Random Dermatology MCQ - IPEX Syndrome

A 6-month-old male infant presents with severe, intractable diarrhea, a widespread eczematous rash, and failure to thrive. Laboratory studies reveal markedly elevated blood glucose and absent insulin levels. Which of the following is the most likely genetic defect and the primary immunologic mechanism underlying this syndrome?

A) FOXP3 mutation; lack of regulatory T cells
B) STAT1 gain-of-function; enhanced interferon signaling
C) WAS gene mutation; cytoskeletal and signaling defects in hematopoietic cells
D) IL2RG mutation; X-linked SCID
E) AIRE mutation; failure of central tolerance

Correct Answer: A) FOXP3 mutation; lack of regulatory T cells

Explanation

This presentation is classic for IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked).

Key Clinical Features of IPEX Syndrome:

• Triad:

  1. Immune dysregulation: Severe, early-onset eczema, food allergies, autoimmune cytopenias.

  2. Polyendocrinopathy: Most commonly type 1 diabetes mellitus (as in this case, with hyperglycemia and no insulin), but also thyroiditis.

  3. Enteropathy: Profuse, watery, intractable diarrhea leading to failure to thrive.

• Inheritance: X-linked recessive (thus affecting males).

• Onset: Symptoms typically appear in the first few months of life.

Genetic Defect and Pathophysiology:

• Gene: Mutations in the FOXP3 gene on the X chromosome.

• Mechanism: The FOXP3 protein is a transcription factor essential for the development and function of regulatory T cells (Tregs).

  • Lack of functional Tregs leads to a catastrophic failure of immune tolerance.

  • This results in widespread autoimmunity against multiple organs (skin, intestines, pancreatic islets) and uncontrolled inflammation.

Why Not the Other Options?

• (B) STAT1 gain-of-function: Causes chronic mucocutaneous candidiasis and other infections due to impaired Th17 responses, not the triad of IPEX.

• (C) WAS gene mutation: Causes Wiskott-Aldrich syndrome (eczema, thrombocytopenia, immunodeficiency). It does not typically cause enteropathy or early-onset diabetes.

• (D) IL2RG mutation: Causes X-linked Severe Combined Immunodeficiency (SCID), characterized by severe, recurrent infections from birth, not autoimmune enteropathy and endocrinopathy.

• (E) AIRE mutation: Causes Autoimmune Polyglandular Syndrome Type 1 (APS-1), which includes mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. The enteropathy and eczema of IPEX are absent.

Management:

• Immunosuppression: High-dose corticosteroids, tacrolimus, or sirolimus to control autoimmunity.

• Definitive treatment: Allogeneic hematopoietic stem cell transplantation.

• Supportive care: Insulin for diabetes, total parenteral nutrition for enteropathy.

Prognosis:
Poor without transplantation; most patients die in early childhood from malnutrition or sepsis.

Note: IPEX syndrome is a paradigm of Treg deficiency. The combination of severe eczema, intractable diarrhea, and early-onset diabetes in a male infant is highly suggestive. Early recognition is critical for referral to a specialized immunology center.