Nijmegen Breakage Syndrome – Definition

Nijmegen breakage syndrome (OMIM #251260) is a rare hereditary disease associated with an increased risk of cancer. It is caused by a defect in the DNA double strand break repair mechanism and increased chromosome breakage. Symptoms are striking facies due to microcephaly and retrognathia, immunodeficiency, and an increased susceptibility to infections. The most commonly associated tumors are malignant lymphomas.

Synonyms:

NBS, OMIN #251260

Gene:

NBN

Gen­e products:

Nibrin

Function:

Part of the MRE11/RAD50 double strand break repair complex

Pattern of inheritance:

Autosomal recessive

Prevalence:

1:100.000 worldwide, more common in the Slavic population of Eastern Europe

Genotype-phenotype correlation

The most commonly detected pathogenic variant in Eastern Europe is c.657_661del5 as well as the other most commonly identified loss of function mutations give rise to conventional disease presentations.

Penetrance:

Unknown

Overview of the Chapters on This Page:

  • Clinical Presentation

  • Special Features of Treatment

  • Surveillance Recommendations

  • Further Information (e.g., Links to Support Groups)

  • Clinical Presentation

  • Special Features of Treatment

  • Surveillance Recommendations

  • Further Information (e.g., Links to Support Groups)

Nijmegen Breakage Syndrome – Diagnosis

Indicative Findings

Immunodeficiency

  • Reduced B-, CD3+, and CD4+ cells (80-89%)
  • Distinct hypogammaglobulinemia (approximately 20%)
  • IgA deficiency (approximately 50%)
  • IgG2 and IgG4 deficiency (in conjunction with normal serum IgG levels)
  • Increase in CD45RO+ memory T cells with a simultaneous reduction in naive CD45RA+ T cells (rare)
  • Stimulation of B and T cell proliferation reduced in vitro

Chromosome Instability

  • Structural aberrations in chromosomes 7 and 14 (as in A-T)
  • Frequent breakpoints 7p13, 7q35, 14q11, and 14q32 (loci for immunoglobulins and T-cell receptor genes)

Sensitivity to Radiation

  • Increased sensitivity to ionizing radiation (as in A-T)

Diagnosis

Typical clinical symptoms combined with a molecular-genetically proven biallelic/homozygous, pathogenic variant in the NBN gene and/or an absence of nibrin in the immunoblot.

  • Analysis of the NBN gene
    • Specific analysis of the c.657_661del5 pathogenic variant (evident in around 100% of individuals of Slavic descent (Poland, Czech Republic, Ukraine) and approximately 70% of individuals of North American descent)
    • NBN sequence analysis is recommended in cases where a homozygous mutation was not identified.
  • Multiple-gene panel

Differential Diagnoses

Clinical Presentation

Clinical Presentation

  • Progressive microcephaly
  • Intrauterine growth restriction
  • Dwarfism
  • Microgenia/retrognathia (resulting in bird-like facies)
  • Immunodeficiency
  • Recurring pulmonary infections (pneumonia, bronchitis, sinusitis, otitis)
  • Premature ovarian failure
  • Timely achievement of developmental milestones in the first year of life, with mildly to moderately low intelligence after 7 years of age.
  • Pigmentation disorders of the skin

Cancer Predisposition

  • 40% incidence of tumors prior to 20 years of age

Entities

  • T-cell lymphomas (55%)
  • B-cell lymphomas (45%)
  • Medulloblastomas
  • Gliomas
  • Rhabdomyosarcomas

Heterozygous carriers (e.g., parents) have an increased risk of developing mammary and prostate carcinomas; genetic testing is definitely called for after the pathogenic variant has been identified.

Special Features of Treatment

  • Avoid exposure to ionizing radiation (X-ray, CT) whenever possible
  • Reduction/omission of radiation exposure, if possible
  • Vitamin E and folic acid supplementation (in cases of chromosomal instability)
  • Intravenous immunoglobulins when there is severe immunodeficiency and a susceptibility to infections
  • Standard chemotherapy for lymphomas (individually adapted to the tolerance)
  • Consider a bone marrow transplant during the first remission
  • Hormone replacement therapy for women with hypergonadotropic hypogonadism
  • Breast self-examination for affected women

Diagnosis of Nijmegen Breakage Syndrome- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Diagnosis of Nijmegen Breakage Syndrome - What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Surveillance Recommendations

Hemato-Oncology

  • Attention to tumour-related symptoms from the time of diagnosis
  • Good sun protection and avoidance of ionising radiation
  • HPV vaccination
  • Full physical examination every year after diagnosis
  • NO blood tests as part of cancer screening

Immunology

  • Immunological monitoring and appropriate therapies according to clinical needs and immunological recommendations

Pulmonology

  • Basic examination at diagnosis, pulmonological function tests according to clinical need, aggressive antibiotic therapy according to antibiogram

Gastroenterology/Nutrition

  • Basic examination at diagnosis, swallowing tests if necessary, nutritional supplementation

Endocrinology

  • Growth documentation (size, weight, head circumference), ovarian function testing for women

Neurology

  • Developmental testing and early support as needed

Orthopaedics

  • Basic examination and if required

 

Nijmegen Breakage Syndrome- Further Information

Sources
  • Nakano Y, Kuiper RP, Nichols KE, Porter CC, Lesmana H, Meade J, Kratz CP, Godley LA, Maese LD, Achatz MI, Khincha PP, Savage SA, Doria AS, Greer MC, Chang VY, Wang LL, Plon SE, Walsh MF. Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders. Clin Cancer Res. 2024 Nov 15;30(22):5009-5020. doi: 10.1158/1078-0432.CCR-24-1098. PMID: 39264246; PMCID: PMC11705613
  • Walsh MF, Chang VY, Kohlmann WK, Scott HS, Cunniff C, Bourdeaut F, Molenaar JJ, Porter CC, Sandlund JT, Plon SE, Wang LL, Savage SA. Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. Clin Cancer Res. 2017 Jun 1;23(11):e23-e31. doi: 10.1158/1078-0432.CCR-17-0465. PMID: 28572264; PMCID: PMC5697784