Darier Disease 

Rare Diseases / By

Darier Disease 

Introduction

  • rare, genetic skin disease characterized by scaly, crusted papules and plaques found in seborrheic areas and flexures, often accompanied by abnormalities of fingernails and oral mucus membrane, as well as palmoplantar pits(1,2,3,4)

Also Called

  • Darier’s disease
  • Darier-White disease
  • dyskeratosis follicularis
  • keratosis follicularis

Epidemiology

Incidence/Prevalence

  • reported prevalence ranges from 1/30,000 to 1/100,000(1,2,3,4)

Risk Factors

  • family history of Darier disease (50% chance of inheriting disease from affected parent)(1,2,3,4)

Associated Conditions

  • neuropsychiatric conditions reported to be associated with Darier disease, including(1,2,3,4)
    • major depression
    • bipolar disorder
    • schizophrenia
    • epilepsy
    • learning difficulties
    • more than 55% lifetime prevalence of neuropsychiatric disorders reported in persons with Darier disease
      •  based on cross-sectional study
      • 100 persons (mean age 48 years) with Darier disease were assessed using adapted version of Schedules for Clinical Assessment in Neuropsychiatry interview, supplemented with clinical notes
      • lifetime-ever psychiatric diagnoses made by consensus of 3 experienced research psychologists/psychiatrists, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV)
      • reported % lifetime prevalences of individual psychiatric conditions included
        • 30% major depressive disorder, 13% depression not otherwise specified
        • 4% bipolar disorder
      • 31% lifetime prevalence of suicidal thoughts, 13% suicide attempts
      • 13% lifetime prevalence of blackouts, periods of loss of consciousness or fainting episodes
      • 3% lifetime prevalence of epilepsy
      • clinical features of Darier disease, including age of onset, associated symptoms, severity, and impact on quality of life not significantly associated with presence of lifetime neuropsychiatric conditions
      • Reference – Br J Dermatol 2010 Sep;163(3):515
    • bipolar disorder and schizophrenia appear associated with Darier disease
      •  based on retrospective population-based cohort study
      • 770 persons with Darier disease identified from Swedish Patient Register were compared to 77,000 age- and sex-matched controls from Swedish Multi-Generation Register
      • comparing persons with vs. without Darier disease
        • 2% vs. 0.5% had history of bipolar disorder (risk ratio 4.3, 95% CI 2.6-7.3)
        • 0.8% vs. 0.3% had history of schizophrenia (risk ratio 2.3, 95% CI 1.1-5.2)
      • Reference – Bipolar Disord 2015 May;17(3):340
    • intellectual disability appears associated with Darier disease
      •  based on retrospective population-based cohort study
      • 770 persons with Darier disease identified from Swedish Patient Register were compared to 7,700 age- and sex-matched controls from Swedish Total Population Register
      • intellectual disability defined as diagnosis of mild or moderate intellectual disability in Patient Register
      • 1.69% of persons with Darier disease reported to have intellectual disability compared to 0.27% of persons without Darier disease (risk ratio 6.2, 95% CI 3.1-12.4)
      • Reference – Br J Dermatol 2015 Jul;173(1):155

Etiology and Pathogenesis

Causes

  • autosomal dominant mutations in ATP2A2 gene on chromosome 12q23-24.1(1,2,3,4)
    • 253 unique mutations reported in 353 families or sporadic patients with Darier disease, with mutations dispersed throughout ATP2A2 gene(1)
    • sporadic mutations have been reported in 40-50% of patients(1,2,3)
    • reported occurrence of sporadic disease may be overstated as some mutations reported initially as sporadic have been found subsequently in family members with previously unreported and/or mild disease, or shown to follow pattern of de novo inheritance(1,3,4)
  • mutations in ATP2A2 have not been found in all patients with Darier disease clinical presentation(1)
    • in analysis of 80 patients with clinically diagnosed Darier disease, no ATP2A2 mutations were found in 17 patients
    • RNA from 1 of these 17 patients was available for analysis and deletion of exon 4 was documented
    • prevalence of specific signs and symptoms were not different between patients with and without ATP2A2 mutation
    • other genetic alterations may exist in gene regions not routinely screened (promoter regions, for example) or other genes that regulate ATP2A2 expression
    • patients with other conditions having a similar clinical presentation may be diagnosed incorrectly with Darier disease (see Differential diagnosis)

