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Darier disease

Daniel Hohl, MD
Section Editor
Jennifer L Hand, MD
Deputy Editor
Rosamaria Corona, MD, DSc


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

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


Darier disease occurs worldwide with a prevalence of 1 to 4 per 100,000 [2,3]. The disease affects both sexes and all ethnic groups.


Mutations in the ATP2A2 gene that encodes a sarco/endoplasmic reticulum Ca2+-adenosine triphosphate (ATP)ase pump (SERCA2) lead to both acantholysis and apoptosis, accounting for the characteristic pathologic finding of acantholytic dyskeratosis in Darier disease [4]. SERCA2 actively transports calcium ions from the cytosol into the lumen of the endoplasmic reticulum to maintain a low cytoplasmic Ca2+ level. Specific mutations of SERCA2 induce defects in protein expression, ATP hydrolysis, calcium transport, and calcium binding and kinetics [5]. SERCA2 mutations also have been associated with impaired synthesis, folding, or trafficking of desmosomal proteins and abnormal cytokeratin expression [6-8].

Despite its ubiquitous expression, the lack of compensatory SERCA3 expression in keratinocytes may explain their particular vulnerability to SERCA2 deficiency. SERCA2 haploinsufficiency has been proposed to underlie the dominant transmission pattern by affecting Ca2+-mediated maturation of cellular adhesion proteins and desmosomes in the endoplasmic reticulum through a stress response, resulting in decreased strength of intercellular adhesion [9].

