Immunodysregulation, polyendocrinopathy and enteropathy X-linked

Other Names: IPEX syndrome; X-linked autoimmunity-allergic dysregulation syndrome; XLAAD; IDDM secretory diarrhea syndrome; DMSD; Autoimmunity-immunodeficiency syndrome x-linked; Diarrhea, polyendocrinopathy, fatal infection syndrome, x-linked; Enteropathy, autoimmune, with hemolytic anemia and polyendocrinopathy; Polyendocrinopathy, immune dysfunction and diarrhea x-linked; XPID

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome primarily affects males and is caused by problems with the immune system. Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a rare autoimmune disease. it affects only males and starts in the first six months of life. The immune system normally protects the body from foreign invaders, such as bacteria and viruses, by recognizing and attacking these invaders and clearing them from the body. However, the immune system can malfunction and attack the body's own tissues and organs instead, which is known as autoimmunity.

IPEX syndrome is characterized by the development of multiple autoimmune disorders in affected individuals. Although IPEX syndrome can affect many different areas of the body, autoimmune disorders involving the intestines, skin, and hormone-producing (endocrine) glands occur most often. IPEX syndrome can be life-threatening in early childhood.

Epidemiology

IPEX syndrome is a rare disorder that affects an estimated 1 in 1.6 million people.

Cause

Mutations in the FOXP3 gene cause IPEX syndrome. The protein produced from this gene is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. This protein is essential for the production and normal function of certain immune cells called regulatory T cells. Regulatory T cells play an important role in controlling immune responses and preventing autoimmune disorders.

Mutations in the FOXP3 gene impair the normal function of regulatory T cells, making it difficult for the body to turn off immune responses when they are not needed. Normal body tissues and organs are attacked, causing the multiple autoimmune disorders that develop in people with IPEX syndrome.

Inheritance

X-linked recessive inheritance

IPEX syndrome is inherited in an X-linked recessive pattern. The FOXP3 gene 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 must be present in both copies of the gene to cause the disorder. 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. Some people have conditions that appear identical to IPEX syndrome, but they do not have mutations in the FOXP3 gene. These conditions do not follow an X-linked inheritance pattern, and females can be affected. Such conditions are classified as IPEX-like syndromes.

Signs and symptoms

Almost all individuals with IPEX syndrome develop a disorder of the intestines called autoimmune enteropathy. Autoimmune enteropathy occurs when certain cells in the intestines are destroyed by a person's immune system. It causes severe diarrhea, which is usually the first symptom of IPEX syndrome. Autoimmune enteropathy typically begins in the first few months of life. It can cause failure to gain weight and grow at the expected rate (failure to thrive) and general wasting and weight loss (cachexia).

People with IPEX syndrome frequently develop inflammation of the skin, called dermatitis. Eczema is the most common type of dermatitis that occurs in this syndrome, and it causes abnormal patches of red, irritated skin. Other skin disorders that cause similar symptoms are sometimes present in IPEX syndrome.

The term polyendocrinopathy is used in IPEX syndrome because individuals can develop multiple disorders of the endocrine glands. Type 1 diabetes mellitus is an autoimmune condition involving the pancreas and is the most common endocrine disorder present in people with IPEX syndrome. It usually develops within the first few months of life and prevents the body from properly controlling the amount of sugar in the blood. Autoimmune thyroid disease may also develop in people with IPEX syndrome. The thyroid gland is a butterfly-shaped organ in the lower neck that produces hormones. This gland is commonly underactive (hypothyroidism) in individuals with this disorder, but may become overactive (hyperthyroidism).

Individuals with IPEX syndrome typically develop other types of autoimmune disorders in addition to those that involve the intestines, skin, and endocrine glands. Autoimmune blood disorders are common; about half of affected individuals have low levels of red blood cells (anemia), platelets (thrombocytopenia), or certain white blood cells (neutropenia) because these cells are attacked by the immune system. In some individuals, IPEX syndrome involves the liver and kidneys.

Diagnosis

The term "IPEX" is an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked.

Suggestive Findings IPEX syndrome should be suspected in males with the following clinical triad, family history, and suggestive laboratory findings.

Clinical triad

• Enteropathy that manifests as chronic watery diarrhea. Onset is typically in the first months of life; villous atrophy with a mononuclear cell infiltrate (activated T cells) in the lamina propria is the most common finding in biopsy.
• Endocrinopathy, most commonly type 1 diabetes mellitus with onset in the first months or years of life. Autoimmune thyroid disease leading to hypothyroidism or hyperthyroidism has also been observed .
• Dermatitis, most commonly eczematous presenting within the first months of life, although prenatal skin desquamation has been reported . Erythroderma, exfoliative dermatitis, psoriasis-like lesions, and pemphigus nodularis have also been observed .

Family history

• Consistent with X-linked inheritance

Note: Lack of a family history consistent with X-linked inheritance does not preclude the diagnosis.

Suggestive laboratory findings

No laboratory findings specifically identify affected individuals. Evidence of immune dysregulation manifested by the following is suggestive of IPEX syndrome:

• Elevated serum concentration of IgE (immunoglobulin E) and in some cases, IgA
• Eosinophilia
• Autoimmune anemia, thrombocytopenia, and/or neutropenia
• Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens
• Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some cases.

The diagnosis of IPEX syndrome is established in a male proband with the typical clinical findings and by the identification of a hemizygous pathogenic variant in FOXP3 by molecular genetic testing.

Treatment

Bone marrow transplantation (BMT) offers the only potential cure for IPEX syndrome. When done at the time of no or mild organ impairment, there is improved resolution of autoimmunity, especially when compared with non-transplanted individuals under chronic immunosuppressive therapy.

T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination with steroids, is considered first-line therapy; granulocyte colony stimulating factor (G-CSF) for autoimmune neutropenia; rituximab for pemphigus nodularis and other autoantibody-mediated disease; nutritional support; standard treatment of diabetes mellitus and autoimmune thyroid disease; topical therapies for dermatitis.

Prevention of secondary complications: Prophylactic antibiotic therapy for those with autoimmune neutropenia or recurrent infections; aggressive management of dermatitis with topical steroids and anti-inflammatory agents to prevent infection.

NIH genetic and rare disease info

• NIH info on Immunodysregulation, polyendocrinopathy and enteropathy X-linked

Immunodysregulation, polyendocrinopathy and enteropathy X-linked is a rare disease.

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