NIJMEGEN BREAKAGE SYNDROME, NBS (ALSO KNOWN AS SEEMANOVA SYNDROME II)
This rare autosomal recessive disorder is characterized by microcephaly, growth retardation, “bird-like” face, premature ovarian failure, and humoral and cellular immunodeficiency. A characteristic feature is a marked discrepancy between the (usually) normal intelligence and severe microcephaly. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis. There is very substantial risk of lymphoreticular malignancy – up to 50 % of patients develop lymphoma, at a median age of less than 11 years (Demuth and Digweed 2007). By age 20, 40 % of all NBS homozygotes have developed cancer (Chrzanowska et al. 2012). Laboratory findings include chromosome instability in cultured lymphocytes with frequent rearrangements involving chromosomes 7 and 14, cellular and chromosomal hypersensitivity to X- irradiation, and radio resistance of DNA replication (Taalman et al. 1989; Erola et al. 2003). Most reported cases are of eastern European (Slavic) origin, especially Czech Republic, Poland, western Russia, and the Ukraine, where a founder mutation (c.657_661del5, p.K219fsX19, in exon 6) is common. The cellular phenotype chromosome breakage and immunodeficiency features of Nijmegen breakage syndrome and AT are similar, but the clinical phenotypes are distinct. The gene for Nijmegen breakage syndrome (NBN, formerly NBS1) encodes a protein (nibrin) (Varon et al. 1998) that is phosphorylated by the ATM protein. Nibrin, together with MRE11 and RAD50, forms a trimeric protein complex known as MRN that is involved in repairing DNA double-strand breaks. From studies of relatives of NBN homozygotes and from studies sequencing NBN in cancer cases and controls, it is clear that heterozygotes have an increased risk of Tumours, including prostate and breast cancer, and melanoma (reviewed in Demuth and Digweed 2007).