Darier disease

INTRODUCTION — Darier disease, also known as Darier-White disease, keratosis follicularis, or dyskeratosis follicularis (MIM #124200), is a rare autosomal dominant genodermatosis characterized by a persistent eruption of red-brown, keratotic papules scattered to confluent in a seborrheic distribution, nail abnormalities, pitting of palms and soles, and mucosal changes [1]. The disease usually starts around puberty and runs a chronic course with exacerbations induced by sun exposure, heat, friction, or infections.

This topic will discuss the pathogenesis, clinical features, diagnosis, and management of Darier disease. Other acantholytic skin disorders, including Hailey-Hailey disease and Grover disease, are discussed separately. (See "Hailey-Hailey disease (benign familial pemphigus)" and "Grover's disease (transient and persistent acantholytic dermatosis)".)

EPIDEMIOLOGY — Darier disease is a rare disorder that affects all ethnic groups. The estimated prevalence ranges from 1 to 4 per 100,000 people [2-5]. In a Singaporean study, the incidence was 0.3 per 1 million people per year [6].

PATHOGENESIS — Mutations in the ATP2A2 gene that encodes a sarco/endoplasmic reticulum Ca²⁺-adenosine triphosphate (ATP)ase pump (SERCA2) lead to both acantholysis and apoptosis, accounting for the characteristic pathologic finding of acantholytic dyskeratosis in Darier disease [7]. SERCA2 actively transports calcium ions from the cytosol into the lumen of the endoplasmic reticulum to maintain a low cytoplasmic Ca²⁺ level. Specific mutations of SERCA2 induce defects in protein expression, ATP hydrolysis, calcium transport, and calcium binding and kinetics [8]. SERCA2 mutations also have been associated with impaired synthesis, folding, or trafficking of desmosomal proteins and abnormal cytokeratin expression [9-11].

Despite its ubiquitous expression, the lack of compensatory SERCA3 expression in keratinocytes may explain their particular vulnerability to SERCA2 deficiency. SERCA2 haploinsufficiency has been proposed to underlie the dominant transmission pattern by affecting Ca²⁺-mediated maturation of cellular adhesion proteins and desmosomes in the endoplasmic reticulum through a stress response, resulting in decreased strength of intercellular adhesion [12].

This mechanism has been used to develop a potential treatment. The glucosylceramide synthase inhibitor miglustat, a pharmacologic chaperone (small-molecule agents that enter cells and interact with mutant proteins allowing their correct folding and routing within the cell) used to treat mild to moderate Gaucher disease and Niemann-Pick type-C disease [13], has been found to restore mature adhesion junctions and desmosomes and increase adhesion strength in Darier keratinocytes [12]. This observation further supports the hypothesis of junctional adhesion protein misfolding as a pathogenetic mechanism in Darier disease. (See "Gaucher disease: Treatment" and "Overview of Niemann-Pick disease".)

Alternatively, it has been proposed that mutant ATP2A2 protein-insoluble aggregates that are not degraded by proteasomes induce endoplasmic reticulum stress and apoptosis, leading to acantholysis and dyskeratosis [14]. However, this hypothesis is based upon in vitro studies using an immortal keratinocyte cell line with strongly overexpressed mutant SERCA2 pumps and may not apply to keratinocytes from Darier skin, which in most cases show a reduced expression of SERCA2 [15,16].

Further pleiotropic faulty SERCA2-controlled Ca²⁺-dependent keratinocyte adhesion in Darier disease appears to be mediated by sphingolipid [17] and protein kinase C (PKC)-alpha signaling [18].

GENETICS — Darier disease is inherited in an autosomal dominant pattern, with complete penetrance and variable expressivity. Indeed, family history is often mistakenly dismissed due to its variable expressivity with clinical presentations too subtle to be recognized.

