Nijmegen breakage syndrome

INTRODUCTION — A number of human genetic disorders cause chromosomal breakage, which is characterized by genome instability that occurs in the basal state (spontaneously) or in response to deoxyribonucleic acid (DNA) damaging agents (table 1). These disorders cause defects in the recognition and/or repair of damage to DNA inflicted by different agents. In most cases, the genome instability is associated with immunodeficiency, a predisposition to develop cancer, and premature aging [1].

This topic review will discuss Nijmegen breakage syndrome (NBS; MIM #251260), which is a chromosomal breakage syndrome associated with immunodeficiency [2,3]. Discussions relating to similar disorders are presented separately. (See "Ataxia-telangiectasia" and "Bloom syndrome".)

EPIDEMIOLOGY — NBS is a rare disorder. The exact incidence is unknown. Most reported NBS patients have an ethnic origin from Eastern Europe, notably Poland, the Czech Republic, and Ukraine [4,5]. One study analyzed newborn screening cards for the most common NBS variant (657del5) [5]. The prevalence of this variant ranged from 1 in 154 to 1 in 190 in three Slavic populations compared with 1 in 866 in a German population reported in a separate study [6]. The incidence of NBS was estimated to be 1 in 95,000 livebirths in Czechoslovakia [5]. A subsequent study of an Eastern Slavic population found a prevalence of 2.3 per 1,000,000 in Belarus, 1.3 per 1,000,000 in Ukraine, and 0.7 per 1,000,000 in Russia for the 657del5 variant [7].

PATHOGENESIS — NBS is an autosomal recessive chromosomal instability disorder that is caused by pathogenic variants in the nibrin (NBN) gene on 8q21 that encodes the protein nibrin (MIM #602667) [8]. The most common variant in patients of Eastern European descent is hypomorphic, leading to a partially functional protein [9]. Other variants are more common in different populations [3].

Nibrin forms a complex with meiotic recombination 11 (MRE11, the protein mutated in ataxia-telangiectasia-like disorder) and RAD50 (a protein involved in DNA double-strand break repair) and then rapidly localizes to the site of DNA double-strand breaks. DNA breaks are not efficiently repaired in the absence of nibrin [10-12]. This protein complex is also involved in meiotic recombination and telomere maintenance [13-15]. In addition, nibrin plays a role in the initiation of base excision repair after oxidative or alkylating stress [16].

CLINICAL MANIFESTATIONS — NBS is characterized by progressive, severe microcephaly and a "bird-like" face; intrauterine growth retardation and short stature; immunodeficiency with recurrent sinopulmonary infections; a predisposition to malignancy, predominantly lymphoid malignancies; and primary ovarian insufficiency (premature ovarian failure) in females [2,3,17].

There is a distinct pattern of malformations:

●Virtually all patients have severe microcephaly, well below the third percentile and 10 to 12 cm in diameter less than mean for age [17]. Microcephaly is present at birth in 75 percent of cases and develops in the rest of patients during early infancy. The microcephaly is progressive and is associated with a decline in cognitive skills that results in mild-to-moderate intellectual disability by 7 to 10 years of age. Autopsy studies and cranial magnetic resonance imaging (MRI) have attributed this problem to stunted brain growth, with particularly severe effects on the frontal lobes and corpus callosum [18,19]. The cerebellum appears to be normal.

●Patients with NBS also have abnormal facies with a sloping forehead, receding mandible, prominent mid-face, long nose, and upward slant of the palpebral fissures. These facial features become more prominent as the microcephaly progresses and are recognizable beginning at approximately three years of age.

●Other malformations occur in as many as 50 percent of patients. These include clinodactyly and syndactyly, atresia/stenosis along the gastrointestinal tract, choanal atresia, cleft lip and palate, hydronephrosis, and hip dysplasia. Hypergonadotropic hypogonadism is common in affected males and leads to infertility [20]. Ovarian dysgenesis and premature ovarian failure occur in affected females [21].

Patients may be small for gestational age at birth, and growth retardation typically occurs in the first two years of life. After that, growth velocity usually returns to normal. However, height is usually below the third percentile because of the initial growth delay.

