IPEX Syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, more commonly known as IPEX syndrome, is a rare genetic disorder that can present early in life with diabetes, diarrhea and eczema. The condition is extremely rare, affecting about 1 in every 1.6 million people, and most often presents in early infancy.

The syndrome is characterized by severe enteropathy, chronic dermatitis, early onset type I diabetes mellitus (T1DM), thyroid disease and other autoimmune symptoms.

In most cases, IPEX syndrome is caused by variations in the FOXP3 gene, which guides the production of regulatory T cells, a type of immune cells. Without a normal FOXP3 gene, other immune cells in the body mistakenly attack healthy tissues.

The FOXP3 gene is carried on the X chromosome and almost exclusively affects boys, who only have one X chromosome (girls can be carriers of this condition). Children with IPEX syndrome are typically treated with immunosuppressive medications, with varying levels of success.

IPEX syndrome is also known as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD), IDDM secretory diarrhea syndrome and XPID.

Autoimmune disorders are the most common symptoms of IPEX syndrome, and most individuals diagnosed with the condition have at least two of the following:

• Autoimmune enteropathy: An autoimmune attack on the gastrointestinal (GI) tract that causes severe, watery diarrhea making it difficult for affected children to properly absorb nutrients, leading to trouble gaining weight and growing properly (failure to thrive).
• Rashes: Inflammatory rashes of the skin are present in most children with IPEX syndrome, with eczema being the most common. Other common rashes include psoriasis, pemphigus and crusting erythematous dermatitis.
• Diabetes: Type I diabetes, which leads to high blood sugar levels as insulin-producing cells in the pancreas are under attack by the immune system. The body’s ability to produce insulin is destroyed and life-long medication will be needed.
• Thyroid disease: Autoimmune attack of the thyroid gland leads to problems with normal production of thyroid hormone. In most cases, this causes a decreased level of thyroid hormone production, known as hypothyroidism, which may make the child feel cold, have low energy, etc. In some individuals the autoimmune attack of the thyroid gland may cause hyperthyroidism (increased thyroid hormone levels) or antithyroid peroxidase antibody positivity (such as Hashimoto’s thyroiditis or Graves’ disease).

Other common symptoms of IPEX syndrome (affecting 30-80% of children with the disorder) include:

• Allergy symptoms
• Failure to thrive in infancy
• Increased IgE levels
• Anemia
• Secretory diarrhea

Less common symptoms include skin, liver and other GI disorders, and in rare cases, arthritis, hair loss, and infections of the muscles, blood or bone.

IPEX syndrome is caused by a faulty FOXP3 gene on the X-chromosome and is inherited in an X-linked recessive pattern. The syndrome typically affects boys because they only have one X chromosome. Girls have two X chromosomes, so if one is affected, the other healthy chromosome can compensate. However, girls with a faulty X-chromosome are still considered carriers and have a 50% chance of passing on the defective gene to their children.

IPEX syndrome may be suspected in children with certain combinations of clinical characteristics including early-onset diarrhea, endocrine problems (particularly early-onset type I diabetes), and rash. At Children’s Hospital of Philadelphia (CHOP), these children are typically evaluated by experts in the Program for Integrated Immunodeficiency and Cellular Therapy (PIICT).

Evaluation for IPEX syndrome typically begins with a thorough medical history and physical examination of your child, as well as a variety of diagnostic tests including:

• Gene sequencing to identify a variation or mutation in the FOXP3 gene. This test is considered the gold standard in diagnosis of IPEX syndrome.
• Specialized blood tests to evaluate the child’s immune system.

Additionally, many individuals with IPEX syndrome have fewer regulatory T cells circulating in their blood. While some children with IPEX syndrome have a normal or increased number of regulatory T cells, the cells do not function appropriately to suppress other immune cells. However, there is no reliable clinical test to assess the function of regulatory T cells, so measurement or functional tests are not an accurate diagnostic test for IPEX syndrome.

Depending on your child’s symptoms, additional tests including X-rays, blood, urine and functional tests may be required to gain a better overall picture of your child’s health. We also perform baseline blood tests while your child is feeling healthy so we can compare results to those obtained if your child becomes ill. Regular blood tests are important for children with IPEX syndrome as they can often identify small problems – and allow your child’s care team to treat those problems – before symptoms worsen and require more definitive treatment.

At CHOP, a team of specialists from immunology and cellular therapy who have experience in assessing and treating emergent and long-term effects of primary immune deficiencies and related conditions work together to develop a coordinated treatment plan to address your child’s unique needs.

Initial treatment will be supportive care, which may include:

• Supplemental feeding for enteropathy
• Topical therapies, such as moisturizers, steroid ointments and immunosuppressant ointments
• Insulin
• Thyroid-replacement therapy
• Immune suppression medications

Most children with IPEX syndrome will eventually need a hematopoietic stem cell transplant, also called a bone marrow transplant. In some cases, a relative can be used as a donor. In other cases, a match may be found through the National Marrow Donor Program's Be the Match Registry.

Bone marrow transplantation offers the only curative therapy for IPEX syndrome. However, it does carry the risk of serious complications including graft-versus-host disease and other long-term effects. Further studies to evaluate long-term outcomes of bone marrow transplant for IPEX syndrome are underway.

Other potential treatments being investigated for IPEX syndrome are gene therapy and gene editing approaches. More studies are needed and it’s still too early to tell if either therapy could offer a viable treatment alternative.

Outcomes for children with classic, untreated IPEX syndrome are generally poor. Many children die within the first two years of life from inadequate organ function, severe malabsorption or sepsis. Improvements in immunosuppressive regimens have lengthened survival, but long-term immunosuppressants do not appear to prevent mortality.

Early bone marrow transplantation can cure IPEX. Some survivors are now 10-plus years post-transplant and doing well. For patients who have developed diabetes or thyroid disease before bone marrow transplant, these conditions will likely continue post-transplant after other signs of IPEX syndrome resolve. Survival and long-term outcomes improve the earlier an IPEX patient receives a transplant, especially if the transplant is received before irreversible organ damage occurs.

• Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Disease, Chapter 13
• National Organization of Rare Diseases: IPEX Syndrome
• Clinical, Immunologic, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome in Frontiers in Immunology