Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

Overview

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is characterized by the development of multiple autoimmune disorders in affected individuals. Autoimmune disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. 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. Most patients with IPEX syndrome are males, and the disease can be life-threatening in early childhood.

Symptoms

Almost all individuals with IPEX syndrome develop a disorder of the intestines called enteropathy. 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. 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 white blood cells (neutropenia) because these cells are attacked by the immune system. In some individuals, IPEX syndrome involves the liver and kidneys.

Causes

Mutations in the FOXP3 gene cause some cases of 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 the immune system and preventing autoimmune disorders. Mutations in the FOXP3 gene lead to reduced numbers or a complete absence of regulatory T cells. Without the proper number of regulatory T cells, the body cannot control immune responses. Normal body tissues and organs are attacked, causing the multiple autoimmune disorders present in people with IPEX syndrome.

About half of individuals diagnosed with IPEX syndrome do not have identified mutations in theFOXP3 gene. In these cases, the cause of the disorder is unknown.

Prevention

When IPEX syndrome is due to mutations in the FOXP3 gene, it 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 a condition that appears identical to IPEX syndrome, but they do not have mutations in the FOXP3 gene. The inheritance pattern for this IPEX-like syndrome is unknown, but females can be affected.

Diagnosis

The diagnosis of IPEX can take several months and delays crucial immunosuppressive treatment. The diagnosis of IPEX depends heavily on the family history, the elimination of other diagnoses of similar presentation, and the clinical presentation. Physicians are responsible for the elimination of other possible diseases prior to an official diagnosis of IPEX. Transient neonatal diabetes, pancreatic hypoplasia, autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy are examples of disorders that must be ruled out by the physician. Laboratory findings in IPEX show elevated IgE levels in the patients’ serum and 60% have shown elevated IgA levels in the serum. It is also necessary to detect anti-enterocyte antibodies in the patients’ serum, which is a common finding in IPEX syndrome. In patients with IPEX CD4+CD25+, T cells are present, but most patients with FOXP3 mutations have decreased or absent Treg cells. Other than the Treg cells, the other T and B cells appear normal. Patients that present with intractable diarrhea should have a biopsy of the intestinal mucosa performed to determine if villous atrophy is a symptom. The laboratory is developing new ways to identify IPEX through the use of endoscopic biopsy. The endoscopic biopsies are taken of the duodenal, colonic mucosa, and gastric mucosa. These biopsies are used to determine the degree of villous atrophy.

Age is not a reason to rule out IPEX as a possible diagnosis. Normally, patients present with intractable diarrhea at approximately 4 months of age. Research has shown that the location of the mutation on the FOXP3 gene determines the severity of the syndrome. Most of the symptoms can be treated individually, allowing patients to live longer and remain undiagnosed. Retrospective research is uncovering new cases with a wide range of ages. The presence of a rash or psoriasiform dermatitis, IDDM, and/or hypothyroidism supports a diagnosis of IPEX. When these symptoms are present, hemolytic anemia, thrombocytopenia, or neutropenia may also be present. If IPEX is suspected based on clinical presentation and family history, the diagnosis will be confirmed by mutation analysis of the FOXP3 gene.

Prognosis

IPEX is a rare disease that has been proven to occur more frequently than previously suspected. The clinical phenotype of IPEX is a direct result of an overactive immune system caused by the proliferation of autoaggressive T and autoantibody-producing B cells. Without prompt diagnosis and treatment, the disease can be fatal within 1 year. Mutation of the transcription factor FOXP3 results in the absence or dysfunction of Tregs and leads to the IPEX phenotype. Patients should be screened for IPEX using immunohistochemical staining of the gastrointestinal mucosa for the FOXP3 protein and villous atrophy.¹⁸ Several experimental treatments are still undergoing research to determine which is the most effective. Patients should be treated by bone marrow transplant, cord blood transfusion, and/or immunosuppressive drugs like cyclosporine A, tacrolimus, or sirolimus; however, all have mixed results. New research is underway to determine a more effective treatment for IPEX patients.

Treatment

Therapeutic options to control the life-threatening symptoms caused by IPEX are limited. Most treatments are ineffective, but 2 experimental approaches show the most promise. The most successful treatments are immunosuppression combined with steroids and bone marrow transplant. In addition to these treatments, supportive measures are sometimes necessary. Parenteral nutrition, insulin injections, red blood cell and platelet transfusion, and prophylactic intravenous gamma globulin are needed to aid the treatments. Most treatments are successful in the short term; however, more long-term success is needed.

Chronic immunosuppression has had positive results in some patients with IPEX, but has been ineffective in others. Patients administered regimens that include a combination of steroids and the calcineurin suppressive agents, cyclosporine A (CsA) or tacrolimus, have shown high levels of improvement; however, long-term use is limited due to its direct renal toxicity. Cyclosporine A given alone leads to immediate results but will not prevent a fatal outcome. When given CsA combined with prednisolone, patients show long-term results with no toxicity present. The treatment is given in the following doses: 2 mg/kg of CsA and 0.5 mg/kg of prednisolone. Complete remission was possible and maintained through the daily low dose of CsA and prophylactic intravenous gamma globulin. Cyclosporine A treatment produced similar results in the study conducted by Powel and colleagues, where 1 patient survived long-term.

Success has been seen with tacrolimus and dexamethasone; however, this combination leads to several side effects. One patient has survived long-term but he suffers from osteoporosis, renal tubular disease, growth failure, and a steroid induced cataract. To overcome the renal toxicity of these treatments, research has been conducted with sirolimus as an effective treatment. Sirolimus, unlike tacrolimus and CsA, does not block calcium fluctuation. Sirolimus is a less-toxic T-cell immunosuppressor that targets and inhibits a serine-threonine kinase, blocking lymphocyte maturation in the late G1 phase. It is believed that it acts on the effector T cells, leaving the regulatory T cells relatively unaffected and fully functional, creating a balance in Treg cells versus effector T cells. Sirolimus was shown to successfully control the gastrointestinal and dermatologic symptoms of IPEX while reducing the inflammatory reactions in all 3 patients in the study. Many of the skin lesions of IPEX patients can be treated with topical steroids and immunomodulatory agents. The lesions have improved with these treatments.

Allogenic bone marrow transplants, hematopoietic stem cell transplants, and submyeloblative cord blood transplants have all been used in the treatment of IPEX. Bone marrow transplants were originally thought of as the essential treatment, but the use of these treatments has shown mixed results. In most cases, the conditioning regimen itself controlled most of the clinical and biologic features of the disease. The engrafted bone marrow is believed to be responsible for the complete remission that is seen in some patients. Since IPEX is caused by a germ-line mutation, autologous bone marrow transplants would not lead to a full remission. The mixed results of bone marrow transplants suggest that further experience is needed to make this an effective treatment. Bone marrow transplants should be performed early in the course of the disease. Treatments should start at the initial onset of symptoms. The discovery of the genetic basis of IPEX allows early infant screening of males at risk. If the infants have the mutation in the FOXP3 gene, then presymptomatic bone marrow transplants can be performed to prevent the clinical manifestations.