SUMMARY

 

1.  Severe congenital neutropenia (SCN) is a primary immunodeficiency characterized by persistent severe neutropenia and infections.  

 

2.  Clinically, patients are diagnosed during the first year of life with severe neutropenia (ANC < 500/mm3) which results in recurrent bacterial infections which can be life-threatening.  In contrast, patients with cyclic neutropenia have a milder clinical course.  

 

3.  The most common infectious complications are cellulitis, skin abscesses, omphalitis, oral ulcers, pneumonia, and otitis media.  

 

4.  There is also an increased risk of developing myelodysplastic syndrome and acute myeloid leukemia in SCN.  The presence of this disease complication is increased in patients who have mutations in the GCSF-R gene.  

 

5.  SCN is a genetically heterogeneous disease with autosomal dominant, autosomal recessive and X-linked forms of inheritance reported.  However, it should be noted that an underlying genetic defect has not been elucidated in up to 40% of patients.  The following genetic defects have been identified to cause SCN:

 

-ELANE/ELA2 (AD) - ELANE (also known as ELA2) encodes for neutrophil elastase. Heterozygous mutations in this gene account for 50-60% of autosomal dominant SCN cases.  Neutrophil elastase is a serine protease synthesized during the early stages of primary granule production in promyelocytes.  The exact mechanism for neutropenia in this disease is not clear.  Mutations in ELANE are also known to cause cyclic neutropenia.      

-HAX1 (AR) - Mutations in the HAX1 gene have been found in a number of patients with autosomal recessive neutropenia including three patients from the original SCN kindred described by Kostmann in 1956.  HAX1 appears to be critical for maintaining the inner mitochondrial membrane potential and protecting against neutrophil apoptosis.  Neurologic disorders including developmental delay and epilepsy have been reported in some patients with HAX1 mutations.  

-WASP (XL) - Missense mutations in the Cdc42 binding site of the WASP protein can result in X-linked neutropenia.  In these patients, WASP protein is expressed.  Patients lack other clinical findings associated with Wiskott-Aldrich syndrome such as eczema, thrombocytopenia, and T cell immunodeficiency.  
-GFI-1 (AD) - Heterozygous mutations in the growth factor-independent 1 (GFI-1) gene causes an autosomal dominant form of SCN (2 patients have been reported).  GFI-1 is a transcription factor which regulates key genes for neutrophil differentiation. 

 

6.  The evaluation of patients for suspected SCN should include a CBC with differential 2 times per week for 6 weeks and testing for antineutrophil antibody levels.  

 

7.  Antineutrophil antibodies during early infancy are often of maternal origin and result from maternal-fetal incompatibility at neutrophil-specific antigen loci.  This type of autoimmune neutropenia often self-resolves over several months as maternal antibodies in circulation gradually diminish.    

 

8.  Bone marrow examination reveals arrest of neutrophil development at the promyelocyte stage.  Marrow cellularity is normal or mildly decreased. 

 

9.  Mutation analysis can confirm the diagnosis of SCN.  Testing for ELANE, HAX1, and WAS are available commercially. 

 

10.  The differential diagnosis for neutropenia is quite broad and includes cyclic neutropenia, CD40L deficiency, XLA, WHIM syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and lysosomal transport defects that result in immunodeficiency and hypopigmentation.  

 

11.  Recombinant G-CSF therapy is the cornerstone of therapy for patients with SCN.  This therapy increases the neutrophil count and decreases the number of serious infections.   Approximately 90% of SCN patients respond to G-CSF with dosing in the range of 5 to 10 mcg/kg per day subcutaneously.  Patients with cyclic neutropenia require significantly lower doses (2-3 mcg/kg per day).  

 

12.  Patients with G-CSFR gene mutations who do not respond to treatment with G-CSF, patients with continued severe bacterial infections, or patients who develop myelodysplasia are candidates for HSCT.       

 

 

 

 

OVERVIEW

 

     Severe congenital neutropenia (SCN) is a primary immunodeficiency characterized by persistent severe neutropenia.  Clinically, patients are diagnosed during the first year of life with neutropenia (ANC < 500/mm3) which results in recurrent bacterial infections which can be life-threatening.  In contrast, patients with cyclic neutropenia have a milder clinical course.  The most common infectious complications are cellulitis, skin abscesses, omphalitis, oral ulcers, pneumonia, and otitis media.  

