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On the basis of clinical, histologic, and electron microscopic findings, three groups of EB are recognized: epidermal, junctional, and dermal .
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In all types of EB, the blisters form as a result of minor trauma. Because of the great differences in prognoses, identification of the type of EB is often very important. In families with the potential of having an infant born with one of the frequently or potentially fatal forms of EB, such as EB letalis
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or generalized EB dystrophica-recessive , a prenatal biopsy at 18 to 20 weeks of gestation is recommended. On electron microscopy, EB letalis shows abnormalities of the hemidesmosomes while generalized EB dystrophica-recessive shows absence of anchoring fibrils.
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There is more variability in the clinical course in some forms of EB than was previously appreciated . For example, within the epidermal type of EB, which usually has a good prognosis, some cases of EB herpetiformis, which is known also as the Dowling-Meara variant, may show generalized blistering that at times is associated with mortality during early infancy . Also, the junctional form of EB can result in scarring as cicatricial junctional EB . Occasionally, dermal EB may be transient and heal within a few months . It is likely that the majority of cases published as Bart's syndrome, which was originally described as congenital absence of the skin , belong in this group .
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Histopathology.
If a fresh blister is available, a specimen for biopsy may be taken from its edge. However, it is advisable to carry out a biopsy also on an induced blister because it will show a blister free of secondary changes. In an existing blister, the location of the blister may have changed as the result of regeneration of keratinocytes at the base of the blister or degeneration of the keratinocytes over the blister. The mode of artificially producing a blister depends on the degree of vulnerability of the skin. However, in most instances, gentle friction with a cotton swab or a pencil eraser is used. The preferred type of biopsy is either a shave or an ellipse. The use of a punch is not recommended because the applied torsion will frequently cause total separation and even loss of the epidermis .
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Even though electron microscopic examination (discussed later) is informative, the light microscopic features seen in the various forms of EB are of diagnostic value.
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In epidermal EB, which includes EB simplex, EB offeet and hands of Weber and Cockayne , and EB herpetiform is (Dowling-Meara) , the primary separation in experimentally induced blisters always occurs within the basal cell layer. Spontaneously arising blisters may be found subepidermally as the result of complete disintegration of the basal cell layer; in bullae of more than 1 day's duration, the cleavage may be found intraepidermally or subcorneally as a result of epidermal regeneration . In sections stained with the PAS technique, the PAS-positive basement membrane zone is located on the dermal side of the blister .
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In junctional EB, the trauma of having a specimen taken for biopsy generally is sufficient to induce separation. This separation is located between the epidermis and the dermis, with
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the PAS-positive basement membrane zone usually remaining with the dermis . In some cases of EB letalis, autopsy has revealed extensive subepithelial separation also in the gastrointestinal, respiratory, and urinary tracts . There are no morphologic or enzymatic abnormalities to distinguish the atrophic benign form of junctional EB from EB letalis .
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In EB dystrophica-dominant and EB dystrophica-recessive, light microscopy shows dermal-epidermal separation. A PAS stain is of little help in ascertaining the exact level of cleavage because the PAS-positive basement
membrane zone often appears hazy . If recognizable, it is seen in contact with the detached epidermis or appears split. In EB dystrophica-dominant, scarring is mild. However, in generalized EB dystrophica-recessive, extensive erosions may occur, resulting in ulcerations and severe scarring. Severe oral involvement can lead to esophageal stenoses (181). In especially severe cases, death may occur. The ulcers and scars of the skin, mouth, and esophagus may give rise to squamous cell carcinomas, which tend to metastasize .
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EB acquisita is not a genodermatosis but an autoimmune disorder .
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Pathogenesis. If possible, all specimens of artificially induced blisters should be subjected to electron microscopic examination and immunofluorescence mapping . The latter procedure consists of exposing cryostat sections to specific antisera against type IV collagen (localized in the lamina densa or basal lamina), against laminin (localized in the lower portion of the lamina lucida), and against bullous pemphigoid antigen (localized in the upper portion of the lamina lucida in the vicinity of the hemidesmosomes). For the latter test, bullous pemphigoid antibodies contained in many bullous pemphigoid sera are used.
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In the epidermal types of EB, electron microscopic examination shows that cleavage is the result of degenerative cytolytic changes occurring in the lower portion of the basal cells between the dermal-epidermal junction and the
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nucleus (EM 4). Immunofluorescence mapping shows that all three antigens (type IV collagen, laminin, bullous pemphigoid antigen) are located beneath the cleavage. Studies in several families with the Dowling-Meara form of EB have revealed point mutations of keratin genes for KRT5 and KRT14 on chromosome 12 and 17, respectively . Different mutations in the KRT5 gene can lead to the Koebner type of EBS or the Weber-Cockayne type.
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In the junctional types of EB, electron microscopic examination often shows the hemidesmosomes to be abnormal, especially in EB letalis. They may be reduced in size or number and may lack their subbasal cell-dense plaque . However, there are exceptions. In one fatal case of EB letalis, the hemidesmosomes were structurally and numerically normal. Also, one patient with nonlethal junctional EB showed similar abnormalities of the hemidesmosomes, as seen in the majority of patients in the lethal group . It is possible that the
abnormalities of the hemidesmosomes are a secondary phenomenon and that the basic cause of the junctional types of EB is a biochemical disorder of a lamina lucida constituent. In favor of this theory is the fact that normal skin shows separation at the dermal-epidermal junction when cultured with blister fluid of patients with EB letalis . Immunofluorescence mapping shows type IV collagen and laminin on the floor of the blister; bullous pemphigoid antigen is present mainly on the blister roof but also in a more spotty distribution and to a much lesser extent on the blister floor . Mutations have been found in any of three polypeptides of laminin-5: alpha-3 (LAMA3), BETA-3 (LAMB3), and GAMMA-2 (LAMC2). The gene is responsible for encoding a portion of laminin 5. This mutation may have significance in reducing adhesion between the epidermis and dermis . A newly found mutation of the gene encoding beta, integrin has been found in the subset of EB letalis with pyloric atresia .
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The dermal types of EB, on electron microscopy, show abnormalities in regard to their anchoring fibrils. Generalized recessive dystrophic EB shows absence of the anchoring fibrils even in nonlesional unscarred skin. On the other hand, in both dominant dystrophic EB and in localized recessive dystrophic EB, structurally normal anchoring fibrils are present but in significantly reduced number . The complete absence of anchoring fibrils in generalized recessive dystrophic EB could be established through the lack of a reaction with monoclonal antibodies to anchoring fibrils . Because type VII collagen is a major structural component of the anchoring fibrils, immunofluorescence staining with polyclonal antibodies to type VII collagen reveals complete absence of staining, even in the unaffected skin of patients with severe dystrophic recessive EB . Similarly, there was no reaction with periodic acid-thiosemicarbazide-silver proteinate, which stains anchoring fibrils selectively . Mutations in the gene encoding type VII collagen (COL 7A1) located at chromosome band 3p21 have been reported to cause these abnormal findings in the dystrophic forms of EB . Immunofluorescence mapping shows all three basement membrane zone constituents-bullous pemphigoid antigen, laminin, and type IV collagen-on top of the cleavage .
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