H HAE ▶Angioedema, Hereditary Hailey-Hailey Disease DIETER METZE Department of Dermatology, University Hospital of Muenster, Muenster, Germany Synonyms Familial benign chronic pemphigus [1] Definition and Characteristics Hailey-Hailey disease is an autosomal dominant skin disorder characterized by erosive plaques. The disease usually starts between the second and fourth decade. The course of the disease is characterized by spontaneous exacerbations and remissions with marked predilection for the intertriginous areas [2]. Hailey-Hailey disease presents with vesicles, papules, crusted erosions, and oozing plaques. Pain and unplea- sant smell lead to a social handicap. Lesions can be triggered on almost all body sites by minor trauma, friction, tape stripping, and inflammation caused by UV radiation, allergens, toxic components or infectious agents. Finger nails may show asymptomatic longitudinal white bands. Mucosal involvement is unusual [1]. Prevalence The disease is rare. Genes Hu et al. identified mutations in the ATP2C1 gene on chromosome 3q21–q24, which encodes the human homologue of an ATP-powered pump that sequesters calcium into the Golgi in yeast [3]. Mutations included nonsense, frameshift insertion and deletions, splice-site mutations, and missense mutations in functional domains [3,4]. Molecular and Systemic Pathophysiology Regulation of cytoplasmic calcium is impaired in cul- tured keratinocytes from Hailey-Hailey disease patients, and the normal epidermal calcium gradient is attenuated in vivo. The ultrastructural hallmark of the disease is a peculiar type of acantholysis, where, despite the dissolution of desmosomes, keratinocytes remain linked together by well-preserved adherens junctions (incomplete acantholysis, Hailey-Hailey-like pattern of acantholysis). The adherens junction-actin system is not only essential for calcium induced formation of desmosomes and organization of the keratin filaments but also possesses cohesive properties [5]. Diagnostic Principles Clinically, the diagnosis can be difficult and must be confirmed by a skin biopsy. Histology of the epidermis shows hyperplasia, incomplete acantholysis with clefts and scale-crusts. The dermis contains a variable inflammatory infiltrate. Therapeutic Principles Pharmacological therapy consists of topical corticoster- oids with or without antiseptics or antibiotics. Other treatments include dermabrasion and carbon dioxide laser vaporization. References 1. Hailey H, Hailey H (1939) Familial benign chronic pemphigus. Arch Dermatol Syphilol 39:679–685 2. Burge SM (1992) Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 126:275–282 3. Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH Jr (2000) Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet 24:61–65 4. Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, Healy E, Dissanayake M, Larregue M, Perrussel M, Lehrach H, Munro CS, Strachan T, Burge S, Hovnanian A, Monaco AP (2000) Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump. Hum Mol Genet 9:1131–1140