Clinical Reference / Dermatopathology: Practical & Conceptual / Oct – Dec 2010 | Vol. 16, No. 4 / Observation | Epidermolysis bullosa pruriginosa—case series of two sporadic cases and one family

Observation | Epidermolysis bullosa pruriginosa—case series of two sporadic cases and one family

Oct – Dec 2010 | Vol. 16, No. 4
Khaled Selim, Mohammed; Ahmed, Elshahat Farag; Fawzy, Mohamed

Introduction

Epidermolysis bullosa pruriginosa (EBP) is a rare distinct variant of dystrophic epidermolysis bullosa (DEB), which was first described in 1994 by McGrath et al. [1] It is characterized clinically by intense pruritus and hypertrophic scarring. All forms of DEB, including EBP, result from mutations in the type VII collagen gene, COL7A1. [2] Most cases are sporadic, less commonly autosomal dominant, and rarely autosomal recessive inheritance are found. [1,3,4] Microscopic studies of EBP show typical findings of DEB [5] and it has been postulated that itching lesions of EBP could represent an abnormal dermal reactivity of some subjects to their inherited bullous disorder.

The study of the molecular basis of classical dominant DEB and EBP shows that both diseases are caused by a missense glycine substitution mutation by different amino acids in the same codon of COL 7A (G2028R and G2028A). [2,6,7] Intriguingly, the spectrum of COL7A1 mutations underlying EBP is not significantly different from that in non-itchy forms of DEB. [8] The reason for the itchy skin phenotype is unclear and the cause of the pruritus cannot be attributed to a specific type of COL7A1 mutation. Previous studies have assessed and excluded causes such as atopy, raised IgE levels, iron deficiency, renal, liver, and thyroid dysfunction, matrix metalloproteinase gene polymorphisms, and filaggrin gene mutations as potential modifiers of phenotype. [4,9]

Here we present two sporadic cases and one family with autosomal dominant inheritance of EB pruriginosa.

Our patients

Patient 1

A 19-year-old patient presented himself with severely itchy skin lesions distributed over trunk and extremities. The condition dated since early childhood. His parents and other siblings were reportedly healthy. Topical or systemic steroids and antihistamines had provided temporary relief in the past. History revealed occasional appearance of small blisters following minor trauma since childhood. These blisters used to rupture and the erosions would heal with severely pruritic papules and scarring. No other family member of the patient had similar features. On examination, many eroded and crusted papulonodular lesions and prurigo-like lesions were seen on the back, chest, shoulders, pubic area, presacral area, and lower legs (Figs. 1-3). Atrophic and hypertrophic scars were seen among the active lesions (Figs. 1-3). Face and flexures were spared. No clinically evident bullae were seen at the time of examination. All toenails were dystrophic or partially lost (Fig. 4).

Fig. 1

Excoriated pruriginous and lichenoid papules on the trunk.

Fig. 2

Close-up view of lichenoid papules and plaques.

Fig. 3

Excoriated pruriginous and lichenoid papules and plaques on the leg.

Fig. 4

Dystrophic toenails.

Patient 2

A 9-year-old female presented herself with an itchy eruption with occasional blistering mainly over the extensor surfaces of the extremities since the age of 2 years. With age, the number of new blisters decreased, but the pruritic papules persisted. On examination, multiple prurigo-like lesions and excoriations were seen on the shins, the dorsal aspect of both feet and both forearms, and also on a localized area on the lower back (Fig. 5). All toenails were dystrophic. No family history of similar conditions was reported.

Fig. 5

Lichenoid and pruriginous papules and plaques and dystrophy of the big toenail.

Patient 3

A 22-year-old woman presented herself with a severely pruritic eruption over the back, the thighs, and both shins (Fig. 6) and a history of intermittent skin blistering since the age of 10. The blisters were provoked by scratching. Her parents were non-consanguineous. She was the third of four siblings, all of whom were examined by the authors and were found to have similar skin lesions which developed during their early teenage years. Their mother was also affected with similar findings, but the father was free of lesions, indicating autosomal dominant inheritance. Examination of the patients and other affected members of the family revealed common features. On examination, many eroded and crusted lichenified plaques and prurigo-like lesions were seen on the back, thighs, and both shins (Fig. 6). There were also a few blisters scattered among the lesions (Fig. 6). Face and flexures were spared. All toenails were dystrophic or partially lost (Fig. 7).

