Epidermolysis Bullosa
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Recently ruptured blister of the buccal mucosa.

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Introduction

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Epidermolysis bullosa (EB) is the generic name given to a collective group of at least 25 hereditary and non-hereditary conditions which produce skin and mucosal blistering of differing severity and presentation (Table 1).  The oral mucosa is involved to one degree or another in most forms, and blistering may vary from a few small vesicles to general sloughing of large areas of skin and membranes with extensive scar formation.  The hereditary defect differs between types.  For example, the Dowling-Meara form of EB simplex resulting from structural abnormalities of keratin filaments from mutations in the keratin-5 and keratin-4 genes, while the severe recessive dystrophic EB type results from poor type VII collagen formation and subsequent abnormalities in the anchoring fibril system.  The complete absence of epiligrin, which is part of the anchoring fibrils, is found in persons with the lethal form of junctional EB.  Interestingly, antibodies in benign mucous membrane pemphigoid are directed at the epiligrin protein, producing the same blistering effect from a different mechanism.

EB can be acquired as well as inherited, although some believe it is best to consider EB acquisita as an unrelated autoimmune disorder.  IgG antibodies in the sera of a large proportion of EB acquisita patients are directed against part of the type VII collagen molecule, the same matrix protein which is missing in hereditary dystrophic EB.  The antigen is most likely a globular termini of type VII collagen.  Expression of the hemidesmosome-associated alpha6ß4 integrin is normal in acquired forms of EB, a feature which helps greatly to distinguish it from benign mucous membrane pemphigoid.

The different forms of EB are based in part on the hereditary pattern, in part on the location and intensity of the blisters, and in part on the microscopic level at which the blisters occur.  In EB simplex, the least severe form of the genetic disease, limited blisters occur without scar formation and with blistering within the epithelium itself, i.e. acantholysis.  Junctional EB may be rather mild or extremely severe, with the blistering occurring within the basement membrane zone.  Dystrophic EB is inherited in a dominant as well as a recessive form, is usually associated with scarring and has blistering below the basement membrane zone.  Acquired forms also show blistering below the zone.

Clinical Features

The skin is involved in all forms of EB, with the mucous membranes and sometimes with other systems (skeletal atrophy) involved in certain types.  The basic clinical feature is the formation of clear fluid-filled blisters from minor or moderate trauma, less commonly from heat or for no obvious reason.  Diagnostic bullae can be created by shearing pressure on the skin or mucous membranes, if necessary, similar to the Nikolsky sign in pemphigus vulgaris.  Once formed, the blisters break open easily, especially mucous membrane blisters, to leave a flat, relatively painless reddish ulcer bed with no inflammatory halo around it unless the lesion becomes secondarily infected.  Scar formation is variable feature of the disease, depending of the hereditary type (Table 1), but may be so severe that loss of fingers and toes occurs.  Scars occurring in oral regions may produce severe gingival retraction, vestibular shortening, ankyloglossia and microstomia (small mouth opening).  This is particularly severe in the Herlitz variant of junctional EB.  Developing tooth buds may also be affected, resulting in hypoplastic enamel defects, especially in the junctional EB variant.  A smooth amelo-dentinal junction is seen the latter form of the disease.

The more severe inherited forms become apparent at birth or shortly thereafter, and the number and size of the blisters become greater with time during the developing years, after which time they stabilize or diminish.  Lethal forms exist.  Patients with severe junctional EB, the most severe form of the disease, seldom survive more than a few years, with large sheets of skin and mucous membrane sloughing with the minor trauma of crawling and lifting things with the hands.

Oral blistering occurs in most forms of the disease (Table 2), and are less likely in the simplex forms and most likely in the dystrophic variants.  Clinically significant oral involvement, however, occurs in only 2% of simplex EB patients and in 15-20% of other forms.  Dental abnormalities include anodontia, enamel hypoplasia and neonatal teeth.  Caries and periodontal disease often result from the poor oral hygiene resulting from fear of causing mucosal sloughing with the toothbrush or poor access because of a constricted labial opening (microstomia).  Oral manifestations of dominantly inherited dystrophic types are typically mild and include gingival erythema, tenderness and recession in addition to occasional bullae.  The recessive types of dystrophic EB are often much more severe, with large scar-forming bullae induced by even the trauma of eating even the softest foods.  Severe esophageal strictures are not uncommon and the soft diet necessitated by the disease is highly cariogenic, producing severe caries at any early age.

EB acquisita may start in childhood or later, with scar-forming blistering occurring at sites of trauma.  It has a variable intensity and long-term cases often develop milia.  Occasional oral involvement occurs.

