Keratosis Follicularis (Darier Disease)

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Background

Keratosis follicularis, also known as Darier disease (DD) or Darier-White disease, is an autosomal dominantly inherited genodermatosis characterized by greasy hyperkeratotic papules in seborrheic regions, nail abnormalities, and mucous membrane changes. See the images below. The disease was first reported independently by Darier and White in 1889. White was first to recognize the genetic nature of keratosis follicularis (Darier disease) by noticing that a mother and her daughter were affected.



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Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington Univ....



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Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University ....

Pathophysiology

Mutations in the gene ATP2A2 cause keratosis follicularis (Darier disease). ATP2A2, located on 12q23-24.1, encodes the sarcoplasmic/endoplasmic reticulum Ca2+ -ATP isoform 2 protein (SERCA2), which is a calcium pump.[1] This pump maintains a low cytoplasmic Ca2+ level by actively transporting calcium ions from the cytosol into the lumen of the endoplasmic reticulum. Although more than 120 familial and sporadic mutations in ATP2A2 have been identified in keratosis follicularis (Darier disease) patients, attempts at genotype-phenotype correlation have not been successful. Some authors have suggested that recurrent ATP2A2 p.(Pro602Leu) mutation differentiates acrokeratosis verruciformis of Hopf from the allelic condition Darier disease.[2]

Family members with confirmed identical ATP2A2 mutations can exhibit differences in the clinical severity of disease, suggesting that other genes or environmental factors affect the expression of keratosis follicularis (Darier disease).[3, 4] A wide variety of ATP2A2 mutations in Darier disease have been identified.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model.[22] Investigators transfected a fibroblast cell line with 51 different mutations seen in keratosis follicularis (Darier disease) pedigrees. The investigators found that the resultant transfected cells showed defects in ATP2A2 protein expression (15 mutants), ATP hydrolysis (29 mutants), calcium transport (4 mutants), and calcium binding and kinetics (3 mutants). In a different study, in which researchers systematically analyzed mutations identical to those found in patients with Darier disease, mutant SERCA2 protein aggregates were found to cause stress to the endoplasmic reticulum, subsequently inducing cell apoptosis.[7] Thus, diverse biochemical mechanisms are responsible for altered protein function.

Although expressivity is variable, penetrance of keratosis follicularis (Darier disease) is high, estimated at 95%. Because the disease-causing mutations in ATP2A2 affect functional domains of the gene, the mechanism of autosomal dominant transmission is believed to be haploinsufficiency, in which a single wild-type functioning ATP2A2 is insufficient to prevent disease. No unique phenotype for genetic homozygotes has been reported.

Abnormal keratinocyte-keratinocyte adhesion and aberrant epidermal keratinization are the primary histologic features of keratosis follicularis (Darier disease). Electron microscopy reveals loss of desmosomes (epithelial intercellular junctions formed by membrane and submembrane protein complexes), breakdown of desmosome-keratin intermediate filament attachment, and perinuclear aggregates of keratin intermediate filaments. The mechanism by which decreased activity of the SERCA2 calcium pump leads to these changes is still under investigation.[23] However, a significant correlation exists between the clinical presentation of keratosis follicularis (Darier disease) and the intensity of histologic features.[24]

Some studies of keratosis follicularis (Darier disease) have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins.[25] In particular, studies have revealed that keratosis follicularis (Darier disease) keratinocytes displayed abnormal trafficking of the desmosomal protein desmoplakin and abnormal expression of cytokeratins 10 and 14.[26, 27] A recent study shows that SERCA2-controlled Ca²+ -dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway.[28]

Alternatively, another hypothesis, based on a canine model of keratosis follicularis (Darier disease), is that keratosis follicularis (Darier disease) calcium dysregulation leads to impaired control of cell cycle checkpoints, leading to increased epidermal sensitivity to skin trauma and subsequent keratinocyte apoptosis.

Two particular ATP receptors have been reported to abnormally localize in vivo in keratosis follicularis(Darier disease) and are speculated to play a role in apoptosis as well as abnormal calcium signaling.[27] More recently, Darier keratinocytes were found to display a constitutive endoplasmic reticulum stress response, with immature adherens junctions and desmosomes, which results in decreased intercellular adhesion strength.[29]

Remarkably, an orphan drug, the α-glucosidase inhibitor miglustat, restores mature adherens junctions and desmosomes in Darier keratinocytes and increases adhesion strength. The observation that miglustat is able to restore proper localization to the plasma membrane of nonmutated proteins retained in the endoplasmic reticulum supports a misfolding mechanism.[29]

Epidemiology

Frequency

Keratosis follicularis (Darier disease) occurs worldwide. The prevalence of keratosis follicularis (Darier disease) has been estimated to range from 1 case in 30,000 population in Scotland to 1 case in 100,000 population in Denmark.

