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Chapter 51. Acantholytic Disorders of the Skin

Susan Burge; Alain Hovnanian

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Acantholytic Diseases at a Glance
  • The acantholytic diseases are a heterogeneous group of diseases with overlapping clinical and histological features.
  • Darier (or Darier–White) disease (DD) and Hailey–Hailey disease (HHD) are autosomal dominant disorders that are caused by defective calcium pumps—a sarco/endoplasmic reticulum pump in DD and a Golgi apparatus pump in HHD.
  • Typical DD presents with greasy keratotic papules in a seborrheic distribution while HHD is characterized by painful oozing erosions in flexures and at sites of trauma.
  • Signs in the nails (DD, HHD), flat-topped warty papules on dorsa of hands and feet (DD) and palmar pits (DD, 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.
  • Histopathological examination of involved skin in DD, HH, and GD reveals breakdown of intercellular contacts between suprabasal keratinocytes (acantholysis) with variable dyskeratosis.
  • Acrokeratosis verruciformis of Hopf (AKV) is autosomal dominant and characterized by signs that mimic acral DD: flat-topped warty papules on dorsa of hands and feet and nail dystrophy. The histology in AKV is not acantholytic, but some (if not most) cases may be limited variants of DD.
  • Treatment options for these diseases include topical corticosteroids (DD, HHD, GD) and topical or oral retinoids (DD, GD, AKV).

Epidemiology

Darier disease (DD) (OMIM #124200) is an autosomal dominant disease affecting both sexes and all ethnic groups. DD was described independently by Darier and White in 1889 (also known as Darier–White disease or keratosis follicularis).1 Estimates of prevalence range from 1 in 30,000 (Northeast England, Scotland, Slovenia)2–4 to 1 in 100,000 (Denmark).5 Penetrance is complete, but spontaneous mutations are frequent.

Etiology and Pathogenesis

The gene for DD was mapped by linkage analysis to chromosome region 12q23-24 in 19936 and ATP2A2 was identified as the defective gene in 1999.7 ATP2A2 encodes sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) isoform 2 (SERCA2), a calcium pump transporting Ca2+ from the cytosol to the lumen of the endoplasmic reticulum (ER).8–11 DD is caused by mutations inactivating one ATP2A2 allele.

ATP2A2 spans 76 kilobases (kb), is organized in 21 exons, and encodes a 4.4-kb transcript, which is alternatively spliced into three isoforms: (1) SERCA2a, (2) SERCA2b, and (3) SERCA2c.12,13 SERCA2a is expressed in the slow-twitch skeletal muscles and cardiac muscle, unaffected in DD.14,15 SERCA2b and SERCA2c are expressed ubiquitously, but SERCA2b is the major isoform detected in the human epidermis.16 Mutations specific for SERCA2b are sufficient to cause DD (despite the presence of functional SERCA2a), confirming the important role of SERCA2b in epidermis.17,18 Most tissues may compensate for deficiencies in SERCA2 by mechanisms such as SERCA3, which is ...

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