 

     There is also an increased risk of developing myelodysplastic syndrome and acute myeloid leukemia in SCN.  The presence of this disease complication is increased in patients who have mutations in the GCSF-R gene.  


     SCN is a genetically heterogeneous disease with autosomal dominant, autosomal recessive and X-linked forms of inheritance reported.  However, it should be noted that an underlying genetic defect has not been elucidated in up to 40% of patients.  The following genetic defects have been identified to cause SCN:

 

-ELANE/ELA2 (AD) - ELANE (also known as ELA2) encodes for neutrophil elastase. Heterozygous mutations in this gene account for 50-60% of autosomal dominant SCN cases.  Neutrophil elastase is a serine protease synthesized during the early stages of primary granule production in promyelocytes.  The exact mechanism for neutropenia in this disease is not clear.  Mutations in ELANE are also known to cause cyclic neutropenia.      

-HAX1 (AR) - Mutations in the HAX1 gene have been found in a number of patients with autosomal recessive neutropenia including three patients from the original SCN kindred described by Kostmann in 1956.  HAX1 appears to be critical for maintaining the inner mitochondrial membrane potential and protecting against neutrophil apoptosis.  Neurologic disorders including developmental delay and epilepsy have been reported in some patients with HAX1 mutations.  

-WASP (XL) - Missense mutations in the Cdc42 binding site of the WASP protein can result in X-linked neutropenia.  In these patients, WASP protein is expressed.  Patients lack other clinical findings associated with Wiskott-Aldrich syndrome such as eczema, thrombocytopenia, and T cell immunodeficiency.  
-GFI-1 (AD) - Heterozygous mutations in the growth factor-independent 1 (GFI-1) gene causes an autosomal dominant form of SCN (2 patients have been reported).  GFI-1 is a transcription factor which regulates key genes for neutrophil differentiation. 

 

 

 

   

EVALUATION

 

The diagnosis of SCN should considered for patients presenting with severe neutropenia (ANC < 500/mm3) and bacterial infections during infancy.  
    
 Step 1:  Screening Studies

 

-CBC with Differential
-Anti-neutrophil antibodies
-Bone marrow biopsy

 

-A CBC with differential 2 times per week for 6 weeks should be checked
-The exclusion of anti-neutrophil antibodies is an essential part of the workup for SCN
-Bone marrow examination reveals arrest of neutrophil development at the promyelocyte stage 

 

 

Step 2:  General Immune Evaluation - this step is recommended given a number of other primary immunodeficiencies such as CD40L deficiency, XLA, WHIM syndrome, dyskeratosis congenita, reticular dysgenesis, and cartilage hair hypoplasia can be associated with neutropenia.

 

-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Antibody titers to vaccine antigens   
-Flow cytometry for B cell, T cell, and NK cell enumeration
-Switched memory B cell  (CD27+IgD-IgM-) enumeration
-T cell proliferation to mitogens

 

 

Step 3:  Genetic confirmation


-ELANE (ELA2), HAX1, WAS gene sequencing

 

-Testing for the ELANE, HAX1, and WAS are available through Cincinnati Childrens laboratories.  ELANE and HAX1 testing is available through Gene Dx.  If other family members are affected, the pattern of inheritance may help guide appropriate genetic testing.  
-Testing for GFI-1 and G-CSFR gene mutations is only available at specialized research centers.  

 

 

 

 

MANAGEMENT

 

      Recombinant G-CSF therapy is the cornerstone of therapy for patients with SCN.  This therapy increases the neutrophil count and decreases the number of serious infections.   Approximately 90% of SCN patients respond to G-CSF with dosing in the range of 5 to 10 mcg/kg per day subcutaneously.  Patients with cyclic neutropenia require significantly lower doses (2-3 mcg/kg per day).  

 

      Patients with G-CSFR gene mutations who do not respond to treatment with G-CSF, patients with continued severe bacterial infections, or patients who develop myelodysplasia are candidates for HSCT.       

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    

 


1.  GENE DX - ELA2 and HAX1 sequencing 

2.  GENE DX - HAX1 sequencing

3  CINCINNATI CHILDRENS - ELA2, HAX1, WAS sequencing

 

 

Literature Resources

 

1.  Bouma 2010 
     Defects of Neutrophil number and function (review)
     

2.  Klein 2011 
     Genetic Etiologies of SCN (review)
     

3.  Oshima 2010 
     HSCT for SCN (18 patients)
     

4.  Carlsson 2011 
     HSCT for SCN (8 patients)