epidermolysis bullosa

**Definition:** Heterogeneous group of genodermatoses characterized by mechanical-trauma-induced blistering of skin and mucous membranes, present from birth or early infancy. The level of the split in the skin determines the subtype.

**Major types (by level of cleavage):** 1. **EB simplex (EBS)** – Most common type. Split within the basal keratinocytes (intraepidermal). Usually autosomal dominant. Mutations in **KRT5 and KRT14** (keratin 5/14) cause basal cell cytolysis. Blisters heal without scarring. Variants: localized (Weber-Cockayne, hands/feet, worse in warm weather), Dowling-Meara (herpetiform grouped blisters, most severe EBS). Plectin mutations (PLEC) are associated with EBS with muscular dystrophy. 2. **Junctional EB (JEB)** – Split in the **lamina lucida**. Autosomal recessive. Mutations in **laminin-332 (LAMA3, LAMB3, LAMC2)**, **collagen XVII (COL17A1)**, or integrin α6β4 (pyloric atresia association, ITGA6/ITGB4). Herlitz JEB is often lethal in infancy: severe mucosal involvement, exuberant granulation tissue (periorificial, perioral), enamel hypoplasia, airway involvement (hoarse cry), and failure to thrive. 3. **Dystrophic EB (DEB)** – Split in the **sublamina densa** (upper dermis) due to defective **type VII collagen (COL7A1)**, the main component of **anchoring fibrils**. Can be autosomal dominant (milder) or recessive (severe; Hallopeau-Siemens). Heals with **scarring, milia, nail dystrophy**. Recessive severe DEB: mitten deformities (pseudosyndactyly) of hands and feet, esophageal strictures (dysphagia), corneal erosions, malnutrition, anemia, and a high risk of **aggressive, metastatic squamous cell carcinoma** (leading cause of death). 4. **Kindler syndrome** – Mixed/variable split levels; **FERMT1 (kindlin-1)** mutation; AR. Features: acral blistering in infancy, photosensitivity, poikiloderma, skin atrophy, and gingival fragility/periodontitis.

**Clinical features:** Blisters/erosions at sites of friction or trauma (hands, feet, elbows, knees), positive Nikolsky sign (variably), mucosal erosions, nail loss or dystrophy, dental anomalies, and complications including infection/sepsis, protein-losing, anemia, and growth failure.

**Diagnosis:** Skin biopsy of freshly induced blister with **immunofluorescence antigen mapping** and/or **transmission electron microscopy** to determine the cleavage plane; confirmed by genetic testing. Routine H&E is often nondiagnostic.

**Management:** Supportive/multidisciplinary: gentle handling, nonadherent dressings (e.g., silicone), wound care, infection control, nutritional support, pain control, management of strictures, and SCC surveillance (especially in recessive DEB). Newer treatments include topical gene therapy (beremagene geperpavec, B-VEC, a HSV-1 vector delivering COL7A1, approved for DEB) and autologous gene-corrected keratinocyte sheets (prademagene zamikeracel, approved for recessive DEB), as well as topical oleogel-S10 (birch triterpenes) for wound healing.

**Differential for blistering disorders (boards high-yield):** - **Bullous pemphigoid** – acquired, autoantibodies against hemidesmosomes (BP180/BP230), subepidermal; linear IgG/C3 at BMZ; elderly. - **Epidermolysis bullosa acquisita (EBA)** – acquired autoimmune; IgG antibodies against **type VII collagen**; adult-onset mechanobullous disease mimicking DEB; sublamina densa split (the "acquired" counterpart of DEB). Associated with IBD (Crohn's). - **Pemphigus vulgaris** – anti-desmoglein 3 (±1); intraepidermal suprabasal split; "tombstone" appearance; positive Nikolsky. - **SJS/TEN** – drug-induced full-thickness epidermal necrosis. - **Staphylococcal scalded skin syndrome** – exfoliative toxin cleaves desmoglein 1 (granular layer). - **Dermatitis herpetiformis** – IgA granular deposits in dermal papillae; gluten-associated.

**Memory aid:** "Simplex = Superficial (keratin, no scar); Junctional = lamina lucida (laminin, lethal Herlitz); Dystrophic = Deep (collagen VII, scarring, SCC)." Also "VII holds the anchor" – anchoring fibrils are type VII collagen.

**Key associations:** Keratin 5/14 → EBS; laminin-332 / collagen XVII / integrin α6β4 → JEB; collagen VII → DEB; kindlin-1 → Kindler; scarring + SCC → recessive DEB; pyloric atresia → JEB with integrin α6β4 defect (and some EBS with plectin/ITGB4).