What is Hailey Hailey disease?

Hailey-Hailey Disease: Clinical Features, Diagnosis, and Management

Hailey-Hailey disease is a rare autosomal dominant genodermatosis characterized by recurrent vesicles and erosions in intertriginous areas, caused by mutations in the ATP2C1 gene, with no standardized treatment regimen and significant impact on quality of life. 1, 2

Clinical Features

Hailey-Hailey disease (HHD), also known as familial benign pemphigus, presents with the following characteristics:

• Epidemiology:

  • Estimated prevalence of 1/50,000
  • No gender or racial predilection
  • Autosomal dominant inheritance with complete penetrance but variable expressivity

• Age of Onset:

  • Typically appears between the third and fourth decades of life
  • Rare cases at extremes of age

• Clinical Presentation:

  • Flaccid vesicles and blisters on erythematous skin
  • Progression to erosions, fissures, and vegetations
  • Maceration and superinfections are common
  • Chronic lesions may form vegetative or verrucous plaques
  • Symptoms include pruritus, burning sensation, and pain

• Distribution:

  • Symmetrical involvement of intertriginous regions
  • Common sites: retroauricular folds, lateral neck, axillae, umbilicus, inguinal, and perianal regions

• Disease Course:

  • Chronic relapsing pattern with spontaneous remissions and multiple recurrences
  • Exacerbations triggered by humidity, friction, heat, trauma, and secondary infections

Pathophysiology

HHD results from a heterozygous mutation in the ATP2C1 gene, which encodes the transmembrane protein hSPA1C. This protein is expressed in all tissues but predominantly in keratinocytes. The mutation leads to:

• Altered calcium signaling in keratinocytes
• Impaired synthesis of junctional proteins
• Compromised adhesion between epidermal keratinocytes
• Acantholysis (separation of keratinocytes)

Diagnosis

The diagnosis of HHD is based on:

1. Clinical features: Characteristic vesiculobullous eruptions in intertriginous areas

2. Histopathology:

   • Marked suprabasal acantholysis
   • Loosely joined keratinocytes creating a "dilapidated brick wall" appearance
   • Few dyskeratotic cells
   • Acantholysis affecting the epidermis but sparing adnexal epithelia (helpful in differentiating from pemphigus vulgaris)

3. Direct immunofluorescence: Negative (important to differentiate from autoimmune blistering disorders)

4. Differential diagnosis:

   • Darier disease
   • Pemphigus vegetans
   • Intertrigo
   • Contact dermatitis
   • Inverse psoriasis

Management

There is no cure for HHD, and treatment is challenging. Management approaches include:

First-Line Treatments

1. Preventive Measures:

   • Control of heat, sweat, and friction
   • Wearing loose, breathable clothing
   • Weight reduction if applicable

2. Topical Therapies:

   • Corticosteroids: For anti-inflammatory effects
   • Calcineurin inhibitors (tacrolimus, pimecrolimus): For steroid-sparing approach
   • Antibiotics: For secondary infections
   • Antifungals: When fungal superinfection is present

Second-Line Treatments

1. Systemic Medications:

   • Antibiotics (tetracyclines, erythromycin): For anti-inflammatory effects and controlling secondary infections
   • Corticosteroids: For severe flares
   • Retinoids (acitretin): For keratinization disorders
   • Immunosuppressants (cyclosporine, methotrexate): For recalcitrant cases

2. Emerging Therapies:

   • Biologics (dupilumab, adalimumab, etanercept)
   • Small-molecule inhibitors (apremilast, upadacitinib, abrocitinib)
   • These have shown promising results in refractory cases but require further validation through large-scale clinical trials 3

Procedural Interventions

For extensive disease recalcitrant to conventional therapy:

1. Laser Therapy:

   • Fractional CO2 laser (wavelength 10600 nm, power 7-10W) has shown success in treatment-resistant cases 4
   • Provides longer remission periods compared to medical therapies

2. Other Procedures:

   • Botulinum toxin type A: Reduces sweating and friction
   • Dermabrasion: Removes affected epidermis
   • Photodynamic therapy: Targets affected cells
   • Surgical excision: For limited, persistent areas

Treatment Algorithm

1. Mild Disease:

   • Topical corticosteroids and/or calcineurin inhibitors
   • Topical antibiotics for superinfection
   • Preventive measures

2. Moderate Disease:

   • Add systemic antibiotics (tetracyclines)
   • Consider short courses of systemic corticosteroids for flares

3. Severe or Recalcitrant Disease:

   • Consider retinoids or immunosuppressants
   • Evaluate for procedural interventions (laser therapy, botulinum toxin)
   • Consider biologics or small-molecule inhibitors in treatment-resistant cases

Clinical Pearls and Pitfalls

• Psychological Impact: Severe disease can significantly affect quality of life and have major psychological and social consequences
• Chronic Management: Patients should understand that treatment aims to control rather than cure the disease
• Superinfection: Always evaluate for and treat bacterial or fungal superinfections
• Treatment Challenges: Lack of evidence-based guidelines and large clinical trials makes assessment of treatment efficacy difficult
• Monitoring: Regular follow-up is essential due to the chronic relapsing nature of the disease

The management of HHD remains challenging due to the lack of standardized therapeutic regimens and large clinical trials. Treatment should be tailored based on disease severity, affected areas, and previous treatment responses.