Darier Disease (DD)

Prevalence: 1-4 per 100,000

Onset: between 6-20 years of age in 70% of cases; peaks in puberty

Male = female

Particular ATP2A2 mutations are associated with acrokeratosis verruciformis of Hopf and the acral hemorrhagic subtype of Darier disease (see Clinical features)

Exacerbating factors:

  • Summer
  • UV (* UVB)
  • Sweating, heat, friction
  • Occlusion
  • infection
  • Lithium carbonate

Autosomal dominant genodermatosis with complete penetrance and variable expressivity

ATP2A2 gene mutation 🡪 endoplasmic reticulum (ER) Ca2+ ATPase (SERCA2b) dysfunction 🡪 abnormal intracellular Ca2+ signaling leading to

1) insufficient Ca2+ influx to ER 🡪 dysfunctional Ca2+ dependent proteins e.g. cadherins 🡪 acantholysis;

&

2) accumulation of unfolded proteins in ER 🡪 ER stress 🡪 apoptosis = dyskeratosis

Course:

  • Chronic & fluctuating

Skin:

  • Seborrheic distribution #1 🡪 Red-brown keratotic ± crusted ± confluent papules
  • Intertriginous involvement (usually mild) 🡪 disabling 2nd maceration/odor
  • Acral lesions: palmar ± plantar pits in most patients ± acrokeratosis verruciformic-like papules on dorsal surface (~50% of patients)

Morphologic variants:

1) guttate hypopigmentation
2) vesiculobullous
3) acral hemorrhagic
4) keratoderma
5) cornifying
6) comedones/cysts
7) periocular nodulocysts
8) alopecia/cutis verticis

Distribution variants

1) intertriginous
2) segmental (type 1 (single hit >2 double hit mutation)

Nails:

  • V-shaped notch
  • Longitudinal erythronychia/leukonychia
  • ± ridging and fissuring

Mucosa:

  • Oral mucosa 🡪 Whitish papules with central depression or cobblestoning (15-50%) may lead to salivary obstruction
  • Occasionally 🡪 anogenital, pharynx, larynx

Complications:

  • Infection (bacteria, yeast, and dermatophytes) 🡪 malodor, vegetating plaques
  • HSV 🡪 Kaposi varicelliform eruption,
  • VZV, HPV
  • Salivary gland duct obstruction
  • SCC

Associations:

  • S. aureus colonization 🡪 worse phenotype
  • Neuropsychiatric disorders (mood disorders, epilepsy, intellectual impairment)
  • ocular involvement (corneal opacities, corneal ulcers)

Histopathology:

Acantholysis

Dyskeratosis

  • “Corps ronds”: enlarged acantholytic keratinocytes in malphighian layer
  • “Grains”: small oval cells in stratum corneum 

Papillomatosis, hyperkeratosis, mild-moderative perivascular inflammatory infiltrate

NB: Grover disease has similar histopathology but usually shows more acantholysis, less dyskeratosis, fewer corps ronds/grains

NB: Hailey-Hailey disease has similar acantholysis, but acantholysis more widespread and not in foci

  • General:
    • Lightweight clothes and sun protection to avoid exacerbators
    • Antimicrobial cleanser to prevent secondary infection
    • Keratolytic emollients to reduce scaling/irritation
  • Topical and intralesional:
    • Topical retinoids monotherapy
    • Topical calcineurin inhibitors
    • Topical 5-fluorouracil
    • Diclofenac sodium
  • Systemic:
    • Isotretinoin, acitretin, and alitretinoin: show improvement in 90% of patients; ± intermittent summertime therapy to prevent exacerbation; not for bullous or intertriginous lesions
    • OCP if premenstrual exacerbations
    • Cyclosporine if no response to oral retinoids
  • Surgical therapy:
    • For focal/recalcitrant lesions (especially flexural and gluteal areas)
    • Excision then split-thickness grafting, dermabrasion, or laser removal (CO2 or erbium:YAG) 🡪 destroy follicular infundibulum
    • Pulsed dye laser and photodynamic therapy

  • Acrokeratosis verruciformis of Hopf (Autosomal dominant Mutation in ATP2A2)
  • Seborrheic dermatitis
  • Grover disease
  • Pemphigus vegetans (Hallopeau type)
  • Pemphigoid vegetans:
    • Blastomycosis-like pyoderma
    • Hailey-Hailey disease
    • Papular acantholytic dyskeratosis