Epidermolysis Bullosa (EB)

Overview

Classification: 4 Main Types

1. EB Simplex (EBS)

Subtypes:

• Generalized Severe (Dowling-Meara / Herpetiformis): Presents at birth; most severe EBS. Grouped "herpetiform" blisters on trunk/proximal extremities. Oral mucosa often involved. Nail shedding/dystrophy. Palmoplantar hyperkeratosis (keratoderma). May affect esophagus and larynx.
• Generalized Intermediate (Koebner): Generalized blistering from birth or early infancy; hands, feet, extremities most affected. Postinflammatory hypo/hyperpigmentation. Mild oral involvement that improves with age.
• Localized (Weber-Cockayne): Mild form; predominantly palmoplantar blistering triggered by friction/heat.
• Uncommon variants: EBS with muscular dystrophy (plectin mutations), EBS with mottled pigmentation, suprabasal EBS subtypes.

2. Junctional EB (JEB)

Subtypes:

• Herlitz JEB (Lethal): Caused by null mutations in laminin-332 genes (LAMA3, LAMB3, LAMC2) → complete absence of laminin-332. Widespread blistering + exuberant granulation tissue around mouth/nose/tracheostomy. High neonatal/infantile mortality.
• Non-Herlitz JEB (GABEB — Generalized Atrophic Benign EB): Most caused by mutations in COL17A1 (Collagen XVII/BP180). Blistering in lamina lucida, with hemidesmosomal abnormalities; nail loss and skin atrophy. Better prognosis than Herlitz.
• JEB with pyloric atresia: Associated with ITGA6/ITGB4 mutations.
• Laryngo-Onycho-Cutaneous syndrome: N-terminal mutations of LAMA3.

Immunofluorescence tip: Absence of laminin α3 staining suggests an α3 gene mutation; ~80% of laminin-332 mutations involve recurrent nonsense mutations in LAMB3.

3. Dystrophic EB (DEB)

Subtypes:

• Dominant DEB: Typically localized; milder scarring. Nail dystrophy is common. Pretibial EB is a classic dominant variant.
• Recessive DEB (RDEB):
  • Mild/Localized RDEB: Acral blistering; mild or absent mucosal involvement.
  • Severe RDEB (Hallopeau-Siemens): Devastating multisystem disease. Presents with generalized blistering at birth, sometimes with congenital absence of skin (Bart syndrome). Progressive scarring → pseudosyndactyly ("mitten hand" deformity), flexion contractures. Oropharyngeal involvement leads to microstomia, esophageal strictures, dental caries, and malnutrition. Anemia (chronic inflammation + hemorrhage). Major complication: invasive squamous cell carcinoma (SCC) — leading cause of death in adults with severe RDEB.

Extracutaneous Complications (Severe Forms)

Diagnosis

1. Clinical history & physical exam — blistering pattern, distribution, age of onset, family history
2. Skin biopsy (perilesional skin):
   • Transmission electron microscopy (TEM) — identifies cleavage plane precisely
   • Immunofluorescence mapping (IFM) — antibodies against laminin-332, collagen XVII, collagen VII, integrin β4 to localize protein defects
3. DNA mutational analysis — confirms diagnosis, guides prognosis, enables:
   • Genetic counseling
   • Prenatal diagnosis (chorionic villus sampling at 8–10 weeks, amniocentesis)
   • Preimplantation genetic diagnosis

RDEB and dominant DEB may have equivalent blistering activity, but only RDEB carries high SCC risk — DNA diagnosis distinguishes them.

Treatment

Supportive (mainstay)

• Wound care: Soak in modified Dakin solution (0.025% sodium hypochlorite) 20 min before dressing changes to debride and reduce bacterial load; apply mupirocin or topical antibiotics; cover with non-adherent, semi-occlusive dressings; avoid tape (causes further blistering); use self-adhering gauze.
• Blister management: New blisters should be lanced with sterile needle to prevent extension; do not remove the blister roof.
• Infection control: S. aureus and S. pyogenes are the most common pathogens. Systemic antibiotics for infected wounds.
• Nutritional support: High-calorie diet; gastrostomy tube placement when oral intake is severely compromised.
• Heat avoidance (especially for EBS): Soft, well-ventilated footwear.
• Hand surgery: For pseudosyndactyly in RDEB; post-op splinting essential to prevent recurrence.

Multidisciplinary care

Emerging/Disease-Modifying Therapies

• Gene therapy: Cell-based gene correction for RDEB (COL7A1-corrected keratinocyte grafts; iPS cell approaches using CRISPR/Cas9).
• Beremagene geperpavec (B-VEC / Vyjuvek): FDA-approved 2023 — topical HSV-1 vector delivering COL7A1 gene directly to wounds in RDEB. First approved gene therapy for EB.
• Protein replacement therapy: Recombinant collagen VII infusions.
• Stem cell transplantation: Bone marrow/allogeneic HSCT in RDEB — trials show partial improvement.
• Angiotensin receptor antagonists: Losartan has shown benefit in RDEB (reduces TGF-β-driven fibrosis). A 2025 systematic review (PMID: 40898775) assessed the safety and efficacy of ARBs in RDEB.

Surveillance & Complications Monitoring (RDEB)

• Regular skin exam for SCC — aggressive behavior, early metastasis; screening from adolescence onward
• CBC for anemia, serum ferritin, albumin, pre-albumin (nutritional markers)
• Barium swallow / endoscopy for esophageal involvement
• Ophthalmologic exams

Clinical Images