Sex

Males and females are equally affected by keratosis follicularis (Darier disease).

Age

Keratosis follicularis (Darier disease) most commonly manifests from age 6-20 years; however, patients have presented as early as age 4 years and as late as age 70 years. Notably, the first case of congenital keratosis follicularis (Darier disease) was diagnosed by biopsy in a child with a significant positive family history for keratosis follicularis (Darier disease), in which at least the 3 proceeding generations of family members were affected.[30]

Prognosis

Patients with keratosis follicularis (Darier disease) experience pruritus and sometimes pain in the affected skin areas. Psychosocial consequences from the appearance and odor of the lesions also constitute the major morbidity of keratosis follicularis (Darier disease). A serious complication associated with keratosis follicularis (Darier disease) is increased susceptibility to cutaneous bacterial and viral infections, in particular herpes simplex virus, human papillomavirus,[31] and poxvirus infections. Initial misdiagnosis of keratosis follicularis (Darier disease) may lead to undertreatment of such infections and may lead to fatal outcomes.[32, 33] However, overall, patients with keratosis follicularis (Darier disease) have a life expectancy similar to that of the general population.

Neuropsychiatric abnormalities such as epilepsy, mental impairment, schizophrenia,[34] and mood disorders have been associated with keratosis follicularis (Darier disease). Several national studies suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for a number of neuropsychiatric disorders,[35] including bipolar disorder,[36] intellectual disability, and subclinical impairments in cognitive ability.[37]

History

Most patients with keratosis follicularis (Darier disease) have a family history of the disease. The pattern of inheritance is autosomal dominant. However, some patients, up to 47% in one series, have no clear family history. These cases may represent sporadic mutations, or these patients may have family members with mild disease that was not recognized.

The first skin lesions typically occur in the teenage years and are frequently associated with pruritus.

Heat, sweat, humidity, sunlight, UVB exposure,[38] lithium, oral corticosteroids, and mechanical trauma have been reported to exacerbate keratosis follicularis (Darier disease). Some females report flares around menstruation.

Even though the severity of keratosis follicularis (Darier disease) fluctuates over time, keratosis follicularis (Darier disease) is a chronic, unremitting condition. In one study, one third of patients noted improvement of the condition with age; however, another one third of patients showed worsening of the disease with age.

Physical Examination

The lesions may first appear as skin-colored or yellow-brown papules with a greasy, warty texture. These lesions are especially common in seborrheic areas such as the forehead, scalp, margin of the scalp, nasolabial folds, ears, chest, and back (see the image below).



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Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington Univ....

Approximately 80% of patients have mild flexural involvement with scattered papules in the groin, axillae, or, in women, submammary skin. In less than 10% of patients, flexural disease predominates, with large, warty, vegetative plaques in the axillae, groin, or perineum. These large flexural lesions are especially bothersome to patients because of their malodor.

Involvement of the hands is very common (approximately 95%). Lesions on the palms include punctate keratoses (80%), palmar pits (80%), and hemorrhagic macules (< 10%). Acrokeratosis verruciformis–like lesions (warty flat-topped papules on the dorsal hands) are present in approximately half the patients. Interestingly, several patients with acrokeratosis verruciformis of Hopf (who have dorsal hand lesions only) have been found to harbor mutations in ATP2A2, suggesting this condition may actually be a localized form of keratosis follicularis (Darier disease).

Nail changes in keratosis follicularis (Darier disease) provide important diagnostic clues (see the image below). White and red longitudinal bands, longitudinal nail ridges, longitudinal splitting, and subungual hyperkeratosis are frequently found. A sandwich of red and white longitudinal bands, often with a V-shaped nick at the free margin of the nail, is the most pathognomonic nail finding in persons with keratosis follicularis (Darier disease). These changes on the hands can also occur on the feet, albeit less commonly.



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Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University ....

Mucosal lesions are detected in approximately 15% of patients, and they appear as white papules with a central depression. These cobblestone lesions are most commonly found in the mouth, but they also may occur on the anogenital mucosa. At times, oral lesions may affect the salivary glands and cause obstruction.[39]

Clinical variants of keratosis follicularis (Darier disease) include hypertrophic and vesicobullous types. Linear or segmental keratosis follicularis (Darier disease) has been shown in some cases to result from genetic mosaicism of ATP2A2. Guttate leukoderma has been noted in some families.[40]

Complications

Renal disease has been reported.[41]

Other Tests

With the discovery that mutations in ATP2A2 cause keratosis follicularis (Darier disease), gene sequencing can be used to confirm the diagnosis.

Procedures

A skin biopsy is helpful in confirming the diagnosis of keratosis follicularis (Darier disease).

