Nijmegen Breakage Syndrome

Clinical characteristics.

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild to moderate intellectual disability. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Approximately 40% of affected individuals have developed malignancies before age 20 years, with the risk being highest for T-cell (55%) and B-cell lymphomas (45%). Other tumors include solid tumors (e.g., medulloblastoma, glioma, and rhabdomyosarcoma). Note, however, that much of what is reported about NBS is based on individuals who are homozygous for the single most common Eastern European pathogenic variant, c.657_661del5.

Diagnosis/testing.

The diagnosis of NBS is established in a proband with the clinical findings listed above who has biallelic pathogenic variants in NBN on molecular genetic testing and/or absent nibrin protein on immunoblotting assay.

Management.

Treatment of manifestations: Vitamin E and folic acid supplementation; use of IVIg in individuals with severe humoral immunodeficiency and frequent infections; standard chemotherapy protocols for lymphoid malignancies (adopted to individual tolerance); consideration of hematopoietic stem cell transplantation; hormone replacement therapy for females who have hypergonadotropic hypogonadism.

Surveillance:

• For affected individuals: Periodic follow up to monitor developmental progress, physical growth and infection frequency; in those with weight loss, assessment for malignancy should be considered; lifelong monitoring of immune biomarkers; careful monitoring by an oncologist; monitoring for pubertal progression in both sexes and premature ovarian insufficiency in females; breast self-examination and ultrasonographic evaluation.
• For carriers (heterozygotes): Parents should be monitored for malignancy, particularly breast cancer in women and prostate cancer in men.

Agents/circumstances to avoid: Because the cells from individuals with NBS are radiosensitive in vitro, doses of radiation used in radiotherapy need to be reduced. Unnecessary exposure to imaging studies that use ionizing radiation (plain radiograph, CT scan) should be avoided and use of MRI and/or ultrasound considered.

Evaluation of relatives at risk: Molecular genetic testing for the NBN pathogenic variants identified in the proband should be offered to apparently asymptomatic sibs of a proband and young adult relatives at risk of being carriers (heterozygotes) in order to identify as early as possible those who would benefit from monitoring for malignancy and to inform treatment options if a malignancy is diagnosed.

Genetic counseling.

NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing are possible if both of the pathogenic variants have been identified in an affected family member.

Suggestive Findings

Nijmegen breakage syndrome (NBS) should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical features

• Disproportionate microcephaly that is progressive
• Craniofacial features that include a sloping forehead, upward slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia
• Growth retardation that is more pronounced from birth until the age of three years, with mild improvement thereafter
• Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis
• Malignancies, predominantly of lymphoid origin
• Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals

Supportive laboratory findings

• Immunodeficiency involving the humoral and cellular systems [Gregorek et al 2002, Michałkiewicz et al 2003, Wolska-Kuśnierz et al 2015]:
  • Severe hypogammaglobulinemia has been found in 20%-24% of affected individuals and IgA deficiency in 50%-57%.
  • Deficiencies of IgG2 and IgG4 are frequent even when the IgG serum concentration is normal.
  • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells, CD3+ T cells, and CD4+ cells; observed in 80%-89% of affected individuals.
  • An increased frequency of T cells with a memory phenotype (CD45RO+) and a concomitant decrease in naïve T cells (CD45RA+) has been reported.
  • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is greatly reduced in most affected individuals.
• Chromosome instability
  • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases.
  • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T cell-receptor genes.
• Radiation sensitivity. Cells from individuals with NBS have a decrease in colony-forming ability following exposure to ionizing radiation and radiomimetics in vitro.
  Note: This test requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically.

Establishing the Diagnosis

The diagnosis of NBS is established in a proband with the clinical features above who has biallelic pathogenic variants in NBN on molecular genetic testing (see Table 1) and/or absent nibrin protein on an immunoblotting assay (see Immunoblotting; below Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel.

Single-gene testing

• Targeted analysis for the pathogenic variant c.657_661del5 can be performed first. The c.657_661del5 pathogenic variant is detected in:
  • ~100% of alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry;
  • ~70% of alleles in individuals of North American ancestry.
• If the common allele is not present in a homozygous form, sequence analysis of NBN can be pursued.

A multigene panel that includes NBN and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Immunoblotting can be used to determine if the nibrin protein is present or absent.

Note: This test requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically.

Clinical Description

Growth. Children with Nijmegen breakage syndrome (NBS) generally are born with weight below normal for gestational age and microcephaly (i.e., head circumference >2 SD below the mean for age and gender). Microcephaly progresses with age – in contrast to linear growth, which may improve with age, causing disproportionate head dimensions compared to the rest of the body. Microcephaly is occasionally masked by hydrocephaly or developmental abnormalities of the brain [Szczałuba 2012].

Growth failure in the early stages of life results in length/height that is usually below the third centile by age two years. Thereafter, linear growth velocity tends to normalize, however many individuals remain shorter than peers (i.e., affected individuals do not experience catch-up growth). Some adults, both females and males, can achieve height within lower normal ranges [Chrzanowska et al 2012].