Fig. 6

Lichenoid and pruriginous papules and plaques on both legs with few blisters.

Fig. 7

Dystrophic nails.

In all of our patients, there were no albopapuloid lesions or milia-like lesions. There were no signs of atopy or any other significant skin disease to account for the pruritus in any patient. Hair, mucosae, and other systemic examination showed no abnormality. Routine laboratory investigations, including complete blood counts, serum biochemistry, urine analysis and chest x-rays were essentially normal in all patients

Histopathlogic examination was done in five patients, in the two sporadic cases and in three members of the family with autosomal dominant inheritance (Fig. 8 and 9). All cases showed hyperkeratosis, mild acanthosis, and a subepidermal blister with dermal fibrosis lacking any inflammatory infiltrate.

Fig. 8A

Patient 1. Subepidermal blister with intact epidermis in the roof and fibrosing granulation tissue in the floor (H&E, X4).

Fig. 8B

Patient 1. Subepidermal blister with intact epidermis in the roof and fibrosing granulation tissue in the floor (H&E, X10).

Fig. 9A

Patient 2. Prominent subepidermal blister (H&E, x4).

Fig. 9B.

Patient 2. Prominent subepidermal blister. Note the intact basal cell layer (H&E, x10).

Direct immunofluorescence testing failed to show any deposit of IgG, IgM, C3, C4, or fibrinogen. Antigen mapping with indirect immunofluorescence revealed the presence of antibodies to collagen type VII in the roof of the blister confirming the level of the cleavage at sublamina densa, which is characteristic of DEB. Collagen VII was normally intact in the perilesional skin compared with the site of the split, where it is very attenuated and only remnants of it are present in the roof of the blister (Figs. 10 and 11).

Fig. 10

Patient 1. Collagen VII is attenuated at the site of the blister with just traces at the roof compared with intact skin (left side), where it looks normal (IIF, x40).

Fig. 11

Patient 2. Collagen VII is normally intact in the perilesional skin (left side) compared with the site of the split, where it is reduced, and only remnants are present in the roof of the blister (IIF, x10).

Electron microscopy and gene mutation studies could not be done due to lack of a facility.

Based on the classical history, physical examination, and histopathological and immunofluorescence studies, a diagnosis of epidermolysis bullosa pruriginosa was established in all cases. The prognosis was explained to the patients and they were treated symptomatically with topical steroids, topical tacrolimus, and oral antihistamines with temporary relief of pruritus.

Discussion

EB pruriginosa is a type of dystrophic EB termed by McGrath in 1994, [1] but a number of reports of a similar condition have appeared in literature since 1946. [10-12]. All forms of DEB, including EBP, result from glycine substitution mutations in the type VII collagen gene, COL7A1. [2] However, there is no specific clear genotype-phenotype correlation in EBP. Type VII collagen is the major component of anchoring fibrils at the dermoepidermal junction (DEJ). Mutations in COL7A1 lead to reduced or abnormal type VII collagen deposition at the DEJ, with structural abnormalities in anchoring fibrils and a sublamina densa plane of blister formation. [2] EBP is characterized clinically by extremely pruritic linear lichenified or nodular prurigo-like lesions predominantly over legs, occasional trauma-induced blistering, excoriations, milia, and albopapuloid lesions on the trunk, appearing at birth or later. [1] Toenail dystrophy is a consistent finding in adult patients. Lesions can occur at any site, although the lower legs are often involved. The presence of toenail dystrophy, which is present in most cases, can give a clue to the true underlying mechanobullous etiology. [1,2] The rarity of intact blisters, adult onset in many cases, prominent nature of some of the scars, and the marked lichenification with severe pruritus lead to a confusion of the condition with more common disorders like lichen simplex chronicus, hypertrophic lichen planus, Nekam’s disease, hypertrophic scarring, and dermatitis artefacta. [1] The exact cause of pruritus in this condition is unknown. Possibly, the exposure of type VII collagen is triggers the activation of the kinin cascade. Bradykinin could be interacting with other mediators to account for the severe pruritus. [13]