Histologic Findings

Acantholysis (loss of epidermal adhesions) and dyskeratosis (abnormal premature keratinization) are the 2 main features of keratosis follicularis (Darier disease). Acantholysis frequently results in the formation of characteristic suprabasal clefts (lacuna) (see the image below). The underlying dermal papillae, covered by a single layer of epithelium (stratum basale), project into these clefts and form villuslike structures. A large keratin plug, often showing focal parakeratosis, overlies each lesion. Hyperkeratosis is also common.



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Acantholysis and dyskeratosis (abnormal keratinization) are the 2 main features of Darier disease. Loss of epidermal adhesion with acantholysis freque....

Two types of dyskeratotic cells are present: corps ronds and grains. Corps ronds are predominantly located in the stratum spinosum and the stratum granulosum. Corps ronds are characterized by an irregular eccentric and sometimes pyknotic nucleus, a clear perinuclear halo, and a brightly eosinophilic cytoplasm. Grains are mostly located in the stratum corneum, and they consist of oval cells with elongated cigar-shaped nuclei and abundant keratohyalin granules. Diagnostic histologic changes are often focal, necessitating a careful search.

Medical Care

Basic measures

Sunscreen, cool cotton clothing, and avoidance of hot environments can help prevent flares, especially during the summer.

Moisturizers with urea or lactic acid can reduce scaling and hyperkeratosis.

A low- or mid-potency topical steroid is sometimes useful for inflammation.

When bacterial overgrowth is suspected or crusting is prominent, application of antiseptics such as triclosan or soaks in astringents such as Burrow or Domeboro solution can be helpful.

Topical medications

Case reports have shown that topical retinoids (adapalene,[43, 44] tazarotene gel 0.01%,[45, 46] tretinoin[47] ) can reduce hyperkeratosis in 3 months. However, irritation is a limiting factor.

Emollients and topical corticosteroids can be used in combination with topical retinoids to reduce irritation.

Topical 5-fluorouracil (5-FU) has been used effectively in some patients.[48, 49]

Tacalcitol lotion and sunscreen combination therapy has been reported for localized Darier disease.[50]

Topical pimecrolimus has been reported to be successful in case reports.[51]

A Spanish group reported the use of the COX inhibitor diclofenac sodium 3% gel successfully in two patients.[52]

Botulinum toxin type A

Injection of botulinum toxin type A was reported in one case to significantly relieve the discomforting symptoms associated with keratosis follicularis (Darier disease) located in the submammary areas.[53]

Systemic medications

Oral retinoids (eg, acitretin, isotretinoin,[47] etretinate, alitretinoin[54, 55] ) have been the most effective medical treatment for keratosis follicularis (Darier disease), achieving some reduction of symptoms in 90% of patients. They reduce hyperkeratosis, smoothen papules, and reduce odor. In a study of 11 patients, 5 with keratosis follicularis (Darier disease) and 6 with pityriasis rubra pilaris, significant improvement occurred with isotretinoin therapy. All 11 patients received isotretinoin at 0.5 mg/kg/d, increasing to a maximum dose of 4 mg/kg/d, for a period of 16 weeks. Greater than 50% improvement occurred in all 5 patients with keratosis follicularis (Darier disease) and in 5 of 6 patients with pityriasis rubra pilaris. One patient showed no clinical improvement. Upon discontinuation of therapy, relapse occurred in all but 1 patient with pityriasis rubra pilaris.[56]

Acitretin is effective at 0.6 mg/kg/d. The starting dose is 10-25 mg/d, which is gradually increased as tolerated. Long-term effects on bone should be monitored.

[57]

Isotretinoin at 0.5-1 mg/kg/d is especially useful in females of childbearing age because pregnancy need only be avoided for 1 month after stopping treatment. Unfortunately, prolonged remissions, such as those noted with isotretinoin for severe acne, are not seen in keratosis follicularis (Darier disease).

Etretinate (not available in the United States) has been reported useful if acitretin fails.[58]

Alitretinoin (not available in the United States) at 30 mg/d has been used successfully by British and German groups for women of childbearing age because of its shorter half-life (2-10 h) compared with acitretin and is therefore an alternative to isotretinoin.[54, 55]

Prolonged use of oral retinoids is limited by their significant adverse effects, including mucosal dryness, photosensitivity, hyperlipidemia, transaminitis, and skeletal hyperostosis. Oral retinoids are teratogenic, and appropriate counseling and contraception must be given.

Oral antibiotics are often necessary to clear secondary bacterial superinfection. They may also be used as prophylaxis to prevent infection.

Oral acyclovir may be used to treat or suppress herpes simplex virus infection.

Oral contraceptives have been reported to help with perimenstrual keratosis follicularis (Darier disease) flares.