Many patients develop café-au-lait spots and depigmented skin lesions. Porokeratosis, a hyperkeratotic disorder, and cutaneous noncaseating granulomas have been reported in patients with NBS [22-24]. Isolated pulmonary granuloma are described [25]. Rubella virus has been identified in granulomatous lesions in patients with NBS and other inborn errors of immunity (primary immunodeficiencies) [26].

Cancer is the leading cause of death for patients with NBS, with 40 percent of patients developing a malignancy before 20 years of age [27,28]. The majority of cancers are lymphomas [28,29], but there have been case reports of glioma, rhabdomyosarcoma, and medulloblastoma [30-32]. Patients appear to have enhanced radiosensitivity [33]. An increased susceptibility to malignancy has been reported in heterozygotes, although they appear to be normal in other respects [34-36]. Regional differences in environmental factors can affect age of onset of tumors [37]. A study of 241 patients with NBS found a cumulative cancer incidence of 40 percent at 10 years and 78 percent at 20 years of follow-up, with the majority of tumors being non-Hodgkin lymphomas [29]. Another study found differences in the age of onset of cancer (predominantly lymphoma) related to geographic area [37]. Patients in the Czech Republic and Slovakia had an earlier onset of malignancy than a similar cohort from Poland. All patients were homozygous for the Slavic founder mutation. Higher naturally occurring background radiation in the Czech Republic and Slovakia may account for the earlier onset of tumors. (See "Radiation-associated sarcomas", section on 'Genetic predisposition'.)

Many patients suffer from recurrent upper and lower respiratory tract infections (pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis). Chronic lung disease with bronchiectasis is the second leading cause of death [27]. Oral candidiasis and gingival hyperplasia have been reported [38]. There are no published reports of opportunistic infections, but there is evidence of more generalized immune dysfunction, with patients exhibiting autoimmune (immune thrombocytopenia and hemolytic anemia) and chronic inflammatory (childhood sarcoidosis) disorders at much higher than expected frequencies [27,39]. Lymphocytic interstitial pneumonitis is described [24].

Primary ovarian insufficiency is common in females with NBS [21].

LABORATORY FINDINGS — Immunodeficiency is common in NBS patients [27,40]. One-third of patients are agammaglobulinemic. As many as 80 percent of the others have absent or low levels of one or more immunoglobulin classes or immunoglobulin G (IgG) subclasses [27,41].

The majority of patients are lymphopenic, with relatively similar diminution of CD4+ and CD8+ T cells [27] as well as decreased CD19+ cells due to a quantitative VDJ (variable, diversity, and joining segments) recombination deficiency [42] and a reduction in class-switched memory B cells [43]. Circulating T cells comprise a higher frequency of CD57+ CD28- cells, indicative of senescence [44], and of CD279, indicative of T lymphocyte exhaustion [45]. In addition, most patients have reduced in vitro proliferative responses to mitogens [27]. At autopsy, the thymus is small and devoid of Hassall's corpuscles, suggesting dysplasia [18]. Lymph nodes have normal architecture, but lymphoid follicles are small, and germinal centers are reduced in number.

The characteristic laboratory abnormality in NBS is chromosome instability. Cultured T cells show an extremely low mitotic index, making cytogenetic analysis difficult, but structural chromosomal aberrations are present in 10 to 35 percent of metaphases [46]. Most of the rearrangements occur in chromosomes 7 and 14 at the locations of immunoglobulin and T cell receptor (TCR) genes and may be present in as many as one-third of tested lymphocytes [2].

Radiation hypersensitivity is documented in both lymphocytes and fibroblasts from patients with NBS [47]. The extent of sensitivity is comparable with that observed in patients with ataxia-telangiectasia.

DIAGNOSIS — The most prominent feature of NBS is severe microcephaly. Although the differential diagnosis of microcephaly is extensive, the relatively mild intellectual disability and characteristic facies should point to the diagnosis of NBS. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Microcephaly'.)

