RARE DISEASE
Darier disease
Darier disease
Darier disease
Synonyms: Darier-White disease, Keratosis follicularis
Synonyms: Darier-White disease, Keratosis follicularis
Synonyms: Darier-White disease, Keratosis follicularis
Drug discovery
0
drugs
With orphan designations
Overview
Darier disease is an autosomal dominant genodermatosis caused by ATP2A2 gene mutations impairing calcium transport (SERCA2), leading to keratinocyte adhesion defects. It presents with hyperkeratotic papules in seborrheic areas, nail dystrophy, and mucosal lesions, exacerbated by heat, UV exposure, and friction [1][2][5]. Chronic with relapsing-remitting course, it correlates with bacterial/viral infections and psychosocial burden [6][9][12].
Burden
Physical: Chronic skin breakdown, recurrent infections (bacterial, HSV), nail/mucosal involvement [6][9][18].
Psychosocial: Depression, anxiety, and reduced quality of life due to disfigurement and odor [1][6][12].
Economic: Frequent healthcare visits, hospitalization for severe flares/complications [6][18].
Therapies
Topical: Retinoids (tretinoin, adapalene), 5-fluorouracil, corticosteroids [4][7][10].
Systemic: Oral retinoids (acitretin, isotretinoin) for severe cases; antimicrobials for infections [4][5][10].
Emerging: MEK inhibitors (trametinib), biologics (dupilumab, tralokinumab) targeting type 2 inflammation [13][18].
Categories: rare genetic diseases, rare skin diseases
Research Papers
321 drug discovery papers about Darier disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
321 drug discovery papers about Darier disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-05 | Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.
Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.
2026-08-01 | Secukinumab in Refractory Generalized Darier’s Disease with a 40-Year Disease Duration: A Case Report
Objective: To report a rare case of refractory generalized Darier’s disease (DD), also known as keratosis follicularis, with a disease duration exceeding 40 years and to explore the therapeutic effect of the interleukin-17A inhibitor secukinumab. Methods: Clinical data were collected. Skin histopathological examination was performed using hematoxylin-eosin (HE) staining, and ATP2A2 gene mutation testing was conducted via whole-exome high-throughput sequencing. The patient was treated with secukinumab. The patient received subcutaneous secukinumab 300 mg once weekly for the first 5 weeks (loading phase), followed by 300 mg every 4 weeks as maintenance therapy. Results: The patient presented with generalized hyperpigmentation, widespread keratotic papules and plaques, some with an oyster-shell appearance, covered with greasy crusts. Histopathology examination further revealed characteristic suprabasal clefts, acantholysis, and dyskeratotic cells (corps ronds and grains). Genetic testing subsequently identified a heterozygous c.479C>T (p.P160L) mutation in the ATP2A2 gene. Following 9 months of secukinumab treatment, the patient experienced partial improvement in pruritus and skin lesions. Conclusion: This case represents a severe form of generalized Darier’s disease with well-defined clinical, pathological, and genetic features. Secukinumab treatment suggested partial clinical improvement, although complete clearance was not achieved. However, the patient discontinued treatment due to financial constraints, and long-term follow-up data are lacking, warranting further investigation. This report provides preliminary experience with biologic therapy for this condition, and the findings require confirmation through controlled studies. Keywords: Darier’s disease, keratosis follicularis, ATP2A2 gene, IL-17A inhibitor, secukinumab, case report, biologic therapy
2026-07-15 | Consensus Recommendations for Management of Darier Disease: A Practical Approach.
Darier disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, encoding the sarco/endoplasmic reticulum calcium ATPase. DD is characterized by chronic, recurrent cutaneous lesions and variable extracutaneous manifestations, resulting in significant impairment of quality of life. Disease onset typically occurs after puberty, with environmental triggers and variable expressivity. The aim of this study was to provide practical, evidence- and consensus-based recommendations for the management of patients with DD, particularly for healthcare professionals in non-expert centers, and to highlight emerging therapeutic avenues. Recommendations were formulated on the basis of a systematic review of the literature and expert consensus from the European Reference Network for Rare and Undiagnosed Skin Disorders (ERN-Skin). Evidence from case reports, case series, and mechanistic studies was considered to provide guidance on symptomatic and advanced targeted therapies. The panel agreed on a total of 68 recommendations. Diagnosis is primarily clinical, supported by family history, histopathology, cytodiagnosis, and, whenever possible, ATP2A2 genetic testing. Genetic counseling should be offered to patients and at-risk relatives. First-line management entails trigger avoidance, skin care using topical antiseptics, emollients, and anti-inflammatory agents, alongside symptomatic control. Topical treatments include corticosteroids, retinoids, and calcineurin inhibitors; systemic therapies (oral retinoids, immunomodulators) are indicated for moderate-to-severe or refractory disease. Physical treatments (ablative lasers, cryotherapy, photodynamic therapy) are reserved for localized treatment-resistant lesions. Targeted therapies (JAK/IL-17/IL-23/IL-4-13/MEK inhibitors), and topical gene therapy, are under evaluation or development. Multidisciplinary management is recommended (neuropsychiatric, ocular, dental, and obstetric). Long-term outcomes remain limited, and durable remission is currently unattainable; treatments must be individualized. DD is a chronic, genetic disorder that significantly impairs quality of life. These practical recommendations provide a framework for diagnosis, management, and follow-up, and highlight the need for clinical trials, registries, and biomarker-driven research to advance therapeutic strategies and explore novel, mechanism-based treatments.