Craniofacial features. The craniofacial features discussed in Suggestive Findings are found in the majority of affected individuals and become more pronounced with age as microcephaly progresses.

Infections. Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in bronchiectasis, and even in pulmonary failure and early death. Chronic diarrhea and urinary tract infections may also occur.

Malignancy. According to Chrzanowska et al [2012], 40% of affected individuals reported to date have developed malignancies before age 20 years. Malignancies are primarily lymphomas [Gładkowska-Dura et al 2008, Wolska-Kuśnierz et al 2015]. Approximately 45% of lymphomas are of B cell origin and 55% are T cell lymphomas. Several children have developed solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma [Hiel et al 2001, Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].

Psychomotor and intellectual development. Developmental milestones are attained at the usual time during the first year. Normal or borderline intellectual development and psychomotor hyperactivity may be observed in early childhood/pre-school age. Intellectual abilities tend to decline from mild to moderate intellectual disability during childhood. Affected children are described as having a cheerful, shy personality with good interpersonal skills.

Fertility. Two reports of gonadal dysfunction in affected females with chromosome instability disorder / syndrome appeared in 1986 [Maraschio et al 1986]. Twenty years later, Varon et al [2006] identified biallelic pathogenic c.741_742dup variants in exon 7 of NBN one of the original women reported by Maraschio and colleagues [1986].

Chrzanowska et al [2000] originally presented observations that strongly suggested an increased risk of premature ovarian failure in women with NBS. Results of a longitudinal study demonstrated that hypergonadotropic hypogonadism was present in a large cohort of affected females, all of whom were homozygous for the common c.657_661del5 pathogenic variant [Chrzanowska et al 2010a].

No detailed studies of fertility in males with NBS have been published; however, puberty initiation and progress are comparable to healthy boys [Chrzanowska et al 2010b]. Warcoin et al [2009] described two adult siblings, a male with oligo-terato-asthenozoospermia and a female with premature ovarian failure, who had biallelic truncating variants in NBN but none of the other clinical features of NBS.

Other findings

• Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [Yoo et al 2008, Pasic et al 2012].
• Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.

Heterozygotes. Heterozygotes are asymptomatic, however, there is clear evidence of increased cancer occurrence among heterozygous relatives of individuals with NBS in the Czech Republic [Seemanová et al 2007]. Furthermore, an increased frequency of the pathogenic c.657_661del5 variant in NBN has been observed in several different cancers including breast cancer, prostate cancer, medulloblastoma, and melanoma, suggesting that pathogenic variants in NBN might play a role in the etiology of these types of cancer [Cybulski et al 2004, Steffen et al 2004, Ciara et al 2010].

Genotype-Phenotype Correlations

The common pathogenic variant, c.657_661del5, and most other loss-of-function variants result in a classic presentation. However, exceptions have been reported. There are two reports of families in which biallelic truncating variants in NBN occur in individuals with milder features:

• Varon et al [2006] described a 53-year-old woman who was homozygous for the NBN truncating allele c.741_742dupGG. This affected woman had a somewhat milder phenotype including microcephaly, chromosome instability, immunodeficiency, and primary amenorrhea. Her sister, with similar clinical manifestations died at 20 years of malignant lymphoma [Maraschio et al 1986]. However, analysis of transcripts from the affected individual’s cells indicated a highly prevalent alternatively spliced form of NBN lacking exons 6 and 7 (where the pathogenic variant is located). This transcript produces a 73-kd form of NBN with an internal deletion.
• Warcoin et al [2009] described a family in which two healthy adult sibs, a sister and a brother, had biallelic truncating variants in NBN (p.Tyr110Ter and p.Trp375Ter). Both were normal on clinical examination and did not have any evidence of short stature, reduced head circumference, or facial dysmorphic features; however, both were referred for fertility defects and were subsequently found to have the cellular phenotypes typical of NBS including chromosome instability, hypersensitivity to ionizing radiation, and impaired checkpoint responses.

Nomenclature

The Nijmegen breakage syndrome was described by Weemaes et al [1981].

Three Czech families with Seemanová syndrome [Seemanová et al 1985] were later identified as having NBS.

Genetic complementation studies are no longer of clinical importance. The report of Jaspers et al [1988] noted a strong similarity between NBS cells and ataxia-telangiectasia (A-T) cells; however, they also described the NBS cells as genetically distinct from A-T, grouping individuals with either Nijmegen breakage syndrome or Czech breakage syndrome into A-T variant group V1 and Germans with "Berlin breakage syndrome" [Wegner et al 1999] into A-T variant group V2 [Jaspers et al 1988]. Subsequently, NBN pathogenic variants were found in all individuals studied from the A-T variant groups V1 and V2, indicating that these individuals had NBS, not ataxia-telangiectasia.

Prevalence

No reliable estimates of world-wide prevalence exist, but it is likely to approximate 1:100,000 live births.

