What is the genetic basis and management of epidermolysis bullosa (EB)?

Genetic Basis and Management of Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders characterized by skin fragility and blister formation, caused by mutations in genes encoding proteins critical for skin integrity and dermal-epidermal adhesion. 1

Classification Based on Molecular Genetics

EB is classified into four major types based on the level of skin cleavage:

• Epidermolysis Bullosa Simplex (EBS): Blisters form within the epidermis due to mutations in genes encoding:

  • Keratins 5 and 14 (KRT5, KRT14) - most common 1
  • Plectin (PLEC) 1
  • Exophilin 5 (EXPH5) 1
  • Transglutaminase 5 (TGM5) in acral peeling skin syndrome 1
  • Desmoplakin (DSP), plakoglobin (JUP), and plakophilin 1 (PKP1) in suprabasal variants 1

• Junctional EB (JEB): Blisters form within the lamina lucida of the basement membrane zone due to mutations in:

  • Laminin-332 (LAMA3, LAMB3, LAMC2) - severe generalized and intermediate forms 1
  • Collagen XVII (COL17A1) - localized forms 1
  • Integrin α6β4 (ITGA6, ITGB4) - associated with pyloric atresia 1

• Dystrophic EB (DEB): Blisters form beneath the lamina densa due to:

  • Collagen VII (COL7A1) mutations - both dominant (DDEB) and recessive (RDEB) forms 1

• Kindler Syndrome: Mixed pattern of blistering at multiple levels due to:

  • Fermitin family homolog 1/kindlin-1 (FERMT1) mutations 1

Diagnostic Approach

The "onion skin" approach to diagnosis involves sequential layers of assessment:

1. Determine the level of skin cleavage through:

   • Immunofluorescence antigen mapping (IFM) 1
   • Transmission electron microscopy 1

2. Assess clinical phenotype:

   • Distribution (localized vs. generalized) 1
   • Severity of cutaneous and extracutaneous involvement 1
   • Specific diagnostic features (e.g., granulation tissue, mottled pigmentation) 1

3. Determine inheritance pattern (autosomal dominant, recessive, etc.) 1

4. Identify protein abnormalities using immunohistochemistry 1

5. Perform mutation analysis for definitive classification 1

Management Approach

Management of EB focuses on preventing complications and treating symptoms:

• Wound care: Meticulous wound management to prevent infection and promote healing 2

• Pain management: Addressing both acute and chronic pain associated with blistering and wound care 2

• Prevention of complications:

  • Monitoring for extracutaneous manifestations 2, 3
  • Regular screening for squamous cell carcinoma (leading cause of mortality) 3

• Emerging therapies:

  • Gene therapy: Correction of underlying genetic defects 4, 5
  • Cell-based therapies: Fibroblasts, bone marrow transplantation, mesenchymal stromal cells 2, 4
  • Protein replacement therapies: Recombinant proteins to restore function 4

Clinical Pearls and Pitfalls

• Diagnostic pitfall: Relying solely on clinical features without molecular confirmation can lead to misclassification, as different genetic mutations can cause similar phenotypes 1, 6

• Management pitfall: Focusing only on skin manifestations while missing important extracutaneous complications that contribute to morbidity and mortality 3

• Genetic counseling: Essential for families due to variable inheritance patterns across EB subtypes 6

• Therapeutic considerations: Treatment approaches should be tailored to the specific EB subtype based on the underlying molecular defect 4, 5

The molecular genetic understanding of EB has advanced significantly, leading to improved classification systems and opening avenues for targeted therapies that address the underlying genetic defects rather than just managing symptoms 2, 5, 3.