2026-07-14 | Dupilumab Add‐On Therapy in Severe Refractory Darier Disease
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-06-23 | P01 Modulation of the µ-opioid pathway for the treatment of pruritus: a systematic review of 1146 patients across dermatological and systemic conditions
Abstract Introduction and aims Pruritus is a debilitating symptom across dermatological and systemic diseases, and conventional therapies often provide incomplete relief. The µ-opioid receptor pathway is a key regulator of itch. A range of µ-pathway-modulating agents are used off-label for refractory pruritus. This review aimed to systematically evaluate the efficacy, safety, and real-world use of µ-opioid pathway modulators for pruritus of dermatological and systemic origin. Methods We conducted a systematic review following PRISMA guidelines (PROSPERO CRD420251207101), with a comprehensive search of four databases. Results were narratively synthesized owing to heterogeneity. Results Of 3274 records identified, 69 studies met inclusion criteria: 14 randomized controlled trials (RCTs) (n = 795) and 55 nonrandomized studies (n = 351). Five RCTs evaluated dermatological conditions (atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris), while 9 RCTs evaluated systemic pruritus, predominantly cholestatic pruritus and uraemic pruritus. RCTs (1980–2023) assessed oral or topical naltrexone, intravenous naloxone, nalmefene and nalbuphine extended release. Most RCTs demonstrated clinically meaningful reductions in pruritus severity, measured using validated itch scales [visual analogue scale, numeric rating scale (NRS) or worst itch NRS], with the strongest evidence observed in atopic dermatitis, cholestatic pruritus, and uraemic pruritus. Nonrandomized studies (1979–2024) included 199 dermatological and 152 systemic cases, reporting improvement across conditions such as Hailey–Hailey disease, Darier disease, psoriasis, dermatomyositis, chronic pruritus, postburn pruritus, systemic sclerosis and cholestatic disease. Adverse events were mostly mild and tolerated. Conclusions µ-Opioid pathway modulators demonstrate promising efficacy with acceptable short-term safety across a broad spectrum of pruritic conditions. Evidence from randomized trials is strongest for naltrexone and nalmefene in cholestatic pruritus, naltrexone in atopic dermatitis and chronic urticaria, and nalbuphine in uraemic pruritus. In addition, signals of benefit from nonrandomized and real-world studies suggest potential utility across a wider range of dermatological and systemic conditions. Larger, high-quality RCTs are needed to define optimal dosing and support further clinical translation.
2026-08-05 | Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.
Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.
2026-08-01 | Secukinumab in Refractory Generalized Darier’s Disease with a 40-Year Disease Duration: A Case Report
Objective: To report a rare case of refractory generalized Darier’s disease (DD), also known as keratosis follicularis, with a disease duration exceeding 40 years and to explore the therapeutic effect of the interleukin-17A inhibitor secukinumab. Methods: Clinical data were collected. Skin histopathological examination was performed using hematoxylin-eosin (HE) staining, and ATP2A2 gene mutation testing was conducted via whole-exome high-throughput sequencing. The patient was treated with secukinumab. The patient received subcutaneous secukinumab 300 mg once weekly for the first 5 weeks (loading phase), followed by 300 mg every 4 weeks as maintenance therapy. Results: The patient presented with generalized hyperpigmentation, widespread keratotic papules and plaques, some with an oyster-shell appearance, covered with greasy crusts. Histopathology examination further revealed characteristic suprabasal clefts, acantholysis, and dyskeratotic cells (corps ronds and grains). Genetic testing subsequently identified a heterozygous c.479C>T (p.P160L) mutation in the ATP2A2 gene. Following 9 months of secukinumab treatment, the patient experienced partial improvement in pruritus and skin lesions. Conclusion: This case represents a severe form of generalized Darier’s disease with well-defined clinical, pathological, and genetic features. Secukinumab treatment suggested partial clinical improvement, although complete clearance was not achieved. However, the patient discontinued treatment due to financial constraints, and long-term follow-up data are lacking, warranting further investigation. This report provides preliminary experience with biologic therapy for this condition, and the findings require confirmation through controlled studies. Keywords: Darier’s disease, keratosis follicularis, ATP2A2 gene, IL-17A inhibitor, secukinumab, case report, biologic therapy
2026-07-15 | Consensus Recommendations for Management of Darier Disease: A Practical Approach.
