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Infantile erythema elevatum diutinum: report of a vesiculo-bullous case

European Journal of Dermatology. Volume 16, Number 6, 683-6, November-December 2006, Clinical report

DOI : 10.1684/ejd.2006.0016

Summary

Author(s) : Carlo Tomasini, Zelda Seia, Paolo Dapavo, Elisabetta Soro, Chiara Addese, Mario Pippione , Department of Biomedical Science and Human Oncology, Second Dermatologic Clinic, University of Turin, Via Cherasco 23, 10126 Turin, Italy.

Summary : Erythema elevatum diutinum (EED) is a localized, low-grade form of leukocytoclastic vasculitis mainly affecting adults, with only a few pediatric cases reported in the literature. The pathogenesis of this dermatosis is unknown, although an Arthus-type reaction to bacterial and viral antigens seems involved. We describe a case of EED in a 9 year-old child suffering from recurrent pharyngotonsillitis induced by Streptococcus pyogenes. Clinical presentation of the dermatosis was atypical, with vesicles and bullae intermingled with red-purple papules and plaques distributed mainly over the extensor aspects of the extremities. Histopathological examination of a vesiculo-bullous lesion revealed a subepidermal bulla containing neutrophils and nuclear dust suggesting dermatitis herpetiformis. Fibrin in vessel walls was observed throughout the dermis. Direct immunofluorescence was negative. A prompt and complete response to sulphone therapy was obtained in conjunction with tonsillectomy. Clinicians should be aware of atypical presentations of EED in children with vesicles and bullae mimicking During’s disease.

Keywords : erythema elevatum diutinum, vesiculo-bullous lesions, children, dermatitis herpetiformis

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ARTICLE

Auteur(s) : Carlo Tomasini, Zelda Seia, Paolo Dapavo, Elisabetta Soro, Chiara Addese, Mario Pippione

Department of Biomedical Science and Human Oncology, Second Dermatologic Clinic, University of Turin, Via Cherasco 23, 10126 Turin, Italy

accepté le 19 Juin 2006

Erythema elevatum diutinum (EED) was originally described in 1888 by Hutchinson and in 1889 by Bury [1, 2]. However, the name EED was first used by Radcliff, Crocker and Williams, who found similarities between the cases of Hutchinson and Bury and their own [3]. This disease is considered rather uncommon, but it is probably less rare than the published cases would suggest, as the diagnosis is often overlooked.EED is a localized, low-grade form of leukocytoclastic vasculitis of unknown pathogenesis occurring most frequently in adults, although any age may be involved [4]. The clinical presentation is highly characteristic with persistent, symmetrical, red-purple papules, nodules, and plaques especially affecting the extensor surfaces of the extremities, the ears, trunk and buttocks. Atypical presentations with vesiculo-bullous, hemorrhagic and ulcerative lesions have occasionally been reported [5, 6]. Arthralgia is sometimes present. The course is exceedingly chronic with a slow healing, fibrotic phase [7, 8].We describe a case of EED in a child presenting with vesiculo-bullous lesions and discuss problems of differential diagnosis that it created.

Case report

A 9-year-old child presented with a 6-month history of red-purple papules, plaques and vesiculo-bullous lesions distributed over the ears and extensor surfaces of the upper and lower extremities and buttocks (figures 1 and 2). Some lesions involuted spontaneously leaving hyperpigmented atrophic scars. The old lesions were asymptomatic, but the new ones were associated with pruritus and a burning sensation. Clinical diagnostic considerations included mainly dermatitis herpetiformis and leukocytoclastic vasculitis. Medical history revealed recurrent episodes of pharyngotonsillitis during the last 12 months. Laboratory investigations showed an elevated erythrocyte sedimentation rate (28 mm/h; normal range 0-14 mm/h) and an elevated antistreptolysin O titre (290 UI/mL; normal range 20-250 UI/mL). Culture of a swab taken from the pharynx was positive for Streptococcus pyogenes. Circulating antibodies to gliadin, transglutaminase, and nuclear antigens were negative. Two skin biopsies were taken: one from a vesiculo-bullous lesion on the right buttock and one from an indurated plaque on the left leg. Histopathologic examination of the biopsy from the periphery of a vesiculo-bullous lesion showed a dense, perivascular superficial and deep dermal infiltrate composed mostly of neutrophils and eosinophils. Extensive leukocytoclasia and focal fibrin necrosis of small vessel walls were also observed. Collections of neutrophils and nuclear dust were seen in edematous papillae and in subepidermal spaces ( (figure 3) ). The biopsy of the long-standing plaque showed a scant infiltrate of neutrophils with nuclear dust throughout zones of marked dermal fibrosis and increased vascularity ( (figure 4) ). Direct immunofluorescence demonstrated IgG and C3 deposits within vessels in the upper dermis. The child was initially treated with clarythromicin 500 mg daily for 10 days with slight improvement of the dermatosis. As EED is an inflammatory disease mainly mediated by neutrophils, we then treated this patient with diamino-diphenyl-sulphone (dapsone), a drug that inhibits lysosomal enzyme activity and interferes with the myeloperoxidase-H₂O₂-halide-mediated cytotoxic system in polymorphonuclear leukocytes [5, 9, 10]. A dose of 50 mg/day was given for two weeks with a prompt and dramatic response, and then the drug was tapered to 25 mg daily for 4 weeks. A maintenance dose of 12.5 mg/day was continued for 6 months with no recurrence of the dermatosis. A tonsillectomy was also performed after that period. At a 2 year-follow-up the patient remained disease-free.

Discussion

EED is a rare skin disease that initially presents as leucocytoclastic vasculitis and later resolves with fibrosis [7, 8]. This disease can occur at any age, with a peak incidence from the third to the sixth decade of life. EED is found in both males and females; the latter are younger than males and usually have concurrent rheumatologic disorders [6, 11]. Only a few pediatric cases have been described in the literature [2, 3, 12-16].

