DARIER DISEASE

Introduction:

Autosomal dominant disease with complete penetrance and variable expressivity.
Named after French Dermatologist Jean Darier.

Epidemiology

Men and women equally affected

Pathogenesis

Clinical Features

Onset

Disease begins between age of six and 20 years

Symptoms

Moderate itching with malodor.

Aggravating Factors

Worse in summers: sweating ,heat, occlusion appear to have a role.
Lithium can provoke skin lesions in darier's disease.

Signs

Skin

Keratotic,crusted,red to brown papules that usually develop in seborrheic distribution.
Lesions can become confluent.
Small hypomelanotic macules may be admixed with keratotic papules.

Dorsal aspect of hands and feet.

In 50% patients flat topped, skin colored or brown papules occur at these sites.

Lesions in Axillae, groin and sub mammary region

Occur in most patients
Usually have mild involvement at these sites
(occasionally prominent involvement at these sites can occur and may result in misdiagnosis of HHD)

Palmo-Planter involvement:

Keratotic, keratin filled depression(pits) may be found

Oral Involvement.

Occurs in 15 to 50 % patients.
Painless white papules can occur.
Palate is the most common sites followed by gingiva, buccal mucosa and tongue.


Nail Changes:

Longitudinal red and white lines.
Longitudinal ridging and fissuring.
Wedge shaped subungual hyperkeratosis
Brittle nails that break distally forming V-shaped notches.

Clinical Subtypes

Acral Hemorrhagic type:

Red to blue-black irregular shaped, sharply demarcated macules can occur on palms, soles and dorsal aspect of hands.
Represents hemorrhage in to acantholytic vesicles.

Segmental types:

Two types:
Both have distribution of lesions along blaschkos lines.

Type 1

Linear streaks.
Age of onset, severity,and histological findings similar to generalized disease.

Types 2

Generalized disease has linear streaks with increased severity.

Complications:

Infection:

Increased frequency of skin infection due to disruption of epidermal barrier.
Patients prone to infections with bacteria, yeast, dermatophytes, HPV and  herpes simplex virus. Suspect HSV infection if sudden onset of vesicular and crusted lesions( hgic) +/- fever and malaise.
Treat with anti virals if HSV infection suspected.

Salivary glands

Oral salivary gland obstruction can occur due to duct obstruction.

Neuropsychiatric disorders

Various conditions like epilepsy,intellectual impairment,mood disorders(depression,bipolar) have been reported.

Others

Ocular complication like corneal ulceration's, Staphylococcal endophthalmitis.
SCC arising in cutaneous or mucosal sites.
Bone cysts, renal agenesis and autoimmune thyroiditis in some patients.

Pathology

Two prominent features.

Acantholysis:

Due to loss of cell adhesion's in suprabasilar cleft. This corresponds to loss of desmosomes and detachment of keratin filaments from desmosomes.

Dyskeratosis:

Due to apoptosis of keratinocytes.
Two types of dyskeratotic cells are observed.
a) Corps ronds: acantholytic enlarged keratinocytes in the malpighian layer with dark staining and partially fragmented nuclei surrounded by a clear cytoplasm and encircled by bright ring of collapsed keratin bundles.
b) Grains: small, oval cells in stratum corneum characterized by  eosinophilic cytoplasm containing shrunken parakeratotic nuclear remnants.Grains are likely derived from corps ronds.

Mild to moderate perivascular infiltrate in superficial dermis.
Overlying epidermis is acantholytic and dyskeratotic foci is thickened and shows papillomatosis and hyperkeratosis.


Differential Diagnosis:

Acrokeratosis of Hopf:

Autosomal Dominant
Described by Hopf
Presents with flat topped wart like papules on dorsal aspect of extremities.(similar to Darier disease)
Separated from Darier disease on the basis of histology: as it lacks acantholysis and dyskeratosis.

Seborrheic Dermatitis.
Grovers Disease.
HHD.

Treatment

Patient education.
Cotton clothing.
Sunscreens especially in summers.
Soap substitute.
Emollients particularly with urea or lactic acid.
Antiseptics like triclosan or betadine


First Line.

Topical Steroids
Topical Retinoids: Adapalene, tazarotene or tretinoin.
Other agents like Protopic, Pimecrolimus or Topical 5FU.

Second Line:

Oral Retinoids:

Acitretin and Isotretinoin.

May be more effective if combined with topical retinoids.
Effective in about 90 % of patients.
Oral retinoids do not induce prolonged remission in Darier disease and long-term treatment is needed to prevent relapse.
Reduce hyperkeratosis, flatten papules and may control odor.

Acitretin:
Dose 10 to 25 mg initially but can be increased gradually to 0.5 mg/kg. Can take 2 to 3 months for maximal effects.

Isotretinoin:
Starting dose at 0.5 to 1 mg per Kg.

Retinoids are teratogenic.Women should avoid pregnancy for three years after discontinuing acitretin and for one month after discontinuation of isotretinoin. Isotretinoin is thus preferred to acitretin for women of childbearing age who have severe Darier disease.


Oral steroids or Cyclosporin 

Reduce inflammation in patients with ‘eczematized’ disease, but papules and erosion's persist


Oral Contraceptives may reduce premenstrual flares.

For patients with localized hypertrophic lesions that do not respond to oral retinoids, surgical excision, laser ablation, or photodynamic therapy are therapeutic options.

Prognosis

Patients with Darier disease have a normal life expectancy, although their quality of life may be significantly impaired. The disease follows a chronic course and relapse is common when treatment is stopped.

Patient Information Leaflet
http://www.bad.org.uk/site/807/default.aspx