NBS is most common in Eastern European/Slavic populations. Studies in Poland, the Czech Republic, and the Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations. The highest reported prevalence is in Sorbians, a Slavic population isolate from southeastern Germany, in whom the carrier frequency is estimated at 1:34 [Maurer et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Nijmegen breakage syndrome (NBS), the following evaluations are recommended (if they were not performed as part of the diagnostic evaluation):

• Assessment of growth
• Evaluation of immunologic status to include:
  • Complete blood count;
  • Absolute number of B-cells, T-cells, and T-cell subsets, with special attention to naïve CD4+CD45RA cells;
  • Proliferative response of peripheral blood mononuclear cells to stimuli;
  • Concentration of total serum immunoglobulins (IgG, IgA, IgM) and IgG subclasses;
  • Evaluation for viruses with lymphotrotropic capacity (i.e., EBV and CMV).
• Evaluation for malignancy, including a focused family history of other individuals with cancer
• Evaluation of the endocrinologic status in females who are of pubertal age to include pelvic ultrasound to evaluate for streak gonads and plasma levels of FSH, LH, and estrogen [Chrzanowska et al 2010a]
• Assessment of cognitive development and intellectual abilities
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Nutrition. Because of chromosome instability, vitamin E and folic acid supplementation in doses appropriate for body weight is recommended.

Infections. In individuals with severe humoral immunodeficiency and frequent infections, Ig replacement therapy should be considered.

• Ig replacement is typically administered either intravenously (IVIg) or subcutaneously (SCIg).
• The spectrum of recurrent infections in NBS is not opportunistic; therefore, the antibiotic selected should be appropriate for the microorganism being treated.

Malignancy. Standard treatment chemotherapy protocols for lymphoid malignancies in NBS need to be adopted according to individual tolerance [Dembowska-Baginska et al 2009, Pastorczak et al 2016]. Treatment of affected individuals with solid tumors is also challenging. Radiotherapy of CNS tumors (medulloblastoma) caused severe complications and death in three individuals with NBS [Chrzanowska et al 1997, Bakhshi et al 2003, Distel et al 2003].

• Although complete clinical remission (for >5 years) can be successfully achieved, in a proportion of affected individuals outcome is complicated by relapse or the development of a second malignancy [Dembowska-Baginska et al 2009, Bienemann et al 2011].
• For individuals who achieve first remission, hematopoietic stem cell transplantation (HSCT) may be considered:
  • The first successful bone marrow transplantation was performed in an individual with NBS who was initially misdiagnosed with Fanconi anemia (FA) [Gennery et al 2004, Gennery et al 2005].
  • Wolska-Kuśnierz et al [2015] summarized the results of HSCT in 14 individuals with NBS, nine of whom were alive [Gennery et al 2005, New et al 2005, Albert et al 2010].
  • Woźniak et al [2015] reported the successful use of non-myeloablative umbilical cord transplantation in a child age 19 months with NBS and severe combined immune deficiency.
  • Further long-term follow up is needed to determine the outcome of HSCT in individuals with NBS.

Puberty and fertility. Females with NBS who are of pubertal age should be referred for evaluation by a gynecologist and/or endocrinologist to evaluate for hypergonadotropic hypogonadism.

• Hormonal replacement therapy should be considered with careful monitoring of secondary sexual characteristics and uterus development.
• Females are infertile; similarly, no male paternity has been reported.

Surveillance

Affected individuals

• Periodic follow-up to monitor developmental progress, physical growth (including weight, length/height, and head circumference) and frequency of infections; monitoring for weight loss, which may signal the presence of a malignancy
• Lifelong monitoring of immune biomarkers to include the parameters listed in Evaluations Following Initial Diagnosis
• Careful follow up by oncologist: in individuals with NBS who are immunodeficient symptoms of lymphoid malignancies can be misleading.
• Monitoring for pubertal progression in both females and males and for premature ovarian insufficiency in females [Chrzanowska et al 2010b]
• Breast self-examination and ultrasonographic evaluation recommended in affected females

Carriers (heterozygotes)

• Parents. As obligate carriers, parents should be monitored for malignancy, in particular breast cancer in women and prostate cancer in men. No consensus tumor screening protocols for carriers have been published.
• At-risk sibs. Evidence of cancer risk in young carriers is insufficient to warrant screening in childhood.

Agents/Circumstances to Avoid

Because the cells from individuals with NBS are as radiosensitive in vitro as those from individuals with ataxia-telangiectasia (another chromosome instability syndrome), conventional doses of radiation used in radiotherapy could be lethal in individuals with NBS. Family members should be made aware of this risk so that they can discuss appropriate treatment options if a malignancy is diagnosed.

Similarly, unnecessary exposure to ionizing radiation should be avoided; instead of radiograph or CT scan, MR imaging and ultrasound examination are strongly recommended.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing for the NBN pathogenic variants identified in the proband to apparently asymptomatic sibs of a proband and young adult relatives at risk of being carriers (heterozygotes) in order to identify as early as possible those who would benefit from monitoring for malignancy