Clinically EED poses problems of differential diagnosis with Sweet’s syndrome, pyoderma gangrenosum, granuloma anulare and, sometimes, dermatitis herpetiformis [17]. In our patient, the early age and the clinical presentation with vesiculo-bullous lesions on the extremities and buttocks strongly suggested During’s disease. Histopathologically the presence of collections of neutrophils in dermal papillae and subepidermal spaces in association with nuclear dust could also evoke this diagnosis, although in dermatitis herpetiformis the infiltrate is usually confined to the superficial dermis and vasculitis is absent. Most importantly, immunopathologically, in dermatitis herpetiformis granular deposits of IgA are found at the tips of dermal papillae [17].

The cause of EED has not yet been definitively established. Disorders that have been associated with EED include bacterial infections, viral infections and rheumatologic diseases [18-25]. Recently, several reports have highlighted haematologic diseases as the most common associations with EED, especially IgA monoclonal gammopathy [26].

Pathogenetically, cutaneous lesions of EED are presumed to be the consequence of an Arthus-type reaction to bacterial and viral agents. Antibodies would bind bacterial or viral antigens forming circulating immune complexes which are then deposited in dermal vessels with activation of the complement cascade, neutrophil attraction and vessel injury [25, 27]. In our case, the presence of immunological deposits in the vessel walls is in keeping with this view.

The occurrence of the dermatosis in childhood is very rare, with only a few documented cases in the literature [2, 3, 12-16, 27, 28] (table 1( Table 1 )). By reviewing the ancient literature on this subject, what would seem to be the first pediatric case of EED was chronicled in 1889 by Bury who described a 12-year-old girl suffering from rheumatic fever who developed purplish plaques on her hands and upper limbs [2]. In 1894 Radcliffe, Crocker and Williams reported on a 6-year-old girl with a similar condition, who had a history of rheumatism [3]. In 1904 Audry published a further case in a 7-year-old boy in whom bullous lesions were observed [12]. In 1960, Kalkoff described a 5-year-old child with EED in whom herpetiform blisters developed on several occasions [13]. In 1966 Thiers showed a 7-year-old child with EED who had recurrent streptococcal throat infections and who developed a bullous eruption [14]. In the series of 13 cases of EED described by Wilkinson et al. in 1992 [27], one patient was a 5-year-old female suffering from chronic gingivitis, nasal obstruction and bilateral conjunctivitis who developed an exceedingly chronic, poorly responsive eruption with blister formation. In 1993, Miyagawa et al. reported on a 3-year-old girl suffering from hyperimmunoglobulinemia D syndrome with recurrent erythematous plaques and vesiculo-bullous lesions of 2 years duration [15]. Interestingly, at 4 months of age the child had staphyloccocal scalded skin syndrome and successively recurrent febrile attacks associated with upper respiratory tract infections.

It is worth noting that in a significant proportion of these cases, the eruption had a vesiculo-bullous presentation. Furthermore, the relationship between streptococcal infection and some pediatric cases of EED would not seem coincidental. The marked reaction to intradermally injected antigens of streptococci with induction of leukocytoclastic vasculits in some patients with EED [19, 25] also supports the view that in EED an Arthus type reaction induced by bacterial antigens may be operative.

What remains unclear is the relationship, if any, between pediatric cases of EED and dermatitis herpetiformis and/or celiac disease, as in a case described by Degos in 1952 [29] and in another patient reported by Rodriguez-Serna [28].

In the presence of cutaneous conditions with no clear-cut clinicopathologic features, as also in the case chronicled by Tasanen et al. [30], direct immunofluorescence studies of biopsies from uninvolved skin and duodenal/jejunal biopsies should be regarded definitely diagnostic for the conundrum.

In sum, we described a case of EED in a child with clinical and histopathologic features mimicking dermatitis herpetiformis. Clinicians should be aware of atypical clinico-pathologic presentations of EED in children in order to avoid misdiagnoses
Table 1 Erythema elevatum diutinum in childhood

Case	Age	Sex	History	Lesions	Site
Bury [2] 1889	12	F	Rheumatic fever 3 years previously	Nodules and purplish plaques	Hands, fingers and one forearm
Radcliffe Crocker [3] 1894	6	F	Family history of rheumatism	Nodules and purplish plaques	Hands, fingers
Audry [12] 1904	9	M	Not reported	Bullous eruption	Limbs and trunk
Kalkoff [13] 1960	5	F	Not reported	Plaques and, 6 months later, herpetiforms blisters	Buttocks and extensor surfaces of the arms and legs and, later, on face, knees and axillae
Thiers [14] 1966	7	M	Recurrent streptococcal throat infections	Bullous eruption	Skin and mucous membranes
Wilkinson [27] 1992	5	F	Chronic gingivitis, nasal obstruction, bilateral conjunctivitis	Papules and plaques with blisters	Buttocks, elbows, knees and dorsa of the feet
Miyagawa [15] 1993	3	F	Chronic upper respiratory tract infection, hypergammaglobulinemia D	Papules, plaques, vesicles	Face, ears, buttocks, extensor surfaces of the limbs, conjunctive, oral mucosa and tongue
Rodriguez-Serna [28] 1993	11	F	Diabetes mellitus, celiac disease, kidney disease	Plaques	Limbs
Hernandez-Cano [16] 1998	10	M	Cyclosporin treatment after liver transplantation	Papules	Hands
Present case	9	M	Recurrent episodes of pharyngotonsillitis	Purplish papules, plaques and vesiculo-bullous lesions	Ears and extensor surfaces of the arms, legs and buttocks

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