Darier Disease and Hailey-Hailey Flashcards
What is the gene for Darier disease? and the mode of inheritance (2)
ATP2A2
Autosomal Dominant
Complete penetrance
Variable expressivity
Which inherited disorders occur due to defects in calcium pumps?
Hailey - Hailey and Darier disease
What is the pathogenesis of Darier disease
Genetic variant in ATP2A2
results in dysfunction of the endoplasmic reticulum calcium pump
interferes with calcium signalling
results in acantholysis and dyskeratosis
Describe the clinical presentation of Dariers disease
Onset of symptoms between the age of 6 and 20, peak onset in puberty
Keratotic, greasy, red-brown papules,
+/- crusting
Predominantly in a seborrhoeic distribution
- face
- lateral aspects of the neck
- trunk
- scalp
Often ass with intertrigenous involvement
Papules can become confluent and form papillomatous masses
Small hypopigmented macules admixed with keratotic papules
Rarely sterile bullae / vesicles occur
Malodour
Other features:
- skin coloured, flat topped papules on dorsal aspects of the hands and feet
- acral haemorrhagic vesicles
- palmarplantar papules and keratin filled depressions
- hyperkeratosis and occ diffuse keratoderma
- Nail changes (wedge shaped subungal hyperkeratosis, brittle nails, V shaped notches, longitudinal ridging, longitudinal red and white lines)
- painless white or rugose plaques in the oral mucosa - cobblestone appearance
- leukoplakia
What are the nail changes ass with Dariers disease
wedge shaped subungal hyperkeratosis
brittle nails,
V shaped notches,
longitudinal ridging,
longitudinal red and white lines
Triggers for Dariers flares?
Seasonal (worse in summer)
- heat
- sweating
- occlusion
- UV radiation (inc UVB)
Drugs
- Interferon Beta
- Lithium
Prognosis of Dariers disease?
Chronic course with fluctuations in severity
What are the complications and associations of Dariers disease?
1/ Secondary infection
- Staph Aureus
- HPV
- HSV
- cowpox
- fungal
- yeast
NB: risk of Kaposi varicelliform eruption
2/ Salivary gland obstruction leading to painful swelling
3/ Neuropsychiatric issues
- depression
- epilepsy
- bipolar
- intellectual disability
- schizophrenia
4/ Ocular issues
- dry eyes
- blepharitis
5/ SCC
6/ possible increase in heart failure and diabetes
Which mutation is associated with neuropsych complications? (dariers)
ATP2A2 mutations in the S4 - M4 region
What are the clinical subtypes of Darier disease?
Acral Haemorrhagic type
Segmental type 1 and 2
What do you expect to see on biopsy of Darier disease?
Acantholysis
Dyskeratosis
- Corp ronds = rounded dyskeratotic cells with eosinophillic cytoplasm
- Grains = small cells with shrunken cytoplams
Hyperkeratosis
What is the name of the plane wart-like keratoses on the dorsal hands in Dariers disease?
Acrokeratosis verruciformis
DDx for Dariers disease?
Seb Derm
Hailey Hailey disease
Pemphgius vegetans / vulgaris
Akrokeratosis verruciformis of Hopf
Epidermal naevus (for segmental Dariers)
How does Rook classify the severity of Dariers disease?
Grade 0: subclinical / subtle / asymptomatic
Grade 1: mild, localised keratotic papules <10% BSA
Grade 2: moderate, extensice papular, subconfluent lesions, crusting, affecting 10 - 30% of BSA
Grade 3: severe, widespread, confluent, crusted, eroded, >30%
Rooks
How is Dariers diagnosed?
Clinical + Histopathology findings
Can do genetic testing, but rarely indicated.
How is Darier disease managed?
General measures:
- avoid irritants
- soap free gentle wash
- emolliants
- simple hygiene to prevent secondary infection
- avoidance of heat / sun
Topical treatment
- Keratolytic agents:
–> urea, lactic acid, - topical antiseptics
–> chlorhexadine wash, bleach baths - topical antibiotics
–> mupirocin, clindamycin - topical antifungals
–> terbinafine, clotrimaxole - topical corticosteroids
–> potent; betamethasone diproprionate 0.05%
–> flexurse: Advantan cream - topical retinoids
- topical calcinurin inhibitors
- 5FU
Systemic:
- Oral retinoids
–> isotretinoin
–> Acitretin - IVIG
- naltrexone
- Treatment of secondary infection
–> oral Abx
–> antivirals
–> antifungals - Botox
Physical treatments:
- excision and graft (localised disease)
- electodisection
- dermabrasion
- ablative laser - CO2 / erbium
- PDT
- +/- radiotherapy
What is the gene involved in Hailey - Hailey disease?
ATP2C1
What is the inheritance of Hailey Hailey disease?
Autosomal Dominant
Complete penetrance
Variable expression
What is the pathophysiology of Hailey Hailey disease?
Hailey Hailey disease is a rare AD condition caused by mutations in the ATP2C1 gene.
