A 6-year-old boy presents with intense pruritus and visible flexural lichenified eczema (marked **A** in the diagram). His mother reports the rash worsens with sweating and wool clothing. On examination, he has hyperlinear palms and Dennie-Morgan infraorbital folds. His older sister has asthma. Which of the following BEST explains the pathophysiology of the lesion marked **A**?

Question

Accepted Answer

A. Loss-of-function mutations in the filaggrin gene causing epidermal barrier dysfunction and increased transepidermal water loss. ## Why Loss-of-function mutations in the filaggrin gene is right

Atopic dermatitis (AD) in the childhood phase (2–12 years) classically presents with **flexural lichenified eczema** (antecubital fossae, popliteal fossae, wrists, ankles, neck), as marked **A** in the diagram. The pathophysiology is multifactorial, but **epidermal barrier dysfunction** is foundational. Loss-of-function mutations in the **FLG gene** (filaggrin, chromosome 1q21) are present in 30–50% of moderate-to-severe AD cases. Filaggrin is essential for stratum corneum maturation and barrier integrity; its deficiency leads to **xerosis, increased transepidermal water loss (TEWL), and increased penetration of allergens and microbes**—perpetuating the itch-scratch cycle and chronic inflammation characteristic of the lichenified plaques seen in **A**. This is the primary mechanistic anchor in Nelson Pediatrics 22e and AAD guidelines.

## Why each distractor is wrong

- **Autoimmune destruction of melanocytes**: This describes vitiligo, not atopic dermatitis. AD is not an autoimmune condition targeting melanocytes; it is a chronic inflammatory disease driven by barrier dysfunction and Th2 hyperactivity.
- **Overproduction of Th1 cytokines (IFN-γ, IL-2) with neutrophilic infiltration**: AD is characterized by **Th2 polarization** with IL-4, IL-5, IL-13, and IL-31 overproduction, not Th1 dominance. Neutrophilic infiltration is not the hallmark; eosinophilia and mast cell activation are typical.
- **Keratinocyte hyperproliferation driven by constitutive STAT3 activation**: This describes psoriasis (marked **B** in the diagram), not atopic dermatitis. Psoriasis presents with extensor scaling plaques and is driven by Th17/IL-23 axis, not filaggrin deficiency.

**High-Yield:** Filaggrin mutations → barrier dysfunction → TEWL and allergen penetration → Th2 inflammation → lichenified flexural eczema in childhood AD.

[cite: Nelson Pediatrics 22e Ch 681; AAD AD Guidelines 2023]

Answer

B. Overproduction of Th1 cytokines (IFN-γ, IL-2) with neutrophilic infiltration

Answer

C. Keratinocyte hyperproliferation driven by constitutive STAT3 activation

Answer

D. Autoimmune destruction of melanocytes leading to depigmented patches

Explanation

Why Loss-of-function mutations in the filaggrin gene is right

Why each distractor is wrong

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