A range of laboratory tests is required for confirmation of the diagnosis. Demonstration of chromosomal rearrangements typically involving chromosomes 7 and 14, as well as chromosomal hypersensitivity to X-irradiation, suggests NBS or an associated disorder such as DNA ligase IV deficiency or Cernunnos/XRCC4-like factor (XLF) deficiency. Immunoblotting and molecular genetic testing are required to confirm the diagnosis. The 657 del 5 mutation of the NBS gene on 8q21 is present in approximately 85 percent of cases in the United States, simplifying the task of genetic confirmation in many cases [3]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'XRCC4 and DNA ligase IV' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Cernunnos/XLF'.)

Some patients with NBS have low numbers of T cells at birth and consequently have low T cell receptor excision circles (TRECs), which are measured on the newborn screening assay for severe combined immunodeficiency (SCID) and other T cell defects that result in T cell lymphopenia [48]. Thus, NBS can be detected on newborn screening in countries that include the TREC assay. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

Prenatal diagnosis and carrier detection using molecular genetic testing is available for those with affected family members whose pathogenic variants are known.

A list of laboratories offering clinical testing for NBS is available on the Genetic Testing Registry (GTR) website.

DIFFERENTIAL DIAGNOSIS — This disease shares the laboratory feature of radiation hypersensitivity observed with ataxia-telangiectasia and ataxia-telangiectasia-like disease. However, NBS can be distinguished from these disorders in that there is no neurodegeneration, but rather microcephaly with mild-to-moderate intellectual disability. In addition, unlike these two disorders, NBS patients do not have telangiectasia, and serum alpha-fetoprotein levels are normal. (See "Ataxia-telangiectasia".)

Development delay, microcephaly, cancer predisposition, and immune abnormalities are also observed in Fanconi anemia. In two patients with suspected Fanconi anemia, the correct diagnosis of NBS was only discovered after chromosomal gene arrangement studies and sequence of the NBS gene [49]. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Clinical features'.)

Deficiency of RAD50, which is part of the MRE11/RAD50/NBS (MRN) complex (see 'Pathogenesis' above), presents with clinical features similar to NBS (eg, microcephaly, "bird-like" face, short stature, and intellectual disability) [50]. However, the first patient reported with RAD50 deficiency (also called Nijmegen breakage syndrome-like disorder [NBSLD]; MIM #613078) had normal immunoglobulin levels, did not have a history of serious infections, and had not developed malignancy by age 23 years despite demonstration of chromosomal instability and radiosensitivity.

Other syndromes sharing some clinical features with NBS that are associated with chromosomal instability and increased susceptibility to malignancy include DNA ligase I deficiency [51], DNA ligase IV deficiency [52], Cernunnos/XRCC4-like factor (XLF) deficiency [53], Bloom syndrome, and Seckel syndrome [54]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'XRCC4 and DNA ligase IV' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Cernunnos/XLF' and "Bloom syndrome".)

TREATMENT — There is no specific treatment for NBS.

Sinopulmonary infections are most common and may lead to bronchiectasis. Subjects should be evaluated for immunodeficiency and treated as appropriate with antibiotic prophylaxis and, in severe antibody deficiency, immune globulin replacement. Live vaccines should be avoided. Allogeneic hematopoietic cell transplantation (HCT) has been performed in patients with NBS.

One case series reported on outcomes of HCT for DNA double-strand break repair disorders [55]. This series included 26 patients with NBS, 19 of whom were alive at the time of last follow-up. Malignancies were the most common indication for HCT. Two patients received preemptive HCT because of their severe combined immunodeficiency (SCID) phenotype. Those treated with myeloablative conditioning had poorer survival compared with patients who received a reduced-intensity conditioning regimen, with increased frequency of early death due to transplant-related toxicity. A single-center study in a series of patients with the 657del5 mutation who received a T cell receptor (TCR) alpha-beta/CD19-depleted graft demonstrated that toxicity outcomes after using submyeloablative doses of treosulfan were similar to low-dose busulfan, with improved engraftment [56]. Other series (which include some of the patients in the first case series described [55]) also demonstrate the utility of HCT [24,28,57]. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Immune globulin therapy in inborn errors of immunity".)