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Literature review current through: Nov 2017. | This topic last updated: Aug 24, 2017.
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  1. Darier FJ. De la psorospermose folliculaire végétante. Annales de dermatologie et de syphilographie 1889; 10:597.
  2. Cooper SM, Burge SM. Darier's disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol 2003; 4:97.
  3. Godic A, Miljkovic J, Kansky A, Vidmar G. Epidemiology of Darier's Disease in Slovenia. Acta Dermatovenerol Alp Pannonica Adriat 2005; 14:43.
  4. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet 1999; 21:271.
  5. Miyauchi Y, Daiho T, Yamasaki K, et al. Comprehensive analysis of expression and function of 51 sarco(endo)plasmic reticulum Ca2+-ATPase mutants associated with Darier disease. J Biol Chem 2006; 281:22882.
  6. 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; 150:821.
  7. Dhitavat J, Cobbold C, Leslie N, et al. Impaired trafficking of the desmoplakins in cultured Darier's disease keratinocytes. J Invest Dermatol 2003; 121:1349.
  8. Leinonen PT, Hägg PM, Peltonen S, 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; 129:1379.
  9. Savignac M, Simon M, Edir A, et al. SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat. J Invest Dermatol 2014; 134:1961.
  10. Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol Med 2009; 1:268.
  11. 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 2011; 124:3568.
  12. Foggia L, Aronchik I, Aberg K, et al. Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease. J Cell Sci 2006; 119:671.
  13. Savignac M, Edir A, Simon M, Hovnanian A. Darier disease : a disease model of impaired calcium homeostasis in the skin. Biochim Biophys Acta 2011; 1813:1111.
  14. Celli A, Mackenzie DS, Zhai Y, 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; 132:1188.
  15. Hobbs RP, Amargo EV, Somasundaram A, et al. The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signaling. FASEB J 2011; 25:990.
  16. Green EK, Gordon-Smith K, Burge SM, et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol 2013; 40:259.
  17. 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; 38:343.
  18. Bchetnia M, Charfeddine C, Kassar S, et al. Clinical and mutational heterogeneity of Darier disease in Tunisian families. Arch Dermatol 2009; 145:654.
  19. Dhitavat J, Macfarlane S, Dode L, et al. Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease. J Invest Dermatol 2003; 120:229.
  20. Bergman R, Sezin T, Indelman M, et al. Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease. Am J Dermatopathol 2012; 34:597.
  21. Berk DR, Taube JM, Bruckner AL, Lane AT. A sporadic patient with acrokeratosis verruciformis of Hopf and a novel ATP2A2 mutation. Br J Dermatol 2010; 163:653.
  22. Ruiz-Perez VL, Carter SA, Healy E, et al. ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum Mol Genet 1999; 8:1621.
  23. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol 1992; 27:40.
  24. Munro CS. The phenotype of Darier's disease: penetrance and expressivity in adults and children. Br J Dermatol 1992; 127:126.
  25. Burge S. Darier's disease--the clinical features and pathogenesis. Clin Exp Dermatol 1994; 19:193.
  26. Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier's disease. Br Dent J 1991; 171:133.
  27. Suárez-Peñaranda JM, Antúnez JR, Del Rio E, et al. Vaginal involvement in a woman with Darier's disease: a case report. Acta Cytol 2005; 49:530.
  28. Vieites B, Seijo-Ríos S, Suárez-Peñaranda JM, et al. Darier's disease with esophageal involvement. Scand J Gastroenterol 2008; 43:1020.
  29. Salopek TG, Krol A, Jimbow K. Case report of Darier disease localized to the vulva in a 5-year-old girl. Pediatr Dermatol 1993; 10:146.
  30. Bernabé DG, Kawata LT, Beneti IM, et al. Multiple white papules in the palate: oral manifestation of Darier's disease. Clin Exp Dermatol 2009; 34:e270.
  31. Gordon-Smith K, Jones LA, Burge SM, et al. The neuropsychiatric phenotype in Darier disease. Br J Dermatol 2010; 163:515.
  32. Dodiuk-Gad R, Lerner M, Breznitz Z, et al. Learning disabilities in Darier's disease patients. J Eur Acad Dermatol Venereol 2014; 28:314.
  33. Jacobsen NJ, Lyons I, Hoogendoorn B, et al. ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes. Hum Mol Genet 1999; 8:1631.
  34. Green E, Elvidge G, Jacobsen N, et al. Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23-q24 region in two pedigrees with bipolar disorder and Darier's disease. Am J Psychiatry 2005; 162:35.
  35. Cederlöf M, Bergen SE, Långström N, et al. The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study. Bipolar Disord 2015; 17:340.
  36. Cederlöf M, Karlsson R, Larsson H, et al. Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study. Br J Dermatol 2015; 173:155.
  37. Nakamura T, Kazuno AA, Nakajima K, et al. Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey. Psychiatry Clin Neurosci 2016; 70:342.
  38. Telfer NR, Burge SM, Ryan TJ. Vesiculo-bullous Darier's disease. Br J Dermatol 1990; 122:831.
  39. Rongioletti F, Cestari R, Rebora A. Verrucous and malodorous vegetations on the legs. Darier's disease, cornifying type. Arch Dermatol 1992; 128:399, 402.
  40. Foresman PL, Goldsmith LA, Ginn L, Beck AL. Hemorrhagic Darier's disease. Arch Dermatol 1993; 129:511.
  41. JONES WN, NIX TE Jr, CLARK WH Jr. HEMORRHAGIC DARIER'S DISEASE. Arch Dermatol 1964; 89:523.
  42. Meziane M, Chraibi R, Kihel N, et al. Linear Darier disease. Dermatol Online J 2008; 14:11.
  43. Sakuntabhai A, Dhitavat J, Burge S, Hovnanian A. Mosaicism for ATP2A2 mutations causes segmental Darier's disease. J Invest Dermatol 2000; 115:1144.
  44. Fölster-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 2012; 166:464.
