Dermatology MCQ - Inflammatory Dermatoses - Genetics of Atopic Eczema

Research into the genetics of atopic eczema has identified key mutations that lead to a defective skin barrier, representing a primary predisposing factor for the disease. Mutations in which of the following genes are most strongly and consistently associated with this impaired barrier function and the subsequent development of atopic eczema?

A. Collagen VII gene (COL7A1)
B. Filaggrin gene (FLG)
C. Keratin 5 and Keratin 14 genes (KRT5, KRT14)
D. Fibrillin-1 gene (FBN1)
E. Steroid sulfatase gene (STS)

Correct Answer: B. Filaggrin gene (FLG)

Explanation:

• The Filaggrin gene (FLG) is the most significant genetic discovery in atopic eczema. Loss-of-function mutations in FLG are a major predisposing factor, with odds ratios as high as 3-5 for the development of the disease. Filaggrin protein is crucial for the formation of the stratum corneum. It aggregates keratin filaments and is later broken down into natural moisturizing factors (NMFs) that maintain skin hydration and a slightly acidic pH. Mutations lead to a defective physical barrier, allowing for increased transepidermal water loss (xerosis) and enhanced penetration of allergens and microbes, which drives the inflammatory process.

• Why the other options are incorrect:

  • A. Collagen VII gene (COL7A1): Mutations in this gene are responsible for Dystrophic Epidermolysis Bullosa, a blistering disorder, and are not associated with atopic eczema.

  • C. Keratin 5 and Keratin 14 genes (KRT5, KRT14): Mutations in these genes cause Epidermolysis Bullosa Simplex, another form of blistering disease.

  • D. Fibrillin-1 gene (FBN1): Mutations in this gene are responsible for Marfan syndrome, a connective tissue disorder.

  • E. Steroid sulfatase gene (STS): Mutations or deletions in this gene are associated with X-linked ichthyosis, a disorder of cornification characterized by widespread, dark, polygonal scales. While it is a disorder of the skin barrier, it is genetically and clinically distinct from atopic eczema.

Key Points for Exams

• Pathophysiological Model: The "Outside-In" Hypothesis is central here. FLG mutations cause a primary barrier defect ("outside"), which allows for the penetration of environmental allergens, leading to immune activation and inflammation ("inside"). This is in contrast to the "Inside-Out" hypothesis, which posits primary immune dysregulation as the initial event.

• Clinical Correlations:

  • Early Onset & Severity: FLG mutations are associated with earlier onset and more persistent, severe eczema.

  • Atopic March: The presence of FLG null mutations increases the risk of a patient progressing from atopic eczema to allergic rhinitis and asthma.

  • Ichthyosis Vulgaris: FLG mutations also cause this common disorder of cornification, characterized by fine, white scale, and it frequently co-exists with atopic eczema.

• Other Genetic Factors: While FLG is the strongest, it is not the only gene involved. Genes involved in immune regulation (e.g., related to Th2 responses, IL-4, IL-13) also play a significant role, explaining why not all atopic eczema patients have FLG mutations.

• Clinical Implication: Understanding the central role of the barrier defect reinforces why daily, consistent emollient use is a cornerstone of management, as it helps to artificially restore the compromised barrier function.