Darier disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, encoding the sarco/endoplasmic reticulum calcium ATPase. DD is characterized by chronic, recurrent cutaneous lesions and variable extracutaneous manifestations, resulting in significant impairment of quality of life. Disease onset typically occurs after puberty, with environmental triggers and variable expressivity. The aim of this study was to provide practical, evidence- and consensus-based recommendations for the management of patients with DD, particularly for healthcare professionals in non-expert centers, and to highlight emerging therapeutic avenues. Recommendations were formulated on the basis of a systematic review of the literature and expert consensus from the European Reference Network for Rare and Undiagnosed Skin Disorders (ERN-Skin). Evidence from case reports, case series, and mechanistic studies was considered to provide guidance on symptomatic and advanced targeted therapies. The panel agreed on a total of 68 recommendations. Diagnosis is primarily clinical, supported by family history, histopathology, cytodiagnosis, and, whenever possible, ATP2A2 genetic testing. Genetic counseling should be offered to patients and at-risk relatives. First-line management entails trigger avoidance, skin care using topical antiseptics, emollients, and anti-inflammatory agents, alongside symptomatic control. Topical treatments include corticosteroids, retinoids, and calcineurin inhibitors; systemic therapies (oral retinoids, immunomodulators) are indicated for moderate-to-severe or refractory disease. Physical treatments (ablative lasers, cryotherapy, photodynamic therapy) are reserved for localized treatment-resistant lesions. Targeted therapies (JAK/IL-17/IL-23/IL-4-13/MEK inhibitors), and topical gene therapy, are under evaluation or development. Multidisciplinary management is recommended (neuropsychiatric, ocular, dental, and obstetric). Long-term outcomes remain limited, and durable remission is currently unattainable; treatments must be individualized. DD is a chronic, genetic disorder that significantly impairs quality of life. These practical recommendations provide a framework for diagnosis, management, and follow-up, and highlight the need for clinical trials, registries, and biomarker-driven research to advance therapeutic strategies and explore novel, mechanism-based treatments.
2026-07-14 | Dupilumab Add‐On Therapy in Severe Refractory Darier Disease
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-06-23 | P01 Modulation of the µ-opioid pathway for the treatment of pruritus: a systematic review of 1146 patients across dermatological and systemic conditions
Abstract Introduction and aims Pruritus is a debilitating symptom across dermatological and systemic diseases, and conventional therapies often provide incomplete relief. The µ-opioid receptor pathway is a key regulator of itch. A range of µ-pathway-modulating agents are used off-label for refractory pruritus. This review aimed to systematically evaluate the efficacy, safety, and real-world use of µ-opioid pathway modulators for pruritus of dermatological and systemic origin. Methods We conducted a systematic review following PRISMA guidelines (PROSPERO CRD420251207101), with a comprehensive search of four databases. Results were narratively synthesized owing to heterogeneity. Results Of 3274 records identified, 69 studies met inclusion criteria: 14 randomized controlled trials (RCTs) (n = 795) and 55 nonrandomized studies (n = 351). Five RCTs evaluated dermatological conditions (atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris), while 9 RCTs evaluated systemic pruritus, predominantly cholestatic pruritus and uraemic pruritus. RCTs (1980–2023) assessed oral or topical naltrexone, intravenous naloxone, nalmefene and nalbuphine extended release. Most RCTs demonstrated clinically meaningful reductions in pruritus severity, measured using validated itch scales [visual analogue scale, numeric rating scale (NRS) or worst itch NRS], with the strongest evidence observed in atopic dermatitis, cholestatic pruritus, and uraemic pruritus. Nonrandomized studies (1979–2024) included 199 dermatological and 152 systemic cases, reporting improvement across conditions such as Hailey–Hailey disease, Darier disease, psoriasis, dermatomyositis, chronic pruritus, postburn pruritus, systemic sclerosis and cholestatic disease. Adverse events were mostly mild and tolerated. Conclusions µ-Opioid pathway modulators demonstrate promising efficacy with acceptable short-term safety across a broad spectrum of pruritic conditions. Evidence from randomized trials is strongest for naltrexone and nalmefene in cholestatic pruritus, naltrexone in atopic dermatitis and chronic urticaria, and nalbuphine in uraemic pruritus. In addition, signals of benefit from nonrandomized and real-world studies suggest potential utility across a wider range of dermatological and systemic conditions. Larger, high-quality RCTs are needed to define optimal dosing and support further clinical translation.
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