SUMMARY

 

1.  JAK 3 deficiency causes an autosomal recessive form of T-B+NK- SCID.  It accounts for approximately 8% of all SCID cases. 

 

2.  JAK 3 is a signal transduction molecule that interacts with the common gamma chain of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 cytokine receptors.  As a result, JAK 3 deficiency results in a clinical phenotype that is identical to X-linked SCID (common gamma chain deficiency).

 

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

 

4.  Sequencing of the JAK 3 gene can confirm the diagnosis.

 

5.  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)

 

6.  Even with supportive therapies, patients with SCID will not survive without a HSCT.  Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and have suffered end organ damage from infections have a much lower success rate

 

 

 

 

OVERVIEW

 

   JAK 3 deficiency is an autosomal recessive form of SCID and results in a T-B+NK- phenotype.  It causes approximately 8% of all SCID cases.  Male or female patients present in early infancy with a typical SCID phenotype: FTT, diarrhea, severe thrush, Pneumocystis jiroveci pneumonia, and severe viral respiratory infections.  

 

     The absolute lymphocyte count will be low (typically below 2800 cells/mm3).  Lymphocyte subset analysis by flow cytometry will show low T cells and low NK cells but normal B cell numbers.  T cell numbers may be normal if maternal T cell engraftment has occurred.  Immunoglobulin levels will be very low (once transplacentally acquired maternal IgG levels decline) despite normal B cell numbers.  

 

     This type of SCID is caused by mutations in JAK 3, which is a signal transduction molecule that interacts with the common gamma chain of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor.  Impaired signaling through these multiple cytokine pathways leads to severe impairment in the development of T cells and NK cells.  IL-2 and IL-7 signaling are particularly important for T cell development while IL-15 signaling is important for NK cell development and proliferation. Although B cell numbers are preserved, B cell activation and class switch recombination are greatly impaired due to a lack of T cell help.  Impaired IL-4 and IL-21 signaling may also contribute to B cell dysfunction.  

 

 

 

EVALUATION

 

JAK 3 deficiency should be considered in male or female patients presenting with a SCID-like phenotype (FTT, diarrhea, thrush, Pneumocystis jiroveci pneumonia, severe respiratory virus infections, infections from live viral vaccines) along with low absolute lymphocyte counts.

 

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

 

-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. 

-Low T cell numbers and low NK cell numbers are seen in most cases of JAK 3 deficiency SCID.  B cell numbers are normal. 

-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic output (or absence of thymic tissue in complete DiGeorge syndrome).  In cases of maternal T-cell engraftment and Omenns syndrome, the circulating T-cells have a predominantly memory (CD45RO) phenotype and have poor proliferation in response to mitogens.   

-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.   

 

 

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 as well as Omenns syndrome.  

-Maternal T cells can occasionally undergo clonal expansion in patients with SCID.  Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation.  Assessing 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:  If lymphocyte subset analysis reveals a T-B+NK- phenotype, further evaluation for JAK 3 deficiency should be pursued. 

 

-Genetic testing for JAK 3 Deficiency (JAK 3)

 

-Genetic testing for JAK 3 is commercially available through correlagen diagnostics.  Concurrent testing for common gamma chain deficiency (X-linked SCID) is advised in males because it can present with an identical immunologic phenotype.  Gene sequencing typically takes 4-6 weeks.  

 

 

 

 

MANAGEMENT

 

     Pending the completion of an immunologic evaluation for suspected X-linked SCID, 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)


     Even with supportive therapies, patients with SCID will not survive without a HSCT.  Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and have suffered end organ damage from infections have a much lower success rate.   

 

 

 

 

RESOURCES

 

Diagnostic Resources   

 


SPECIFIC RESOURCES FOR JAK 3 DEFICIENCY SCID:

     1.  Correlagen Genetic Testing for JAK3 Deficiency SCID

 

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. Notarangelo 2001

    SCID  caused by JAK3 Mutations