Celecoxib, through cyclooxygenase-2 (COX-2) inhibition, was suggested as a possible therapeutic strategy based on one in vitro study which showed that COX-2 inhibition may restore downregulation of ATP2A2/SERCA2 expression in keratinocytes caused by ultraviolet B (UVB) irradiation.[59]

Surgical Care

Dermabrasion has been used to smooth the hyperkeratotic lesions of keratosis follicularis (Darier disease), with acceptable results.[60]

Electrosurgery[61] and Mohs micrographic surgery have been used to treat localized keratosis follicularis (Darier disease) areas, with good results.

Laser ablation of recalcitrant plaques has been reported. In one report, 3 patients were treated with carbon dioxide lasers,[62, 63, 64] 2 with Er:YAG lasers,[65] and 2 with pulsed-dye lasers.[66] In all of these cases, treatment was successful, with only one patient developing disease recurrence in her axilla 7 months after treatment. Other reports describe resolution of disease using 1550-nm erbium-doped fractional fiber laser and other fractionated resurfacing devices.[67, 68]

Carbon dioxide laser ablation with adjunctive dermabrasion, curettage, and shave excision in various combinations have also been reported to cause disease remission for 8 months to 2 years.[69]

Electron beam therapy has been used successfully for localized, recalcitrant Darier’s disease in a 51-year-old female.[70]

Photodynamic therapy with 5-aminolevulinic acid was used to treat keratosis follicularis (Darier disease) lesions in 6 patients, with 4 patients showing sustained improvement or clearance for a follow-up period of 6 months to 3 years.[71, 72]

Surgical excision of hypertrophic intertriginous keratosis follicularis has been described in one case report.[73]

Medication Summary

The goals of pharmacotherapy for keratosis follicularis (Darier disease) are to reduce morbidity and prevent complications.

Adapalene (Differin)

Clinical Context:  Adapalene modulates cellular differentiation, inflammation, and keratinization. It may be tolerated by individuals who cannot tolerate tretinoin creams. It is available as 0.1% gel or solution.

Tazarotene (Avage, Tazorac)

Clinical Context:  Tazarotene is a retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; it may also have anti-inflammatory and immunomodulatory properties.

Tretinoin topical (Avita, Renova, Retin-A, Tretin X)

Clinical Context:  Tretinoin inhibits microcomedo formation and eliminates lesions present. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is available as 0.025, 0.05, and 0.1% creams or 0.01 and 0.025% gels.

Acitretin (Soriatane)

Clinical Context:  Acitretin is a metabolite of etretinate and is related to retinoic acid and retinol (vitamin A). The mechanism of action is unknown but it is thought to exert a therapeutic effect by modulating keratinocyte differentiation, hyperproliferation, and tissue infiltration by inflammatory cells. Its mechanism of action on keratosis follicularis (Darier disease) is unknown.

Isotretinoin (Amnesteem, Claravis, Sotret)

Clinical Context:  Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Class Summary

These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. They also modulate keratinocyte differentiation.

What keratosis follicularis (Darier disease)?What is the pathophysiology of keratosis follicularis (Darier disease)?What is the role of calcium regulation in the pathophysiology of keratosis follicularis (Darier disease)?What is the prevalence of keratosis follicularis (Darier disease)?What are the sexual predilections of keratosis follicularis (Darier disease)?Which age groups have the highest prevalence of keratosis follicularis (Darier disease)?What is the prognosis of keratosis follicularis (Darier disease)?Which clinical history findings are characteristic of keratosis follicularis (Darier disease)?Which physical findings are characteristic of keratosis follicularis (Darier disease)?What are the possible complications of keratosis follicularis (Darier disease)?Which conditions should be included in the differential diagnoses of keratosis follicularis (Darier disease)?What are the differential diagnoses for Keratosis Follicularis (Darier Disease)?How is a diagnosis of keratosis follicularis (Darier disease) confirmed?What is the role of biopsy in the diagnosis of keratosis follicularis (Darier disease)?Which histologic findings are characteristic of keratosis follicularis (Darier disease)?How is keratosis follicularis (Darier disease) treated?What is the role of topical medications in the treatment of keratosis follicularis (Darier disease)?What is the role of botulinum toxin type A in the treatment of keratosis follicularis (Darier disease)?What is the role of oral medications in the treatment of keratosis follicularis (Darier disease)?What is the role of surgery in the treatment of keratosis follicularis (Darier disease)?What is the goal of drug treatment for keratosis follicularis (Darier disease)?Which medications in the drug class Retinoid-like Agents are used in the treatment of Keratosis Follicularis (Darier Disease)?

Author

Pui-Yan Kwok, MD, PhD, Henry Bachrach Distinguished Professor, Department of Dermatology and Cardiovascular Research Institute, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jillian Wong Millsop, MD, MS, Resident Physician, Department of Dermatology, University of California, Davis, School of Medicine

Disclosure: Nothing to disclose.

