SUMMARY

 

1.  Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disorder characterized by the following clinical features:

 

-Profound diarrhea - from autoimmune enteropathy starting in infancy resulting in failure to thrive (small bowel biopsy reveals villous atrophy)
-Autoimmune disease (diabetes, thyroid disease, autoimmune cytopenias)
-Atopic dermatitis
-Poor prognosis - death occurs in early childhood without treatment.  

 

2.  IPEX is caused by mutations in the FOXP3 gene.  Foxp3 is a master transcription factor responsible for the development and function of T regulatory cells (Tregs).  Tregs function to suppress peripheral autoreactive T cells through a contact-dependent and cytokine-mediated mechanism.  Treg dysfunction leads to loss of peripheral tolerance and activation of self-reactive lymphocytes which cause autoimmune disease.  

 

3.  Elevated IgE levels and eosinophilia are the most consistent (but non-specific) laboratory findings. Quantitative and functional humoral and cell-mediated immune studies are typically normal.  Phagocyte function and complement levels are also normal.  A variety of autoantibodies can be present. 

 

4.  Flow cytometry typically reveals a lack of Treg (CD4+CD25+Foxp3+) cells.  However, Foxp3 protein can still be detected in patients with missense mutations (the protein is non-functional).  

 

5.  Mutation analysis of the Foxp3 gene can confirm the diagnosis.  

 

6.  One-half of patients with an IPEX phenotype lack mutations in Foxp3.  These "IPEX-like" patients likely have other gene defects that impair Treg development or function (CD25 deficiency is one such etiology). 

 

7.  IPEX and IPEX-like patients are typically treated with immunosuppressive agents that target T cell activation such as cyclosporine, FK-506, and rapamycin.  Nutritional support such as total parenteral nutrition is frequently required.  

 

8.  Hematopoietic stem cell transplantation is curative and should be considered early (before disease manifestations accumulate) for patients if a matched donor is available. 

 

 

 

                                                                                                                 

 

OVERVIEW

 

    Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disorder characterized by the following clinical features:

 

-Profound diarrhea - from autoimmune enteropathy starting in infancy resulting in failure to thrive (bowel biopsy reveals villous atrophy)
-Autoimmune disease (diabetes, thyroid disease, autoimmune cytopenias)
-Atopic dermatitis
-Death occurring in early childhood without treatment

 

     IPEX is caused by mutations in the FOXP3 gene.  Foxp3 is a master transcription factor responsible for the development and function of T regulatory cells (Tregs).  Tregs function to suppress peripheral autoreactive T cells through a contact-dependent and cytokine-mediated mechanism.  Treg dysfunction leads to loss of peripheral tolerance and activation of self-reactive lymphocytes which cause autoimmune disease.  

 

     Elevated IgE levels and eosinophilia are the most consistent (but non-specific) laboratory findings. Quantitative and functional humoral and cell-mediated immunity studies are typically normal.  Phagocyte function and complement levels are also normal. 

 

     A variety of self-reactive antibodies can be present including anti-islet cell, anti-insulin, anti-GAD, anti-thyroid peroxidase, anti-thyroglobulin, anti-enterocyte, anti-platelet, or anti-neutrophil antibodies. 

         

 

                                 

EVALUATION

 

Male infants presenting with the clinical triad of autoimmune enteropathy with villous blunting, endocrinopathy (Type I diabetes, thyroid disease) and severe dermatitis warrant further evaluation for IPEX syndrome.  Female patients with IPEX-like syndrome can present with a very similar clinical phenotype.  
     
Step 1:  Immune Evaluation

 

-CBC with Differential
-Quantitative immunoglobulins (IgG, IgM, IgA, IgE) 
-Antibody titers to vaccine antigens   
-Flow cytometry for B cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens

 

-The CBC reveals eosinophilia.  Anemia, thrombocytopenia, or neutropenia may be present  this should prompt additional testing such as direct/indirect coombs, anti-platelet Ab, and anti-platelet Ab.  
-Patients have elevated IgE levels with normal IgG, IgA, and IgM.  
-Protein (Tetanus, Diptheria) and polysaccharide (Pneumococcus) vaccine responses should be evaluated.  Patients typically have normal specific antibody responses.  
-Lymphocyte subset values and T cell proliferation to mitogens are normal unless a patient is taking immunosuppressive medications. 

 

 

Step 2:   Additional Studies

 

-Serum glucose and anti-islet antibodies
-TSH, Free T4, anti-thyroglobulin antibodies, and anti-thyroid perxidase antibodies
-Small bowel biopsy

 

-Serum glucose and anti-islet antibodies should be checked to screen for type I diabetes, the most common autoimmune manifestation in this syndrome. 
-Autoimmune thyroid disease is also a common disease manifestation
-Villous atrophy is seen in small bowel biopsy specimens from IPEX patients.  However, this is a relatively non-specific finding that can be seen in other conditions such as celiac disease.  

 

 

Step 3:  Foxp3 Flow Cytometry

 

-FOXP3 Flow Cytometry

 

-Flow cytometry for Foxp3 protein is commercially available.
-The detection of Foxp3 by flow cytometry does not rule out IPEX as patients with missense mutations can still express non-functional protein.    

 

 

Step 4:  Gene Sequencing

 

-FOXP3 Gene Sequencing 

 

-FOXP3 gene sequencing is commercially available through Cincinnati Childrens molecular genetics laboratory.  
-More than one-half of patients lack mutations in the FOXP3 gene.  These patients may have other gene mutations that cause an IPEX phenotype (ex. CD25 deficiency).  

 

 

                                                                   

MANAGEMENT

       

    IPEX and IPEX-like patients are typically treated with immunosuppressive agents that target T cell activation such as cyclosporine, FK-506, and rapamycin.  Nutritional support such as total parenteral nutrition is frequently required.  

     Patients with IPEX syndrome have significant morbidity and mortality in childhood even with supportive therapies.  As a result, hematopoietic stem cell transplantation (HSCT) is a consideration for patients.  
HSCT is curative and should be initiated as soon as possible (before disease manifestations accumulate) for patients with a matched donor.  Recent results with the use of reduced intensity conditioning have been encouraging.  

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    

 

1. Cincinnati Childrens Foxp3 Flow Cytometry

2. Cincinnati Childrens Foxp3 Gene Sequencing

 

 

Literature Resources

 

 

1.  Torgerson 2007 
     IPEX (review)
     

2.  Rao 2007 
     Successful BMT for IPEX using reduced intensity conditioning (4 patients)
     

3.  Dorsey 2009 
     FOXP3 expression following reduced intensity conditioning BMT for IPEX (1 case)
     

4.  Baud 2001 
     Treatment of IPEX with BMT (1 case - death from HLH)