Pathogenesis

  • genetic mutations in ATP2A2 gene disrupt function of SERCA2 (sarco/endoplasmic reticulum ATPase type 2), an endoplasmic reticulum calcium adenosine triphosphatase (ATPase) pump(1,2,3,4)
    • disruption of calcium homeostasis may affect cell differentiation(4), contributing to dyskeratosis (abnormal keratinization of keratinocytes) (Biochem Biophys Res Commun 2004 Oct 1;322(4):1237)
    • disruption of calcium-dependent assembly of desmosomes may cause acantholysis due to loss of adhesion among suprabasillary keratinocytes(3,4)
    • disruption of endoplasmic reticulum calcium homeostasis can cause endoplasmic reticulum stress in keratinocytes (FEBS J 2019 Jan;286(2):413)
    • persistent endoplasmic reticulum stress may result in apoptotic keratinocytes, observed histologically as corps ronds in Darier disease (Biochim Biophys Acta 2011 May;1813(5):1111full-text)
  • high degree of disease penetrance may be due to haploinsufficiency, where expression of wild type allele is insufficient for normal function(1,2,4)
  • some alterations in ATP2A2 may correlate with variations in clinical presentation of Darier disease or cause allelic disease variants
    • clinical localized variants, such as macular presentation and segmental Darier disease are likely due to genetic mosaicism caused by postzygotic somatic mutation(2,4)
    • mutations in ATP2A2 gene have been reported in two additional conditions which share similarities to known variants of Darier disease and may be considered allelic disease and/or variants of Darier disease (Biochem Biophys Res Commun 2004 Oct 1;322(4):1237)
      • acrokeratosis verruciformis of Hopf presents with papules on dorsa of hands and feet, with punctated keratosis on palms and soles and sometimes nail involvement but is not usually characterized by dyskeratosis or acantholysis on histological examination(1,3)
      • acantholytic epidermal dyskeratotic nevi present as localized and unilateral keratotic papules that follow Blaschko’s lines and demonstrate dyskeratosis and acantholysis on histological examination (Biochem Biophys Res Commun 2004 Oct 1;322(4):1237)
  • database of reported ATP2A2 mutations, and clinical features when available, can be found at Leiden Open‐source Variation Database (LOVD)Hum Mutat 2011 May;32(5):557

History and Physical

Clinical Presentation

  • patients usually present in adolescence or young adulthood, often with family history of symptoms or disease(1,2,3,4)
  • characteristic presenting signs and symptoms
    • papules are scaly, crusted and found predominately in seborrheic areas (face, scalp, chest, neck, and upper back) and flexures(1,2,3,4)
      • papules may coalesce to form verrucous lesions with keratotic crusts in some areas, particularly flexural sites(2,3,4)
      • palmoplantar pits and papules common(1,2,3,4)
      • white papules and nodules may be seen in oral mucosa(1,2,3,4)
    • lesional pruritus is most frequent symptom(2,4)
    • color may be similar to surrounding skin or have a brown coloration
    • nail abnormalities include
      • pathognomonic nail sign is combination of red and white sandwiched streaks associated with V-shaped notch (“candy-cane” nails)(4)
      • nails may be brittle and weak(2)
    •  coalesced papules may form vegetative lesions and become malodorous, especially in flexural areas where secondary infection is frequent(2,3,4)
  • severity of symptoms is variable and often classified as mild, moderate or severe(1)
  • less common signs and symptoms
  • less common clinical variants(1,3,4)
    • acral, characterized by palmoplantar papules
    • comedonal, characterized by prominent comedonal plaques or acne-like lesions
    • cornifying, characterized by conspicuous hyperkeratotic plaques occurring on non flexural sites, usually lower limbs
    • localized, segmental, linear, or zosteriform variants, which may follow Blaschko’s lines or dermatomes, and usually caused by genetic mosaicism due to postzygotic somatic mutation of ATP2A2 gene
    • vesicobullous, erosive, or hemorrhagic variants, characterized by vesicles and bullae which may erode or hemorrhage
    • mutations in ATP2A2 gene have been reported in two additional conditions which share similarities to known variants of Darier disease and may be considered allelic disease and/or variants of Darier disease (Biochem Biophys Res Commun 2004 Oct 1;322(4):1237)
      • acrokeratosis verruciformis of Hopf presents with papules on dorsa of hands and feet, with punctated keratosis on palms and soles and sometimes nail involvement but is not usually characterized by dyskeratosis or acantholysis on histological examination(1,3)
      • acantholytic epidermal dyskeratotic nevi present as localized and unilateral keratotic papules that follow Blaschko’s lines and demonstrate dyskeratosis and acantholysis on histological examination (Biochem Biophys Res Commun 2004 Oct 1;322(4):1237)