Tina Bhutani, MD, Clinical Research Fellow, Department of Dermatology, University of California School of Medicine, San Francisco

Disclosure: Nothing to disclose.

Wilson Liao, MD, Associate Professor, Department of Dermatology, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Sarah Fitzmaurice, MD, Jillian Wong Millsop, MD, MS, Tina Bhutani, MD, and Wilson Liao, MD, to the development and writing of this article.

References

  1. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999 Mar. 21(3):271-7. [View Abstract]
  2. Ronan A, Ingrey A, Murray N, Chee P. Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease. Am J Med Genet A. 2017 May 12. [View Abstract]
  3. Onozuka T, Sawamura D, Yokota K, Shimizu H. Mutational analysis of the ATP2A2 gene in two Darier disease families with intrafamilial variability. Br J Dermatol. 2004 Apr. 150(4):652-7. [View Abstract]
  4. Bchetnia M, Charfeddine C, Kassar S, Zribi H, Guettiti HT, Ellouze F. Clinical and mutational heterogeneity of Darier disease in Tunisian families. Arch Dermatol. 2009 Jun. 145(6):654-6. [View Abstract]
  5. Shi HJ, Li M, Zhang GL, et al. Novel splice-site and frameshift ATP2A2 mutations in Chinese patients with Darier disease. Clin Exp Dermatol. 2012. [View Abstract]
  6. Folster-Holst R, Nellen RG, Jensen JM, et al. Molecular genetic support for the rule of dichotomy in type 2 segmental Darier disease. Br J Dermatol. Feb 2012. 166:464-6. [View Abstract]
  7. Wang Y, Bruce AT, Tu C, et al. Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytes. J Cell Sci. Nov 2011. 124:3568-80. [View Abstract]
  8. Harboe TL, Willems P, Jespersgaard C, et al. Mosaicism in segmental Darier disease: an in-depth molecular analysis quantifying proportions of mutated alleles in various tissues. Dermatology. Jul 2011. 222:292-6. [View Abstract]
  9. Pedace L, Barboni L, Pozzetto E, Amantea A, Zambruno G, Preziosi N, et al. Molecular characterization of 11 Italian patients with Darier disease. Eur J Dermatol. May-Jun 2011. 21:334-8. [View Abstract]
  10. Klausegger A, Nischler E, Wagner RN, Pletschacher F, Hintner H, Bauer JW. Seven novel mutations in the ATP2A2 gene of Austrian patients with Darier's disease. Arch Dermatol Res. 2011 Jul. 303(5):371-4. [View Abstract]
  11. Godic A, Strazisar M, Zupan A, Korosec B, Kansky A, Glavac D. Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes. Eur J Dermatol. 2010 May-Jun. 20(3):271-5. [View Abstract]
  12. Li CR, Cui PG, Jia H, et al. Identification of a novel mutation in a Chinese patient with mild Darier’s disease. Int J Dermatol. Nov 2010. 49:1286-8. [View Abstract]
  13. Huo J, Liu Y, Ma J, Xiao S. A novel splice-site mutation of ATP2A2 gene in a Chinese family with Darier disease. Arch Dermatol Res. Dec 2010. 302:769-72. [View Abstract]
  14. Lu FY, Xu L, Yin XG, Wan P, Zhang XD, Chen WW, et al. Identification of mutation c.632G>A (p.G211D) in the ATP2A2 gene and genotype-phenotype correlation in a large Chinese family with Darier's disease. Int J Dermatol. 2011 Nov. 50(11):1366-70. [View Abstract]
  15. Shi HJ, Li M, Zhang GL, Xu SX, Shao MH, Gu Y, et al. Novel splice-site and frameshift ATP2A2 mutations in Chinese patients with Darier disease. Clin Exp Dermatol. 2012 Aug. 37(6):677-9. [View Abstract]
  16. Shi BJ, Xue M, Zhong GS, Jiang Y, Chen DY, Feng J, et al. The ATP2A2 gene in patients with Darier's disease: one novel splicing mutation. Int J Dermatol. 2012 Sep. 51(9):1074-7. [View Abstract]
  17. Ueo D, Hamada T, Hashimoto T, Hatano Y, Okamoto O, Fujiwara S. Late-onset Darier's disease due to a novel missense mutation in the ATP2A2 gene: a different missense mutation affecting the same codon has been previously reported in acrokeratosis verruciformis. J Dermatol. 2013 Apr. 40(4):280-1. [View Abstract]