Haploinsufficiency (where one copy of the wild-type gene is not able to prevent disease) is thought to be the mechanism for the autosomal dominant inheritance pattern, but aggregates of mutant SERCA2 (sarco/endoplasmic reticulum Ca²⁺-adenosine triphosphate [ATP]ase pump) were also proposed to exert a dominant negative effect. (See 'Pathogenesis' above.)

Nearly 300 familial and sporadic mutations in ATP2A2 have been identified in patients with Darier disease, primarily missense mutations and frameshift mutations [19,20]. The observation that family members with identical ATP2A2 mutations may have significant differences in the clinical manifestations of the disease suggests that other genes or environmental factors affect disease expression [21]. Along these lines, most studies could not identify robust genotype-phenotype correlations [20]. However, the allelic acrokeratosis verruciformis of Hopf is caused by specific mutations in exon 14 encoding for the Ca²⁺-binding domain of SERCA2 [22-25] and mutations in the S4-M4 region, with a severe neuropsychiatric phenotype of Darier disease [26]. Whether other particular clinical subtypes, such as acral hemorrhagic or comedonal presentations, are due to specific mutations is more controversial [20,27].

HISTOPATHOLOGY — Acantholysis and dyskeratosis are the main histologic features of Darier disease. Acantholysis is due to the loss of cell adhesion by desmosomes and detachment of keratin filaments from desmosomes, leading to characteristic rounding up of keratinocytes with suprabasal cleft formation. Dyskeratosis is a result of keratinocyte apoptosis and characterized by nuclear condensation and perinuclear keratin clumping.

Two types of dyskeratotic cells are present in Darier disease:

●"Corps ronds" – Corp ronds are acantholytic, enlarged, round keratinocytes predominantly located in the stratum spinosum and stratum granulosum characterized by an irregular, eccentric, and sometimes pyknotic nucleus; a clear perinuclear halo; and encircled by a brightly eosinophilic ring of collapsed keratin bundles.

●"Grains" – Grains are mostly located in the stratum corneum and consist of small, oval cells characterized by an intensely eosinophilic cytoplasm composed of collapsed keratin bundles and centered by elongated, shrunken, cigar-shaped nuclei.

The epidermis with such acantholytic and dyskeratotic foci is thickened, contains large keratin plugs that fill the pilosebaceous follicles but are also found outside of follicles, and shows focal parakeratosis, papillomatosis, and hyperkeratosis. The underlying dermal papillae, covered by a single layer of epithelium (stratum basale), project into the clefts forming villus-like structures (picture 1).

CLINICAL FEATURES

Skin lesions — In approximately 70 percent of patients, the initial lesions of Darier disease typically appear between the ages of 6 and 20 years and peak during the teenage years. The appearance is that of skin-colored or red-brown, keratotic, sometimes yellowish, crusted papules with a greasy, warty texture [28]. The lesions typically involve the seborrheic areas (ie, forehead, scalp, notably the hairline, nasolabial folds, lateral aspects of the neck, presternal and interscapular areas) and may coalesce to form large, crusted, papillomatous masses (picture 2A-E).

Most patients also have mild involvement of the intertriginous areas (groin, axillae, and, in women, submammary fold). In a small subset of patients, flexural disease predominates with large, warty, vegetative plaques in the axillae, groin, or perineum. Flexural lesions may be disabling because of maceration and malodor.

The hands are involved in most patients. Palmar lesions include punctate keratoses, pits, and, less frequently, hemorrhagic macules. In severe cases, palmoplantar hyperkeratosis may occur (picture 3). Many patients have warty, flat-topped papules on the dorsa of the hands and feet. These are clinically indistinguishable from acrokeratosis verruciformis, an allelic autosomal dominant clinical subtype of Darier disease, which affects preferentially the dorsa of the hands and feet. (See 'Acrokeratosis verruciformis of Hopf' below.)

