SUMMARY

 

1.  CD45 deficiency causes a rare form of T-B+NK+ SCID which has been reported in a small number of patients.

 

2.  Patients typically present with a classic SCID phenotype during infancy (FTT, opportunistic infections, oral candidiasis, and severe viral infections).

 

3.  Laboratory findings include a decreased absolute lymphocyte count and total T cell count.  B cell numbers are normal.  CD45 expression by flow cytometry is absent.  In vitro T cell proliferation to mitogens is markedly decreased.  Despite the presence of B cells, patients have low immunoglobulins and vaccine responses due to absent T cell co-stimulatory signaling.   

 

4.  CD45 is a transmembrane tyrosine phosphatase involved in T cell receptor signaling and T cell development in the thymus.  A deficiency of CD45 leads to a marked impairment in T cell development. 

 

5.  This diagnosis should be suspected in patients with a T-B+NK+ SCID phenotype with absent CD45 surface expression.  Sequencing of the CD45 gene can confirm the diagnosis.

 

6.  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).

 

7.  Stem cell transplantation is the definitive treatment for SCID.  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 

 

 

 

 

OVERVIEW

 

 

    CD45 deficiency causes a rare form of T-B+NK+ SCID which has been reported in a small number of patients.  Patients typically present with a classic SCID phenotype during infancy (FTT, opportunistic infections, oral candidiasis, and severe viral infections).
   
    Laboratory findings include a decreased absolute lymphocyte count and total T cell count.  B cell numbers are normal.  CD45 expression by flow cytometry is absent.  In vitro T cell proliferation to mitogens is markedly decreased.  Despite the presence of B cells, patients have low immunoglobulins and vaccine responses due to absent T cell co-stimulatory signaling.   
     
    CD45 is a transmembrane tyrosine phosphatase involved in T cell receptor signaling and T cell development in the thymus.  A deficiency of CD45 leads to a marked impairment in T cell development.

 

 

 

 

EVALUATION

 

The diagnosis should be suspected in patients presenting with pyogenic arthritis and an autosomal dominant inheritance pattern. Severe cystic acne may be present in patients after puberty. 
 

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)

-CXR

 

-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 are seen in CD45 deficiency SCID.  B cell numbers are normal.  

-CD45 surface expression will be absent or markedly reduced.  However, it should be noted that in cases of maternal engraftment, maternally derived CD45RO T cell may be detected in circulation.  

-Extremely low T cell proliferation to mitogens is seen (<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.  

 

 

STEP 3:  Genetic Testing

 

-CD45 Gene Sequencing 

 

-Genetic testing for CD45 is currently only available at specialized research centers.  However, the lack genetic confirmation should not delay live saving HSCT. 

 

 

 

 

MANAGEMENT


     Pending the completion of an immunologic evaluation for suspected CD3 complex deficiency 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)

 

 

         

                                                                 

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.  Kung 2000 
     SCID in a patient with CD45 Deficiency
  

2.  Tchillian 2001 
     SCID in a patient with CD45 Deficiency