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.Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów.Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest przyczyną naw...

Nijmegen Breakage Syndrome Detected By Newborn Screening for T Cell Receptor Excision Circles (TRECs)

“…NBS has been reported primarily in Eastern Europeans, where founder mutations occur [28]. Our case expands our appreciation of the association of NBS with hydrocephalus and hydronephrosis and illustrates the utility of WES as applied to diagnose the underlying cause of idiopathic T lymphopenia found by TREC screening.…”

“…Perinatal hydrocephalus as seen in our patient has been reported in two children with NBS [8]. Hydronephrosis, renal anomalies such as horseshoe or dysplastic kidneys, skeletal anomalies such as clinodactyly and partial syndactyly, café au lait spots and vitiligo have all been seen, but are not constant features and are also found in other conditions [8,28]. It is therefore difficult to identify NBS based on early clinical signs.…”

“…Peripheral blood lymphoblastoid cell lines (LCL) from the patient NBS20LA and controls were made with Epstein-Barr virus as described [11], and 50 μg of nuclear protein lysate from each was electrophoresed on a 6 % SDS-polyacrylamide gel (PAGE), blotted onto PVDF membrane (BioRad, (11) 99 (8) 63 (4) 72 (4) 267-1860 652-2449 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) 946-2791 (14-34) CD19+ B-cells/mL (%)…”

Follicular Lymphoma and Nijmegen Breakage Syndrome: Case Report

“…1 Ender görülen bir sendromdur ve sıklığının 1/100.000 canlı doğum olduğu ön görülmektedir, özellikle Doğu Avrupa'da sıklığın arttığı bilinmektedir. 2 Nijmegen Kırık Sendrom'lu hastaların %90'ında kromozom 8q21 bandında yerleşen NBS1 geninde homozigot 657del5 mutasyonu bulunmaktadır.…”

“…5 Bu hastalığın belirgin klinik özellikleri tipik yüz görünümü, immun yetersizlik, hafif-ılımlı gelişme geriliği, prematür ovaryan yetersizlik, iyonize radyasyona artmış hassasiyet, 20 yaşından önce malignite gelişimidir. 1,6 Tipik yüz görünümü; alnın geride olması, yüzün orta kısmında belirginlik, mandibulada gerilik, uzun burun, uzun filtrum, yukarı çekik palpebral fissürler ve ilerleyici mikrosefalidir. 1,7 Bizim hastamız da bu özelliklere sahipti.…”