This gene encodes for proteins involved in calcium signalling in the golgi apparatus.
Abnormal calicum signalling results in acanthloysis in the stratum corneum
When do disease manifestations of Hailey Hailey normally present?
Normally in the 2nd or 3rd decade of life
Can be in the 4th and 5th decade
How does Hailey Hailey present?
Vesicular and erosive papules and plaques
Prediliction for the intrigenous zones:
* Axillae
* Groin
* Peiranal
* Vulval
* Submammory
* Lateral neck
Starts as flaccid vesicles which are easily de-roofed resulting in eroded, macerated plaques with crusting
Often with central clearing leading to a **circinate border of crust and small vesicels **
Malodourous
Heal with Scarring and PIH
Nail changes: Longitudinal leukonychia
What are the triggers for Hailey Hailey disease?
Heat, friction, humidity, sweating
What are the key DDx for Hailey Hailey Disease?
Pemphigus Vegetans / Foleaceous
Intertrigo
Dariers disease
Irritant dermatitis
Vulval disease - LSC
What are the key histopathology findings of Dairiers disease?
**Acantholysis **
* often a single layer of basal keratinocytes remaining of the BM, with a delapidated brick wall appearance
Minimal keratinocyts apoptosis when compared to Dariers (few corp rounds / grains)
Perivascualar lymphocytic infiltrate
What are the complications of Hailey Hailey disease?
**1. Infection **
* Staph Aureus and other bacterial infections
* Fungal infections
* Viral infections - HSV
**2. Malignancy **- SCC, ?secondary to HPV
3. Impact on QoL and mood
**
What are the clinical subtypes / variants of Hailey Hailey disease?
**Segmental 1: **Mosiacism due to a post zygotic mutation in ATP2C1 gene. Leading to areas of unaffected skin and areas of affected skin
Segmental 2: Mosiacism due to a post zygotic mutation in the ‘normal ATP2C1’ gene. Leading to areas of homozygous mutation and more severe disease. The remaining skin is heterozygous and still affected.
What is your approach to treatment of Hailey Hailey disease?
1. General measures
* Loose fitting clothing
* Avoid Friction / heat / sweating
* General hygeine - regular showers
* Avoid Irritants - soap free wash, bland emolliants
- Antibacterial washes
- Barrier creams - zinc oxide
2. Topical treatment:
* TCS - lowest dose possible (due to risk of AEs in intrigneous zones)
* ILS to stuborn plaques
- Topical calcinurin inhibitors have variable reported efficacy
- Case reports of:
- 5 FU
- Botox injections
- Vitamin D analouges
3. Physical therapy
* Excision and grafting
* Dermabrasion
* CO2 ablative laser
* PDT
* Radiotherapy
4. Systemic treatment
* Very limited evidence of effect
* Doxycycline
* Naltrexone
* Oral retinoids
* MTx
* Aza
* Dapsone
* MMF
* IVIG
Describe what you see? What is the DDx?
Prominant acantholysis throughout the spinous layer
Dilapidated brick wall appearance
Overlying scal and crust
Lack of dyskeratosis
List some DDx for dariers disease?
Seborrhoeic: seborrhoeic dermatitis, Grover disease, acne, confluent and reticulate papillomatosis, candida
Erosive: HSV, bullous impetigo, Hailey-Hailey, pemphigus vulgaris
Vegetating: Hailey-Hailey, pemphigus vegetans, SCC
Comedonal: acne, familial dyskeratotic comedones, comedo-like acantholytic dyskeratosis
Acral: plane warts, Acrokeratosis verruciformis of Hopf
Freckled: Grover disease, Dowling-Degos (acantholytic variant)
Genital: genital warts, VIN, Hailey-Hailey, papular vulvocrural acantholytic disease
How do you explain Dariers to a patient?
Genetic condition cause by a mutation in ATP2A2 gene encoding calcium pump SERCA2
Complete penetrance, variable expressivity (other genes or environmental factors may influence expressivity)
Chronic, relapsing course, becomes less severe in old age in 30% (may worsen in others)
Treatments may control but not cure the disease – goals of treatment are improvement of skin appearance, relief of symptoms, prevention/treatment of infectious complications
What dose of topical retinoids might you prescribe for Dariers disease?
tretinoin 0.1%
adapalene 0.1%,
tazarotene 0.05%
can irritate, start at low concentration, use emollients and topical corticosteroids adjunctively
What does of oral retinoids might you use for acitretin / isotretinoin?
Acitretin 0.25-0.5mg/kg
Isotretinoin 0.5-1mg/kg
(continue for at least 3-4 months)
What type of laser can you use to treat Dariers?
Laser ablation: scarring is the desired end point
CO2 non-fractionated or fractionated ablative laser
What is the DDx of Hailey Hailey?
Intertrigo,
Candidiasis,
Irritant dermatitis,
Allergic contact dermatitis,
Lichen simplex chronicus,
Inverse psoriasis,
Pemphigus vegetans,
Flexural Darier’s disease