Nail changes — Changes of the finger nails are present in most patients with Darier disease and provide an important diagnostic clue [4,29]. White (picture 4) and red longitudinal bands (ie, linear erythronychia) (picture 5), longitudinal nail ridges and splitting, notching of the free nail border (picture 6), and wedge-shaped subungual hyperkeratosis are common. A sandwich of red and white longitudinal bands, often with a V-shaped nick at the free margin of the nail, is a pathognomonic finding (picture 7). Less commonly, these nail changes also occur on the toes. (See "Overview of nail disorders", section on 'Darier disease'.)

Mucosal lesions — Mucosal lesions consisting of white papules with a central depression may be frequently seen in patients with Darier disease (picture 8). These cobblestone lesions are found in the oral cavity and pharynx in approximately half of the cases but may also occur in the esophagus and on the anogenital mucosa [30-33]. At times, oral lesions may cause blockage of the salivary ducts, particularly of the parotid gland, and xerostomia [34].

Ocular lesions — Ocular lesions, particularly located on the anterior rim of the eyelid, are present in more than 50 percent of cases and are often associated with blepharitis, dry eye, and, very rarely, with corneal lesions [35].

Symptoms — Most patients with Darier disease complain of moderate itch, while intertriginous lesions may cause pain. Particularly distressing are malodor and appearance, which often lead to social isolation.

CLINICAL VARIANTS — Clinical variants of Darier disease include hypertrophic, verrucous, vesicobullous (dyshidrotic), erosive, and predominantly intertriginous forms. Segmental, acral hemorrhagic, and acrokeratosis verruciformis of Hopf are other distinctive variants of the disease [20,27,36-39].

Segmental variant — Linear or segmental forms of Darier disease may result from genetic mosaicism of ATP2A2 [40]. Type 1 mosaicism, reflecting a postzygotic somatic mutation in ATP2A2 early during embryogenesis, presents with one or more unilateral bands of keratotic papules following the Blaschko lines [41]. Type 2 mosaicism reflects a postzygotic mutation causing loss of heterozygosity at the ATP2A2 locus and manifests with more severely affected linear bands of lesions superimposed on generalized disease [42].

Acral hemorrhagic variant — Acral hemorrhagic Darier disease is an uncommon variant presenting with hemorrhagic macules, papules, or blisters located on the extremities, sometimes induced by trauma [38,43-45]. This variant has been reported within families, but no specific genotype-phenotype correlation has been established.

Acrokeratosis verruciformis of Hopf — Acrokeratosis verruciformis of Hopf (AKV; MIM #101900) is an autosomal dominant allelic "forme fruste" of Darier disease, caused in most cases by a specific ATP2A2 missense mutation [p.(Pro602Leu)] [22,24,25]. In his original report, Hopf also described nail changes and palmoplantar pits in his patients.

AKV is characterized by asymptomatic, skin-colored, flat-topped, wart-like papules on the dorsal aspects of the hands and feet and palmoplantar pits and punctate keratoses (picture 9A-B). Histologically, AKV demonstrates undulating hyperkeratosis, papillomatosis, and hypergranulosis creating a "church spire" appearance, but acantholysis is generally absent (picture 10), although the examination of serial sections from AKV lesions may show overlapping features with Darier disease [46].

Lesions of AKV are a common finding in patients with classic Darier disease. Warty lesions on the extremities may be an early manifestation of the disease, preceding the appearance of typical keratotic papules in a seborrheic distribution, particularly after intense sun exposure [4,24].

ASSOCIATED CONDITIONS

Neuropsychiatric abnormalities — Although neuropsychiatric abnormalities such as epilepsy, intellectual impairment, and mood disorders have been reported in association with Darier disease [47-49], it is controversial whether particular mutations in ATP2A2 or a closely linked susceptibility gene are associated with these disorders [27,47,50,51]. Several studies support a pleiotropic effect of ATP2A2 mutations on developmental delay and psychiatric morbidity in patients with Darier disease, but disfigurement and social isolation associated with severe skin disease are also contributing factors leading to depression and suicidal ideation [48,52-54]. A higher frequency of ATP2A2 gene-disrupting mutations have been found in patients with Darier disease and affective psychosis bipolar disorders or schizophrenia compared with those without neuropsychiatric disorders [26].

