SUMMARY

 

1.  Reticular dysgenesis is a rare autosomal recessive form of SCID that results in a T-B-NK- phenotype.  Patients also have profound neutropenia.   

 

2.  Mutations in the mitochondrial adenylate kinase 2 (AK2) have been found to cause reticular dysgenesis. 

 

3.  Lymphocyte subset analysis typically shows a near absence of T cells and NK cells.  B cells may be absent or low normal.  The immunoglobulin levels are markedly decreased despite the presence of B cells due to an absence of T cell co-stimulatory signaling.  

 

4.  Severe neutropenia is present, a finding that is unique to this type of SCID.  The neutropenia is poorly responsive to granulocyte colony stimulating factor (GCSF).  The bone marrow is hypoplastic with arrest in granulocyte development at the myelocyte stage.  

 

5.  Patients typically present with a classic SCID phenotype during infancy (FTT, candidiasis, diarrhea, Pneumocystis jiroveci pneumonia, and severe viral infections).  

 

6.  The presence of a T-B-NK- phenotype coupled with profound neutropenia strongly suggests the diagnosis.  Demonstration of decreased AK2 protein expression can support the diagnosis.  Sequencing of the AK2 gene would provide a definitive diagnosis.  

 

7.  In addition to treatment of acute infections, the following immediate management steps must be implemented:

 

- Avoid all live viral vaccines

 -Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)

 -Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole 

 -IVIG replacement therapy

 -Start HLA-typing for the patient and any siblings for possible hematopoietic stem cell transplantation (HSCT)

 

8.  Stem cell transplantation is the definitive treatment for this condition.  Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and who have suffered end organ damage from infections have a much lower success rate.   

 

 

 

 

OVERVIEW

    
     Reticular dysgenesis is a rare autosomal recessive form of SCID that results in a T-B-NK- phenotype.  Patients also have profound neutropenia.  Mutations in the mitochondrial adenylate kinase 2 (AK2) have been found to cause reticular dysgenesis. The exact mechanism of how this mutation results in SCID has not been elucidated.  

 

     Lymphocyte subset analysis typically shows a near absence of T cells and NK cells.  B cells may be absent or low normal.  In some cases, the T cells may be present due to maternal T cell engraftment (which appears to occur frequently in reticular dysgenesis). The immunoglobulin levels are absent despite the presence of B cells due to an absence of T cell co-stimulatory signaling.  

 

     Severe neutropenia is present, a finding that is unique to this type of SCID.  The neutropenia is poorly responsive to granulocyte colony stimulating factor (GCSF).  The bone marrow is hypoplastic with arrest in granulocyte development at the myelocyte stage.  

 

     Patients typically present with a classic SCID phenotype during infancy (FTT, candidiasis, diarrhea, Pneumocystis jiroveci pneumonia, and severe viral infections).    

 

 

 

EVALUATION

 

Reticular dysgenesis should be considered male or female patients presenting with a SCID-like phenotype (FTT, diarrhea, thrush, Pneumocystis jiroveci pneumonia, severe respiratory virus infections) along with low absolute lymphocyte counts and severe neutropenia.

 

STEP 1:  Immune Evaluation 

 

-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-Naïve (CD45RA) and memory (CD45RO) T-cell enumeration by flow cytometry
-T-cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM levels 
-Specific Antibody levels (if older than 6 months)
-Chest X-Ray
-Bone Marrow Aspiration

 

-The absolute lymphocyte count (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage).  SCID presents with an ALC less than 2800 cells/mm3 in 95% of cases.  Severe neutropenia is present.  
-Low T cell and NK cell numbers are present while B cell numbers can be low or normal.  
-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic output.  In cases of maternal T cell engraftment the circulating T cells have a predominantly memory (CD45RO) phenotype and have poor proliferation in response to mitogens.   In one study, 6/6 patients with reticular dysgenesis demonstrated maternal engraftment.  
-Extremely low T cell proliferation to mitogens is seen in SCID (<10% of control).  The large blood volume required to perform mitogen proliferation is often an issue with small infants.  Performing the proliferation assay with one stimulus (PHA) is acceptable and requires less blood.  
-Immunoglobulin levels before 6 months of age may reflect transplacentally aquired maternal IgG).  However, immunoglobulin levels can be low prior to 6 months in SCID due to accelerated consumption from recurrent infections. 
-A chest X-ray may reveal absent thymic tissue.   
-The bone marrow is hypoplastic with arrest in granulocyte development at the myelocyte stage.  

 

STEP 2: Additional Immune Evaluation.  The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required.  

 

-TREC Analysis
-TCR Gene Rearrangement PCR (TCR Spectratyping)
-Maternal Engraftment Study 

 

-TRECs (T-cell receptor excision circles) are loops of DNA excised during TCR rearrangement in the thymus.  Because TRECs are not replicated with cell division, they are gradually diluted as T-cells become activated and expand.  Thus, naïve T-cells that are recent thymic emigrants have high TREC numbers.  SCID patients typically have very low TREC numbers.
-TCR gene rearrangement is useful for identifying oligoclonally expanded T-cells.  This can be seen in maternal engraftment.  
-Maternal T cells can occasionally undergo clonal expansion in patients with SCID.  Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation.  An evaluation for the presence of maternal cells in circulation (maternal engraftment) is useful because it can affect the selection of a stem cell donor and it may necessitate immunosuppression prior to transplantation.  

 

STEP 3:  Gene Sequencing

 

-A definitive diagnosis for reticular dysgenesis can be made by demonstrating the absence of adenylate kinase 2 protein levels or by identification of mutation in the AK2 gene.  This testing is available commercially (Gene Dx)

 

 

 

 

MANAGEMENT

 

     For patients who have immunologic findings consistent with reticular dysgenesis, HSCT is curative and life-saving.  Pending the completion of an immunologic evaluation, it is critical to initiate certain measures to prevent life-threatening complications for patients.  The following precautions should be implemented immediately: 

 

1.  Avoid all live viral vaccines (rotavirus, varicella, MMR, BCG)
      - Severe vaccine strain disease can occur if SCID patients receive these vaccines. 

 

2.  Only irradiated, CMV negative blood products should be used 
      - Leukocytes from non-irradiated blood can cause graft versus host disease and CMV can cause severe infections.   

 

3.  Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
     - 4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week 

 

4.  IVIG replacement therapy

 

5.  High resolution HLA-typing for the patient and any siblings 
     - For possible Hematopoietic Stem Cell Transplantation (HSCT)
    

     Stem cell transplantation is the definitive treatment for this condition.  Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and who have suffered end organ damage from infections have a much lower success rate.   

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources  

The following tests resources are accessible on the SCID overview diagnostic resources page:  

 

1.Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell (CD19), 
    and NK cell (CD16/56).   
2.Naïve (CD45 RA) and Memory (CD45 RO) T cells by Flow Cytometry
3.T-cell proliferation to Mitogens and Specific Antigens (candida, tetanus)
4.TREC (T-cell receptor excision circle) Analysis
5.T-cell Receptor Gene Rearrangement (TCR Spectratyping)

 

 

Literature Resources

 

1.  Pannicke 2008 
     Reticular Dysgenesis is caused by mutations in Adenylate Kinase 2
     

2.  Lagresle-Peyrou 2009 
     Reticular Dysgenesis and Adenylate Kinase 2 Deficiency