Pathology and Differential Diagnosis

The histopathologic appearance of EB varies with the type being examined, and the trauma of the biopsy itself is usually enough to induce cleavage in the tissues.  Simplex forms show intraepithelial clefting or acantholysis.  Junctional and dystrophic forms show a subepithelial bulla, with or without chronic inflammation of the underlying fibrovascular stroma.  Occasional infiltrates will contain eosinophils.  In the mouth, intact blisters are seldom present and so the pathologist must carefully review to attachment of epithelium at the edge of a biopsied ulcer bed.  Simplex forms with show acantholysis instead of subepithelial blistering, but this feature might be artifactually produced by partial epithelial repair.  Routine staining reveals cleavage through the basal cell layer, above the PAS-positive basement membrane, with basal cell nuclei remaining attached to the basement membrane.  Sometimes the entire basal layer is destroyed.  Epithelia adjacent to the blister shows vacuolated basal cells with displacement of the nuclei away from the basement membrane end of the cell.  No histochemical abnormality has been found.

Junctional EB forms demonstrate cleavage along the epidermal-dermal interface, following the contours of the rete ridges.  The PAS-positive basement membrane usually remains with the dermis.  EB letalis may show similar separation of the gastrointestinal, respiratory and urinary tract epithelia.  Vesicles may be seen in the stratum germinativum of intact skin adjacent to a blister.  There are no distinguishing features separating the atrophic benign form of junctional EB from EB letalis.  

Dystrophic forms show dermal-epidermal separation, and PAS staining often shows a hazy basement membrane, making it difficult to determine the exact level of cleavage.  When recognizable, however, the cleft is at the lower attachment of the basement membrane, i.e. the membrane remains attached to the blister epithelium.  Scar formation appears as dense, keloid-type collagenic tissue, perhaps with scattered perivascular lymphocytes.

Because the various subtypes of EB can be clinically indistinguishable one from another, electron microscopy, immunofluorescence and immunohistochemistry are often performed in order to proper map the location of the cleavage.  Electron microscopic examination shows clefting at the level of the lamina lucida of the basement membrane in the junctional forms and below this level in the dystrophic forms (abnormal appearance or numbers of anchoring fibrils), with degenerative cytolytic changes seen in the lower portions of the basal cells in the epidermal or simplex types.  Abnormal hemidesmosomes are found in the majority of patients in the lethal cases, being either reduced in size or numbers, or lacking their sub-basal cell-dense plaque.   

Fluorescing antisera against type IV collagen (localized in the lamina densa or basal lamina) and against bullous pemphigoid antigen (localized in the upper portion of the lamina lucida near the hemidesmosomes) may allow localization of the clefting defect.  Immunohistochemistry of perilesional tissue may help to identify specific defects in order to further classify and subtype the condition.  Immunofluorescence mapping shows all 3 antigens (type IV collagen, laminin, bullous pemphigoid antigen) beneath the cleft in epidermal or simplex types, and shows type IV collagen and  laminin of the floor of the blister, with bullous pemphigoid antigen mostly remaining attached to the epithelial roof of the blister, in the junctional types.  Immunofluorescence staining with polyclonal antibodies against type type VII collagen in the dystrophic or dermal types will be negative because this collagen is a major structural component of the anchoring fibrils and is entirely destroyed by the disease process.  These types do, however, show all 3 basement membrane zone constituents (type IV collagen, laminin and bullous pemphigoid antigen) on top of the cleft.

Point mutations of keratin genes for K5 and K14 on chromosomes 12 and 17, respectively, have been found in families with the Dowling-Meara form of EB.  Likewise, mutations of the LAMB3 gene (responsible for encoding a portion of Laminin 5) have been found in families with atrophic benign junctional EB, and a gene encoding beta4 integrin has been found in the subset of EB letalis with pyloric atresia.  Mutations in the gene encoding type VII collage (COL 7A1), located at chromosome band 3p21 has been found in dystrophic forms of EB.

Since EB acquisita is an autoimmune disease, it shows subepithelial deposits of IgG and C3 on direct immunofluorescence, and shows circulating antibodies against IgG on indirect immunofluorescence, causing confusion with benign mucous membrane pemphigoid.  The IgG is located in the lamina lucida in pemphigoid, however, while in the upper dermis (just beneath the lamina densa) in EB acquisita.  Immunoelectron microscopy may be required to ascertain the difference.  Also, type IV collagen and laminin are found in the blister floor in pemphigoid but in the blister roof in EB acquisita.  Standard immunoperoxidase staining of type IV collagen in formalin-fixed tissue will also show it in these different locations in the two diseases. 

Treatment and Prognosis

References (Chronologic Order)

Note: Click on underlined author's names for additional detail.

General references:

Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia, W. B. Saunders; 1995.

Elder D, Elenitsas R, Jaworsky C, Johnson B Jr. Lever's Histopathology of the skin, 8th edition. Philadelphia; Lippincott-Raven, 1997.

Sapp JP, Eversole LR, Wysocki GP. Contemporary oral and maxillofacial pathology. Mosby; St. Louis, 1997.

Odell EW, Morgan PR. Biopsy pathology of the oral tissues. London; Chapman & hall Medical, 1998.

Specific references:

Wright JT, Fine JD, Johnson L. Hereditary epidermolysis bullosa: oral manifestations and dental management. Pediatr Dent 1993; 15:242-247.

Table 1: Classification of the various forms of epidermolysis bullosa (EB). Modified from Wright et al, 1993 & Elder et al, 1997.

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