Hailey-hailey disease on sun-exposed areas.

Sir,

Hailey–Hailey disease (HHD) was first described in 1939 as familial benign chronic pemphigus (FBCP). It is an autosomal dominant disorder with incomplete penetrance, with approximately two-thirds of the patients having a family history of the disorder.[1] The disease is due to a mutation of the ATP2C1 gene on chromosome 3q21-q24 which is responsible for controlling Ca2+ concentrations in the cytoplasm and Golgi in human keratinocytes.[23] Cytosolic Ca2+ concentrations, in turn, play a major role in the regulation of keratinocyte differentiation. Involucrin, a protein that envelopes keratinocytes is expressed in response to increased intracellular Ca2+ concentrations. It is responsible for keratinocyte adhesion. Alberg et al., found that the levels of involucrin are decreased in HHD.[4]

A 40-year-old lady presented with painful erythematous plaques of 20-day duration involving the front and sides of the neck and the extensor aspect of both forearms, associated with fever and itching. There was no history of joint pains and family history was negative for a similar ailment. She denied any history of herpes simplex or intake of drugs. Cutaneous examination revealed multiple tender erythematous plaques ranging from 2 to 6 cm. Margins of some of the plaques showed papules and pustules with scaling and central hyperpigmentation [Figures 1 and 2]. On the basis of clinical features, Sweet's syndrome was provisionally diagnosed. Tinea corporis was considered, as a few plaques showed marginal activity but fungal elements were absent on a potassium hydroxide (KOH) mount. Although erythema multiforme was considered in the differential diagnosis, target lesions were absent and history was negative for herpes simplex and drugs. Pemphigus erythematosus was also considered, but immunoglobulin G (IgG) antibodies to desmoglein-3 and direct immunofloresence (DIF) were negative. Routine laboratory investigations were unremarkable. Antibodies against herpes simplex virus 1 and 2 (HSV1 and 2) were negative. Test for antinuclear antibodies (ANA) was negative. A skin biopsy taken from the extensor aspect of the right forearm showed intraepidermal bulla with complete and partial acantholysis of suprabasal and upper layers of the epidermal keratinocytes giving the appearance of a ‘dilapidated brick wall’ which clinched the diagnosis of FBCP [Figures 3 and 4]. Direct immunofluoresence of skin biopsy did not show immune deposits. Ultraviolet (UV) provocation test could not be done as the patient did not give her consent. She was given a course of antibiotics and analgesics and her symptoms regressed. The case is being presented for its atypical presentation.

Figure 1

Erythematous plaques on the right side of neck and upper part of front of chest

Figure 2

Erythematous plaque on the extensor aspect of right fore arm

Figure 3

Histopathology of skin H and E, ×10 showing intraepidermal bulla with complete and partial acantholysis of suprabasal and upper layers of the epidermis giving the appearance of a ‘dilapidated brick wall’

Figure 4

Histopathology of skin H and E, ×40 showing complete and partial acantholysis of upper layers of epidermis

Lesions in FBCP often begin in early adulthood and affect both sexes equally. Epidermis is the site of defect in FBCP. De bobbeleer et al. could reproduce in vitro classic histologic and ultrastructural features of FBCP by seeding suspension of lesional keratinocytes onto heterozygous dead de-epidermized dermis.[5]

Although the course of the disease is unpredictable, morbidity in majority of the patients declined where the duration of the disease was longer than 20 years.[6] HHD typically involves the axillary, genitocrural, and inframammary folds.[7] This is attributed to minor trauma in the form of maceration, heat, and friction. Lesions are usually symmetrical. However, our case presented with erythematous plaques on sun-exposed areas, that is, the right side of the neck and extensor aspects of both forearms. A review of the literature revealed a single case report of FBCP of six-month duration involving typical sites, who developed lesions later on sun-exposed areas. He was a 63-year-old man who had multiple diseases (chronic obstructive pulmonary disease, paroxysmal atrial fibrillation, degenerative joint disease) and was on various medications (warfarin, aminophylline, N-acetylcystiene, ipratropium bromide, prednisolone).[8] However, the reported case is a young healthy lady and not on any medication. The exact role of sunlight in the provocation of FBCP in the reported case could not be established as the patient did not consent to the UV provocation test which could have helped in establishing its role in the pathogenesis of FBCP.

Unusual sites include vulva,[9] conjunctiva,[10] and mucosa.[11] Rarely, it may present as erythroderma.[12] Lesions may be triggered by trauma, bacterial or fungal infections, and dermatoses. Eczema herpeticum may occur rarely in patients of FBCP. Such association was reported only in four cases in the literature.[13] Lesions tend to recur at sites of previous involvement. Longitudinal leukonychia, seen 71% in one study, may help in the diagnosis of HHD.[6] However, this nail finding was not observed in the reported case. Variants of classic HHD include segmental unilateral disease, seborrheic dermatitis, and perianal disease simulating condyloma accuminata.

Treatment is difficult; however, there are report of improvement with systemic or topical antistaphylococcal antibiotics, antifungals, corticosteroids, cyclosporine,[14] retinoids,[15] topical calcineurin inhibitors and calcitriol, botulinum toxin, dapsone, dermabrasion,[16] carbon dioxide (CO2) laser,[17] photodynamic therapy,[18] and grafting.[19] FBCP patients have an increased risk of developing contact allergy to topical therapy.[20] Skin grafting with split-thickness skin graft is indicated in recalcitrant cases of FBCP. Topical gentamicin was found to be effective in inducing remission in an FBCP patient. It can induce readthrough of premature stop mutations in the epidermis.[21]