birth that becomes progressively more pronounced, distinctive facial features (receding forehead, prominent midface, receding mandible, and upslanting palpebral fissures), growth retardation, combined immunodeficiency affecting both humoral and cellular immunity, and a strong predisposition to malignancy — particularly lymphomas and leukemias, which represent the leading cause of death. Intellectual disability, typically mild to moderate, is present in most patients. The immunodeficiency in NBS leads to recurrent sinopulmonary infections, which are a significant source of morbidity. Patients frequently exhibit hypogammaglobulinemia and T-cell deficiency. Chromosomal instability, particularly involving chromosomes 7 and 14, is a hallmark laboratory finding. Ovarian failure occurs in affected females, while males may have normal or impaired fertility. Skin findings may include café-au-lait spots and vitiligo, though the telangiectasias characteristic of ataxia-telangiectasia are typically absent. Notably, unlike ataxia-telangiectasia, cerebellar ataxia is not a feature of NBS. There is no curative treatment for Nijmegen breakage syndrome. Management is supportive and multidisciplinary, including immunoglobulin replacement therapy for antibody deficiency, aggressive treatment of infections, and vigilant cancer surveillance. Hematopoietic stem cell transplantation (HSCT) has been performed in some patients, particularly those with severe immunodeficiency or malignancy, with variable outcomes. Radiation therapy and radiomimetic chemotherapy agents must be used with extreme caution or avoided due to the underlying DNA repair defect, which causes heightened sensitivity to ionizing radiation and increased risk of severe toxicity. The majority of NBS patients are of Slavic origin, with a common founder mutation (c.657_661del5) accounting for over 90% of pathogenic alleles in this population.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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