History

History of Present Illness (HPI)

  • symptoms generally begin in adolescence or young adulthood, peaking in puberty for most patients(1,2,3,4)
  • symptoms follow variable, recurring course(1,3)
  • symptoms may be exacerbated by heat, high humidity, sweating, sunlight, mechanical irritation, stress, or infections(1,2,4)
  • symptoms may be exacerbated during premenstrual period in some women(2)

Medication History

Past Medical History

  • ask about history of neuropsychiatric conditions, including major depression, bipolar disorder, schizophrenia, epilepsy, and learning difficulties(1,2,3,4)

Family History (FH)

  • ask about family history of symptoms and skin conditions, including Darier disease(1,2,3,4)
  • some reported sporadic cases may actually be inherited since family members can have unreported and/or mild disease(1,3,4)
  • ask about family history of neuropsychiatric conditions, including major depression, bipolar disorder, schizophrenia, epilepsy, and learning difficulties(1,2,3,4)

Diagnosis

Making the Diagnosis

  • diagnosis is based primarily on clinical presentation of adolescent or young adult with scaly, crusted papules and plaques found in seborrheic areas and flexures, often accompanied by abnormalities of fingernails and oral mucus membrane, as well as palmoplantar pits(1,2,3,4)
  • skin biopsy and genetic testing may be done to confirm diagnosis or rule out other conditions

Differential Diagnosis

Testing Overview

Biopsy and Pathology

  • defining histological features on skin biopsy are acantholysis and dyskeratosis(2,3,4)
    • acantholysis results in formation of suprabasillary clefts, due to loss of cell adhesion(2,3,4)
    • dyskeratosis results from premature and abnormal keratinization(3,4)
    • dyskeratotic cells (apoptotic and abnormal keratinocytes) are seen as corps ronds in stratum spinosum and grains in upper layers of epidermis(3)
    • hyperkeratosis may be seen in epidermis overlying dyskeratotic cells(3,4)
  • acrokeratosis verruciformis of Hopf may be allelic variant of Darier disease and is characterized by
    • distinctive feature of circumscribed epidermal elevations that resemble church spires
    • hyperkeratosis, hypergranulosis, acanthosis, and papillomatosis
    • obvious dyskeratosis and acantholysis, distinguishing features of Darier disease, rarely seen
    • Reference – J Invest Dermatol 2003 Feb;120(2):229full-text

Genetic Testing

  • mutation analysis of ATP2A2 gene can aid in confirmation of diagnosis(1)
  • registry of genetic testing sites can be found at NCBI Genetic Testing Registry