Type 1 diabetes — A large, population-based study using data from the Swedish National Patient Register found that patients with Darier disease (n = 770) had a nearly twofold increased risk of type 1 diabetes compared with age-, sex-, and county of residence-matched individuals without Darier disease [55]. These findings suggest that Darier disease may be a non-immunity-related risk factor for type 1 diabetes [56]. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents".)

CLINICAL COURSE AND COMPLICATIONS — Although the severity of Darier disease is variable, the condition generally runs a chronic course with frequent exacerbations. Exacerbating factors include heat, sweat, sun exposure, friction, or infection [28,57]. Lithium carbonate (commonly used to treat bipolar disorder) [42,58], calcium channel blockers [59], or interferon beta-1a [60] can provoke flares of Darier disease and should be avoided.

Bacterial, particularly staphylococcal, and fungal infections are frequent complications and can be severe or even fatal [61]. The malodor of the skin lesions is a source of considerable distress for patients and may lead to social isolation.

Widespread herpes simplex virus infection (eczema herpeticum, also known as Kaposi varicelliform eruption) and smallpox virus infection may rarely occur in patients with Darier disease [62,63]. In a retrospective study of 79 patients with Darier disease, herpes simplex virus was detected in lesional skin in 11 patients (14 percent) [64]. Eczema herpeticum is suspected if there is a sudden eruption of vesicular and crusted lesions with skin pain and fever. However, superinfection with herpes simplex virus may present as impetiginized erosions in the absence of vesicles or pustules [64]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Eczema herpeticum'.)

Ocular complications include warty, hyperkeratotic plaques with debris accumulation on the eyelid margin and chronic blepharitis (picture 11) [65]. Corneal ulcerations, recurrent herpetic keratitis, and staphylococcal endophthalmitis following cataract surgery have also been reported [66-68].

There are a few reports of squamous cell carcinomas arising in cutaneous or mucosal sites chronically affected by Darier disease [69,70].

DIAGNOSIS — The diagnosis of Darier disease is suggested by the clinical finding of a persistent eruption of skin-colored or yellow-brown, keratotic papules involving seborrheic areas such as forehead, hairline, nasolabial folds, ears, chest, and back (picture 2A-E). Nail changes, including white and red longitudinal bands, a V-shaped nick at the free nail margin, and subungual hyperkeratosis, are an important diagnostic clue (picture 7). A sandwich of red and white longitudinal bands, often with a V-shaped nick at the free margin of the nail, is a pathognomonic finding. (See 'Clinical features' above.)

A skin biopsy for histologic examination is needed to confirm the diagnosis. The histologic diagnosis is based upon the finding of focal suprabasal acantholysis and dyskeratosis with characteristic eosinophilic "corps ronds" and "grains" in the epidermis and stratum corneum. (See 'Histopathology' above.)

When bacterial or fungal superinfection is suspected, bacterial and fungal cultures of the involved sites are useful to determine appropriate antibiotic or antifungal treatment. In patients with vesicular lesions suggesting herpes virus superinfection (eczema herpeticum), a Tzanck smear and/or viral culture can confirm the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Viral culture'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Darier disease may include severe seborrheic dermatitis, Hailey-Hailey disease, and Grover disease. However, Darier disease is readily distinguished by the clinical involvement of acral skin, nails, and oral mucosa:

●Seborrheic dermatitis – The skin lesions of seborrheic dermatitis are erythematous plaques with yellowish, greasy scales involving the scalp, eyebrows, nasolabial folds, or, occasionally, flexural areas such as axillae and groin (picture 12A-C). Seborrheic dermatitis does not involve hands, feet, or nails, and there is no family history. Histology shows focal parakeratosis, psoriasiform acanthosis, and mild to moderate spongiosis; the complete absence of acantholytic dyskeratosis is a key criterion to differentiate seborrheic dermatitis from Darier disease. (See "Seborrheic dermatitis in adolescents and adults".)

