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Hailey-Hailey disease (Benign familial pemphigus)

26 March 2013, by SOARES-DE-ALMEIDA L. & FERNANDES S.

1 - CLINICAL AND PATHOLOGY

In 1939, the brothers Howard and Hugh Hailey described an uncommon autosomal dominant inherited disorder, Hailey-Hailey disease (HH), caused by mutations in the ATP2C1 gene which interfere with intracellular calcium-pump mechanism resulting primarily in a loss of cellular adhesion (acantholysis) in the stratum spinosum of the epidermis.

The initial lesions of HH usually develop during the second or third decades of life and are characterized by recurrent erythematous eroded, macerated or crusted plaques, sometimes with overlying flaccid vesicles, involving the flexural areas. The lesions are symmetrically distributed on the neck, axillae, groin, perianal and inframammary folds. Pruritus and pain are usual symptoms. In patients with limited or atypical disease, longitu­dinal leukonychia may serve as a diagnostic clue.

Some factors can exacerbate the pre-existing skin lesions, like friction, heat, microbial colonization and secondary infections which usually lead to malodor. An important, but rare, complication is the development of cutaneous squamous cell carcinoma, particularly in chronic anogenital lesions, probably related to the increased predisposition to infections with oncogenic strains of HPV and the impairment of the structural integrity of the epidermis.

Pathologically in the early lesions it is possible to identify lacunae formed by suprabasilar clefts that progress to widespread pronounced acantholysis of the full-thickness epidermis, sometimes referred to as a “dilapidated brick wall”. Dermal papillae protrude into the blister cavities and are referred to as “villi”. A variable patchy acute or chronic inflammatory infiltrate of lymphocytes and eosinophils is identified, and in chronic lesions epidermal hyperplasia, parakeratosis and focal crusts are found. Absence of adnexal involvement is an important feature to differentiate HH from pemphigus. Direct and indirect immunofluorescence studies are negative in HH.

2 - TREATMENT STRATEGY

It is essential to explain to patients that HH has a chronic course with crops, and it is also important to provide specific recommendations on general measures, such as minimization of heat or friction, and wearing lightweight clothes. In case of secondary skin infections, topical and/or systemic antimicrobial agents are indicated and sometimes it is useful to start long-term antimicrobial cleansers as a preventive measure.

Currently, no clear long-term effective therapies exist. A few treatments are used, with variable results. Topical steroids are often part of the treatment schedule, and in intertriginous areas low-potency agents are preferred to minimize the potential side effects. Some topical treatments show benefits, like tacrolimus, or pimecrolimus cream, cyclosporine, 5-fluorouracil, calcitriol and tacalcitol.

Refractory disease may respond to phototherapy with targeted narrow-band Ultraviolet B therapy, and even some surgical modalities are used to the treatment of limited extent disease, like dermabrasion, laser therapy (laser CO2, erbium:YAG or long-pulsed alexandrite laser), and photodynamic therapy with 5-amino levulinic acid or even local electron-beam therapy. Experience with surgical excision is limited, and the best results were obtained in patients whose wounds were resurfaced with split skin grafts.

There is no sufficient evidence of efficacy to support the use of systemic treatments, but some reports show improvement with oral corticosteroids or retinoids (e.g. 25 mg of acitretin daily) and immunomodulatory drugs such as cyclosporine (2.8 to 3.4 mg/kg per day), methotrexate (7.5 mg weekly), dapsone (50-200 mg per day)or alefacept 15 mg weekly). The use of oral erythromycin (600 mg t.i.d.) or doxycycline (100 mg per day for a three-month period) is also suggested. Some authors report positive results with the use of Botulinum toxin type A.

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