Nijmegen breakage syndrome
Nijmegen breakage syndrome (NBS) is a rare genetic disorder characterized by chromosomal instability, which leads to a heightened sensitivity to radiation and an increased risk of developing malignant lymphomas. This condition is inherited in an autosomal recessive manner, primarily due to mutations in the NBS1 gene, which encodes the nibrin protein responsible for repairing DNA double-strand breaks. Individuals with NBS typically exhibit symptoms such as microcephaly, growth retardation, cognitive disabilities, and distinctive facial features.
The incidence of NBS is low, with fewer than 200 known cases, predominantly among Slavic populations. Many affected individuals also experience immune deficiencies, making them prone to recurrent infections, as well as issues related to sexual maturation, particularly in females. Diagnosis often involves cytogenetic analyses and DNA sequencing to identify mutations in the NBS1 gene.
Management of NBS includes treating infections, supporting immune function, and using hormone replacement therapy for female patients. Cancer treatments must be approached cautiously to avoid further DNA damage. Despite ongoing research into new therapies, the long-term prognosis for individuals with Nijmegen breakage syndrome remains challenging, with many facing severe health complications or early mortality due to malignancies or infections.
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Nijmegen breakage syndrome
ALSO KNOWN AS: Berlin breakage syndrome, Seemanova syndrome, ataxia telangiectasia variant V1
RELATED CONDITIONS: Bloom syndrome, Fanconi anemia, ataxia telangiectasia
DEFINITION: Nijmegen breakage syndrome is a rare autosomal recessive condition that causes chromosomal instability, sensitivity to radiation, and increased incidence of malignant lymphomas.
Risk factors: A risk factor for Nijmegen breakage syndrome is the inheritance of a mutation in both copies of the NBS1 gene.
Etiology and the disease process: The NBS1 gene encodes the nibrin protein, which helps heal double-stranded breaks (DSBs) in deoxyribonucleic acid (DNA) molecules. Sometimes, double-stranded breaks occur as a result of DNA-severing agents or as a normal physiological process during gamete and antibody production. Without the capacity to repair double-stranded breaks, cells are unable to repair damage to DNA, make antibodies to fight infections, or produce viable gametes.
Incidence: As of the mid 2020s, there were fewer than 200 estimated cases of Nijmegen breakage syndrome worldwide, mostly located in central and Eastern Europe in people of Slavic descent. One in 100,000 newborns worldwide are thought to be carriers of the mutation that leads to Nijmegen breakage syndrome, but in some Slavic populations, the ratio approaches 1 in 155.
Symptoms: Children born with Nijmegen breakage syndrome show microcephaly (small head), growth retardation, progressive cognitive disabilities, and characteristic facial features (birdlike face, sloping forehead, and receding jaw). The immune system is unable to fight infections, and recurrent sinus, pulmonary, and ear infections are common. More than half of Nijmegen breakage syndrome patients also show skin pigmentation irregularities. At puberty, female Nijmegen breakage syndrome patients fail to experience sexual maturation. Their ovaries are small and poorly developed (premature ovarian failure). Finally, Nijmegen breakage syndrome patients show increased tendencies to develop lymphomas.
Screening and diagnosis: Cytogenetic analyses, which isolate and view chromosomes from individual cells, show chromosomal instabilities that typically involve chromosomes 7 and 14. Immunologic testing shows an inability of immune cells to divide rapidly or properly synthesize antibodies in response to infections. Nijmegen breakage syndrome patients are also extremely sensitive to ionizing radiation or clastogens (substances that cause chromosome breaks). DNA sequencing of the NBS1 gene should reveal loss-of-function mutations in this gene.
Treatment and therapy: Antibiotic treatments and intravenous administration of antibodies are used to treat recurrent infections that accompany immune system deficiency. Bone marrow transplants can permanently treat the immune system defects in children with Nijmegen breakage syndrome. Prepubescent female patients are treated with hormone replacement therapy to allow the development of secondary sexual characteristics and prevent osteoporosis. Cancer treatments in patients with Nijmegen breakage syndrome patients must avoid radiation and chemotherapeutic agents that damage DNA since they can cause toxic complications. The immunodeficiency that accompanies Nijmegen breakage syndrome makes it difficult to destroy cancer cells. Nijmegen breakage syndrome patients are susceptible to multiple types of cancer. New treatments are being developed for Nijmegen breakage syndrome patients. Hematopoietic Stem Cell Transplantation, gene therapy, and molecular treatments have helped to improve outcomes for patients.
Prognosis, prevention, and outcomes: Prophylactic antibiotics are prescribed to prevent recurring infections, and vitamin E supplements are recommended to ameliorate chromosome instability. The long-term prognosis for Nijmegen breakage syndrome patients is typically quite poor. Most patients die from aggressive malignancy or complications from infections.
Bibliography
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Millichap, J. Gordon. Neurological Syndromes: A Clinical Guide to Symptoms and Diagnosis. New York: Springer, 2013.
“Nijmegen Breakage Syndrome.” MedlinePlus, 1 May 2017, medlineplus.gov/genetics/condition/nijmegen-breakage-syndrome. Accessed 14 June 2024.
Varon, Raymonda, Ilja Demuth, and Martin Digweed. “Nijmegen Breakage Syndrome - GeneReviews®.” NCBI, 30 Nov. 2023, www.ncbi.nlm.nih.gov/books/NBK1176. Accessed 14 June 2024.