●Hailey-Hailey disease (familial benign pemphigus) – Hailey-Hailey disease (HHD) primarily affects the intertriginous areas and may be difficult to differentiate from Darier disease with flexural involvement (picture 13). Nail dystrophy is typically absent in HHD. Histology shows areas of partial suprabasal acantholysis with the characteristic appearance of a "dilapidated brick wall" (picture 14). (See "Hailey-Hailey disease (benign familial pemphigus)".)

●Grover disease (transient and persistent acantholytic dermatosis) – Grover disease is an uncommon pruritic, papular, or papulovesicular rash that most commonly affects the trunk, but the papules are not confluent as in Darier disease (picture 15). The face, oral cavity, palms, soles, or nails are not involved, and there is no family history. Histology shows subtle and focal acantholysis, with intraepidermal clefts and dyskeratotic cells (picture 16). (See "Grover's disease (transient and persistent acantholytic dermatosis)".)

OVERVIEW OF TREATMENTS — There is no cure for Darier disease. The goals of treatment are the improvement of skin appearance, relief of symptoms (eg, irritation, pruritus, or malodor), and prevention or treatment of infectious complications.

Topical treatments — Topical therapies for Darier disease are aimed at controlling skin inflammation, reducing hyperkeratosis, and flattening the papular lesions. Topical treatments include:

●Topical corticosteroids – Low- to medium-potency topical corticosteroids (groups 4 to 6 (table 1)) may reduce skin inflammation. Although their efficacy has not been evaluated in clinical trials, they are frequently used in patients with Darier disease on the basis of their anti-inflammatory properties and clinical experience.

●Topical retinoids – Topical retinoids, including tretinoin 0.1% [71], adapalene 0.1% [72], and tazarotene 0.05% [73], have been used in patients with mild or localized disease to reduce hyperkeratosis and flatten papular lesions. As monotherapy, their efficacy has not been evaluated in clinical trials. Based upon clinical experience, topical retinoids are preferred to other topical agents, such as topical vitamin D analogues. Irritation is common and can be reduced by alternate-day application and liberal use of emollients.

●Other topical agents – There are isolated reports of response to treatment with topical fluorouracil, tacrolimus [74], pimecrolimus [75], tacalcitol [76], and diclofenac sodium 3% gel [77]. Several case reports suggest that topical fluorouracil (1 or 5%) may be particularly efficacious in combination with oral alitretinoin [78]. (See 'Systemic treatments' below.)

Systemic treatments

●Oral retinoids – Oral retinoids, including acitretin, isotretinoin, etretinate, and alitretinoin, decrease hyperkeratosis, smoothen papules, reduce odor, and produce significant clinical improvements in most patients with severe or generalized Darier disease. Etretinate is no longer available in the United States, Canada, and many other countries and has been replaced by acitretin. Oral alitretinoin is available in Europe and Canada but not in the United States. (See 'Patients with severe or generalized disease' below.)

The efficacy of oral retinoids for the treatment of Darier disease has not been evaluated in randomized trials, and evidence is limited to small observational studies [79-81]:

•In a double-blind study including 26 patients with Darier disease treated with 30 mg per day of acitretin or etretinate for four months, remission or marked improvement was achieved in 18 of 24 patients who took the drug for the duration of the study period, without difference between the two drugs [81].

•Alitretinoin, a vitamin A analogue known to have anti-inflammatory and immunomodulating properties, has been successfully used in a few patients [82,83] but may induce considerable adverse effects, including worsening of the skin lesions, pyogenic granuloma, erosions, and fever [84].

Oral retinoids do not induce prolonged remission in Darier disease, and long-term treatment is needed to prevent relapse.

