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Epidermolysis bullosa (EB) complex

Complex of rare genetic conditions in which bullous lesions affecting primarily the skin arise after exposure to mechanical trauma.

Introduction

Complex of rare genetic conditions in which bullous lesions affecting primarily the skin arise after exposure to mechanical trauma.

Classification

Major forms:

Characterised loss of tissue integrity. Each major EB type has further subtypes which may differ in terms of their genetic, biological or clinical characteristics.
  • Dystrophic epidermolysis bullosa (DEB): Upper dermis
  • Junctional EB: Dermo-epidermal interface
  • EB simplex (EBS) (M/C, least severe form): Within epidermis
  • Kindler syndrome (KS): All 3 levels
Introduction to the epidermis, keratin filaments, and EB simplex: Schematic representation of skin tissue and detailed view of the bottom portion of the epidermis, highlighting the cytoplasmic network of keratin IFs attached to hemidesmosome cell-ECM and desmosome cell-cell contacts in basal keratinocytes. The plane of tissue rupture seen in the simplex, junctional, and dystrophic forms of EB are highlighted. The molecular configuration of the K5/K14 coiled-coil heterodimer, the smallest subunit participating in the formation of 10-nm IFs, is shown in a schematic manner. The main secondary structure elements are: N-terminal head and C-terminal tail domains; α-helical coils 1A, 1B, 2A, and 2B; and linkers L1, L12, and L2. | Coulombe, P. A., Kerns, M. L., & Fuchs, E. (2009). Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility. The Journal of clinical investigation, 119(7), 1784–1793. https://doi.org/10.1172/JCI38177

Pathophysiology

Each EB subtype is known to arise from mutations within the genes encoding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis.

Representation of the proteins affected in different types of inherited epidermolysis bullosa | Boeira, V. L., Souza, E. S., Rocha, B., Oliveira, P. D., Oliveira, M., Rêgo, V. R., & Follador, I. (2013). Inherited epidermolysis bullosa: clinical and therapeutic aspects. Anais brasileiros de dermatologia, 88(2), 185–198. https://doi.org/10.1590/S0365-05962013000200001
An illustration of the differences between healthy skin (a) and RDEB skin (b) at the dermal–epidermal junction | Tolar J, Wagner JE . A biologic Velcro patch. N Engl J Med 2015;372:382–384.

Clinical features

Hallmark cutaneous features:

All EB types manifest with trauma-induced skin blistering and fragility, but the individual types vary in terms of severity and associated extracutaneous manifestations
  • Milia (tiny firm white papules, resembling cysts or pustules)
  • Nail dystrophy or absence
  • Scarring (usually atrophic)
Clinical manifestations in epidermolysis bullosa. Upper panel: Junctional EB with mechanically induced blisters, wounds, and loss of nails in the right foot. Lower panel: Moderate dystrophic EB with mechanically induced skin fragility, inflammation, scarring, joint contractures and loss of nails in the left hand | Bruckner-Tuderman L. (2019). Newer Treatment Modalities in Epidermolysis Bullosa. Indian dermatology online journal, 10(3), 244–250. https://doi.org/10.4103/idoj.IDOJ_287_18

EB simplex:

  • Localized EBS “Weber-Cockayne disease” (M/C EB overall): Blistering on palms and soles
  • Generalized EBS:
    • EBS-Dowling Meara (DM): Presence of intact vesicles or small blisters in grouped or arcuate configuration
    • EBS generalized other or non-Dowling-Meara generalized EBS “EBS-Koebner (EBS-K)”: Non-herpetiform blisters and erosions arising on any skin surface
  • The blistered foot of an infant with localized EBS. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Circinate grouping of blisters arising on the skin of a patient with the Dowling-Meara variant of generalized EBS. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12

Junctional EB (JEB):

Enamel hypoplasia (characteristic): Manifested as localized or more extensive thimble-like pitting of some or all of the tooth surfaces
Rather profound enamel pitting in a patient with JEB | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Non-Herlitz JEB (JEB-nH) (80% JEB cases, less severe): Generalized disorder characterized by the presence of blistering, atrophic scarring, and nail dystrophy or absence
  • JEB-Herlitz (JEB-H) (20% JEB cases): Exuberant granulation tissue which usually arises within the first several months to one to two years of life
  • Inverse JEB (rare): Severe blistering and erosions confined to intertriginous skin sites, esophagus, and vagina
  • JEB with pyloric atresia presents with generalized blistering at birth and congenital atresia of the pylorus (and rarely of other portions of the gastrointestinal tract)
  • LOC syndrome is characterized by localized blistering and scarring, particularly on the face and neck, in association with upper airway disease activity and nail abnormalities
Exuberant granulation tissue arising on the nape of the neck of a child with Herlitz JEB. | | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12

Dystrophic EB (DEB):

Separated into two major types, based on the mode of transmission (autosomal dominant versus autosomal recessive)
  • Dominant dystrophic EB (DDEB): Generalized blistering at birth which, with time, is associated with mila, atrophic (or less commonly, hypertrophic) scarring, and nail dystrophy.
  • Atrophic scarring and postinflammatory hypopigmentation on the extremity of a patient with DDEB. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Hypertrophic scarring in a patient with generalized DDEB. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Dystrophy of all twenty nails in a patient with DDEB. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Recessive dystrophic EB (RDEB):
    • Severe generalized RDEB “Hallopeau-Siemens RDEB” (M/severe subtype, one of the most devastating multiorgan genetically transmitted diseases of mankind): Generalized blistering at birth, progressive and oftentimes mutilating scarring of the skin, corneal blisters/scarring, profound growth retardation, multifactorial anemia, failure to thrive (less common than in JEB-H), esophageal strictures, and debilitating hand & foot deformities (“mitten deformities”; pseudosyndactyly)
    • Non-Hallopeau-Siemens RDEB
    • Inverse RDEB
  • Partial mitten deformity of the hand of a child with severe generalized RDEB. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12
  • Complete mutilating deformities of the hands of a young adult with severe generalized RDEB. | Fine J. D. (2010). Inherited epidermolysis bullosa. Orphanet
    journal of rare diseases, 5, 12. https://doi.org/10.1186/1750-1172-5-12

Extracutaneous manifestations:

Extracutaneous manifestations in EB | Bardhan, A., Bruckner-Tuderman, L., Chapple, I.L.C. et al. Epidermolysis bullosa. Nat Rev Dis Primers 6, 78 (2020). https://doi.org/10.1038/s41572-020-0210-0

Diagnosis

EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis.

Diagnostic algorithm for EB | Bardhan, A., Bruckner-Tuderman, L., Chapple, I.L.C. et al. Epidermolysis bullosa. Nat Rev Dis Primers 6, 78 (2020). https://doi.org/10.1038/s41572-020-0210-0

Management

Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications.

Summary:

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. | Epidermolysis bullosa. Nat Rev Dis Primers 6, 79 (2020). https://doi.org/10.1038/s41572-020-00220-7

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