Other Diagnostic Testing

  • dermoscopy and reflectance confocal microscopy are non-invasive tools that can be used to characterize skin lesions
    • central yellowish or brownish starlike area with whitish halo is typical feature identified with manual dermoscope in case series of 11 adults (mean age 34 years) from 7 families with biopsy-confirmed Darier disease (J Eur Acad Dermatol Venereol 2016 Aug;30(8):1392)
    • correlation of skin lesion features using reflectance confocal microscopy with dermoscopic and histologic findings reported in case series of 6 persons with biopsy-confirmed Darier disease
      • dermoscopic findings of white halo around starlike brownish area over pinkish background
      • confocal microscopy showed
        • disarranged honey-comb pattern
        • parakeratosis and hyperkeratosis
        • suprabasal acantholysis with dyskeratosis and numerous adjacent corps ronds and grains
        • tortuous and dilated papillae at dermal-epidermal junction
      • Reference – Skin Res Technol 2019 May;25(3):404
    • hyperparakeratosis identified by dermoscopy and confocal microscopy in case series of 2 adults (mean age 27 years) with biopsy-confirmed Darier disease (J Am Acad Dermatol 2015 Sep;73(3):e97)

Management

Management Overview

  • curative treatments not currently available(1,2,3,4)
  • management focused on relief of symptoms and treatment of any secondary infections(2,3)
  • treatment decisions depend on severity of disorder and response to more conservative management options(4)
    • first line approaches focus primarily on reducing irritation and exacerbation of disease(4)
      • keep skin cool and dry by avoiding sweating and wearing cool, cotton clothing(4)
      • use soap substitutes(4)
      • use simple emollients on affected skin(4)
      • avoid sun exposure and use sun block(4)
      • consider topical medications including
    • second line approaches include
      • oral retinoids (acitretin 10–25 mg/day orally, isotretinoin 0.5-1.0 mg/kg/day orally), which are reported to be effective in up to 90% of persons and are often used for generalized or severe Darier disease, or for persons unresponsive to topical treatment(4)
      • topical 5-fluorouracil 1%-5% cream, which is reported to be effective with good safety profile(4)
    • third line approaches include
  • management of secondary infections includes
    • topical antibacterial soaps, antibiotics, and antifungals(3)
    • systemic antibiotics(2,3), antivirals(4), and antifungals(2,3)

Conservative Management

  • lifestyle-based approaches focus primarily on reducing irritation and exacerbating factors(2,3,4)
    • keep skin cool and dry, and avoid mechanical irritation(1,2,3,4)
      • whenever possible, avoid high temperatures, high humidity, and activities causing increased sweating
      • wear comfortable, loose cotton clothing
    • use soap substitutes to reduce irritation(3,4)
    • use simple, non-irritating emollients on affected skin(3,4)
    • use of topical antibacterial soaps may reduce incidence and severity of pyogenic infections(3)
    • protect skin from UV light (sun exposure) and wear sunblock to reduce disease exacerbation(1,2,3,4)
    • stress reduction may reduce disease exacerbation(1)
    • patient support groups can be helpful(4)

Medications

Topical Medications

  • topical therapies such as retinoids and corticosteroids are widely used for treatment of skin lesions(2)
    • topical retinoids reported to be useful in cases of mild or localized disease but use can be limited by irritation(4)
      • topical retinoic acid and isotretinoin 0.05%-0.1% gel reported to be effective but often cause irritation
      • more selective retinoids (tazarotene 0.01%-0.05% gel, adapalene) reported to be potentially less irritating but may be less effective
      • if irritation occurs, treatment may be applied on alternate days to begin, increasing to once daily if tolerable
    • although evidence is lacking, topical corticosteroid creams may be helpful in some patients and use is widespread(4)
    • alternating topical corticosteroid with topical retinoid may alleviate irritation caused by retinoid(4)
  • topical 5-fluorouracil 1% reported to be effective for some patients, with good short-term safety profile, but efficacy may decrease over time in case reports and series
  • intermittent use of topical antifungals and antibiotics may prevent microorganism colonization and reduce odor of lesions(3)
  • topical diclofenac sodium 3% gel twice daily reported to provide symptom relief in 2 adults (mean age 50 years) with Darier disease in case series (level 3 [lacking direct] evidence) (J Am Acad Dermatol 2014 Apr;70(4):e89full-text)
  • topical tacrolimus 0.1% ointment twice daily reported to result in complete remission at 6 weeks, followed by absence of relapse at 1 year on maintenance dose of tacrolimus 0.03% ointment once daily in 22-year-old woman with Darier disease in case report (level 3 [lacking direct] evidence) (J Eur Acad Dermatol Venereol 2006 Jan;20(1):84)

