Darier disease: Current insights and challenges in pathogenesis and management

Abstract

Darier disease is a rare autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene encoding for sarcoendoplasmic reticulum Ca²⁺ ATPase isoform 2. The skin disease is characterized by a chronic relapsing course with recurrent reddish-brown keratotic papules and plaques located mainly in seborrhoeic areas. Due to chronic inflammation and epidermal barrier defects of the skin, patients often develop severe bacterial and viral superinfections. Therapeutic options are limited, mainly symptomatic and in most cases unsatisfactory in the long term. Patients are advised to avoid aggravating factors such as high temperature, high humidity, UV radiation and mechanical irritation. To prevent superinfection, antiseptics and periodic use of topical corticosteroids are fundamental in treatment. In case of bacterial and viral superinfection, systemic anti-infective therapy is often necessary. Currently, the most effective treatment option for extensive and persistent skin lesions is systemic retinoids, which are thought to mainly target the epidermal compartment (e.g. by reducing hyperkeratosis). One hallmark of Darier disease patients is chronic skin inflammation. We and others have previously reported Th17 cells in the dermal infiltrate of inflamed Darier disease skin. Counteracting inflammation by blocking the IL-23/IL-17 axis improved skin manifestations in a small cohort of previously therapy-resistant patients over 1 year. Furthermore, several other topical treatment options for mild disease as well as various ablative therapies and surgical excision have been proposed to be effective in some patients with hypertrophic skin lesions. This article aims to outline the pathogenesis, clinical features, diagnosis/differential diagnosis and available treatment modalities of Darier disease.

FIGURE 1

Histological features of DD. (a–d) H&E‐stained histological lesional skin sections of patients with DD: (a) columnar parakeratosis (blue arrows), moderate superficial inflammation (red arrows), single dyskeratotic cells (black arrows), incipient suprabasal fissuring (yellow arrows); (b) suprabasal fissuring (yellow arrows), moderate inflammation (red arrows), parakeratosis (blue arrow); (c) highly proliferating basal keratinocytes (green arrows point to mitotic keratinocytes); (d) single dyskeratotic keratinocyte in basal layer (corps ronds, black arrow); (e–h) IL‐17‐skewed immunologic infiltrate of DD (e) immunofluorescence staining of CD3 (red) and IL‐17A (green) in a FFPE skin section of a patient with DD; (f–h) zoom‐in to dermal inflammatory infiltrate of (e), (f) IL‐17A⁺ cells, (g) CD3⁺ cells (T cells), (h) double staining of IL17‐A and CD3. White arrows indicate double‐positive cells (IL‐17A‐producing T cells).

FIGURE 2

Classical skin lesions of DD: Hyperkeratotic erythematous papules and plaques in seborrhoeic areas on the trunk and in submammary area (a–c), acral wart‐like lesions (d, e). Classic mucous membrane features: (f) buccal ‘cobblestone‐like’ papules and leukokeratosis. Classic nail abnormalities: (g) red longitudinal streaks on the nails, (h) V‐shaped notches on the nails. Non‐classical lesions: Keloid‐like vegetations on ear and scalp margins/neck, trunk and limbs (i–k) acral haemorrhagic blisters (l).