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Keywords:

  • anchoring fibril;
  • cutaneous amyloidosis;
  • pretibial dystrophic epidermolysis bullosa

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. References

Here, we describe the case of a patient with pretibial dystrophic epidermolysis bullosa (PDEB) with amyloid deposition. The patient was a 40-year-old Japanese woman who presented a blistering eruption in the pretibial area with flat violaceous-brown lichenoid papules. The histology of the blister revealed a subepidermal bulla with antibodies bound to basement membrane antigens on the blister roof by immunoflourescent mapping. Electron microscopy revealed a blister cleavage plane below the lamina densa. The histology of the lichenoid papules showed amyloid deposition in the papillary dermis. Because it was confined to just beneath the bulla base of the blister specimen, the amyloid deposition may have been derived from degenerated keratinocytes induced by damage to the epidermal–dermal junction due to blister formation in PDEB in this case. PDEB, in general, is often misdiagnosed as lichen amyloidosis; however, some PDEB cases could actually be associated with amyloid deposition.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. References

Dystrophic epidermolysis bullosa (DEB) is a heterogeneous inherited mechanobullous disorder that presents subepidermal blistering. Pretibial dystrophic epidermolysis bullosa (PDEB) is a rare form of dominant dystrophic epidermolysis bullosa (DDEB) and clinically characterized by pruritic lichenoid papules and trauma-induced blisters predominantly affecting the pretibial region. Primary cutaneous amyloidosis most often occurs in the pretibial region as lichen amyloidosis, and is also clinically characterized by the development of pruritic lichenoid papules. In this paper, we report a case of a Japanese woman with PDEB and amyloid deposition and suggest the correlation between the two disorders.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. References

A 40-year-old Japanese woman had a more than 30-year history of a persistent blistering eruption in the pretibial area of both legs. Since her high school years, she had also had a pruritic eruption in the same area. She reported that her paternal grandmother also had a blistering eruption in the pretibial area. She refused to provide further information on her family history. Visual examination revealed flat, violaceous, brown, lichenoid papules that coalesced to form a well-demarcated plaque on the bilateral shins with extension to the lateral aspects of the calf (Fig. 1a,b). Several tense and clear blisters, scars and small erosions were also present (Fig. 1c). The toenails were all short and dystrophic.

image

Figure 1.  (a,b) Flat, violaceous, brown, lichenoid papules that coalesced to form a well-demarcated plaque on bilateral shins. (c) Tense and clear blisters, scars and small erosions were shown.

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The histology of the vesicle biopsy revealed a subepidermal bulla with dermal fibrosis and milia (Fig. 2a). Direct and indirect immunofluorescence (IF) gave negative results. Basement membrane antigen mapping using monoclonal antibodies revealed that the N-terminal domain and collagenous domain of type VII collagen, type IV collagen, laminin 5 (GB3 antigen), 19-DEJ-1 antigen, α6-integrin, β4-integrin, BP180 and BP230 were localized at the roof of the blister (Fig. 2b). Transmission electron microscopy (EM) of a blistered skin specimen revealed a cleavage below the lamina densa (Fig. 2c). The anchoring fibrils were thin and low in number (Fig. 2d). Stellate bodies were not seen in the basal cells.

image

Figure 2.  (a) The histology of the vesicle revealed a subepidermal bulla with dermal fibrosis and milia (hematoxylin–eosin, original magnification ×100). (b) Immunofluorescence mapping revealed the binding of LH7.2 (N-terminal domain of type VII collagen) to the blister roof (original magnification ×200). (c) A blister cleavage plane was observed below the lamina densa (electron microscopy, original magnification ×7000). (d) The anchoring fibrils were thin and low in number (electron microscopy, original magnification ×17 000).

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The histology of a skin biopsy specimen taken from a flat papule showed amorphous homogeneous eosinophilic globules between the collagen fibers in the papillary dermis without apparent blister formation (Fig. 3a). Immunohistochemistry showed the labeling on these deposits with antibodies against amyloid P (rabbit anti-human; DAKO, Glostrup, Denmark) (Fig. 3b) and epidermal keratins (rabbit polyclonal antikeratin; DAKO, Glostrup, Denmark) (Fig. 4a). On electron microscopy, these deposits appeared as 7–10-nm non-branching non-anastomosing fibrils (Fig. 3c,d). The specimen of the vesicle was reexamined, and keratin-positive globules were also found in the dermis only beneath the blister floor (Fig. 4b).

image

Figure 3.  (a) The histology of a skin biopsy specimen taken from a flat papule showed amorphous homogeneous eosinophilic material in the papillary dermis (hematoxylin–eosin, original magnification ×200). (b) Immunohistochemistry showed the labeling of these deposits with antibodies against amyloid P (original magnification ×400). (c) On electron microscopy, the amyloid appeared as electron dense globules in the dermis (original magnification ×2500). (d) The globules consisted of 7–10-nm non-branching non-anastomosing fibrils (electron microscopy, original magnification ×30 000).