Systemic Medications

Oral Retinoids
  • oral retinoids reported to be effective in up to 90% of persons and are often used for generalized or severe Darier disease, or for persons unresponsive to topical treatment(3,4)
    • adjust dosing according to symptoms(4), but typical starting doses include
      • acitretin 10 mg/day orally, not to exceed 50 mg/day orally (BAD Grade A, Level 1+)
      • isotretinoin 0.5-1 mg/kg/day orally(4)
    • oral retinoids reported to not be appropriate treatment for persons with intertriginous or bullous forms of disease(3)
  • due to the teratogenic side effects, using contraception during and after treatment with oral retinoids is considered mandatory for women of childbearing age(3)
    • pregnancy is contraindicated for 3 years after stopping treatment with acitretin and for 1 month with isotretinoin(4)
    • isotretinoin is usual choice for treating women of childbearing age(4)
  • dose-dependent side effects that may requiring persons to discontinue treatment or receive intermittent treatment include(2,4), and may include
    • drying and soreness of mucus membranes(3,4)
    • nosebleeds(3,4)
    • skin fragility(4)
    • pruritus(3,4)
    • sensitivity to light(3)
    • elevated triglycerides and cholesterol(4)
    • abnormalities in renal and hepatic function(4)
  • isotretinoin reported to provide symptom improvement in 94% of patients with Darier disease at 16 weeks (level 3 [lacking direct] evidence)
    •  based on uncontrolled trial
    • 104 patients (mean age 36 years) with Darier disease were treated with isotretinoin 0.25 mg/kg orally twice daily for up to 16 weeks, with dose increased every week until suitable maintenance dose reached, followed by rest period of ≥ 8 weeks (short-term course I)
      • patients had up to 2 additional short-term courses (labelled II and III), if significant flare of disease occurred
      • if chronic therapy required, patients were treated with individualized dosages for up to 6 months, with ≥ 2-week rest period in between each course (long-term course)
    • treatment response graded on 8-point scale (range -2 for clearly worsening to +5 for clear), with “clearly improving” being combination of all scores +2 to +5
    • patients reporting “clearly improving” (self-evaluation) compared with baseline
      • 67% of 104 patients (p < 0.001) at 1-4 weeks of short-term course I
      • 83% of 98 patients (p < 0.001) at 5-8 weeks of short-term course I
      • 94% of 104 patients overall (up to 16 weeks of short-term course I; p < 0.001)
      • 85% of 27 patients (p < 0.001) for short-term course II
      • 100% of 10 patients (p < 0.001) for short-term course III
      • 94% of 35 patients (p < 0.001) for long-term course I
      • 90% of 10 patients (p < 0.01) for long-term course II
    • side effects resulting in discontinuation of treatment included
      • drug toxicity in 5 (4.8%) patients during short-term treatment
      • elevated serum triglyceride levels in 6 (5.8%) patients during long-term treatment
    • Reference – J Am Acad Dermatol 1982 Apr;6(4 Pt 2 Suppl):721
  • alitretinoin 30 mg/day orally reported to provide complete remission at 1 month in 38-year-old woman with Darier disease in case report (level 3 [lacking direct] evidence) (J Am Acad Dermatol 2014 Aug;71(2):e46full-text)
  • alitretinoin 30 mg/day orally combined with occasional use of topical 5-fluorouracil reported to provide sustained remission at 3.5 years follow-up in 43-year-old man initially presenting with Darier disease affecting > 50% of body surface area in case report (level 3 [lacking direct] evidence) (JAAD Case Rep 2019 Jan;5(1):75full-text)
  • no adverse effects reported, in terms of height, weight, laboratory markers and skeletal development, with maintenance dose of acitretin (0.3 mg/kg/day orally) for > 13 years in 17-year-old teenager with biopsy-confirmed Darier disease in case series of 3 children with severe hyperkeratotic disorders (level 3 [lacking direct] evidence) (J Dermatol 2018 Aug;45(8):1003)
Other Systemic Medications
  • oral contraceptives reported to provide symptom relief in women reporting premenstrual exacerbation of disease(3,4)
  • naltrexone 5 mg orally once daily and magnesium 200 mg orally once daily reported to provide symptom relief at ≥ 8 weeks follow-up in 2 adults with mild to moderate disease but not in 4 adults with severe Darier disease in case series (level 3 [lacking direct] evidence) (J Eur Acad Dermatol Venereol 2019 May;33(5):950)
  • doxycycline 100 mg/day orally reported to result in complete remission at 1 month, followed by absence of relapse at 3 month follow-up while on maintenance dose of 50 mg/day orally, in 77-year-old adult with severe, recalcitrant Darier disease in case report (level 3 [lacking direct] evidence) (Case Rep Dermatol 2015 Sep;7(3):311full-text)
  • prednisolone 40 mg/day orally, reduced over 4 weeks, reported to provide effective treatment of inflammatory component of vesiculobullous variant of Darier disease(2,4)
  • cetirizine 10-40 mg/day orally reported to reduce burning sensation despite persistent eruptions in 55-year-old woman with vesiculobullous Darier disease and 7-month history of eruptions in case report (level 3 [lacking direct] evidence) (J Drugs Dermatol 2019 Feb 1;18(2):213)

