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.

Key Data

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Synonyms NBS, OMIN #251260
Gene NBN
Gene product Nibrin
Function Part of the MRE11/RAD50 double strand break repair complex
Heredity 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
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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

Predisposition to Cancer

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.

Therapeutic Considerations

  • 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

Surveillance Recommendations

Surveillance Recommendations

Evidence-based standards are lacking for early detection, particularly during childhood. The AACR consensus recommendations are listed below:

  • Hematology-oncology: medical history and clinical examination, annual blood count, metabolic profile, including lactate dehydrogenase (LDH), HPV vaccination

  • Dermatology: annual skin screening

  • Pulmonology: basic examination for the diagnosis, pulmonary function test in accordance with clinical requirements, aggressive antibiotic treatment after an antibiogram

  • Gastroenterology/Nutrition: baseline examination for the diagnosis, swallowing tests as needed, dietary supplementation

  • Endocrinology: growth documentation (size, weight, head circumference), ovarian function testing for women

  • Neurology: developmental testing and early support as needed

  • Orthopedics: basic examination and if required

  • Dental: six-monthly checkups

In addition, it is helpful to monitor the immunoglobulin levels according to immunological recommendations.