Dermatology MCQ - Inflammatory Dermatoses - Filaggrin genetics

Which of the following statements most accurately describes the genetic and pathophysiological role of filaggrin in atopic eczema?

A. Filaggrin mutations are somatic, acquired later in life, and primarily lead to the production of abnormal, immunogenic filaggrin peptides that trigger an autoimmune response.
B. Filaggrin loss-of-function mutations are inherited, result in a defective stratum corneum, and are the strongest known genetic risk factor for the development of atopic eczema.
C. Filaggrin is an enzyme involved in lipid metabolism; its mutation disrupts the composition of lamellar bodies, leading to a defective lipid barrier but intact keratinocyte function.
D. Filaggrin mutations are a consequence of chronic inflammation in atopic eczema, and their presence correlates with disease severity but does not play a primary causal role.
E. Filaggrin functions primarily as an antimicrobial peptide in the epidermis, and its deficiency leads directly to recurrent cutaneous infections, which then secondarily cause eczematous inflammation.

Correct Answer: B. Filaggrin loss-of-function mutations are inherited, result in a defective stratum corneum, and are the strongest known genetic risk factor for the development of atopic eczema.

Answer & Explanation

Explanation:
This statement encapsulates the core understanding of filaggrin's role in atopic eczema.

• Inherited: Filaggrin gene (FLG) mutations are germline, null mutations (primarily in Europeans), meaning they are inherited and present from birth.

• Defective Stratum Corneum: Filaggrin is a key structural protein that is proteolytically broken down into natural moisturizing factor (NMF). Its deficiency leads to impaired keratinocyte aggregation, reduced NMF, elevated skin pH, and a fundamentally compromised physical and functional epidermal barrier.

• Strongest Genetic Risk Factor: The discovery of FLG mutations represented a breakthrough, as it is the most significant and consistently replicated genetic risk factor identified for atopic eczema, conferring a high population-attributable risk.

The other options are incorrect:

• A. Filaggrin mutations are germline, not somatic. The pathophysiology is not autoimmune; it is rooted in barrier failure and immune dysregulation.

• C. Filaggrin is a structural protein, not an enzyme for lipid metabolism. While lipid abnormalities occur in atopic skin, they are not the primary direct result of a filaggrin defect.

• D. This reverses cause and effect. The mutations are primary and causal, predisposing an individual to the disease, rather than being a consequence of inflammation.

• E. While filaggrin has some antimicrobial properties, this is not its primary function. The increased infection rate is secondary to the barrier breakdown and dysbiosis, not the direct cause of the eczema.

Key Associations for Filaggrin in Atopic Eczema

• Histopathology: While not diagnostic, a skin biopsy may show features of spongiotic dermatitis. The primary defect is ultrastructural, visible under electron microscopy as abnormal keratohyalin granules.

• Associated Conditions: The presence of an FLG mutation is strongly associated with:

  • Ichthyosis Vulgaris: Characterized by generalized xerosis and prominent scaling, especially on the extensor surfaces.

  • Atopic Keratoconus: A severe eye complication.

  • The "Atopic March": FLG mutation carriers have a significantly higher risk of progressing from atopic eczema to asthma and allergic sensitization (especially to peanut and egg), as the defective skin barrier allows for epicutaneous sensitization.

• Prognosis: Individuals with FLG mutations often have earlier-onset, more persistent, and generally more severe atopic eczema.

• Management Implications: Understanding the barrier defect underscores the critical importance of daily, full-body emollient therapy as a cornerstone of management. This is not just symptomatic treatment for dryness but a proactive strategy to support the defective barrier, reduce allergen penetration, and potentially prevent disease flares.