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Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Orpha number ORPHA37042
Synonym(s) Autoimmune enteropathy type 1
IPEX
Prevalence <1 / 1 000 000
Inheritance X-linked recessive
Age of onset Infancy
Neonatal
ICD-10
  • E31.0
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT -

Summary

Immunodysregulation - polyendocrinopathy - enteropathy - X-linked (IPEX) syndrome is a severe congenital systemic autoimmune disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections.

Prevalence is unknown. Less than 150 cases have been reported to date but the disease has probably been underestimated.

IPEX syndrome usually develops during the first few days or weeks of life and affects exclusively boys. It manifests with the sequential appearance of the triad of enteropathy, autoimmune disease, and cutaneous involvement, but the clinical features and severity of the disease can vary considerably between individuals. Severe autoimmune enteropathy manifests with intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive. Vomiting, ileus, gastritis or colitis can also be observed. Patients also present with autoimmune endocrinopathies, generally insulin-dependent diabetes mellitus (type 1 DM), but also thryroiditis leading to hypothyroidism or hyperthyroidism. Skin involvement consists of a generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis. Less frequently, alopecia or onychodystrophy can be observed. Patients may develop autoimmune cytopenias, thrombocytopenia, hemolytic anemia and neutropenia. Autoimmune involvement may also lead to pneumonitis, hepatitis, nephritis, myositis, splenomegaly and/or lymphadenopathy. Local or systemic infections (e.g. pneumonia, Staphylococcus aureus infections, candidiasis) may occur but seem to be due to loss of skin and gut barriers, immunosuppressive therapies, and poor nutrition rather than a primary immunodeficiency.

IPEX syndrome is caused by mutations in the FOXP3 gene (Xp11.23). This gene codes for a forkhead transcription factor which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in downregulation of immune responses and self-tolerance.

Diagnosis is based on clinical examination, family history, and laboratory findings revealing autoimmune enteropathy (anti-enterocyte, harmonin and villin autoantibodies), type 1 DM (antibodies against insulin, pancreatic islet cells, or anti-glutamate decarboxylase), thyroiditis (anti-thyroglobulin and anti-microsome peroxidase antibodies) and cytopenia (anti-platelets and anti-neutrophils antibodies, positive Coombs test). Molecular genetic testing confirms the diagnosis.

Differential diagnosis includes Wiskott-Aldrich and Omenn syndromes, STAT1 deficiency, CD25 deficiency, IL10R deficiency, STAT5b deficiency, transient neonatal diabetes, severe combined immunodeficiency or intermediate forms of combined immunodeficiency, X-linked thrombocytopenia and pancreatic hypoplasia or agenesis (see these terms).

Prenatal diagnosis from chorionic villus samples is possible after determination of the fetal sex by karyotype analysis for families in which the disease-causing mutation has been identified.

Transmission is X-linked recessive. There is a 50% risk of transmission when the fetus is a male. 50% of females will be carriers.

The only curative treatment for IPEX is hematopoietic stem cells transplantation (HSCT), which is much more successful when performed in the early stages of the disease. Supportive measures include monotherapy or combined immunosuppressive therapy with glucocorticoids (prednisone and methylprednisolone), cyclosporin A (CSA), tacrolimus, azathriopine, rapamycin, lifelong insulin and thyroid hormones supplementation in case of organ failure, topical CSA for skin manifestations, and parenteral nutrition for severe cases of enteropathy.

Without timely diagnosis and treatment, the disease is usually fatal within the first 2 years of life. Some may survive into childhood. With HSCT, life expectancy is likely to be normal although feeding difficulties may persist for many months post HSCT. Neurodevelopment is normal.

Expert reviewer(s)

  • Dr Andrew GENNERY

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Detailed information

Clinical genetics review
  • EN (2011)
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