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  • The acantholytic diseases are a heterogeneous group of diseases with overlapping clinical and histologic features.

  • Darier-White disease (DD) and Hailey-Hailey disease (HHD) are uncommon diseases inherited in an autosomal dominant pattern. A defective calcium pump of the sarcoplasmic/endoplasmic reticulum causes DD, and a faulty calcium and manganese pump of the Golgi apparatus underlies HHD.

  • Whereas typical DD presents with greasy keratotic papules in a seborrhoeic distribution, HHD is characterized by painful, oozing erosions in flexures and at sites of trauma.

  • Nail changes (DD and HHD), flat-topped warty papules on dorsa of hands and feet (DD), and palmar pits (DD and HHD) or palmar keratotic papules (DD) help to confirm the diagnosis.

  • Hypertrophic malodorous flexural disease is particularly disabling in DD and HHD.

  • Grover disease (GD) is a sporadic papular condition of uncertain etiology that presents most often in sun-damaged skin. Intractable pruritus is common.

  • Histopathologicl examination of involved skin in DD, HH, and GD reveals breakdown of intercellular contacts between suprabasal keratinocytes (acantholysis) with variable dyskeratosis.

  • Mosaic forms (type 1 and 2) following the lines of Blaschko have been identified in DD and HHD.

  • Acrokeratosis verruciformis of Hopf (AKV) mimics acral DD with flat-topped, warty papules on the dorsal hands and feet and nail dystrophy. The histology of AKV is not acantholytic, but several reports have identified a specific ATP2A2 mutation in patients with AKV, which indicate that some (if not most) cases are allelic variants of DD with limited manifestations.

  • Papular acantholytic dyskeratosis (PAD) presents as whitish papules of the genitocrural or anogenital areas (or both). PAD has been associated with a somatic ATP2A2 mutation and with constitutive ATP2C1 mutations, indicating that it can be part of the clinical spectrum of DD or HHD.

  • Treatment options for these diseases include topical corticosteroids (DD, HHD, GD) and topical or oral retinoids (DD, GD, AKV), but disease-specific therapies are lacking.


Acantholytic diseases are characterized by loss of intercellular cohesion between keratinocytes, resulting in cell separation. Acantholysis can be the major histologic finding but can also be associated with dyskeratosis corresponding to abnormal keratinization with “corps ronds and grains.” Acantholysis is caused by rupture of the desmosomal junctions. However, the most frequent acantholytic diseases (pemphigus, Darier disease [DD], Hailey-Hailey disease [HHD], and Grover disease [GD]) are not caused by primary defects in desmosomal components. This chapter describes DD, HHD, and GD; pemphigus is covered in Chap. 52. The relationship between acrokeratosis verruciformis (AKV), also known as Hopf disease, and DD has been debated for decades. AKV can now be considered as a clinical variant of DD since the same Pro602Leu mutation in ATP2A2 has been identified in five unrelated patients with AKV. Papular acantholytic dyskeratosis (PAD) is presented as a possible clinical form of DD and HHD because PAD has been associated with a somatic ATP2A2 mutation and germinal ATP2C1 mutations in distinct patients.


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