SUMMARY

 

1.    Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by chromosomal instability, radiosensitivity, immunodeficiency, and increased risk of malignancy.  

 

2.    NBS patients have a number of additional abnormal clinical features:  

 

IUGR
Short stature 
Severe microcephaly 
Bird-like facies (sloping forehead, receding chin/micrognathia, long nose)
Vitiligo
Café au lait spots

 

3.    The immunodeficiency in NBS is characterized by agammaglobulinemia (30%), IgA deficiency, or IgG subclass deficiency.  The majority of patients have T cell lymphopenia and decreased proliferative responses to mitogens.     

 

4.    NBS is caused by mutations in the NBS1 gene which encodes for the protein Nibrin.  Nibrin functions to help repair double-strand DNA breaks.   

 

5.    NBS1, Mre11 and RAD50 are members of the MRN complex that recognizes double-stranded DNA breaks and recruits ATM to the break site.  ATM is responsible for phosphorylation of proteins such as p53 which induce cell cycle arrest.  The delay in cell cycle progression allows time for repair of the damage rather than transmission of the defect to daughter cells.  The MRN complex also contributes to the maintenance of telomeres.  

 

6.    Sequencing of the NBS1 gene can confirm the diagnosis.  

 

7.    Supportive therapies for immunodeficiency include immunoglobulin therapy and prophylactic antibiotics.  Radiotherapy should be avoided as patients have increased radiation therapy and risk for malignancy.  There is no curative therapy for this disease.  

 

8.    Malignancy (mainly lymphoma) is the leading cause of death for NBS patients.  The mean age of cancer-related death is 9.2 years.  

 

 

 

                                                                                                               

OVERVIEW

 

     Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by chromosomal instability, radiosensitivity, immunodeficiency and increased risk of malignancy.  NBS patients have a number of additional abnormal clinical features:  

 

 IUGR
 Short stature (decreased linear growth)
 Severe microcephaly (present at birth in 75% of cases)
 Bird-like facies (sloping forehead, receding chin/micrognathia, long nose)
 Vitiligo
 Café au lait spots

 

     The immunodeficiency in NBS is characterized by agammaglobulinemia (30%), IgA deficiency, or IgG subclass deficiency.  The majority of patients have T cell lymphopenia and decreased proliferative responses to mitogens.     
     
     NBS is caused by mutations in the NBS1 gene which encodes for the protein nibrin.  Nibrin, Mre11 and RAD50 are members of the MRN complex that recognizes double-stranded DNA breaks and recruits ATM to the break site.  ATM is responsible for phosphorylation of proteins such as p53 that induce cell cycle arrest.  The delay in cell cycle progression allows time for repair of the damage rather than transmission of the defect to daughter cells.  The MRN complex also contributes to the maintenance of telomeres.         

 

 

                                 

EVALUATION

 

Nijmegen breakage syndrome should be suspected in patients with immunodeficiency and characteristic clinical features (short stature, microcephaly, bird-like facies, skin abnormalities).   

 

Step 1:  Immune Evaluation

 

-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Antibody titers to vaccine antigens   
-Flow cytometry for B cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens

 

-Patients may have low quantitative immunoglobulin levels 

-Protein (Tetanus, Diptheria) and polysaccharide (Pneumococcus) vaccine antibody response should be evaluated.  Patients may have reduced specific antibody response.  

-Lymphopenia with reduced T cell numbers has been reported in a majority of patients.  

-T cell proliferation to mitogens is reduced in most patients.  

 

Step 2:  Gene Sequencing


-NBS1 Gene Sequencing 

 

-NBS1 gene sequencing is commercially available through UCLA laboratories.  ​

                                                                   

MANAGEMENT

 

    Supportive therapies for immunodeficiency include immunoglobulin replacement therapy and prophylactic antibiotics. 
     
     Typical IVIG replacement is started with 400-600mg/kg of every 4 weeks.  Trough levels should be maintained above 800mg/dl.  The total dose or dosing frequency may be increased to achieve desired troughs and clinical response.  
     
     The addition of prophylactic antibiotics can be considered in certain patients who continue to have infections despite appropriate immunoglobulin replacement.  Two sample prophylaxis regimens are outlined below:

 

Amoxicillin 20mg/kg divided twice daily.  Maximum of 500mg twice daily.
Azithromycin 10mg/kg once weekly.  Maximum of 1 gram once weekly.

 

      Radiotherapy should be avoided as patients have increased radiation therapy and risk for malignancy.  There is no curative therapy for this disease.  

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources      

 

1. UCLA NBS1 Gene Sequencing

 

 

Literature Resources

 

 

1.  Digweed 2004 
     Nijmegen Breakage Syndrome (review)
     

2.  Gregorek 2002 
     Humoral abnormalities in 40 children with NBS
     

3.  Lamarche 2010 
     The MRN complex in double-strand break repair and telomere maintenance