Other Medications

Surgery and Procedures

Skin Excision and Resurfacing

  • treatments including surgical excision and grafting, laser resurfacing, and dermabrasion reported to provide long-term remissions and may be considered for proliferative lesions, localized refractory lesions in flexural and gluteal areas, or in cases of severe disease when other treatment options have failed(2,3,4)
    • depth of excision or ablation is important as superficial treatments often result in early relapse(4)
    • to provide better outcomes and avoid repetitive destructive treatment, excision procedures should include papillary dermis (containing sebaceous glands)(3,4)
  • surgical treatment of hypertrophic lesions reported in case reports include
  • ablative laser procedures reported in case reports include
  • nonablative laser procedures reported in small case series and case reports include

Other Procedures

  • photodynamic therapy
    • inconsistent results reported for photodynamic therapy procedures in persons with Darier disease in small case series and case reports
      • 500-700 nm photodynamic therapy using topical 5-aminolaevulinic acid as photosensitizer reported to be beneficial adjunct therapy for adults receiving systemic retinoid treatment (level 3 [lacking direct] evidence)
        •  based on case series
        • 6 adults (5 women and 1 man; age range 28-73 years) with localized plaques had photodynamic therapy using topical 20% 5-aminolaevulinic acid as photosensitizer
        • 1 woman stopped photodynamic treatment due to pain intolerance, 3 adults receiving concomitant oral retinoids reported symptom improvement and no recurrence at 6 months to 3 years follow-up, and 2 women no longer taking oral retinoids experienced symptom relapse
        • adverse effects included mild pruritus following application of 5-aminolaevulinic acid, pain during photodynamic therapy, and localized wound infection in 1 woman
        • Reference – Br J Dermatol 2003 Sep;149(3):606
      • 633 nm photodynamic therapy using topical methylaminolevulinate as photosensitizer associated with sustained symptom improvement for > 27 months posttreatment in 30-year-old woman who had failed response to topical treatments (level 3 [lacking direct] evidence) (Australas J Dermatol 2010 Feb;51(1):32)
      • 420 nm photodynamic therapy using topical 5-aminolaevulinic acid as photosensitizer associated with initial rapid clearance of skin lesions but subsequent induction and exacerbation of Darier disease in, and adjacent to, treated areas in 46-year-old woman (level 3 [lacking direct] evidence) (J Eur Acad Dermatol Venereol 2006 Aug;20(7):870)
    • most common acute adverse effect is pain and scarring is rare (Br J Dermatol 2019 Apr;180(4):730)

