SUMMARY

 

1. Omenn syndrome is a form of SCID that results from hypomorphic gene mutations that allow for limited oligoclonal T-cell development.  These T cells are autoreacive and exhibit uncontrolled proliferation, leading to the infiltration of various organs such as the skin, spleen, liver, and lymph nodes.  

 

2.  Patients present in infancy with chronic viral respiratory infections, opportunistic infections, FTT, and diarrhea (similar to classic SCID).  However, unlike classic SCID, patients also present with the following clinical features:


- Lymphadenopathy
- Hepatosplenomegaly
- Erythroderma and scaly desquamative rash (this may result in alopecia, bacterial superinfection, and protein loss).  

 

3.   The characteristic laboratory features of Omenn syndrome are as follows:


- Normal absolute lymphocyte count - The ALC can be normal due to the presence of oligoclonally expanded T cells.
- Marked eosinophilia and Elevated IgE 
- Low IgG, IgA, IgM and Specific Antibody Response 
- Normal CD3+ T cell numbers  - In contrast to classic SCID, the total T cell numbers may be normal due to autoreactive, oligoclonally expanded T cells.  These activated T cells have a memory (CD45RO) phenotype and are HLA-DR positive [normally infants have mainly naïve (CD45RA) T cells which are HLA-DR negative]. 
- Oligoclonal T-cell Repertoire  - Analysis of TCR gene rearrangement by PCR reveals the presence of oligoclonal peaks rather than a typical gaussian distribution. 
- Variable B cell and NK cell numbers  - The presence of B and NK cells will vary based on the molecular cause of the Omenn syndrome.  
- Reduced T cell Proliferation to mitogens  - Despite normal absolute T cell numbers, the oligoclonally expanded T cells typically proliferate poorly to mitogens.  

 

4.  Originally, Omenn syndrome was believed to result only from RAG1 or RAG2 mutations.  It is now recognized that a number of hypomorphic SCID gene mutations can result in this phenotype:  


- RAG1, RAG2
- Artemis
- Common Gamma Chain (CD132)
- IL-7 Receptor
- DNA Ligase 4
- RMRP (Cartilage Hair Hypoplasia)

 

5.  In addition, an Omenn syndrome-like phenotype has been reported in syndromes resulting in thymic aplasia (22q11.2 deletion and CHARGE syndrome).  In 22q11.2 deletion, this phenotype is referred to as atypical complete DiGeorge syndrome.  

 

6.  The elevated IgE and eosinophilia in Omenn syndrome can be explained by the fact that expanded T cell clones in this disease consistently exhibit a Th2 phenotype with secretion of IL-4, IL-13 and IL-5.              

 

7.  Autoreactive T cells in Omenn syndrome appear to result from failed central and peripheral tolerance (decreased AIRE gene expression and decreased T regulatory cells have been reported).  

 

8.  The differential diagnosis for Omenn syndrome includes SCID with maternal engraftment (elevated IgE and eosinophila would not be present this situation), Wiskott-Aldrich syndrome, IPEX syndrome, Hyper-IgE syndrome, severe atopic dermatitis, and Netherton syndrome.  

 

9.  In addition to the 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).

 

10.  Immunosuppressive therapies are required for the treatment of dermatitis and hepatosplenomegaly resulting from autoreactive, oligoclonal T cell infiltration.  

 

11.  Even with supportive therapies, patients with Omenn syndrome will not survive without a HSCT.  T cell depleted haploidentical transplants have a poor success rate in Omenn syndrome (approximately 50%).  Matched sibling or matched unrelated transplants are preferred.  Successful outcomes with myeloablative or reduced intensity conditioning have been reported.  

 

 

 

                                                                                                             

OVERVIEW

 

     In 1965, Gilbert Omenn (a Harvard medical student) described 12 infants born to a consanguinous Irish family who presented at birth with severe generalized erythroderma, eosinophilia and profound immunodeficiency.  Omenn syndrome is a form of SCID that results from hypomorphic gene mutations that allow for limited oligoclonal T-cell development.  These T cells are autoreactive and exhibit uncontrolled proliferation, leading to the infiltration of various organs such as the skin, spleen, liver, and lymph nodes.  

 

     Patients present in infancy with chronic viral respiratory infections, opportunistic infections, FTT, and diarrhea (similar to classic SCID).  However, unlike classic SCID, patients also present with the following clinical features:


- Lymphadenopathy
- Hepatosplenomegaly
- Erythroderma and scaly desquamative rash - this may result in alopecia, bacterial superinfection, and protein loss.  

 

     The characteristic laboratory features of Omenn syndrome are as follows:


- Normal absolute lymphocyte count  - The ALC can be normal due to the presence of oligoclonally expanded T cells.
- Eosinophilia and Elevated IgE 
- Low IgG, IgA, IgM and Specific Antibody Response  - Patients invariably have low IgG and specific antibody responses similar to classic SCID despite the ability to generate high IgE levels.  The IgG may be normal in infants younger than 6 months, due to transplacentally acquired maternal IgG in circulation. 
- Normal CD3+ T cell numbers - In contrast to classic SCID, the total T cell numbers may be normal due to autoreactive, oligoclonally expanded T cells.  These activated T cells have a memory (CD45RO) phenotype and are HLA-DR positive [normally infants have mainly naïve (CD45RA) T cells which are HLA-DR negative]. 
- Oligoclonal T-cell Repertoire - Analysis of TCR gene rearrangement by PCR reveals the presence of oligoclonal peaks rather than a typical gaussian distribution. 
- Variable B cell and NK cell numbers - The presence of B and NK cells will vary based on the molecular cause of the Omenn syndrome.  For example, B cells would be expected to be very low in RAG1, RAG2 or Artemis mutations but normal for common gamma chain and IL-7 receptor mutations. 
- Reduced in vitro T cell Proliferation to mitogens - Despite normal absolute T cell numbers, the oligoclonally expanded T cells typically proliferate poorly to mitogens.  

