Dermatology MCQ - Inflammatory Dermatoses - Pathophysiology of Atopic Eczema

A 4-year-old child with severe atopic eczema is being evaluated. Research into the underlying pathophysiology of his condition would most likely reveal a primary defect in which of the following?

A. Overexpression of interleukin-17 (IL-17) by Th17 cells
B. A gain-of-function mutation in the gene encoding desmoglein-1
C. A significant loss-of-function mutation in the gene encoding filaggrin
D. Uncontrolled activation of neutrophilic inflammation
E. A defect in the DNA repair enzyme due to a mutation in the XPA gene

Correct Answer: C. A significant loss-of-function mutation in the gene encoding filaggrin

Answer & Explanation

Explanation:
The pathophysiology of atopic eczema is complex and multifactorial, involving barrier dysfunction, immune dysregulation, and environmental factors. However, the single most significant genetic discovery is the association with loss-of-function mutations in the filaggrin gene (FLG).

• Filaggrin's Role: Filaggrin is a key protein in the stratum corneum. It is essential for the aggregation of keratin filaments, formation of the cornified envelope, and, upon degradation, it contributes to the skin's natural moisturizing factor (NMF) and the acidic pH of the skin surface.

• Consequence of Mutation: A filaggrin deficiency leads to a compromised epidermal barrier, allowing for increased transepidermal water loss (xerosis) and enhanced penetration of allergens and microbes. This barrier defect is considered a primary event that facilitates the subsequent immunological cascade, including the sensitization to allergens.

The other options are incorrect as they describe the pathophysiology of other conditions:

• A. Overexpression of interleukin-17 (IL-17) by Th17 cells is the hallmark of psoriasis, not atopic eczema. The dominant immune axis in atopic eczema involves Th2 cytokines (IL-4, IL-13, IL-31).

• B. A gain-of-function mutation in the gene encoding desmoglein-1 is the pathogenic mechanism in pemphigus foliaceus, where it leads to antibody-mediated acantholysis.

• D. Uncontrolled activation of neutrophilic inflammation is characteristic of conditions like pustular psoriasis, Sweet's syndrome, and pyoderma gangrenosum, not atopic eczema.

• E. A defect in the DNA repair enzyme due to a mutation in the XPA gene is the cause of xeroderma pigmentosum.

Key Associations for Atopic Eczema Pathophysiology

• Immune Dysregulation: There is a biphasic model. The acute phase is driven by Th2 cytokines (IL-4, IL-13, IL-31), which promote IgE production and itching. The chronic phase involves a shift to a Th1/Th22 profile with cytokines like IFN-γ and IL-22, leading to epidermal hyperplasia.

• Role of IL-31: This cytokine, primarily produced by Th2 cells, is a major pruritogen and is directly linked to the intense itch that is a defining feature of the disease.

• Microbiome: Staphylococcus aureus colonization and infection are extremely common in atopic skin, further exacerbating inflammation through superantigen production.

• Clinical Correlation: Understanding the filaggrin defect explains the clinical findings of dry, rough skin (xerosis), the associated condition of ichthyosis vulgaris, and the "atopic march" progression to food allergy, asthma, and allergic rhinitis, as a defective skin barrier is a major route of sensitization.