Radiation Therapy

  • radiation therapy reported to provide symptom relief in persons with Darier disease in small case series and case reports
  • symptom relief reported in therapeutic field of persons with Darier disease receiving radiation therapy for cancer in case reports

Management of Associated Complications

  • management of secondary bacterial, viral, or fungal infections of lesions may include
    • topical antibacterial soaps(3)
    • topical antibiotics and antifungals(2,3)
    • systemic antibiotics(2,3), antivirals(4), and antifungals(2,3)
    • combined corticosteroid and antibiotic approaches may be used, as superinfection with viruses and bacteria is common(4)

Consultation and Referral

Follow-up

Complications

  • secondary bacterial, viral, or fungal infections of lesions are common,(2,4) and often include
    • Staphylococcus aureus(2,4)
    • herpes simplex viruses
  • less common infections have been reported in case reports, including
  • Kaposi varicelliform eruptions may be common complication of viral infection(2)
  • ocular complications of secondary infections reported in case reports, including
  • exacerbation of disease may occur if patient or household contact receives smallpox (vaccinia) vaccination (MMWR Recomm Rep 2003 Feb 21;52(RR-4):1), relevant predominantly to select members of military personnel (Military Health System) and clinical and medical laboratory professional (2015 Recommendations of the Advisory Committee on Immunization Practices, Center for Disease Control)
  • intermittent swellings of salivary glands due to metaplasia of ductal lining and obstruction reported with oral lesions in some patients(4)
  • rare malignancies arising within Darier lesions reported in case reports, including
    • basal cell carcinoma within linear collection of keratotic papules in 34-year-old woman with type 2 segmental Darier disease (J Skin Cancer 2012;2012:839561full-text)
    • squamous cell carcinoma with histological features of Darier disease nested within tumor and without evidence of human papilloma virus in 62-year-old woman (Clin Exp Dermatol 2009 Dec;34(8):e1015)
    • amputation of leg below knee due to deep invasion of squamous cell carcinoma, with diffuse hypertrophic Darier involvement in surrounding skin, in 63-year-old man (Br J Dermatol 2008 Dec;159(6):1378)
    • oral squamous cell carcinoma in association with keratotic lesions in 54-year-old woman with chronic oral ulceration (Oral Oncol 2004 Sep;40(8):856)

