Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive condition causing chromosomal instability as a result of impaired double-stranded DNA and DNA damage repair mechanisms.

Clinical features of NBS include:

• intrauterine growth restriction;
• progressive microcephaly;
• distinctive facial features (such as a sloping forehead, upward-slanted palpebral fissures, prominent nose and midface, large ears and retrognathia);
• short stature (most pronounced until the age of two);
• recurrent infections (particularly respiratory, due to panhypogammaglobulinaemia);
• predisposition to malignancies (mainly lymphoma, though medulloblastoma, glioma and rhabdomyosarcoma have been reported);
• borderline delays in development in childhood;
• decline in intellectual ability; and
• premature ovarian failure in women.

NBS may be suspected when a patient presents in clinic, or following investigations that indicate panhypogammaglobulinaemia, chromosome instability (‘breakage’ testing) or radiation sensitivity.

NBS is caused by pathogenic variants in both copies of the NBN (nibrin) gene, located on chromosome 8q21. There is a common founder variant (5 base pair deletion) in NBN (c.657_661del5) found in the majority of patients with NBS, for which patients can be tested before the whole of the gene is sequenced.

For information about testing, see Presentation: Child with pancytopenia.

NBS is inherited in an autosomal recessive pattern. In most cases, both parents of the affected individual will be found to be heterozygous carriers for the condition, and any child they have together in the future will have a 25% (one-in-four) chance of being affected. There is some evidence to suggest that heterozygous carriers of pathogenic variants in NBN may be at increased chance of certain solid organ cancers, such as breast or prostate cancer, but further data is required to confirm these associations. At present, cascade testing is offered for the purpose of informing carrier status for reproductive decision making, but would not typically be offered for the sole purpose of informing cancer risk.

The Human Fertilisation and Embryology Authority has approved the use of pre-implantation genomic testing for monogenic conditions (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples in which both members are a carrier of a likely pathogenic variant in NBN. It is best practice that discussions regarding PGT-M and other family planning options are undertaken by a specialist genetic counsellor or clinical geneticist. Other options may include prenatal testing with termination of affected embryos, adoption, gamete donation or natural conception and pregnancy with testing of children after birth.

Management of patients with NBS is complex and should be delivered via a multidisciplinary team; detailed suggested approaches have been published by several authors (see the resources list below). Therapeutic doses of ionizing radiation should be avoided. Patients require long-term monitoring for growth, pubertal progression, development, malignancy and immunodeficiency. Hematopoietic stem cell transplantation can also be considered for malignancy or severe immunodeficiency.

For clinicians

• GeneReviews: Nijmegen breakage syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• OMIM: 251260 Nijmegen breakage syndrome
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Wolska-Kuśnierz B, Pastorczak A, Fendler W and others. ‘Hematopoietic stem cell transplantation positively affects the natural history of cancer in Nijmegen breakage syndrome’. Clinical Cancer Research 2021: volume 27, issue 2, pages 575–584. DOI: 1158/1078-0432.CCR-20-2574
• Wolska-Kuśnierz B, Gregorek H, Chrzanowska K and others. ‘Nijmegen breakage syndrome: Clinical and immunological features, long-term outcome and treatment options – a retrospective analysis’. Journal of Clinical Immunology 2015: volume 35, issue 6, pages 538–549. DOI: 10.1007/s10875-015-0186-9

For patients

• Oxford University Hospitals NHS Foundation Trust: Genetic testing for Nijmegen breakage syndrome