Nijmegen breakage syndrome (NBS)

Abstract

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.

Figure 1

(a, b). Facial phenotype in NBS: face (a) and profile (b) of a girl aged 3.5 years. Note microcephaly, sloping forehead, small nose, receding chin, and relatively large ears.

Figure 2

Lack of breast development in a 16-year-old girl. Note multiple pigmented nevi on the arm.

Figure 3

(a, b). Hypoplastic and hypermobile thumb (a), and duplicated thumb (b).

Figure 4

The NBN gene and nibrin. The exon structure of the gene is shown with the sites of mutations in NBS patients. The full length nibrin protein, with an apparent molecular weight of 95 kDa and the two protein fragments arising from the c.657_661del5 mutation are shown. The locations of serine residues targeted by the ATM kinase and acetylated lysine residues are indicated as are the relative locations of the FHA, BRCT, Mre11-binding and ATM-interaction domains.

Figure 5

Diagnostic flow-chart for NBS (see text for details).