Filaggrin Gene Mutation Background
FLG loss-of-function variants are the strongest known genetic risk factor for atopic dermatitis.
- FLG: Gene (Chromosome 1q21, EDC locus)
- ~10%: Carrier frequency (European populations, short placeholder)
- ~3x: AD risk increase (Short placeholder estimate)
- Semi-dominant: Inheritance (Short placeholder note)
Profilaggrin to filaggrin processing
Short placeholder: profilaggrin is proteolytically cleaved into filaggrin monomers.
Stratum Corneum Barrier Breakdown
Loss of filaggrin weakens the corneocyte-lipid brick-and-mortar architecture.
- 15-20: Barrier layers (Corneocyte layers, short placeholder)
- Reduced: Lipid loss (Ceramide content, short placeholder)
- Elevated: pH shift (Surface pH, short placeholder)
- Increased: Gap frequency (Short placeholder metric)
Brick and mortar disruption
Short placeholder: corneocytes loosen and lipid mortar becomes discontinuous.
Transepidermal Water Loss Increase
A defective barrier lets water escape far faster than normal skin.
- ~5 g/m²h: Normal TEWL (Short placeholder baseline)
- 2-5x: AD skin TEWL (Short placeholder elevation)
- Marked: NMF reduction (Natural moisturizing factor, placeholder)
- Modulating: Humidity effect (Short placeholder note)
Water gradient escape
Short placeholder: water diffuses outward along the disrupted lipid pathway.
Allergen and Microbe Penetration
Gaps in the barrier allow allergens and microbes to enter and trigger immune activation.
- Elevated: Th2 activation (Short placeholder immune note)
- Increased: S. aureus colonization (Short placeholder metric)
- Higher risk: IgE sensitization (Short placeholder note)
- Accelerated: Atopic march (Short placeholder concept)
Outside-in penetration route
Short placeholder: allergen particles diffuse through fissures into the epidermis.
Barrier Repair Strategy Implications
Restoring lipids and hydration can partially compensate for filaggrin deficiency.
- First-line: Emollient use (Short placeholder therapy note)
- Optimized: Ceramide ratio (Short placeholder formulation note)
- Improved: Flare reduction (Short placeholder outcome)
- Early infancy: Prevention window (Short placeholder timing note)
Restorative barrier therapy
Short placeholder: proactive emollient therapy reduces flare frequency and severity.
Short placeholder: early barrier repair may reduce atopic march progression.