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image

Figure 4.  (a) Immunohistochemistry showed a distinct labeling of amyloid deposits (as well as the epidermis) using an antibody against epidermal keratin (original magnification ×100). (b) Keratin droplets were also observed in the dermis only beneath the blister floor in the specimen of the vesicle (keratin, original magnification ×100).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. References

In DEB cases, it may be difficult to distinguish mild recessive cases from sporadic dominant disease.1 Although our patient did not agree to undergo genetic mutation analysis, it is probable that she had DDEB, because her paternal grandmother suffered from recurrent pretibial blisters. Our patient had a mild form of DEB (PDEB) with a late onset of pruritic, flat, violaceous papules. The histology of such papules showed histological, immunohistochemical and electron microscopic features similar to those of localized cutaneous amyloidosis, although the amount of deposits was relatively low and the level of the deposition was slightly deeper than usual cutaneous amyloidosis. The correlation between PDEB and amyloid deposition has been unclear. Our review of the published work revealed very few reports on localized cutaneous amyloidosis associated with PDEB,1 and all showed the occurrence of PDEB and lichen amyloidosis as coincidental. Because localized primary cutaneous amyloidosis is more common in Asian than in white people,2 most of these cases were observed in Asian countries. However, the amyloid deposition in this patient may be the result of scratching, because PDEB patients often suffer from severe itching. It is well known that amyloid deposition can be induced by scratching or friction3 as in the cases of “towel melanosis” or “nylon brush amyloidosis” in Japan,4 although it is still debatable whether scratching or friction can actually induce amyloid deposition.5 The other explanation is that the amyloid deposition in this patient could have been derived from degenerated keratinocytes induced by damage to the epidermal–dermal junction due to blister formation in PDEB. In general, the amyloid substance found in primary cutaneous amyloidosis is thought to be derived from the epidermis. Hashimoto and his colleagues established the fibrillary theory of amyloidogenesis,6 on the basis of the electron microscopy finding that amyloid substances coexist with filamentous bodies (degenerated keratinocytes) and the immunohistochemical finding that amyloid has a common antigenicity with keratin filaments. Cytokeratin profiles in localized cutaneous amyloids have also been revealed by immunohistochemistry.7 Keratin-positive globules were found not only in the upper dermis in the specimen of a flat papule, but also beneath the blister floor in the specimen of a vesicle in this case. This is probably because keratinocytes degenerated as a result of the blister formation and dropped into the dermis. Recently, Chiang et al.8 reported a case of Weber–Cockayne type of epidermolysis bullosa simplex associated with amyloid deposit in an Asian man, and suggested the same mechanisms of amyloid deposition. In the first report on eight cases of epidermolysis bullosa (EB) pruriginosa,9 McGrath referred to an unpublished case of EB pruriginosa with amyloid deposition, and reported that the deposition was possibly derived from damaged keratinocytes and that it could be an example of EB pruriginosa with subsequent amyloid deposition.

The true prevalence of amyloid deposition in association with PDEB or EB is unknown. Because the clinical features in this case were very similar to those in already reported cases,10,11 it is possible that some of the reported cases of PDEB had an association with subsequent amyloid deposition, but that this association was missed due to its low amount. Because the racial predilection for dark-skinned individuals is very clear in primary cutaneous amyloidosis, amyloid deposition in patients with EB could also be common in Asian or dark-skinned people as in this patient. Note that the clinical features of fragile blisters and erosions, which are often overshadowed by pruritic lichenified papules in the pretibial regions of PDEB patients, can easily be misdiagnosed as lichen amyloidosis, prurigo nodularis or lichen planus. However, some PDEB cases could actually be associated with amyloid deposition, and amyloid deposition could influence the clinical features of PDEB.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. References