Histopathologically, a split may be evident at the dermo-epidermal junction, although frank blisters are rarely seen. Ultrastructurally, there is a sublamina densa level of blister formation and quantitative or qualitative changes in anchoring fibrils at the dermo-epidermal junction. Reduction in number of anchoring fibrils is found in lesional, perilesional, and non-lesional skin of patients with EB pruriginosa. [1] Molecular screening of the COL7A1 gene is the gold standard diagnostic test and can be done by taking a peripheral blood sample for DNA extraction. Both, dominant dystrophic classical EB and EB pruriginosa, show a missense glycine substitution mutation by different amino acids in the same codon of COL 7A. [6,7]

In the present case series, the clinical, histopathological and immunofluorescence findings were almost identical. The main complaint was recalcitrant severely itchy chronic skin lesions with poor response to all available medications. Diagnosis was established on the basis of the presence of intensely itchy lesions since childhood, including prurigo-like lesions and lichen planus-like papules over trunk, shoulders, and lower limbs, dystrophy of all toenails (and not finger nails), associated scarring, and occasional blisters, and normal hair and mucosae with the histopathology revealing a subepidermal cleft with characteristic immunofluorescence studies. Electron microscopy and gene mutation studies could not be done due to lack of facility. However, the clinical picture and histopathological and immunofluorescence studies were classic and quite sufficient for diagnosis. The affected family in our study consisted of 4 siblings and the mother, but the father was free, supporting the role of autosomal dominant inheritance in some cases of EBP.

EBP can be mistaken for the more common acquired disorders, such as nodular prurigo, lichen simplex, hypertrophic lichen planus, hypertrophic scarring, cutaneous amyloidosis, Nekam’s disease, or dermatitis artefacta. The rarity of intact blisters, the prominent nature of some of the scars, and the marked lichenification with severe pruritus shows overlap with these more common non-EB related dermatoses. However, none of the above conditions would reveal a subepidermal cleft on histopathology with characteristic immunofluorescence findings of EBP.

The condition is a genodermatosis and there is no definite treatment to date. Nevertheless, some reports of helpful interventions in EBP have been published. These include topical treatments (e.g., tacrolimus), systemic agents (e.g., ciclosporin or thalidomide), and cryotherapy. Symptomatic treatment for pruritus includes use of oral antihistaminics, topical steroids, topical tacrolimus, and a short course of low dose oral steroids. Gene therapy and genetic counselling are possibly the most promising approach to a patient with this condition.

In conclusion, although EBP is a rare condition it must be put in differential diagnosis of any recalcitrant itchy skin diseases with lichenoid and/or pruriginous skin lesions and hypertrophic scarring.

Summary

Background: Epidermolysis bullosa pruriginosa is (EBP) is a rare distinct variant of dystrophic EB. EBP usually results from sporadic or dominantly transmitted mutations in the type VII collagen gene, COL7A1. It is characterized clinically by extremely pruritic, lichenified or nodular lesions predominantly over shins, milia formation and albopapuloid lesions on the trunk, appearing at birth or later. Toenail dystrophy is a consistent finding in adult patients. The rarity of intact blisters, adult onset in many cases, prominent nature of some of the scars and the marked lichenification with severe pruritus lead to a confusion with commoner disorders, like lichen simplex chronicus, hypertrophic lichen planus, Nekam’s disease, hypertrophic scarring and dermatitis artefacta. Treatment is unsatisfactory. Patients/Methods: We present two sporadic cases and one family with autosomal dominant inheritance of EBP. The familial case was one of five cases of same family (four siblings and the mother) all of whom had similar skin lesions, which developed during their early teenage years. Results: All patients presented themselves with similar clinical features including widespread prurigo-like lesions and toenail dystrophy. The diagnosis in all patients was confirmed with help of characteristic histopathology with subepidermal blisters. Treatment was symptomatic with oral antihistamine, topical tacrolimus, and topical steroids. Conclusions: Although EBP is a rare condition it must be put in differential diagnosis of any recalcitrant itchy skin diseases with lichenoid and/or pruriginous skin lesions and hypertrophic scarring.

Mohamed Khaled Selim, M.D., Elshahat Farag Ahmed, M.D., and Mohamed Fawzy, M.D. are from the Department of Dermatology, Mansoura University in Egypt. This article was reviewed by Almut Böer, M.D. Contact corresponding author via email: mkhaled4@yahoo.com

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