  18. Green EK, Gordon-Smith K, Burge SM, Grozeva D, Munro CS, Tavadia S, et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol. 2013 Apr. 40(4):259-66. [View Abstract]
  19. Pengjun Z, Jianwen R, Biao Y. A novel missense mutation of ATP2A2 gene in a Chinese family with Darier disease. Int J Dermatol. 2014 Mar. 53(3):e204-5. [View Abstract]
  20. Miyabe C, Mitsuhashi Y, Saito M, Tsuboi R. Novel mutation in the ATP2A2 gene in a Japanese Darier's disease patient with extremely hyperkeratotic lesions. J Dermatol. 2012 Apr. 39(4):401-3. [View Abstract]
  21. Shi BJ, Xue M, Zhu YJ, Wang SP, Du Y, Chen DY, et al. Exon 12 of the ATP2A2 gene in patients with Darier disease: one novel mutation and one previously described. J Eur Acad Dermatol Venereol. 2014 Feb 19. [View Abstract]
  22. Miyauchi Y, Daiho T, Yamasaki K, Takahashi H, Ishida-Yamamoto A, Danko S. Comprehensive analysis of expression and function of 51 sarco(endo)plasmic reticulum Ca2+-ATPase mutants associated with Darier disease. J Biol Chem. 2006 Aug 11. 281(32):22882-95. [View Abstract]
  23. Müller EJ, Caldelari R, Kolly C, Williamson L, Baumann D, Richard G, et al. Consequences of depleted SERCA2-gated calcium stores in the skin. J Invest Dermatol. 2006 Apr. 126(4):721-31. [View Abstract]
  24. Kassar S, Tounsi-Kettiti H, Charfeddine C, Zribi H, Bchetnia M, Jerbi E, et al. Histological characterization of Darier's disease in Tunisian families. J Eur Acad Dermatol Venereol. 2009 Oct. 23(10):1178-83. [View Abstract]
  25. Dhitavat J, Fairclough RJ, Hovnanian A, Burge SM. Calcium pumps and keratinocytes: lessons from Darier's disease and Hailey-Hailey disease. Br J Dermatol. 2004 May. 150(5):821-8. [View Abstract]
  26. Dhitavat J, Cobbold C, Leslie N, Burge S, Hovnanian A. Impaired trafficking of the desmoplakins in cultured Darier's disease keratinocytes. J Invest Dermatol. 2003 Dec. 121(6):1349-55. [View Abstract]
  27. Leinonen PT, Hägg PM, Peltonen S, Jouhilahti EM, Melkko J, Korkiamäki T, et al. Reevaluation of the normal epidermal calcium gradient, and analysis of calcium levels and ATP receptors in Hailey-Hailey and Darier epidermis. J Invest Dermatol. 2009 Jun. 129(6):1379-87. [View Abstract]
  28. Celli A, Mackenzie DS, Zhai Y, Tu CL, Bikle DD, Holleran WM, et al. SERCA2-controlled Ca²+-dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway: a therapeutic target for Darier's disease. J Invest Dermatol. 2012 Apr. 132(4):1188-95. [View Abstract]
  29. Savignac M, Simon M, Edir A, Guibbal L, Hovnanian A. SERCA2 Dysfunction in Darier Disease Causes Endoplasmic Reticulum Stress and Impaired Cell-to-Cell Adhesion Strength: Rescue by Miglustat. J Invest Dermatol. 2014 Jul. 134(7):1961-70. [View Abstract]
  30. Fong G, Capaldi L, Sweeney SM, Wiss K, Mahalingam M. Congenital Darier disease. J Am Acad Dermatol. 2008 Aug. 59(2 Suppl 1):S50-1. [View Abstract]
  31. Matsumoto A, Gregory N, Rady PL, Tyring SK, Carlson JA. Brief Report: HPV-17 Infection in Darier Disease With Acrokeratosis Verrucosis of Hopf. Am J Dermatopathol. 2017 May. 39 (5):370-373. [View Abstract]
  32. Okada E, Nagai Y, Motegi S, Tamura A, Ishikawa O. Fatal case of Darier's disease with recurrent severe infections. Acta Derm Venereol. 2009. 89(4):408-9. [View Abstract]
  33. Woo SM, Won CH, Cho S. Darier's disease: variable clinical presentation and a fatal outcome. Clin Exp Dermatol. 2009 Jul. 34(5):628-9. [View Abstract]
  34. Tang C, Chan M, Lee J, Hariram J. Darier's disease and schizophrenia. East Asian Arch Psychiatry. 2010 Dec. 20(4):190-2. [View Abstract]
  35. Dodiuk-Gad RP, Cohen-Barak E, Khayat M, Milo H, Amariglio-Diskin L, Danial-Faran N, et al. Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects. Br J Dermatol. 2016 Mar. 174 (3):562-8. [View Abstract]
  36. Cederlöf M, Bergen SE, Långström N, Larsson H, Boman M, Craddock N, et al. The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study. Bipolar Disord. 2015 May. 17 (3):340-4. [View Abstract]
