Hailey-Hailey Disease (HHD)

Prevalence similar to DD

Onset: 20s-30s, may be delayed to 40s-50s

  • Autosomal dominant 
  • Complete penetrance
  • Variable expressivity
  • ATP2C1 gene mutation 🡪 Golgi apparatus Ca2+ ATPase dysfunction 🡪 abnormal intracellular Ca2+ signaling 🡪 acantholysis

NB: as ER is responsible for protein synthesis and Golgi for protein processing, no dyskeratosis or apoptosis is usually seen with HHD 

NB: Mnemonic to remember mutation – Hailey Hailey like the comet; you want TO (“2”) SEE (“C”) ONE (“1”)

Clinical course: variable

  • Flares and remissions 
  • Some attenuate with age
  • Normal life expectancy

Morphology:

  • Flaccid vesicles OR macerated/crusted circinate erosions on erythematous or normal base 
  • +/- Malodorous 
  • +/- vegetating 
  • +/- painful fissures
  • Heal w/o scarring, but dyspigmentation may be seen

Distribution: 

  • Intertriginous sites

Nails: 

  • Longitudinal leukonychia

Mucosa:

  • Rarely involves buccal, vaginal, conjunctival

Exacerbators: 

  • Friction 
  • Heat, sweating
  • Microbial staphylococcal colonization 

Complications:

  • Secondary infections (bacteria, fungi) 🡪 malodor, vegetating plaques
  • Kaposi varicelliform eruption 
  • Risk of SCC (co-factor is HPV in anogenital)

Clinical subtypes:

  • Segmental type 1: postzygotic mutation 🡪 mosaic distribution
  • Segmental type 2: postzygotic inactivation of the normal ATP2C1 allele (loss of heterozygosity)

  • Widespread epidermal acantholysis 🡪 “dilapidated brick wall” of keratinocytes
  • Dermal papillae protrude into blister cavities 🡪 “villi”
  • No apoptosis/necrosis, rarely dyskeratotic “corps ronds” seen 
  • Chronic lesions: epidermal hyperplasia, parakeratosis, focal crusts
    • NB: DD shows abundant dyskeratotic cells/foci 

NB: Grover disease may be indistinguishable on histopathology, but clinically very different

  • General:
    • Lightweight clothes to avoid friction/sweating
    • Weight reduction
    • Bleach baths or antimicrobial cleansers to prevent bacterial colonization
    • Antiperspirants (e.g. aluminum acetate), absorbent pads and/or zinc paste
  • Topical and intralesional:
    • Intermittent mid-strong potency topical corticosteroids alone or combined w/ antibiotics ± antifungals (if colonization) for flares
    • If heavy colonizations – consider systemic antibiotics
    • Topical calcineurin inhibitors for flares or maintenance
    • Anecdotal reports of topical 5-fluorouracil and vitamin D analogues
    • Intermittent botox injections for hyperhidrosis
    • Topical aminoglycosides
  • Systemic therapy:
    • Magnesium + low dose naltrexone is promising
    • Anecdotal reports w/ tetracyclines and systemic immunosuppressants
    • Dupilumab
  • Surgical therapy:
    • Consider if unresponsive to above measures, uncertain long-term benefit
    • Wide excision + grafting
    • Superficial ablation: dermabrasion, ablative laser (CO2, erbium:YAG), PDT

  • Intertrigo
  • Candidiasis
  • Irritant Contact
  • Lichen simplex chronicus,
  • Inverse psoriasis

Vegetating intertriginous lesions may resemble:

  • Pemphigus vegetans (Hallopeau type) or Pemphigoid vegetans distinguished by positive DIF of perilesional skin

Darier disease vs. Hailey-Hailey disease:

  • Pattern of distribution (HHD favors flexural vs DD seborrheic)
  • Histopathology (acantholysis in HHD vs less acantholysis and more dyskeratosis in DD)
  • DD has more prominent nail/mucosal changes