Adverse effects of systemic retinoids include mucosal dryness, headache, delayed dark adaptation, diffuse hair loss (telogen effluvium), pyogenic granuloma, photosensitivity, hyperlipidemia, transaminase elevation, and skeletal hyperostosis. Oral retinoids are teratogenic, and appropriate counseling and contraception must be given to women of childbearing age.

●Other treatments – In a small case series, low-dose naltrexone at 5 mg per day showed beneficial effects in moderate, but not severe, cases [85]. In a single case report, low-dose intravenous immunoglobulins significantly reduced crusted lesions and itching [86].

Surgical or destructive therapies — Approaches for localized hypertrophic, erosive, or recalcitrant lesions that are resistant to conventional treatment include dermabrasion; electrosurgery; laser ablation; surgical excision; photodynamic or photon and electron beam therapy; and injection of botulinum toxin similar to the more established topical treatment targeting excessive sweating in Hailey-Hailey disease (benign chronic familial pemphigus; OMIM #169600) [87-100]. Recurrence of lesions following excision and physical treatment is common.

APPROACH TO MANAGEMENT

General measures — All patients with Darier disease should be educated about simple measures to reduce the impact of exacerbating factors and control skin irritation. These measures include:

●Keeping the skin cool and minimizing perspiration. Flares may be prevented by wearing lightweight cotton clothes, avoiding hot environments, and using sunscreens, especially during the summer.

●Regular use of moisturizers containing keratolytics such as topical urea or lactic acid. Moisturizers reduce irritation, decrease scaling and hyperkeratosis, and improve the skin appearance.

●Use of antiseptic washes containing triclosan or chlorhexidine gluconate or bleach baths (one-fourth cup [60 mL] of household bleach in a full tub of water). Antiseptics reduce the burden of skin bacteria and odor. Patients may also be instructed to soak in astringents, such as aluminum acetate, if crusting is prominent or bacterial overgrowth is suspected.

Patients with mild or localized disease — For patients with mild or localized disease, avoidance of triggers, regular use of emollients, and intermittent use of medium-potency topical corticosteroids (groups 4 and 5 (table 1)), often combined with antibiotics (eg, gentamicin, fusidic acid), are generally sufficient to control symptoms. (See 'General measures' above.)

For patients with mild or localized disease that is not controlled by emollients and topical corticosteroids, we suggest topical retinoids. Tretinoin 0.05% or 0.1% cream, adapalene 0.1% cream, or tazarotene 0.05% or 0.1% cream are applied to the involved skin once daily for three months.

Because of the irritancy potential of topical retinoids, treatment is started with the lowest retinoid concentration applied on alternate days. After the first two weeks of treatment, frequency of application and retinoid concentration are gradually increased as tolerated. Emollients are used liberally in conjunction with topical retinoids. Intermittent use of medium-potency topical corticosteroids (groups 4 and 5 (table 1)) may reduce retinoid-induced irritation.

Treatment with topical retinoids should not be started during pregnancy and should be discontinued in patients who become pregnant, although there is no direct evidence that topical retinoids cause congenital malformations [101,102].

Patients with severe or generalized disease — We suggest oral retinoids such as acitretin or isotretinoin for patients with severe or extensive Darier disease. Treatment is generally started with a low dose (10 to 25 mg per day) to avoid initial exacerbation of the disease; the dose is then gradually increased as tolerated, up to 0.5 mg/kg per day for acitretin and 1 mg/kg per day for isotretinoin.

Alitretinoin is started at a dose of 10 mg per day and may be increased to 30 mg per day. Treatment should be continued for a minimum of three to four months to achieve reduction of hyperkeratosis, flattening of papular lesions, and reduction of malodor. Long-term treatment is needed to prevent relapse.

Common side effects of systemic retinoids include mucosal and skin dryness, cheilitis, headache, delayed dark adaptation, diffuse hair loss, pyogenic granuloma, photosensitivity, hyperlipidemia, and elevation of liver transaminase levels. Long-term use induces skeletal hyperostosis on ligaments. Measurement of baseline serum lipid and liver enzyme levels is indicated before initiating acitretin or isotretinoin therapy. Monitoring of serum lipid and liver enzyme levels for the first two months and then every three months is adequate for patients on long-term retinoid therapy.

