Clinical Guidance

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

Source: GeneReviews — "Nijmegen Breakage Syndrome"

Diagnostic Criteria

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 deficiency that is more pronounced from birth until age two 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

Source: GeneReviews — "Nijmegen Breakage Syndrome"

Differential Diagnosis

Microcephaly, growth delay, immunodeficiency, and/or bone marrow failure are common manifestations of several inherited disorders, mainly related to defective sensing, processing, and repair of double-strand DNA breaks. Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. See . The early growth failure in Nijmegen breakage syndrome (NBS) may suggest other disorders of growth, such as thyroid hormone or growth hormone deficiency, or primary disorders of bone growth (e.g., skeletal dysplasias). Because malignancy may be the presenting finding in NBS, the diagnosis of NBS should be considered before radiotherapy is initiated in individuals with microcephaly who have solid tumors and are younger than age three years . Table 3. Disorders to Consider in the Differential Diagnosis of Nijmegen Breakage Syndrome

Management Guidelines

No clinical practice guidelines for Nijmegen breakage syndrome (NBS) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NBS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Nijmegen Breakage Syndrome

Source: GeneReviews — "Nijmegen Breakage Syndrome"

Clinical Guidance

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 the risk associated with radiotherapy 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, MRI and/or ultrasound examination are strongly recommended. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given.

Source: GeneReviews — "Nijmegen Breakage Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Nijmegen Breakage Syndrome"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with Individuals with Nijmegen Breakage Syndrome

System/Concern | Evaluation | Frequency

Constitutional

| Monitor weight, length/height, head circumference. | Monthly until age 1 yr; every 3-6 mos until age 2-3 yrs; annually thereafter

Immunology

| • Monitor types frequency of infections.

• Absolute number of B cells, T cells, T-cell subsets, w/special attention to nave CD4+CD45RA cells

• Proliferative response of peripheral blood mononuclear cells to stimuli

• Concentration of total serum immunoglobulins (IgG, IgA, IgM) IgG subclasses

• Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV)

| • Eval of cellular immunity proliferative response to mitogens or antigens every 12 mos

• Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started)

• Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected

Malignancy

| • Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, /or hepatosplenomegaly.

• Assessment should be considered using ultrasonography, MRI, biopsy.

| Annually

Breast self-exam | Monthly in females when HRT is administered.

Endocrine

| • Monitor pubertal progression in females males.

• Assess for premature ovarian insufficiency in females.

|

Neurodevelopment

| Assess cognitive development intellectual abilities. | Before starting school repeated periodically to ensure educa...

Source: GeneReviews — "Nijmegen Breakage Syndrome"