IPEX Syndrome

Clinical characteristics: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is characterized by systemic autoimmunity, typically beginning in the first year of life, which includes the triad of enteropathy (manifesting as malabsorption and watery diarrhea), endocrinopathy (most commonly type 1 insulin-dependent diabetes mellitus), and eczematous dermatitis. In addition to these manifestations, many children have other autoimmune phenomena including cytopenias, autoimmune hepatitis, nephropathy, lymphadenopathy, splenomegaly, alopecia, arthritis, and interstitial lung disease related to immune dysregulation. Fetal presentation of IPEX syndrome includes hydrops, echogenic bowel, skin desquamation, intrauterine growth deficiency, and fetal akinesia. Without aggressive immunosuppression or hematopoietic stem cell transplantation (HSCT), the majority of affected males will die within the first one to two years of life from metabolic derangements, severe malabsorption, or sepsis. Individuals with a milder phenotype have survived into the second or third decade of life, but this is uncommon.

Diagnosis/testing: The diagnosis is established in a male proband with typical clinical findings, absent regulatory T cells (Treg) in blood or tissues, decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry (although FOXP3 levels in Treg can be normal in some individuals), and a hemizygous pathogenic variant in FOXP3 identified by molecular genetic testing. Heterozygous females have not been reported to have clinical findings typical of IPEX syndrome.

Management: Targeted therapies: HSCT offers the only potential cure for IPEX syndrome. T cell-directed immune suppression can include either an mTOR inhibitor (sirolimus) or calcineurin inhibitor (cyclosporin A or tacrolimus), alone or in combination with corticosteroids.

Supportive care: Total parenteral nutrition (TPN) with fluids and electrolyte support is needed until intestinal function can be established with immune suppression. Treatment of type 1 insulin-dependent diabetes mellitus with insulin and carbohydrate management is standard, as is management of autoimmune thyroid disease. Skin conditions are managed with topical therapies, which can include steroids, tacrolimus, and emollients. Autoimmune neutropenia has been successfully treated with granulocyte colony-stimulating factor; pemphigus nodularis has been treated with rituximab (anti-CD20), and rituximab has been used for other autoantibody-mediated disease. Prophylactic antibiotic therapy may be required for autoimmune neutropenia or recurrent infections with central venous access and TPN. Aggressive management of dermatitis with topical steroids and anti-inflammatory agents as needed to prevent cutaneous infections.

Surveillance: Monitor growth, nutritional intake, and stooling patterns at each visit; glucose tolerance test, hemoglobin A1c, and thyroid function tests every three to six months; skin exam at each visit; complete blood count, blood urea nitrogen, creatinine, urinalysis, and serum aspartate transaminase and alanine transaminase every three to six months.

Agents/circumstances to avoid: Withhold immunizations until after HSCT, if possible.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk males either prenatally or immediately after birth to enable early diagnosis and HSCT and/or immune suppression treatment in affected males before significant organ damage occurs.

Genetic counseling: IPEX syndrome is inherited in an X-linked manner. The risk to sibs of the proband depends on the genetic status of the mother. If the mother of the proband has a FOXP3 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous (to date, IPEX syndrome has not been reported in females who are heterozygous for a FOXP3 pathogenic variant). Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Once the FOXP3 pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal/preimplantation genetic testing are possible.