IPEX syndrome (FOXP3 deficiency)

IPEX syndrome (also known as FOXP3 deficiency) is a rare X-linked recessive genetic condition associated with life-threatening systemic autoimmunity. It is caused by hemizygous pathogenic variants in the FOXP3 gene, which encodes a master transcription factor essential to development and maintenance of CD4+ CD25+ regulatory T (Treg) cells. Affected patients present with a classic triad of eczema, type 1 diabetes and chronic diarrhoea.

Affected patients typically present shortly after birth with severe systemic autoimmune manifestations:

• type 1 diabetes;
• skin manifestations, typically atopic dermatitis – though pemphigoid, bullae and granulomas are also noted;
• chronic, intractable diarrhoea;
• thyroid disease;
• renal dysfunction;
• autoimmune cytopaenias; and
• recurrent infections.

Patients typically have eosinophilia with elevated serum IgE.

Rarely, myelodysplastic syndrome, developmental delay and malignancies have been described in IPEX syndrome.

Most cases present in the first few months of life, although milder or atypical phenotypes may present in later childhood.

Fetal manifestations, such as hydrops, skin desquamation and echogenic bowel, have also been described.

IPEX syndrome is caused by hemizygous pathogenic variants in the FOXP3 gene, which lies on the X chromosome. The gene encodes Foxp3, a member of the forkhead/winged helix family of transcription factors.

The C-terminal forkhead binding domain is particularly important for function, and most deleterious variants affect or abolish this region. A wide variety of variants are seen, including insertions, deletions, missense and splice-site variants, which result in the loss of function of the transcription factor.

IPEX syndrome may be diagnosed following clinical evaluation and laboratory tests with molecular confirmation.

The European Society for Immunodeficiencies diagnostic criteria is shown below.

• At least one of the following:
  • severe and protracted enteropathy with villous atrophy in a male infant; and/or
  • severe, often multiple endocrinopathies; and
• exclusion of hypogammaglobulinaemia; and
• at least one of the following:
  • normal Foxp3 expression by CD4+CD25+ on flow analysis;
  • no overt T cell defect (proliferations are normal); and/or
  • elevated IgA and IgE levels.

For information about genomic testing, see ‘Infant with features of very early-onset inflammatory bowel disease‘ and ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

IPEX syndrome may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to paediatric immunology services. Please refer to the local pathway for your region for this condition.

IPEX syndrome is inherited in an X-linked recessive pattern.

• X-linked recessive conditions are usually only present in males.
• Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
• Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
• Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Typically, mothers are asymptomatic carriers, though de novo variants commonly arise.

Reproductive options are available and genetic counselling, ideally prior to conception, is recommended.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

A specialist multidisciplinary approach is required in the management of IPEX syndrome.

Overall management should include:

• immunosuppressive treatments, such as mTOR inhibitors (sirolimus) or calcineurin inhibitors (cyclosporin A);
• corticosteroids, which may be used in conjunction;
• parental nutrition;
• insulin treatment and dietary management for type 1 diabetes; and
• rituximab (anti-CD20) or infliximab (anti-TNF), which may be used to control widespread inflammation.

The primary curative treatment for IPEX syndrome is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HCT soon after birth tend to have the best outcomes with fewer complications. Five-year survival rates are >90% with HSCT when the patient is less than three months old. However, this survival rate declines with increasing age of transplantation and presence of active infections at the time of transplant. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

IPEX syndrome may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnostic criteria
• GeneReviews: IPEX syndrome
• OMIM: 304790 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked

References:

• Barzaghi F, Amaya Hernandez LC, Neven B and others. ‘Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study‘. The Journal of Allergy and Clinical Immunology 2018: volume 141, issue 3, pages 1,036–1,049. DOI: 10.1016/j.jaci.2017.10.041
• Voarino M, Consonni F and Gambineri E. ‘Expanding the spectrum of IPEX: From new clinical findings to novel treatments‘. Current Opinion in Allergy and Clinical Immunology 2024: volume 24, issue 6, pages 457–463. DOI: 10.1097/ACI.0000000000001033

For patients

• Immune Deficiency Foundation: IPEX syndrome
• Immunodeficiency UK: Primary immunodeficiency