Acitretin, alitretinoin, and isotretinoin are teratogenic. Appropriate counseling and contraception must be given to women of childbearing age before starting oral retinoids. Women should avoid pregnancy for three years after discontinuing acitretin and for one month after discontinuation of isotretinoin or alitretinoin. Isotretinoin or alitretinoin are thus preferred to acitretin for women of childbearing age who have severe Darier disease. Oral retinoids should never be combined with systemic methotrexate or tetracyclines. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Adverse effects'.)

For patients with localized hypertrophic lesions that do not respond to oral retinoids, surgical excision, laser ablation, or photodynamic therapy are therapeutic options. However, these approaches are associated with pain and/or scarring, and their long-term benefits are uncertain. (See 'Surgical or destructive therapies' above.)

Treatment of complications — Malodor due to microbial or fungal colonization or secondary infection is generally treated with topical antibiotics or antifungals (eg, mupirocin 2% cream, gentamicin 0.1% cream, fusidic acid 2% cream, or ketoconazole 2% cream). Antibacterial washes, such as chlorhexidine gluconate 4% wash, may be used as an adjunct to topical antibiotics. Patients with extensive cutaneous infection that does not respond to topical treatment may require systemic treatment with oral antibiotics or antifungals guided by culture results.

Patients with eczema herpeticum are treated with oral acyclovir or valacyclovir. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Cutaneous disease'.)

GENETIC COUNSELING — For patients with Darier disease, offering referral for genetics services to discuss inheritance pattern, recurrence risk, and the pros and cons of genetic testing is appropriate. Because Darier disease is an autosomal dominant disorder, an affected person will have up to a one in two chance of having a child who is also affected.

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.

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Darier disease, also known as dyskeratosis follicularis, is a rare autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene on 12q23-24.1, which encodes a sarcoplasmic/endoplasmic reticulum calcium pump (SERCA2), resulting in acantholysis and keratinocyte apoptosis. (See 'Pathogenesis' above.)

●Clinical presentation – The initial lesions of Darier disease appear during the teenage years as skin-colored or yellow-brown, keratotic papules that involve the face, chest, back, and, less frequently, the flexural areas (picture 2A-E). Nail changes, including red and white longitudinal bands with a V-shaped nick at the free margin of the nail, are frequent and characteristic (picture 7). (See 'Clinical features' above and 'Clinical variants' above.)

●Diagnosis – The diagnosis of Darier disease is suggested by the clinical finding of a persistent eruption of keratotic papules involving the seborrheic areas. A skin biopsy is needed to confirm the diagnosis. Acantholysis and dyskeratosis are the histologic hallmarks of Darier disease (picture 1). (See 'Diagnosis' above.)

●Management:

•Mild or localized disease – For patients with mild disease, we suggest regular use of emollients and intermittent use of medium-potency topical corticosteroids (groups 4 and 5 (table 1)), in addition to general skin care measures, as first-line therapy (Grade 2C). For patients with limited disease that is not controlled by emollients and topical corticosteroids, we suggest topical retinoids, such as tretinoin 0.05% cream, adapalene 0.1% cream, or tazarotene 0.05% cream (Grade 2C). Topical retinoids are applied once a day for three months. (See 'General measures' above and 'Patients with mild or localized disease' above.)

•Severe or extensive disease – We suggest oral retinoids such as acitretin, isotretinoin, or alitretinoin for patients with severe or extensive Darier disease (Grade 2C). Acitretin or isotretinoin is given at a dose of 0.5 mg/kg per day for three to four months, and alitretinoin is given at a dose of 10 or 30 mg per day. (See 'Patients with severe or generalized disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Pui-Yan Kwok, MD, PhD, who contributed to earlier versions of this topic review.