What are the other Names for this Condition? (Also known as/Synonyms)

• Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome
• IPEX Syndrome

What is Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome? (Definition/Background Information)

• Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked (IPEX) Syndrome, also known as Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome, is a severe congenital systemic autoimmune disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections
• Less than 150 cases have been reported to date but the disease has probably been underestimated 
• IPEX Syndrome is caused by mutations in the FOXP3 gene (Xp11.23). This gene codes for a forkhead transcription factor, which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in downregulation of immune responses and self-tolerance
• IPEX Syndrome usually develops during the first few days or weeks of life and affects exclusively boys 
• The disease manifests with the sequential appearance of the triad of enteropathy, autoimmune disease, and cutaneous involvement, but the clinical features and severity of the disease can vary considerably between individuals
• The only curative treatment for IPEX Syndrome is hematopoietic stem cells transplantation (HSCT), which is much more successful when performed in the early stages of the disease
• Without timely diagnosis and treatment, the disease is usually fatal within the first 2 years of life. Some may survive into childhood. With HSCT, life expectancy is likely to be normal although feeding difficulties may persist for many months post HSCT

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome? (Age and Sex Distribution)

• Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome is an extremely rare congenital disorder. The presentation of symptoms may occur at birth or infancy
• Currently, fewer than 150 cases have been described in the medical literature 
• The condition exclusively affects males, since it is an X-linked disorder

What are the Risk Factors for Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome is an inherited disorder
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome? (Etiology)

Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome (IPEX Syndrome) is caused by mutations in the FOXP3 gene (Xp11.23).

• This gene codes for a forkhead transcription factor, which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in downregulation of immune responses and self-tolerance
• The disorder is inherited in an X-linked manner

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome?

Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome presents with signs and symptoms of the triad of enteropathy, autoimmune disease, and cutaneous involvement, which appear in a sequential manner. The clinical features and severity of the disease can vary considerably between individuals.

The signs and symptoms of severe autoimmune enteropathy include:

• Intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive 
• Vomiting 
• Ileus
• Gastritis 
• Colitis 

The signs and symptoms of autoimmune endocrinopathies include:

• Insulin-dependent diabetes mellitus (type 1 DM)
• Thryroiditis leading to hypothyroidism or hyperthyroidism
• Autoimmune cytopenia
• Thrombocytopenia
• Hemolytic anemia
• Neutropenia
• Pneumonitis
• Hepatitis
• Nephritis
• Myositis
• Splenomegaly and/or lymphadenopathy

The signs and symptoms of cutaneous involvement may include:

• Generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis 
• Alopecia 
• Onychodystrophy

In addition, local or systemic infections (e.g. pneumonia, Staphylococcus aureus infections, and candidiasis) may occur but seem to be due to loss of skin and gut barriers, immunosuppressive therapies, and poor nutrition rather than a primary immunodeficiency.

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How is Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome Diagnosed?

Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome is diagnosed on the basis of the following information:

• Clinical examination 
• Family history
• Laboratory findings revealing autoimmune enteropathy (anti-enterocyte, harmonin and villin autoantibodies), type 1 DM (antibodies against insulin, pancreatic islet cells, or anti-glutamate decarboxylase), thyroiditis (anti-thyroglobulin and anti-microsome peroxidase antibodies) and cytopenia (anti-platelets and anti-neutrophils antibodies, positive Coombs test)
• Molecular genetic testing confirms the diagnosis

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome?

The complications of Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome may include:

• Failure to thrive 
• Frequent infections such as pneumonia

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome Treated?

The following is information on treatment modalities for Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome:

• The only curative treatment for IPEX is hematopoietic stem cells transplantation (HSCT), which is much more successful when performed in the early stages of the disease 
• Supportive measures include monotherapy or combined immunosuppressive therapy with glucocorticoids (prednisone and methylprednisolone), cyclosporin A (CSA), tacrolimus, azathriopine, rapamycin, lifelong insulin and thyroid hormones supplementation in case of organ failure, topical CSA for skin manifestations, and parenteral nutrition for severe cases of enteropathy

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome be Prevented?

Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome? (Outcomes/Resolutions)

• Without timely diagnosis and treatment, the prognosis for Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome is poor, since the disease is usually fatal within the first 2 years of life. Some affected babies may survive into childhood 
• With HSCT, life expectancy is likely to be normal although feeding difficulties may persist for many months post HSCT. Neurodevelopment is normal

(Source: Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Additional and Relevant Useful Information for Immunodysregulation, Polyendocrinopathy and Enteropathy X-Linked Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/