Prognosis

  • chronic clinical course with recurring flares, most often due to trigger factors which include mechanical trauma, heat, humidity, sunlight, infections, and excessive sweating(3)
  • increased area of affected skin and disease severity, and younger age of disease onset associated with reduced health-related quality of life in adults with Darier disease
    • based on cross-sectional study
    • 74 adults (mean age 43 years) with Darier disease from 33 families assessed with 3 health-related quality of life questionnaires, including Dermatology Life Quality Index (DLQI)
    • variables associated with health-related reduced quality of life, as measured by DLQI (higher scores associated with reduced quality of life), include
      • area of affected skin (range 2.2 with < 10% skin affected to 9.4 with > 29% skin affected, p = 0.001)
      • disease severity (range 1.9 with mild disease to 9.3 with severe disease, p = 0.001)
      • age of disease onset (range 3.7 at > 18 years to 8.3 at ≤ 12 years, p = 0.006)
    • DLQI best predicted reduced health-related quality of life for
      • work and school score (p < 0.005) as area of affected skin increased
      • daily activity score (p < 0.001) and leisure score (p<0.01) as disease severity increased
      • personal relationship score (p < 0.05) with younger age of disease onset
    • Reference – J Eur Acad Dermatol Venereol 2013 Jan;27(1):51
  • secondary infections reported to lead to additional complications and worse prognosis
    • positive culture of Staphylococcus aureus on lesional skin associated with greater disease severity in adults with Darier disease in Israel
      • based on cross-sectional study
      • 75 adults (mean age 43 years) with Darier disease in Israel had medical interview, physical examination, and were swabbed for bacteria
      • in 74 patients receiving lesional skin swabs, 81% tested positive for bacteria, with 12 different species detected
      • 68% of patients tested positive for Staphylococcus aureus, with positive culture correlating with
        • increased area of affected skin (p = 0.0001)
        • increased severity of disease (p < 0.0001)
        • reduced health-related quality of life as measured by Dermatology Life Quality Index (DLQI questionnaire; p = 0.0002) and Visual Analogue Scale (EQ-5D questionnaire; p = 0.007)
      • authors note prevalence of positive cultures may be elevated due to climate of high temperature and humidity in Israel
      • in 35 patients with reported recall on questionnaire of history of symptomatic infection
        • 70% reported exacerbation of disease due to infection
        • most common symptoms reported were localized cutaneous oozing (60%), pruritus (56.7%) and bad smell (53.3%)
        • 30% reported hospitalization due to infection
      • Candida species were identified in lesional skin culture in 3 of 74 patients (4%)
      • Reference – J Eur Acad Dermatol Venereol 2013 Nov;27(11):1405
    • deaths from complications of secondary infections reported in case reports, including
      • wide spread erythema, and severe sepsis and hypoglycemia, leading to death in 44-year-old man with 20-year history of complications, including frequent episodes of local infection with multiple microorganisms, Kaposi varicelliform eruption, and several episodes of sepsis (JAAD Case Rep 2015 Jan;1(1):41full-text)
      • fatal infectious complications due to methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Pseudomonas in 34-year-old man with extensive eroded hemorrhagic lesions (Clin Exp Dermatol 2009 Jul;34(5):628)
      • acute renal failure, secondary to sepsis and dehydration, leading to death in 25-year-old man with widespread vesiculo-bullous Darier disease and history of recurring bacterial and viral secondary infections (Acta Derm Venereol 2009;89(4):408)
      • widespread cutaneous herpes simplex virus (type-2) infection, followed by systemic dissemination, leading to severe acute respiratory distress syndrome and subsequent death in 67-year-old man receiving corticotherapy (Eur J Dermatol 2005 Jul;15(4):293)

Prevention and Screening

Prevention

  • not applicable

Screening

  • genetic testing is available but not generally recommended as correlation between genotype and phenotype is poor
    • disease symptoms and severity varies between persons with same mutation(1)
    • positive test for gene mutation may not predict future disease severity in asymptomatic family members or offspring of persons with disease (J R Soc Med 2003 Sep;96(9):439full-text)
  • international registry of genetic testing sites can be found in NCBI Genetic Testing Registry

Guidelines and Resources

Guidelines

United Kingdom Guidelines

Review Articles

MEDLINE Search

Patient Information

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

  1. Nellen RG, Steijlen PM, van Steensel MA, et al. Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease. Hum Mutat. 2017 Apr;38(4):343-356.
  2. Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016 Mar;43(3):275-9.
  3. Engin B, Kutlubay Z, Erkan E, et al. Darier disease: A fold (intertriginous) dermatosis. Clin Dermatol. 2015 Jul;33(4):448-51.
  4. Cooper SM, Burge SM. Darier’s disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol. 2003;4(2):97-105.

Related Posts

  • Poncets disease

    Poncets disease In patients with visceral (usually lymph nodes) or pulmonary TB, an acute symmetric…

  • Blount disease

    Blount disease Blount disease is a varus deformity of the knee (i.e., the tibia is…

  • Cricoarytenoid disease

    What is cricoarytenoid disease? How can it impact anesthetic complications? The CA joint is a…

  • Graves disease

    What is Graves disease? Graves' disease is also an autoimmune thyroid disease and is pathologically…

Related Posts:

15585

Sign up to receive the trending updates and tons of Health Tips

Join SeekhealthZ and never miss the latest health information

15856