Skin nontumor
Blistering disorders
Hailey-Hailey disease (HHD)

Author: Narina Grove, M.D., M.A. (see Authors page)
Editorial Board Member Review: Hillary Rose Elwood, M.D.

Revised: 27 July 2017, last major update July 2017

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed Search: Hailey-Hailey disease[title]
Cite this page: Hailey-Hailey disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/skinnontumorhaileyhailey.html. Accessed October 20th, 2017.
Definition / general
  • Autosomal dominant genodermatosis characterized by intraepidermal vesicles located predominately in intertriginous area
  • Vesicles may progress to bullae, then rupture, forming a crust
  • Histology shows intraepidermal acantholysis due to nonfunctional desmosomal protein complexes
Essential features
  • Genodermatosis with autosomal dominant inheritance pattern (mutation in ATPC1 gene), 1/3 of cases are sporadic
  • Presents in second to forth decades, improves with age
  • Vesicles / bullae in intertriginous areas (axillae, groin, perianal and inframammary areas). exacerbated by perspiration
  • Rarely involves other areas
  • Relapsing remitting clinical course
  • Secondary infection (bacterial, herpetic) can be problematic and serious
  • Main treatment is topical steroids and topical antimicrobials
Terminology
  • Also called benign familial pemphigus
  • Papular acantholytic dermatosis in genitocrural region may be a localized form of H-H disease
ICD-10 coding
  • Q82.8
Epidemiology
Sites
  • Axillae, groin, perianal and inframammary areas
  • Rarely involves other sites
Pathophysiology
  • Mutation in ATP2C1, a calcium pump important in normal function of desmosomal protein complex
  • Dissociation of intracellular and extracellular domains of desmosomal cadherin and E-cadherin (adherens junction associated protein)
  • Faulty calcium pump action leads to disorganized function of desmogleins, which are calcium dependent adherence proteins (cadherins) (Indian Dermatol Online J 2016;7:147)
  • Hailey-Hailey and Darier disease share similar pathogenesis, as opposed to pemphigus vulgaris, in which autoantibodies develop against desmosomal proteins
Etiology
  • Blistering lesions in affected individuals may be induced by trauma, heat, UV light, perspiration
  • May be complicated by secondary infection with scabies, bacteria, herpes or yeast
Clinical features
  • Pruritic / burning, often malodorous lesions
  • Papular, verrucous, annular and vesiculopustular variants are rare
  • Nikolski sign may be positive
  • 1/3 of cases are sporadic
  • Healing accompanied by hyperpigmentation, but scarring is rare
  • Longitudinal leukonychia (asymptomatic white longitudinal bands on the fingernails in 70% of patients)
  • Superinfection by Candida albicans, herpes virus and Staphylococcus aureus are frequent complications
  • Cases of complication by squamous cell carcinoma have been reported
  • Symptoms worsen during summer, often disappear during winter
Case reports
Treatment
  • Topical steroids and topical antimicrobials are the first line treatments
  • Botulinum toxin A injections
  • Cryotherapy
  • Photodynamic therapy
  • Oral magnesium chloride
  • Laser ablation
  • Electron beam radiotherapy
  • Dermabrasion
  • Glycopyrrolate
  • Afamelanotide
Clinical images

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Hailey-Hailey in right axilla

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Hailey-Hailey under breast

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Hyperpigmented plaques over groin

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Hailey-Hailey lesions on left groin

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Figure 2b. Showing
longitudinal leukonychia
and ridging
Microscopic (histologic) description
  • Suprabasilar and intraepidermal clefting
  • Acantholysis of keratinocytes resembling dilapidated brick wall
  • Epidermal hyperplasia
  • No pronounced dyskeratosis but dyskeratotic keratinocytes have well defined nucleus and preserved cytoplasm (unlike pemphigus vulgaris)
  • Corps ronds and grains are rare
  • Adnexal structures are spared
  • Dermis shows variable chronic inflammatory infiltrate
  • Parakeratotic crust may contain neutrophils and bacteria
  • Immunofluorescence negative
Microscopic (histologic) images

Images hosted on Pathout server:
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Broad intraepidermal vesicles with “dilapidated brick appearance”
Contributed by Savita Ries, M.D., Long Beach Memorial Medical Center, Long Beach, CA



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Image 3: Hailey-Hailey disease

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Figure 1: HHD on
right sole, groin
and trunk
Molecular / cytogenetics description
  • Autosomal dominant condition with incomplete penetrance
  • ATPase calcium transporting type 2C member 1 gene (ATP2C1) on chromosome 3q21-q24 encodes a CA2+/ Mn2+ ATPase channel pump SPCA1
Differential diagnosis
  • Darier Disease
    • ATP2A2 mutation
    • Less acantholysis, more dyskeratosis
    • Involves "seborrheic" areas of the body, including scalp, face, upper chest, back
    • Acantholytic zones involve adnexal structures (particularly hair follicles)
    • Numerous corps ronds and grains
  • Grover disease
    • Narrow vesicles involving only a few rete ridges but may be histologically identical to Hailey-Hailey disease
    • Different clinical distribution of lesions
    • Acquired rather than inherited (no family history)
  • Papular acantholytic dermatosis of the genitocrural region
    • Localized variant of Hailey-Hailey or Darier disease involving only the perigenital areas
  • Pemphigus vulgaris
    • No predilection for intertriginous areas
    • Intact epithelium in adjacent epidermis
    • Involvement of adnexal structures
    • Eosinophils on histology
    • Less acantholysis, more dyskeratosis
    • Autoimmune mediated direct immunofluorescence is positive
  • Relapsing linear acantholytic dermatosis
    • Vesicles follow the lines of Blaschko
Additional references
Board review question #1
    What is the underlying pathogenesis of Hailey-Hailey disease?

  1. ATP2A2 mutation
  2. ATP2C1mutation
  3. Autoantibodies against desmosomal proteins
  4. Autoantibodies against non collagenous domain of type VII collagen
  5. Autoantibodies against the hemidesmosomal antigens bullous pemphigoid antigen 1 (BP1) and 2 (BP2)
Board review answer #1
B. Hailey-Hailey is caused by an autosomal dominant mutation in ATP2C1, a calcium pump important in normal function of desmosomal protein complex. This mutation causes dissociation of intracellular and extracellular domains of desmosomal cadherin and E-cadherin (adherens junction associated protein), and a faulty calcium pump action leads to disorganized function of desmogleins, which are calcium dependent adherence proteins (cadherins).
Board review question #2
    What differential diagnosis of Hailey-Hailey is also inherited in an autosomal dominant manner?

  1. Darier Disease
  2. Grover Disease
  3. Papular acantholytic dermatosis of the genitocrural region
  4. Pemphigus Vulgaris
  5. Relapsing linear acantholytic dermatosis
Board review answer #2
A. Darier Disease is the only other genodermatosis transmitted in an autosomal dominant manner. The disease is due to the mutation in ATP2A2 that encodes sarco / endoplasmic reticulum Ca(2+) ATPase isoform 2 (SERCA2).