Clinical characteristics: Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).
Diagnosis/testing: The diagnosis of NBS is established in a proband with characteristic clinical features and biallelic pathogenic variants in NBN on molecular genetic testing and/or absent nibrin protein on immunoblotting assay.
Management: Treatment of manifestations: Standard antimicrobial therapies for infections; immunoglobulin replacement therapy in individuals with severe hypogammaglobulinemia and frequent infections; acellular vaccines; standard treatment of bronchiectasis and pulmonary infections; chemotherapy protocols for lymphoid malignancies adapted to individual tolerance; treatment of solid tumors adapted to individual tolerance; consideration of hematopoietic stem cell transplantation; hormone replacement therapy for females who have hypergonadotropic hypogonadism.
For affected individuals. Periodic follow up to monitor physical growth, infection frequency, and developmental progress; lifelong monitoring of immune biomarkers; monitor for malignancy and particularly in those with weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, and hepatosplenomegaly (assessment should be considered using ultrasonography, MRI, biopsy); monitor pubertal progression in both sexes and for premature ovarian insufficiency in females; monthly breast self-examination when hormone replacement therapy is administered; assess cognitive developmental and intellectual abilities before starting school and follow up periodically.
For heterozygous adults. Monitor for malignancy, particularly breast cancer in women and prostate cancer in men.
Agents/circumstances to avoid: Because the cells from individuals with NBS are radiosensitive in vitro, doses of radiation used in radiotherapy need to be reduced. Unnecessary exposure to imaging studies that use ionizing radiation (plain radiograph, CT scan) should be avoided and use of MRI and/or ultrasound considered. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given.
Evaluation of relatives at risk: It is appropriate to offer molecular genetic testing for the familial NBN pathogenic variants to apparently asymptomatic adult relatives of an affected individual in order to identify family members who are heterozygous for an NBN pathogenic variant and would benefit from monitoring for malignancy.
Genetic counseling: NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial NBN pathogenic variants. Heterozygotes are not at risk for NBS. However, heterozygous NBN pathogenic variants may be associated with an increased risk for breast cancer in women and prostate cancer in men. Carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
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