DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME DARIER DISEASE
Synonymous Darier-White disease, DD, keratosis follicularis
Estimated prevalence -
OMIM 124200
Inheritance Autosomal Dominant
Gene (s) ATP2A2 (108740)

Definition

Darier’s disease is a genetic disorder of keratinization first described independently by Darier and White in 1889. The disease is characterized by the development of keratotic papules in seborrheic areas, specific nail changes, with suprabasal acantholysis and dyskeratosis on histological examination of skin lesions. The disease is caused by mutations in ATP2A2 encoding a Ca2+ pump of the endoplasmic reticulum.

Clinical Description

Onset of the disease is usually around puberty. The majority of patients will develop the first lesions between 10 and 20 years of age. Typical lesions are greasy keratotic papules, skin coloured, yellow-brown or brown, which can be isolated or form relatively large, crusted and confluent plaques. The sites of predilection are the seborrhoeic areas of the trunck and face: the upper chest, the back, the sides of the neck, the forehead, the ears, and the scalp. Flexures are also frequently involved (the groins, the axillae, the anogenital region). Skin lesions can become vegetating in the folds, are often infected, malodorous and responsible for major discomfort. They can be limited or form extensive plaques during acute phases. Careful examination of the palms and soles will frequently find small pits or punctuated keratoses which are highly suggestive, if not specific, of DD. Hands and feet can also show discrete flat, skin-coloured papules on the dorsum of the hands and feet, similar to acrokeratosis verruciformis of Hopf. Nails abnormailities are almost constant features and highly specific of the disease. The nails are fragile and split easily, they show the specific combination of red and white longitudinal stripes, have a V-shaped nick at the free margin of the nail and subungual hyperkeratosis. Lesions of the mucous membranes have been described. The hard palate, the oral mucosa, the oesophagus, vulva and rectum may be the site of whitish small papules, often densely grouped (leucoplakia). The condition runs a chronic relapsing course, with exacerbations throughout life. Some patients will have a relatively mild disease, while others will develop a more severe form, sometimes within the same family. In particular, the skin lesions are exacerbated by exposure to sunlight or artificial UVB radiation, heat, sweating, friction and infections. Patients with Darier’s disease appear to have an increased susceptibility to herpes simplex and chronic pyogenic infections.

Pathogenesis

The gene for Darier's disease was mapped by linkage analysis to chromosome 12q23-24 in 1993, with no evidence for genetic heterogeneity in affected families. ATP2A2 was identified as the defective gene by candidate positional cloning in 1999. ATP2A2 encodes the sarco/endoplasmic reticulum (endoplasmic reticulum) Ca2+-ATPase isoform 2 (SERCA2), a calcium pump transporting Ca2+ from the cytosol to the lumen of the endoplasmic reticulum.
ATP2A2 spans 76 kb, is organized in 21 exons and is transcribed into three mRNAs of 4.4 kb, encoding SERCA2a, SERCA2b and SERCA2c isoforms. SERCA2b is the major isoform expressed in the human epidermis. At least 120 ATP2A2 mutations have now been reported in Darier's disease patients, the majority of which being different from family to family. Mutations are distributed across the entire molecule, with no evidence for clustering or mutation hot spots.
The majority of the mutations are missense mutations (50%) or in-frame deletions or insertions (8%) which predict the synthesis of a structurally abnormal protein. Other mutations include nonsense mutations (12%) and frameshift mutations (23%) which lead to premature termination codon (PTC) and predict loss of protein expression through nonsense mRNA decay. The remaining mutations are splice-site mutations (7%) the consequences of which on the mutated protein remain to be documented. Genotype-phenotype comparison has suggested that ATP2A2 missense mutations are more frequent in severe or atypical forms. However, considerable inter- and intra-familial variability in the disease phenotype indicates that additional factors influence disease expression.
Functional analysis of ATP2A2 mutations have shown that a majority of them lead to loss of protein expression or loss of Ca2+ transport activity, supporting a disease mechanism by haploinsufficiency. However, a few mutations show evidence for a dominant negative effect. As a result, Ca2+ stores of the endoplasmic reticulum are reduced and trafficking of desmoplakin to the plasma membrane is impaired. Abnormal Ca2+ signaling is thought to have complex effects on protein post-translational modifications in the ER, on desmosome formation and gene expression leading to major defects in cellular adhesion and terminal epidermal differentiation.

Diagnosis

Histology examination of a skin lesion shows hyperkeratosis, focal dyskeratosis (premature and abnormal keratinisation of single keratinocytes) associated with suprabasal acantholysis (cell separation above the basal layer) leading to suprabasal cleft. The rounded eosinophilic dyskeratotic cells are called “corps ronds” in the stratum spinosum, and “grains” in the upper layers of the epidermis. They are thought to correspond to apoptotic keratinocytes.

Treatment

Patients with mild disease will benefit from advice about sun protection (sun avoidance and blocks in the summer), and avoidance of heat. When skin lesions are limited, emollients containing urea or lactic acid can reduce crusting. Antiseptics (topical or in bath) and antibiotics are helpful to prevent or treat pyogenic infection. Topical applications of tretinoin or isotretinoin improve hyperkeratosis of localised lesions, although irritation limits their value. Topical steroids may help in reducing irritation, but are not effective alone. New retinoids such as Tazarotene may be tolerated better. Herpes infection should be suspected when lesions are painful and exacerbated, which requires antiviral treatment with acyclovir.
For those with more severe disease, oral retinoids such as acitretin (Soriatane) is the most effective treatment against abnormal keratinisation. Their efficiency lasts only as long as the treatment is continued. The initial dose is usually 25 to 30 mg per day for 2 to 4 weeks, and if well tolerated, the doses can be increased up to 60 mg for 2 months. Possible side-effects must be monitored carefully, including elevated liver enzymes, triglycerides, cholesterol, skin fragility, mucosal dryness and nosebleed. In children, hyperostosis and extra-osseous calcification can occur. In females, oral contraception is mandatory 1 month before, during and 2 years after treatment. After initial clearing of the lesions, the dose should be reduced progressively and stopped (in winter) or maintained as low as possible to avoid relapse. The disease can cause considerable social handicap and can require a specific psychological support by a medical psychologist. Genetic counselling should be offered, although prenatal diagnosis of the disease is questionable in the majority of cases.