  37. Cederlöf M, Karlsson R, Larsson H, Almqvist C, Magnusson PK, Nordlind K, et al. Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study. Br J Dermatol. 2015 Jul. 173 (1):155-8. [View Abstract]
  38. Otley CC, Momtaz K. Induction of Darier-White disease with UVB radiation in a clinically photo-insensitive patient. J Am Acad Dermatol. 1996 May. 34(5 Pt 2):931-4. [View Abstract]
  39. Bernabé DG, Kawata LT, Beneti IM, Crivelini MM, Biasoli ER. Multiple white papules in the palate: oral manifestation of Darier's disease. Clin Exp Dermatol. 2009 Oct. 34(7):e270-1. [View Abstract]
  40. Kansal NK, Hazarika N, Rao S. Familial Case of Darier Disease with Guttate Leukoderma: A Case Series from India. Indian Dermatol Online J. 2018 Jan-Feb. 9 (1):62-63. [View Abstract]
  41. Matsuoka LY, Wortsman J. Renal involvement in Darier disease. J Am Acad Dermatol. 2016 Dec. 75 (6):e235. [View Abstract]
  42. Mansura A, Maly A, Ramot Y, Zlotogorski A. Acantholytic dermatosis of the vulva. Dermatol Online J. 2015 May 18. 21 (5):[View Abstract]
  43. Casals M, Campoy A, Aspiolea F, Carrasco MA, Camps A. Successful treatment of linear Darier's disease with topical adapalene. J Eur Acad Dermatol Venereol. 2009 Feb. 23(2):237-8. [View Abstract]
  44. Abe M, Inoue C, Yokoyama Y, Ishikawa O. Successful treatment of Darier's disease with adapalene gel. Pediatr Dermatol. 2011 Mar-Apr. 28(2):197-8. [View Abstract]
  45. Burkhart CG, Burkhart CN. Tazarotene gel for Darier's disease. J Am Acad Dermatol. 1998 Jun. 38(6 Pt 1):1001-2. [View Abstract]
  46. Oster-Schmidt C. The treatment of Darier's disease with topical tazarotene. Br J Dermatol. 1999 Sep. 141(3):603-4. [View Abstract]
  47. Dicken CH, Bauer EA, Hazen PG, Krueger GG, Marks JG Jr, McGuire JS, et al. Isotretinoin treatment of Darier's disease. J Am Acad Dermatol. 1982 Apr. 6(4 Pt 2 Suppl):721-6. [View Abstract]
  48. Schmidt H, Ochsendorf FR, Wolter M, Geisslinger G, Ludwig RJ, Kaufmann R. Topical 5-fluorouracil in Darier disease. Br J Dermatol. 2008 Jun. 158(6):1393-6. [View Abstract]
  49. Yoon TY, Kim JW, Kim MK. Successful treatment of Darier disease with topical 5-fluorouracil. Br J Dermatol. 2006 Jun. 154(6):1210-2. [View Abstract]
  50. Abe M, Yasuda M, Yokoyama Y, Ishikawa O. Successful treatment of combination therapy with tacalcitol lotion associated with sunscreen for localized Darier's disease. J Dermatol. 2010 Aug. 37(8):718-21. [View Abstract]
  51. Pérez-Carmona L, Fleta-Asín B, Moreno-García-Del-Real C, Jaén-Olasolo P. Successful treatment of Darier's disease with topical pimecrolimus. Eur J Dermatol. 2011 Mar-Apr. 21(2):301-2. [View Abstract]
  52. Millán-Parrilla F, Rodrigo-Nicolás B, Molés-Poveda P, Armengot-Carbó M, Quecedo-Estébanez E, Gimeno-Carpio E. Improvement of Darier disease with diclofenac sodium 3% gel. J Am Acad Dermatol. 2014 Apr. 70(4):e89-90. [View Abstract]
  53. Kontochristopoulos G, Katsavou AN, Kalogirou O, Agelidis S, Zakopoulou N. Letter: Botulinum toxin type A: an alternative symptomatic management of Darier's disease. Dermatol Surg. 2007 Jul. 33(7):882-3. [View Abstract]
  54. Letulé V, Herzinger T, Ruzicka T, Molin S. Treatment of Darier disease with oral alitretinoin. Clin Exp Dermatol. 2013 Jul. 38(5):523-5. [View Abstract]
  55. Zamiri M, Munro CS. Successful treatment with oral alitretinoin in women of childbearing potential with Darier's disease. Br J Dermatol. 2013 Sep. 169(3):709-10. [View Abstract]
  56. Farb RM, Lazarus GS, Chiaramonti A, Goldsmith LA, Gilgor RS, Balakrishnan CV. The effect of 13-cis retinoic acid on epidermal lysosomal hydrolase activity in Darier's disease and pityriasis rubra pilaris. J Invest Dermatol. 1980 Aug. 75(2):133-5. [View Abstract]
