SUMMARY

 

1. Cyclic neutropenia is a rare autosomal dominant immunodeficiency characterized by recurrent neutropenia occurring every 3 weeks (range 14-35 days) and lasting for 3-6 days. Unlike congenital neutropenias the disease course is typically milder, but can be severe in some cases.

 

2. Symptoms usually begin during the first year of life and consist of recurrent fevers, gingivitis, stomatitis, and bacterial skin infections during neutropenic episodes. The symptoms are episodic and there is a very predictable recurrence every 3-4 weeks. Patients are generally well between periods of neutropenia.

 

3. Necrotizing enterocolitis with bowel performation and sepis (from clostridium septicum or gram negative organisms) is a rare but potentially fatal infectious complication during episodes of neutropenia.

 

4. The prognosis is typically good with a benign course. Symptoms tend to decrease in severity with age. Most patients survive to adulthood but approximately 10% of patients experience life-threatening infections.

 

5. Cyclic neutropenia is caused by mutations in the ELA2 gene. Mutations in the ELA2 gene can also result in a form of severe congenital neutropenia, although the mutation sites typically differ from patients with cyclic neutropenia.

 

6. The diagnosis of cyclic neutropenia is made by documentation of regular oscillations in the absolute neutrophil count with ANC nadir below 200. This typically requires monitoring of the neutrophil count 2-3 times per week for 6 to 8 weeks. The presence of normal neutrophil counts between episodes differentiates this disease from congenital neutropenias. The diagnosis is confirmed by sequencing of the ELA2 gene.

 

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

 

8. Treatment with G-CSF can increase the ANC and can reduce gingival inflammation, bacterial infections and the risk of NEC/sepsis. Most patients respond to a G-CSF dose of 2-3 mcg/kg subcutaneously every 1-2 days (goal ANC nadir > 500). G-CSF can be stopped in some older patients if the neutropenia spontaneously improves with age.

 

9. Aggressive IV antibiotic therapy is indicated for patients presenting with fever, neutropenia, and abdominal pain/tenderness as this may indicate the presence of necrotizing enterocolitis.

 

 

                                                                                                               

OVERVIEW

 

          Cyclic neutropenia is a rare dominantly inherited immunodeficiency characterized by recurrent neutropenia occurring every 3 weeks (range 14-35 days) and lasting for 3-6 days. Unlike congenital neutropenias the disease course is typically milder, but can be severe in some cases.

 

          Symptoms usually begin during the first year of life and consist of recurrent fevers, gingivitis, stomatitis, and bacterial skin infections during neutropenic episodes. The symptoms are episodic and there is a very predictable recurrence every 3-4 weeks. Patients are generally well between periods of neutropenia.

 

          Necrotizing enterocolitis with bowel performation and sepis (from clostridium septicum or gram negative organisms) is a rare but potentially fatal infectious complication during episodes of neutropenia.

 

          The prognosis is typically good with a benign course. Symptoms tend to decrease in severity with age. Most patients survive to adulthood but approximately 10% of patients experience life-threatening infections.

 

 

 

PATHOGENESIS

 

         Cyclic neutropenia is caused by mutations in the ELA2 gene. Mutations in the ELA2 gene can also result in a form of severe congenital neutropenia, although the mutation sites typically differ from patients with cyclic neutropenia. The exact mechanism of the cyclic neutropenia has not been elucidated. Examination of bone marrow during episodes of neutropenia reveals hypocellular marrow with arrest in myelocyte maturation.

 

                                 

EVALUATION

 

The diagnosis of cyclic neutropenia should be considered in patients with episodic fever associated with neutropenia.

 

 

Step 1: Documentation of intermittent neutropenia

         

                      - CBC with Differential

 

-Monitoring of absolute neutrophil counts 2-3 times per week for 8 weeks may be required to document the neutrophil nadir. The ANC is typically <200 during the nadir. The neutrophil counts should recover to normal levels following the nadir.

 

 

 

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

 

-ELA2 gene sequencing

 

-This is the definitive test for establishing a diagnosis of cyclic neutropenia and is commercially available.

 

 

 

                                                                   

MANAGEMENT

 

          Treatment with G-CSF can increase the ANC and can reduce gingival inflammation, bacterial infections and the risk of NEC/sepsis. Most patients respond to a G-CSF dose of 2-3 mcg/kg subcutaneously every 1-2 days (goal ANC nadir > 500). G-CSF can be stopped in some older patients if the neutropenia spontaneously improves with age. Aggressive IV antibiotic therapy is indicated for patients presenting with fever, neutropenia, and abdominal pain/tenderness as this may indicate the presence of necrotizing enterocolitis.

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources  

 

1.  GENE DX - ELA2 sequencing (consent & order form)