Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the NBN gene, which encodes a protein essential for DNA double-stranded break repair. Chromosomal instability results from impaired DNA damage repair mechanisms. Presentation is with microcephaly from birth, distinctive facial features, poor growth, immunodeficiency and an increased risk of lymphoid malignancies.

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);
• mild growth restriction and short stature (most pronounced until two years of age);
• recurrent infections (particularly respiratory, due to panhypogammaglobulinaemia);
• predisposition to malignancies (mainly lymphoma, though medulloblastoma, glioma and rhabdomyosarcoma have been reported);
• irregular skin pigmentation (hypo and hyper-pigmented macules);
• 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.

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.

NBS is caused by pathogenic variants in both copies of the NBN gene, which encodes the nibrin protein, located on chromosome 8q21. Variants are typically loss-of-function types, including frameshift, nonsense, and those impacting splice sites. All reported variants have been in exons 6 to 10.

There is a common Slavic founder variant (five 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.

A diagnosis may be suspected on the basis of suggestive clinical findings, including progressive microcephaly, characteristic craniofacial features, growth deficiency, malignancies and recurrent infections. This would be supported by laboratory evidence of immunodeficiency, chromosomal instability (notably rearrangements involving chromosomes 7 and 14) and increased cellular radiosensitivity.

Molecular testing for NBN variants confirms the diagnosis, with the most common pathogenic variant being c.657_661del5.

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

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to haematology services. Please refer to the local pathway for your region for this condition.

NBS is inherited in an autosomal recessive pattern. If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
• 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves.
• 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

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 in heterozygous carriers.

The parents of individuals affected with NBS are likely to be carriers of the condition and therefore have a 25% (one-in-four) chance of having another affected child. Genomic counselling is particularly important so that any future pregnancies can be managed appropriately. Options include preimplantation genomic testing for monogenic conditions (PGT-M) and prenatal testing. For more information, see Presentation: Pregnancy at risk of an autosomal recessive condition.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management of patients with NBS is complex and should be delivered through 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.

Resources 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; NBS
• US 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: 10.1158/1078-0432.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

Resources for patients

• Oxford University Hospitals NHS Foundation Trust: Genetic testing for Nijmegen breakage syndrome (R259)