IPEX Syndrome

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is a rare congenital T-cell deficiency associated with transcription factor FOXP3 dysfunction. This factor regulates the development of a regulatory T cell line and dysfunctions usually result in autoimmunity. The condition manifests as autoimmune enteropathy, eczematous dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions. The only form of management for IPEX is bone marrow transplantation.

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Epidemiology and Etiology

Epidemiology

  • Occurs in 1 in 1.6 million people
  • Fewer than 300 cases of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome have ever been reported

Etiology

  • Has an X-linked recessive inheritance pattern, so primarily affects males
  • Caused by a mutation in the gene that encodes the forkhead box protein 3 transcription factor (FOXP3), located at Xp11.23-Xq13.3
X-linked recessive inheritance

The pattern of inheritance of X-linked agammaglobulinemia. Note that the mother must contribute the defective X gene to the male child in order for him to express this phenotype.

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Pathophysiology

  • The mutation causes a dysfunctional activation of regulatory T cells toward host tissues (autoimmunity).
  • Disruptions of the FOXP3 regulatory pathway can lead to organ-specific autoimmune diseases involving the skin, gastrointestinal (GI) tract, and endocrine glands.
  • Also associated with the loss of CD4+ CD25+ T regulatory cells, which are linked to autoimmunity

Clinical Presentation

Signs of systemic autoimmunity begin presenting in the 1st year of life.

  • Classic triad presentation: 
    1. Enteropathy: 
      • Chronic diarrhea (most common first symptom)
      • Underlying food allergies or infection
    2. Endocrinopathy: 
      • Hyper- or hypothyroidism
      • Thyroiditis
      • Type 1 diabetes mellitus
      • Atypical growth hormone deficiency
      • Hypoadrenalism 
    3. Dermatitis: 
      • Eczema or eczematous dermatitis
      • Nail dystrophy
  • Other symptoms include:
    • Lymphadenopathy
    • Cytopenias
    • Increased susceptibility to infections
    • Renal disease
    • Acute respiratory distress syndrome
    • Weight loss
    • Alopecia
    • Splenomegaly
    • Arthritis
    • Failure to thrive

Diagnosis and Management

Diagnosis

Diagnostic testing for IPEX syndrome follows systematic criteria consistent with:

  • Clinical examination: a classic triad of autoimmunity in a male infant or child (dermatitis, enteropathy, and thyroid disorder or insulin-dependent diabetes)
  • Family history: most mutations are familial; sporadic cases are rare
  • Genetic testing: hemizygous pathogenic variant in FOXP3
  • Laboratory findings: severely reduced/absent CD4+ CD25+ regulatory T cells

Management

Numerous medications are used and administration depends on each patient’s manifestations:

  • Corticosteroids: first-line treatment
  • Cyclosporin A, sirolimus, or FK506: T-cell–directed immune suppression
  • Bone marrow transplant: only potential cure for IPEX syndrome
  • Total parenteral nutrition (TPN): provides nutrition in cases of severe enteropathies
  • Standard treatment for diabetes mellitus and autoimmune thyroid disease (e.g., insulin and thyroid hormone supplementation)
  • Granulocyte colony-stimulating factor and prophylactic antibiotic therapy to address the associated autoimmune neutropenia
  • Topical steroids and anti-inflammatory agents: to treat eczema

Differential Diagnosis

The following conditions are differential diagnoses for IPEX syndrome:

  • Wiskott-Aldrich syndrome: an X-linked mixed disorder of B- and T-cell deficiency. The syndrome is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Presents as eczema, bleeding disorders, recurrent opportunistic infections, and autoimmunity.
  • Omenn syndrome: an autosomal recessive form of severe combined immunodeficiency (SCID) caused by mutations in the RAG1 or RAG2 genes. Presents with chronic diarrhea; erythroderma; desquamation; alopecia; failure to thrive; lymphadenopathy; hepatosplenomegaly; recurrent fungal, bacterial, and viral infections; and elevated levels of eosinophils and serum IgE.  
  • Transient neonatal diabetes: a form of diabetes that presents within the first few weeks of life but is transient. Usually caused by dysfunctional genes in chromosome 6. Affected infants go into remission within a few months, although the possibility of relapse into permanent diabetes in adolescence or adulthood remains. Presents as hyperglycemia, dehydration, and failure to thrive in infancy.
  • Severe combined immunodeficiency (SCID): the most severe form of primary immunodeficiency, SCID is a genetic disorder that involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Presents as severe and recurrent opportunistic infections and is diagnosed through quantitative PCR and flow cytometry.
  • X-linked thrombocytopenia: a bleeding disorder that affects males due to its X-linked recessive inheritance pattern. Characterized by low levels of platelets and presents with bleeding that occurs spontaneously or after minor trauma.
  • Pancreatic hypoplasia or agenesis: the congenital underdevelopment or complete lack of embryonic development of the pancreas. The pancreas is of endodermal origin, normally developing from the foregut. May present asymptomatically or with hyperglycemia, abdominal pain, diabetes mellitus, bile duct obstruction, or signs of pancreatitis.

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