  57. Liang J, Chen P, Chen H, Tian X, Wu Z, Zhang S, et al. Long-term safety and efficacy of continuous acitretin monotherapy for three children with different severe hyperkeratotic disorders in China. J Dermatol. 2018 May 14. [View Abstract]
  58. Suzuki K, Aoki M, Kawana S. Localized Darier's disease of the scalp: successful treatment with oral etretinate. Dermatology. 2004. 208(1):83-4. [View Abstract]
  59. Kamijo M, Nishiyama C, Takagi A, Nakano N, Hara M, Ikeda S, et al. Cyclooxygenase-2 inhibition restores ultraviolet B-induced downregulation of ATP2A2/SERCA2 in keratinocytes: possible therapeutic approach of cyclooxygenase-2 inhibition for treatment of Darier disease. Br J Dermatol. 2012 May. 166(5):1017-22. [View Abstract]
  60. Wheeland RG, Gilmore WA. The surgical treatment of hypertrophic Darier's disease. J Dermatol Surg Oncol. 1985 Apr. 11(4):420-3. [View Abstract]
  61. Toombs EL, Peck GL. Electrosurgical treatment of etretinate-resistant Darier's disease. J Dermatol Surg Oncol. 1989 Dec. 15(12):1277-80. [View Abstract]
  62. Brown VL, Kelly SE, Burge SM, Walker NP. Extensive recalcitrant Darier disease successfully treated with laser ablation. Br J Dermatol. 2010 Jan. 162(1):227-9. [View Abstract]
  63. McElroy JA, Mehregan DA, Roenigk RK. Carbon dioxide laser vaporization of recalcitrant symptomatic plaques of Hailey-Hailey disease and Darier's disease. J Am Acad Dermatol. 1990 Nov. 23(5 Pt 1):893-7. [View Abstract]
  64. Minsue Chen T, Wanitphakdeedecha R, Nguyen TH. Carbon dioxide laser ablation and adjunctive destruction for Darier-White disease (keratosis follicularis). Dermatol Surg. 2008 Oct. 34(10):1431-4. [View Abstract]
  65. Beier C, Kaufmann R. Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease. Arch Dermatol. 1999 Apr. 135(4):423-7. [View Abstract]
  66. Roos S, Karsai S, Ockenfel HM, Raulin C. Successful treatment of Darier disease with the flashlamp-pumped pulsed-dye laser. Arch Dermatol. 2008 Aug. 144(8):1073-5. [View Abstract]
  67. Katz TM, Firoz BF, Goldberg LH, Friedman PM. Treatment of Darier's disease using a 1,550-nm erbium-doped fiber laser. Dermatol Surg. 2010. 36(1):142-6. [View Abstract]
  68. Krakowski AC, Nguyen TA, Eichenfield LF. Treatment of segmental keratosis follicularis (Darier disease) using ablative fractional laser resurfacing. Dermatol Surg. 2015 Apr. 41 (4):516-8. [View Abstract]
  69. Minsue Chen T, Wanitphakdeedecha R, Nguyen TH. Carbon dioxide laser ablation and adjunctive destruction for Darier-White disease (keratosis follicularis). Dermatol Surg. 2008 Oct. 34(10):1431-4. [View Abstract]
  70. Kittridge A, Wahlgren C, Fuhrer R, Zirwas M, Patton T. Treatment of recalcitrant Darier's disease with electron beam therapy. Dermatol Ther. 2010 May-Jun. 23(3):302-4. [View Abstract]
  71. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's disease with photodynamic therapy. Br J Dermatol. 2003 Sep. 149(3):606-10. [View Abstract]
  72. Avery HL, Hughes BR, Coley C, Cooper HL. Clinical improvement in Darier's disease with photodynamic therapy. Australas J Dermatol. 2010 Feb. 51(1):32-5. [View Abstract]
  73. Ahcan U, Dolenc-Voljc M, Zivec K, Zorman P, Jurcic V. The surgical treatment of hypertrophic intertriginous Darier's disease. J Plast Reconstr Aesthet Surg. 2009 Nov. 62(11):e442-6. [View Abstract]

Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Acantholysis and dyskeratosis (abnormal keratinization) are the 2 main features of Darier disease. Loss of epidermal adhesion with acantholysis frequently results in the formation of suprabasal clefts (lacunae).

Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Acantholysis and dyskeratosis (abnormal keratinization) are the 2 main features of Darier disease. Loss of epidermal adhesion with acantholysis frequently results in the formation of suprabasal clefts (lacunae).