Patients with NBS have a high risk of developing malignancy, predominantly lymphomas, with over 40 percent developing a malignancy by the age of 20 years. Parents/caregivers should be counseled about the presenting signs of lymphoma and other malignancies. Preliminary data suggest that monitoring for appearance of certain biomarkers that can precede malignancy (eg, monoclonal proteins, immunoglobulin/TCR gene rearrangements, and viral infections including Epstein-Barr virus and hepatitis) may be useful [58]. In one study, patients diagnosed with cancer who received HCT had higher 20-year overall survival than those who did not receive HCT. In the group of patients who underwent preemptive HCT, only one patient developed cancer, a rate seven times lower compared with nontransplanted patients [29].

Patients with NBS have increased sensitivity to both radiation therapy and chemotherapy, which complicates treatment of malignancies [33,59]. Radiotherapy should be avoided if possible, but, if necessary, significantly decreased doses should be used. Several patients with lymphoma have been treated successfully with decreased doses of chemotherapy [60-62]. Patients with malignancy who have a worse prognosis typically also have a significant coexistent immunodeficiency. Less toxic chemotherapy regimens should be use for this group, if possible, with the addition of infection prophylaxis [63]. (See "Radiation-associated sarcomas", section on 'Genetic predisposition'.)

Females with NBS should be monitored for primary ovarian insufficiency [21].

PROGNOSIS — Life expectancy is reduced because of the tendency for NBS patients to develop malignancies at a young age. In a report by the International Nijmegen Breakage Syndrome Study Group published in 2000, only 8 out of 22 known cases of NBS with malignancy were still alive at the end of an unstated follow-up period. The median age at the time of death was seven years (range 2 to 21 years) [27]. Other patients succumb to fatal infections. A subsequent report of 149 patients with NBS gave an overall survival probability of 35 percent by 30 years, with the oldest cohort member reported as 33.7 years of age, with a median age at death of 11 years (range 2 to 33.6 years) [28]. (See 'Clinical manifestations' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Overview – Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by chromosomal instability and radiation hypersensitivity, immunodeficiency, short stature, microcephaly and a "bird-like" face, and a predisposition to malignancy. (See 'Introduction' above.)

●Pathogenesis – NBS is caused by pathogenic variants in the nibrin (NBN) gene, which encodes for the protein, nibrin, which is involved in double-strand deoxyribonucleic acid (DNA) break repair, meiotic recombination, and telomere maintenance. (See 'Pathogenesis' above.)

●Clinical manifestations – The characteristic clinical features of NBS include severe microcephaly and a "bird-like" face, short stature, immunodeficiency with recurrent sinopulmonary infections, and a predisposition to malignancy. Carriers also have an increased risk of malignancy. (See 'Clinical manifestations' above.)

●Laboratory findings – The characteristic laboratory abnormality in NBS is chromosome instability. Most patients are lymphopenic, and approximately one-third have agammaglobulinemia. Alpha-fetoprotein levels are normal. (See 'Laboratory findings' above.)

●Diagnosis – The diagnosis is based upon the presence of characteristic clinical manifestation and confirmed by the demonstration of chromosomal rearrangements typically involving chromosomes 7 and 14, as well as chromosomal hypersensitivity to X-irradiation. The diagnosis can also be confirmed by identification of pathogenic variants in the NBN gene. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis includes ataxia-telangiectasia, Fanconi anemia, RAD50 (a protein involved in DNA double-strand break repair) deficiency, DNA ligase I and IV defects, Cernunnos/XLF (X-ray repair, complementing defective, in Chinese hamster, 4 [XRCC4]-like factor [XLF]) deficiency, Bloom syndrome, and Seckel syndrome. (See 'Differential diagnosis' above.)

●Management – There is no specific treatment for NBS. Subjects should be evaluated for immunodeficiency and treated as appropriate. Parents/caregivers should be counseled about the presenting signs of lymphoma and other malignancies. Radiation therapy should be avoided, if possible. Hematopoietic cell transplantation (HCT) is an option for selected patients and may reduce the risk of developing malignancy. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.