 

     The differential diagnosis for Omenn syndrome includes SCID with maternal engraftment (elevated IgE and eosinophila would not be present), Wiskott-Aldrich syndrome, IPEX syndrome, Hyper-IgE syndrome, severe atopic dermatitis, and Netherton syndrome.  

         

 

 

 

PATHOGENESIS

 

     Originally, Omenn syndrome was believed to result only from RAG1 or RAG2 mutations.  It is now recognized that a number of leaky SCID gene mutations can result in this phenotype:  


- RAG1, RAG2
- Artemis
- Common Gamma Chain (CD132)
- IL-7 Receptor
- DNA Ligase 4
- RMRP (Cartilage Hair Hypoplasia)

 

     In addition, an Omenn syndrome-like phenotype has been reported in syndromes resulting in thymic aplasia (22q11.2 deletion and CHARGE syndrome).  In 22q11.2 deletion, this phenotype is referred to as atypical complete DiGeorge syndrome.  

 

     The elevated IgE and eosinophilia in Omenn syndrome can be explained by the fact that expanded T cell clones in this disease consistently exhibit a Th2 phenotype with secretion of IL-4 and IL-13 (which promote IgE isotype switching) and IL-5 (which promotes eosinophilia).  In addition, there is decreased T-regulatory cell derived IL-10 (which normally functions to suppress IgE production and eosinophilia).  

 

     Autoreactive T cells in Omenn syndrome appear to result from failed central and peripheral tolerance.  Reduced AIRE gene expression in thymic tissue and decreased peripheral FOXP3+ T regulatory cells have been reported in Omenn syndrome patients.          

 

 

                                 

EVALUATION

 

The diagnosis of Omenn syndrome should be considered in patients presenting with a SCID-like phenotype (FTT, diarrhea, thrush, PJP, severe respiratory virus infections, infections from live viral vaccines) along with erythroderma, hepatosplenomegaly, and lymphadenopathy.

 

Step 1:  Immunologic Screening Tests

 

-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, IgE levels 
-Specific Antibody levels (if older than 6 months)
-Chest X-Ray

 

-Eosinophilia is present on the CBC.  The absolute lymphocyte count may be normal in Omenn syndrome unlike classic SCID. 
-Normal T cell numbers and present in Omenn syndrome.  B cell numbers and NK cell numbers may be decreased depending on the type of SCID mutation.  
-The oligoclonally expanded T cells in Omenn syndrome have a predominantly memory (CD45RO) phenotype with poor response to mitogens.   Maternally engrafted T cells will also have a memory phenotype with poor response to mitogens (however, elevated IgE and eosinophilia are not present in this situation).    
-Elevated IgE is a hallmark of Omenn syndrome.  IgG, IgM and IgA are low.  However, IgG levels may be normal for infants younger than 6 months due to maternal IgG in circulation. 
-Specific antibody responses to vaccine antigens are low.
-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 Omenn syndrome and SCID.  

 

-TREC Analysis
-TCR Gene Rearrangement PCR (TCR Spectratyping)

 

-TRECs (T-cell receptor excision circles) are loops of DNA excised during TCR rearrangement.  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.  Omenn syndrome patients typically have very low TREC numbers.
-TCR gene rearrangement is useful for identifying oligoclonally expanded T-cells in Omenn syndrome.  Oligoclonally expanded T cells can also be seen in maternal T cell engraftment.  

 

 

Step 3:  Genetic testing for SCID mutations - This can help to confirm a diagnosis of Omenn syndrome.  The presence or absence of B cells and NK cells as well as family inheritance patterns may be useful for directing appropriate testing.  The presence of characteristic clinical features should direct testing for syndromes such as 22q11.2 deletion, CHARGE syndrome, and Cartilage Hair Hypoplasia.   

 

-Genetic testing for SCID mutations (RAG1, RAG2, Artemis, IL7-R, common gamma chain)
-FISH or Genome Wide Array for 22q11.2 deletion
-CHD7 gene sequencing (CHARGE syndrome)
-RMRP gene sequencing (Cartilage Hair Hypoplasia)

 

-Genetic testing for a number of SCID mutations is commercially available (correlagen diagnostics).
-Genome wide array, CHD7 sequencing and RMRP sequencing are commercially available (GeneDx).    

 

 

 

                                                                   

MANAGEMENT

 

    Pending the completion of an immunologic evaluation for suspected Omenn syndrome, it is critical to initiate certain measures to prevent life-threatening complications for patients.  Despite having a normal number of total T cells, patients are profoundly immunocompromised.  The following precautions should be implemented immediately: 

 

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


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.   


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


IVIG replacement therapy


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

 

     Immunosuppressive therapies are required for treatment of dermatitis and hepatosplenomegaly resulting from autoreactive oligoclonal T cells.  

Even with supportive therapies, patients with Omenn syndrome will not survive without a HSCT.  T cell depleted haploidentical transplants have a poor success rate in Omenn syndrome (approximately 50%).  Matched sibling or matched unrelated transplants are preferred.  Successful outcomes with myeloablative or reduced intensity conditioning have been reported.  

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    

 

1.  CORRELAGEN - SCID genes 
2.  GENE DX - RMRP sequencing
3.  GENE DX - Genome Wide Array CGH
4.  GENE DX - CHD7 sequencing

 

 

Literature Resources

 

1.  Villa 2008 
     Omenn Syndrome Review

 

2.  Mazzolari 2005 
     HSCT in Omenn Syndrome (11 patients)

 

3.  Nahum 2009 
     Matched Unrelated BMT for Omenn Syndrome (6 patients)