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IPEX Syndrome : A Rare Autoimmune Genetic Disorder

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IPEX syndrome is a rare genetic disorder that primarily affects males and is characterized by multiple autoimmune diseases. Read to know more.

Written by

Dr. Sameeha M S

Medically reviewed by

Dr. Nagaraj

Published At December 23, 2022
Reviewed AtJune 23, 2023

Introduction

IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome) is a rare disease of immune dysregulation. It commonly affects males and causes immune system disorders. In addition, the affected individual presents with a clinical triad of eczematous dermatitis, watery diarrhea, and endocrinopathy. In IPEX syndrome, systemic autoimmunity is seen during the first year of life. IPEX syndrome affects one in every 1.6 million people and often occurs due to abnormalities in the FOXP3 gene controlling T cell production. Without a normal FOXP3 gene, immune cells attack the body tissues, resulting in immune dysregulation and autoimmune disorders.

What Is IPEX Syndrome?

Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX syndrome) is a very rare genetic disorder related to the dysfunction of the gene FOXP3, which is involved in regulating T cells. Genetic mutations in the FOXP3 gene result in the dysfunction of CD4 cells and autoimmunity. Due to increased autoimmune activity, there will be autoimmune enteropathy, nail dystrophy, eczematous dermatitis, autoimmune endocrinopathies, bullous pemphigoid, and alopecia universalis.

In IPEX syndrome, the immune system's malfunction attacks the body's tissues and organs, resulting in autoimmune disorders involving the skin, intestine, and endocrine glands. Most individuals with IPEX syndrome develop intestinal disorders called autoimmune enteropathy. Autoimmune enteropathy begins in the first few months of life and causes failure in weight gain and expected growth. It results in frequent diarrhea, the first symptom of IPEX syndrome.

IPEX syndrome develops inflammation of the skin and eczema. It causes skin irritation and irregular red patches. Affected individuals typically develop other autoimmune disorders besides the skin, intestine, and endocrine glands. Autoimmune blood disorders result in anemia, thrombocytopenia, and neutropenia. Some people also see autoimmune disorders affecting the liver and kidneys.

What Are the Causes of IPEX Syndrome?

Mutations involving the FOXP3 gene cause IPEX syndrome. The FOXP3 gene is involved in immune cells' production and normal functioning, known as regulatory T cells. These cells play a significant role in preventing autoimmune disorders and controlling the body's immune response. Mutations in the FOXP3 gene disrupt the normal function of T cells and alter the body's immune response. This damages normal body tissues and organs, causing multiple autoimmune disorders in IPEX syndrome.

What Are the Symptoms Associated With IPEX Syndrome?

  • Diarrhea.

  • Gastritis.

  • Vomiting.

  • Colitis.

  • Type 1 diabetes.

  • Dermatitis.

  • Enteropathy.

  • Nephritis.

  • Hepatitis.

  • Interstitial lung disease.

  • Nephropathy.

  • Cytopenia.

  • Cheilitis.

  • Alopecia.

  • Food allergy.

  • Autoimmune hemolytic anemia.

  • Hematologic abnormalities.

  • Onychodystrophy.

  • Renal dysfunction.

  • Thyroid dysfunction.

  • Splenomegaly.

  • Recurrent infections.

  • Lymphadenopathy.

  • Arthritis.

  • Neutropenia.

  • Thrombocytopenia.

How Is IPEX Syndrome Inherited?

IPEX syndrome is an X-linked recessive disorder. The causative gene FOXP3 is located on the X chromosome. Males have only one copy of the X chromosome; thus, a single copy of the altered gene is sufficient to cause IPEX syndrome. In females, two copies of the mutated gene must be present to cause the disorder. Thus males are affected more as compared to females. However, in some people, IPEX syndrome is observed without any mutations in the FOXP3 gene and does not follow an X-linked inheritance pattern. In such cases, the conditions are termed IPEX-like syndromes.

How Is IPEX Syndrome Diagnosed?

Early detection of IPEX syndrome is necessary to provide immediate treatment and reduce complications. Diagnosis of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome is made with the help of the following criteria.

  • Classical triad (the classical symptoms associated with IPEX syndrome includes a triad of dermatitis, type 1 diabetes, and enteropathy).

  • Early onset of multiple autoimmunities.

  • Late onset of progressive or multiorgan autoimmunity.

  • Significant family history.

  • Laboratory tests (complete blood count, thyroid function test, nutritional markers, kidney function test, HbA1c, fasting glucose, plasma immunoglobulins, and biopsy).

  • Test for detecting specific autoantibodies for IPEX syndrome.

  • Genetic analysis (NGS or Sanger sequencing).

  • Multiple panel genetic testing and single gene testing.

The affected individuals show elevated serum IgE and IgA concentration, autoimmune anemia, eosinophilia, and a reduced number of FOXP3 Treg cells.

What Are the Treatment Options for IPEX Syndrome?

1. Treatment of Manifestations - Bone marrow transplantation is the potential treatment for IPEX syndrome. In affected individuals with mild organ impairment, bone marrow transplantation significantly improves the symptoms. Other treatment options to manage the primary symptoms are the following:

  • Immune suppression of T-cells (Tacrolimus, Sirolimus, and Cyclosporin -A).

  • Rituximab for the treatment of pemphigus nodularis.

  • G-CSF (granulocyte colony-stimulating factor) for autoimmune neutropenia.

  • Treatment for diabetes mellitus.

  • Topical medications for dermatitis.

  • Medications for thyroid diseases.

  • Nutritional support.

2. Prevention of Complications - Prophylactic antibiotic therapy for recurrent infections and autoimmune neutropenia, anti-inflammatory agents to prevent infections, and topical steroids to reduce skin irritations.

3. Surveillance - Apart from treating symptoms associated with IPEX syndrome and preventing complications, systematic monitoring for evidence of autoimmune diseases with lab tests is done every three to six months in individuals with IPEX syndrome. Other than this, monitoring nutritional intake, growth parameters, drug side effects, and immunosuppression related to bone marrow transplantation is also done.

4. Genetic Counseling - IPEX syndrome is an X-linked inherited disorder. Thus carrier testing to identify relative risk, prenatal genetic testing, and preimplantation diagnosis can be made for families with IPEX syndrome to rule out the chances of developing the disease and plan treatment accordingly.

Conclusion

Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome (IPEX) is characterized by severe autoimmunity that typically develops during the first year of life. This syndrome presents with a clinical triad of endocrinopathy, watery diarrhea, and eczematous dermatitis. In most cases, there will be autoimmune hepatitis, splenomegaly, arthritis, lung disease, cytopenias, lymphadenopathy, and nephropathy. Treatment of IPEX syndrome involves treatment of manifestations, prevention of secondary complications, and systematic surveillance.

Dr. Nagaraj
Dr. Nagaraj

Diabetology

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