Ann Dermatol.  2015 Dec;27(6):658-666. 10.5021/ad.2015.27.6.658.

Recently Identified Forms of Epidermolysis Bullosa

Affiliations
  • 1St John's Institute of Dermatology, King's College London (Guy's Campus), London, UK. john.mcgrath@kcl.ac.uk

Abstract

Epidermolysis bullosa (EB) comprises a collection of clinically diverse inherited blistering diseases that affect the skin and, in some subtypes, mucous membranes and other organs. Currently classified into four main subtypes (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, mainly based on the level of skin cleavage), the spectrum of EB extends to more than 30 clinical subtypes with pathogenic mutations in at least 18 distinct genes. This review focuses on three recent additions to variants of EB: all are autosomal recessive, and result from mutations in either DST-e (coding for epidermal dystonin, also known as the 230 kDa bullous pemphigoid antigen, BP230), EXPH5 (coding for exophilin-5, also known as Slac2-b), or ITGA3 (coding for the integrin alpha-3 subunit). Each of these new forms of EB is reviewed with respect to the initial gene discovery, clinical features, the current mutation database, and skin pathology. Awareness of these recently described forms of EB is helpful in the clinical evaluation of patients with EB and in defining genotype-phenotype correlation for inherited blistering skin diseases.

Keyword

Basement membrane; Blister; Epidermolysis bullosa; Hemidesmosome; Mutation; Transport vesicles

MeSH Terms

Basement Membrane
Blister
Epidermolysis Bullosa*
Genetic Association Studies
Hemidesmosomes
Humans
Mucous Membrane
Pathology
Pemphigoid, Bullous
Skin
Skin Diseases
Transport Vesicles

Figure

  • Fig. 1 The molecular basis of epidermolysis bullosa. Mutations in structural components of hemidesmosomes, desmosomes, corneodesmosomes, intermediate filaments, actin microfilaments, focal contacts, and cell vesicle transport underlie a spectrum of skin fragility phenotypes.

  • Fig. 2 Clinical features associated with autosomal recessive mutations in DST-e. An intra-epidermal blister on the heel resulting from a homozygous nonsense mutation in DST-e.

  • Fig. 3 Transmission electron microscopy of the dermal-epidermal junction in an individual with autosomal recessive mutations in DST-e. (A) Complete lack of hemidesmosomal inner plaques (arrows) in skin from an affected individual. (B) Clearly discernible inner and outer hemidesmosomal plaques are visible in healthy, unaffected skin. Scale bar=0.2 µm.

  • Fig. 4 Immunofluorescence microscopy labeling of skin for DST-e (BP230). (A) In healthy control skin, there is bright linear staining at the dermal-epidermal junction. (B) In contrast, in skin from a patient with biallelic DST-e mutations, there is a complete absence of immunostaining. Scale bar=50 µm.

  • Fig. 5 Clinical features associated with autosomal recessive mutations in EXPH5. There is minor trauma-induced blistering and erosions on both knees, as well as surrounding patchy erythema.

  • Fig. 6 Skin microscopic abnormalities resulting from mutations in EXPH5. (A) Semi-thin section reveals acanthosis and mild hyperkeratosis. There is also pallor within the basal keratinocyte layer and evidence of darkly stained, condensed cellular material Scale bar=50 µm (Richardson's stain). (B) Transmission electron microscopy confirms a low level, intra-epidermal cleavage (asterisks) between basal keratinocyte nuclei and the cell membrane. Scale bar=5 µm. (C) Higher magnification establishes that the intracellular darkly stained material seen on light microscopy is composed of aggregated keratin tonofilaments (arrow). Scale bar=0.5 µm. (D) Some keratinocytes have numerous perinuclear vesicles (arrow). Scale bar=0.5 µm.

  • Fig. 7 Immunofluorescence microscopy labeling of skin for exophilin-5. (A) In healthy control skin, there is bright pan-epidermal cytoplasmic staining. (B) In contrast, in skin from a patient with biallelic EXPH5 mutations, there is a complete absence of immunostaining. Scale bar=50 µm.

  • Fig. 8 Transmission electron microscopy of the dermal-epidermal junction in an individual with autosomal recessive mutations in ITGA3. (A) There is cleavage formation within the lamina lucida consistent with a junctional from of epidermolysis bullosa. (B) There is also evidence of focal reduplication of the lamina densa. (C) The ultrastructural appearances of keratin tonofilaments, hemidesmosomes, and anchoring fibrils show no major structural abnormalities. Scale bar=0.5 µm.

  • Fig. 9 Immunofluorescence microscopy labeling of skin for the α3 integrin and β1 integrin subunits. (A) In healthy control skin, there is α3 integrin labeling at the cell margins of basal keratinocytes. (B) In contrast, in skin from a patient with biallelic ITGA3 mutations, there is a complete absence of α3 integrin immunostaining. (C) Immunostaining for β1 integrin in healthy control skin shows a similar pattern of labeling to α3 integrin. (D) In skin from a patient with biallelic ITGA3 mutations, no abnormalities in β1 integrin labeling are noted, with the appearances resembling the healthy control skin. Scale bar=50 µm.


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