Hailey-Hailey disease (ORPHA:2841)
A rare, genetic, chronic epidermal disorder characterized by diffuse bilateral (or, rarely, localized segmental) erythematous plaques with blistering, erosions, maceration, and frequent secondary infection involving the flexural areas.
Epidemiology
The prevalence of familial benign chronic pemphigus (FBCP) is unknown, but no significant difference in sex or ethnic frequency has been noted.
Clinical description
Skin lesions starting as flaccid vesicles on erythematous to normal skin, appear during adolescence or more commonly between the age of 20 and 40 years. Large, macerated, exudative plaques of superficial erosions with crusting are usually seen at the time of diagnosis. Further progression to large, vegetative, malodorous plaques with painful fissures can occur. Involvement sites consist of areas of friction and intertriginous regions (including the neck, axillae, groin, perineum, and the submammary area), affected in a symmetric fashion. Additional feature, observed in approximately 70% of patients, is the presence of longitudal white bands in the fingernails. Segmental forms of the disease present as unilateral, linear, patchy or otherwise confined involvement, often in relation to the Blashko lines. FBPC has a chronic course of repeated remissions and relapses. Triggering or exacerbating factors include sweating, friction, ultraviolet radiation, and secondary infections. Postinflammatory hyperpigmentation is a common sequela.
Etiology
FBCP is caused by heterozygous, loss-of-function mutations in the ATP2C1 gene (3q22.1) which encodes the calcium(Ca2+)-transporting ATPase type 2C member 1 protein, an adenosine triphosphate (ATP)-powered, magnesium-dependent Ca2+ pump involved in Ca2+ sequestering inside the Golgi apparatus. The exact mechanism is unknown, but mutations in ATP2C1 result in altered cellular connections within desmosomes and adherens junctions of the epidermis, secondary to high cytosolic Ca2+ levels.
Diagnostic methods
Histopathological analysis of the lesions shows a widespread and often incomplete acantholysis in the suprabasal layer, which produces a characteristic "dilapidated brick wall" appearance. Direct immunofluorescence staining is negative. Family history and molecular analysis of the ATP2C1 can contribute to confirming the diagnosis.
Differential diagnosis
Differential diagnosis includes intertrigo, candidiasis, inverse psoriasis, lichen simplex chronicus, other subtypes of pemphigus (such as pemphigus vegetans), tinea corporis, and Darier disease.
Antenatal diagnosis
Prenatal testing is possible when the pathogenetic variant has been identified in the family, but is a subject of ethical consideration.
Genetic counseling
FBCP is inherited in an autosomal dominant manner with full penetrance and variable expressivity. About one third of cases occur de novo. Somatic mutations underlie segmental forms of the disease. Genetic counseling can inform the affected individuals of the 50% risk of disease occurrence in their children.
Management and treatment
There is no specific therapy, but drying the affected areas and avoiding friction is essential as well as employing measures to prevent bacterial, fungal and viral infections. Topical medical treatment (including antimicrobials, corticosteroids, calcineurin inhibitors and botulinum toxin injections) may alleviate milder symptoms. There is no strong evidence to support the use of systemic therapies although doxycycline and low-dose naltrexone may provide some benefit. For those with refractory disease, more aggressive treatment with laser ablation, dermabrasion and/or surgery may be considered.
Prognosis
The quality of life in patients with FBCP is significantly impaired, but they have a normal life expectancy, and the intensity of the disease usually diminishes with age.

                            Last update: 
                            July 2024


                            - Expert reviewer(s): 
                            Dr Sung Kyung CHO  - Dr Victoria WERTH