Nijmegen Breakage Syndrome

Nijmegen breakage syndrome is a rare autosomal recessive chromosomal instability disorder caused by biallelic NBN variants, with microcephaly, growth retardation, immunodeficiency, radiosensitivity and a very high risk of lymphoma. The founder variant 657del5 is frequent in Slavic populations.

Pathophysiology. NBN encodes nibrin, a component of the MRN complex that senses and repairs DNA double strand breaks and drives V(D)J recombination. Loss impairs DNA repair and immune diversity and causes sensitivity to ionising radiation.

Microcephaly is present at birth and progresses, with usually mild to moderate cognitive impairment.

Lymphoid malignancy is the main cause of death, and full dose chemotherapy and radiotherapy can be fatal.

• Progressive microcephaly with sloping forehead, receding mandible and prominent mid-face
• Growth retardation
• Recurrent sinopulmonary infections, bronchiectasis
• Hypogammaglobulinaemia (low IgG and IgA) and low T-cell numbers
• Lymphoma (mostly B-cell non-Hodgkin) and leukaemia, often in the first two decades
• Premature ovarian failure in females
• Café-au-lait macules and vitiligo
• Mild to moderate intellectual disability that develops during childhood

• Clinical suspicion: progressive microcephaly with recurrent infection and a typical face.
• Genetic testing of NBN with testing for the Slavic 657del5 founder variant, and deletion and duplication analysis.
• Cytogenetics: spontaneous chromosomal breaks and rearrangements involving chromosomes 7 and 14, and increased radiosensitivity.
• Immunological assessment: immunoglobulins with IgG subclasses, vaccine responses and lymphocyte subsets.
• Brain MRI and growth assessment.
• Hormone tests in girls: FSH, LH and oestradiol.

Differential diagnosis.

• Ataxia telangiectasia and ataxia telangiectasia like disorder
• Bloom syndrome
• Fanconi anaemia
• DNA ligase IV deficiency and Cernunnos deficiency
• Seckel syndrome and other primary microcephalies
• Common variable immunodeficiency

• Avoid ionising radiation: use MRI and ultrasound rather than CT or X-ray where possible, and avoid radiotherapy.
• Immunodeficiency: immunoglobulin replacement 0.4 to 0.6 g/kg intravenously every 3 to 4 weeks (or subcutaneous weekly equivalent) for hypogammaglobulinaemia with infections. Antibiotic prophylaxis with co-trimoxazole (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week; adults 960 mg three times weekly) when cell mediated immunity is low.
• Prompt treatment of infection with antibiotics, and chest physiotherapy for bronchiectasis.
• Lymphoma surveillance: clinical examination and full blood count every 3 to 6 months, with imaging by MRI or ultrasound for symptoms.
• Lymphoma treatment: reduced dose chemotherapy, omitting or sharply reducing cyclophosphamide, methotrexate and other drugs that carry marked toxicity, and avoiding radiotherapy. Rituximab 375 mg/m2 may be given for CD20-positive disease. Specialist input is essential.
• Haematopoietic stem cell transplant with reduced intensity conditioning (no total body irradiation) in selected cases.
• Endocrine care: growth assessment and sex hormone replacement for ovarian failure.
• Developmental support: early intervention, speech therapy and school support.
• Genetic counselling: each sibling has a 25% chance of being affected, and carriers may have a modestly raised cancer risk.

Special groups.

• Heterozygous carriers: no routine treatment is needed, though cancer risk is slightly raised.

Monitoring. Clinical review every 3 months in childhood. Immunoglobulin levels and full blood count every 3 to 6 months, and yearly growth, development and endocrine review.

Referral and escalation. Refer to clinical genetics, immunology and paediatric haematology oncology. Urgent for fever, persistent cough, lymphadenopathy, night sweats or unexplained weight loss.