Nijmegen breakage syndrome: case report and review of literature

Nijmegen Breakage Syndrome (NBS) is a rare autosomalrecessive DNA repair disorder characterized by genomic instability andincreased risk of haematopoietic malignancies observed in morethan 40% of the patients by the time they are 20 years old. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a frame shift and protein truncation. Nibrin (NBN) plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signalling pathway in apoptosis and senescence. Cardinal symptoms of Nijmegen breakage syndrome are characteristic: 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 sino-pulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis. 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. We present here a case of Nijmegen breakage syndrome associated with Hodgkin lymphomas and Combined variable immunodeficiency.


Introduction
Nijmegen breakage syndrome is a rare autosomal recessive disease, belonging to a group of disorders often called chromosome instability syndromes, characterized by microcephaly at birth without neurological manifestations. Other important clinical features, more noticeable with age, include mild growth delay, premature ovarian insufficiency, predisposition to recurrent infections of various organs and a very high risk to develop malignancies in early age, most frequently of haematological origin. Combined immunodeficiency of both cellular and humoral response is an essential feature of the disease [1]. World-wide prevalence of NBS is estimated at 1:100,000 live births. However, NBS is particularly common in Eastern Europe with carrier frequencies as high as 1:155 in some populations.

Patient and observation
We present here a case of Nijmegen breakage syndrome in an 8-yearold girl born of consanguineous parentage. Her birth histories, her family social history, and developmental milestones were unremarkable. She was born at a local birthing centre, at full term with no antenatal or perinatal complications, attended solely by midwives, she was exclusively breast-fed, food diversification was started at 6 months old, her weight, length and psychomotor development were within the normal range, the child was described as a good eater on a normal diet, and was thriving appropriately.
Furthermore, the girl presented recurrent episodes of respiratory tract infections such as pneumonia and sinusitis since 2 years of age, indeed there was history of 5 hospitalizations at a health centre; the last one goes back to the age of 6, then she was sent back to our department for a complete management. On admission, our patient had characteristic facial appearance with a combination of receding forehead, receding mandible and prominent midface, she had also epicanthal folds, large ears, and sparse. In addition, profound microcephaly was noticed (-3SD) that contrasted with normal developmental milestones and good comprehension, while no motor problems and no delayed speech were observed. On the other side, mild growth delay was observed (-2SD on the weight and length) with  [4]. The gene underlying NBS is NBN whose product, nibrin (p95), that is part of a trimeric complex together with MRE11 and RAD50 (the MRN complex). This complex is evolutionarily highly conserved, and consists of the proteins Mre11, Rad50 and Xrs2, whereby Xrs2 represents the functional orthologue of nibrin. The MRN complex is involved in DNA double strand break (DSB) repair by both homologous recombination and nonhomologous end joining, the two principle DSB repair pathways of mammalian cells. Nibrin is apparently a sensor of DSBs as it is required for relocation of the complex to the sites of DSBs after irradiation [5]. In addition to a direct role in DNA repair, the complex is also involved in the activation of ATM, the protein mutated in Ataxia telangiectasia, and thus in the triggering of cell cycle checkpoints [6]. The vast majority of NBS patients are homozygous for a founder mutation, c.657_661del5 (p.K219fsX19), in exon 6 of the gene [4]. Alternative translation of the NBN mRNA leads to a carboxyterminal fragment, p70-nibrin, with residual function [7].
Nijmegen breakage syndrome is a rare disease and there are no reliable estimates of its prevalence. The number of known patients identified worldwide increased significantly when the disease-causing gene, NBN, was identified. Apart from over 150 subjects reported in the medical literature [8]. The disease seems to occur worldwide, but with a distinctly higher prevalence among Central European and Eastern European populations, i.e. in the Czech Republic, Poland, Russia and Ukraine [9,10]. The proportion of patients identified in these populations correlates with a high carrier frequency of the major NBN mutation, c.657_661del5 (p.K219fsX19), estimated to be 1 case per 177 new-borns, clearly the result of a founder effect [11]. The clinical phenotype of NBS consists of several cardinal features, such as progressive microcephaly, which influences facial phenotype, mild growth delay, premature ovarian failure, cellular and humoral immunodeficiency predisposing to recurrent infections, and an exceptionally high risk of cancer development at an early age. A hallmark symptom of NBS is microcephaly, which is observed from birth onwards and should alert a neonatologist or a paediatrician, [12,13]. Microcephaly in NBS is progressive and can be as severe as in older children contrasting with normal developmental milestones in the majority of NBS children [13]. It is striking to observe an infant or a toddler with severe microcephaly but with no motor problems and with very good comprehension.
On the other side, delayed speech development is common, and speech therapy is needed to correct articulation problems. Intelligence was shown to vary from normal to mild or moderate mental retardation. The dysmorphic facial features are very similar among all patients with NBS and become more obvious with age. In fact, the prominent midface is emphasized by the sloping forehead and the receding mandible, which seems to be secondary to the underdevelopment of the cranium. Other facial characteristics are subtler and diverse as palpebral fissures are upwardly slanted in most patients, and the shape of the nose may be both long and beaked as well as upturned with anteverted nostrils. In individual patients, cleft lip/palate or choanal atresia have also been described. NBS patients are prone to various infections, sinusitis, pneumonia and/or bronchopneumonia that result in bronchiectasis in some patients, are particularly frequent with, in some cases, a fatal outcome.
Agammaglobulinemia has been reported for about one third of NBS patients whilst in others the humoral immune deficiency is more variable, deficiencies of IgA or IgG4, alone or in combination are, however, common. A minority of patients, about 10%, have normal Ig status [14]. Cellular immunity is more consistently deficient in NBS patients. T-lymphocyte proliferation in response to mitogenic stimuli is reduced in more than 90% of patients. Whilst CD8+ cells are generally within the normal range, reduced proportions of CD3+ and CD4+ T cells are found in most patients. Consequently, the CD4+/CD8+ ratio is reduced. Mild to moderate lymphopenia has also been reported and in a study of such patients a failure of T cell regeneration in the thymus was postulated to be compensated for by non-thymic pathways [15]. Moreover, patients with NBS have a high risk for developing malignancy, the major cause of death in these individuals. Of all the chromosomal instability syndromes, the

Competing interests
The authors declare no competing interests.