  45. Flores-Terry MÁ, García-Arpa M, Llamas-Velasco M, et al. Acral Hemorrhagic Darier Disease. Actas Dermosifiliogr 2017; 108:e49.
  46. Vender R, Vender R. Acral Hemorrhagic Darier's Disease: A Case Report. J Cutan Med Surg 2016; 20:478.
  47. Jörg B, Erhard H, Rütten A. [A hemorrhagic acral form of dyskeratosis follicularis Darier]. Hautarzt 2000; 51:857.
  48. 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.
  49. Harman M, Durdu M, İbiloğlu I. Acrokeratosis verruciformis of Hopf exhibiting Darier disease-like cytological features. Clin Exp Dermatol 2016; 41:761.
  50. Mayuzumi N, Ikeda S, Kawada H, et al. Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. Br J Dermatol 2005; 152:697.
  51. Ehrt U, Brieger P. Comorbidity of keratosis follicularis (Darier's Disease) and bipolar affective disorder: an indication for valproate instead of lithium. Gen Hosp Psychiatry 2000; 22:128.
  52. Nath AK, Udayashankar C. Diltiazem worsens Darier's disease. Int J Dermatol 2014; 53:e1.
  53. Okada E, Nagai Y, Motegi S, et al. Fatal case of Darier's disease with recurrent severe infections. Acta Derm Venereol 2009; 89:408.
  54. Woo SM, Won CH, Cho S. Darier's disease: variable clinical presentation and a fatal outcome. Clin Exp Dermatol 2009; 34:628.
  55. Haase O, Moser A, Rose C, et al. Generalized cowpox infection in a patient with Darier disease. Br J Dermatol 2011; 164:1116.
  56. Vogt KA, Lohse CM, El-Azhary RA, et al. Kaposi varicelliform eruption in patients with Darier disease: a 20-year retrospective study. J Am Acad Dermatol 2015; 72:481.
  57. Czyz C, Sharma P, Grossniklaus HE, et al. Clinical and pathologic eyelid alterations in a patient with Darier disease. Ophthal Plast Reconstr Surg 2011; 27:e170.
  58. Carlsson AM, Barrett GD. Postoperative endophthalmitis in a patient with Darier-White disease. Can J Ophthalmol 2007; 42:134.
  59. Mielke J, Grüb M, Besch D, Schlote T. Recurrent corneal ulcerations with perforation in keratosis follicularis (Darier-White disease). Br J Ophthalmol 2002; 86:1192.
  60. Radia M, Gilhooley MJ, Panos C, Claoué C. Recurrent presumed herpes simplex keratitis and episcleritis in keratosis follicularis (Darier's disease). BMJ Case Rep 2015; 2015.
  61. Calzavara-Pinton PG, Venturini M, Sala R, et al. Methylaminolaevulinate-based photodynamic therapy of Bowen's disease and squamous cell carcinoma. Br J Dermatol 2008; 159:137.
  62. Matsui K, Makino T, Nakano H, et al. Squamous cell carcinoma arising from Darier's disease. Clin Exp Dermatol 2009; 34:e1015.
  63. Dogan S, Karaduman A, Erkin G, Gokoz O. Effective treatment of linear Darier's disease with topical retinoids: case report and review of the literature. Acta Dermatovenerol Croat 2011; 19:206.
  64. Casals M, Campoy A, Aspiolea F, et al. Successful treatment of linear Darier's disease with topical adapalene. J Eur Acad Dermatol Venereol 2009; 23:237.
  65. Burkhart CG, Burkhart CN. Tazarotene gel for Darier's disease. J Am Acad Dermatol 1998; 38:1001.
  66. Rubegni P, Poggiali S, Sbano P, et al. A case of Darier's disease successfully treated with topical tacrolimus. J Eur Acad Dermatol Venereol 2006; 20:84.
  67. 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; 21:301.
  68. 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; 37:718.
  69. Millán-Parrilla F, Rodrigo-Nicolás B, Molés-Poveda P, et al. Improvement of Darier disease with diclofenac sodium 3% gel. J Am Acad Dermatol 2014; 70:e89.
  70. Farb RM, Lazarus GS, Chiaramonti A, et al. The effect of 13-cis retinoic acid on epidermal lysosomal hydrolase activity in Darier's disease and pityriasis rubra pilaris. J Invest Dermatol 1980; 75:133.
  71. Suzuki K, Aoki M, Kawana S. Localized Darier's disease of the scalp: successful treatment with oral etretinate. Dermatology 2004; 208:83.
  72. Christophersen J, Geiger JM, Danneskiold-Samsoe P, et al. A double-blind comparison of acitretin and etretinate in the treatment of Darier's disease. Acta Derm Venereol 1992; 72:150.
  73. Letulé V, Herzinger T, Ruzicka T, Molin S. Treatment of Darier disease with oral alitretinoin. Clin Exp Dermatol 2013; 38:523.
  74. Anuset D, Goutorbe C, Bernard P, Reguiai Z. Efficacy of oral alitretinoin for the treatment of Darier disease: a case report. J Am Acad Dermatol 2014; 71:e46.
  75. Balestri R, Patrizi A, Bardazzi F. Alitretinoin and Darier disease: "All that glisters is not gold". J Am Acad Dermatol 2015; 72:363.
  76. Wheeland RG, Gilmore WA. The surgical treatment of hypertrophic Darier's disease. J Dermatol Surg Oncol 1985; 11:420.
  77. Toombs EL, Peck GL. Electrosurgical treatment of etretinate-resistant Darier's disease. J Dermatol Surg Oncol 1989; 15:1277.
  78. Ahcan U, Dolenc-Voljc M, Zivec K, et al. The surgical treatment of hypertrophic intertriginous Darier's disease. J Plast Reconstr Aesthet Surg 2009; 62:e442.
  79. Brown VL, Kelly SE, Burge SM, Walker NP. Extensive recalcitrant Darier disease successfully treated with laser ablation. Br J Dermatol 2010; 162:227.
  80. 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; 23:893.
  81. Minsue Chen T, Wanitphakdeedecha R, Nguyen TH. Carbon dioxide laser ablation and adjunctive destruction for Darier-White disease (keratosis follicularis). Dermatol Surg 2008; 34:1431.
  82. Beier C, Kaufmann R. Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease. Arch Dermatol 1999; 135:423.
  83. Roos S, Karsai S, Ockenfel HM, Raulin C. Successful treatment of Darier disease with the flashlamp-pumped pulsed-dye laser. Arch Dermatol 2008; 144:1073.
  84. 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; 36:142.
  85. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's disease with photodynamic therapy. Br J Dermatol 2003; 149:606.
  86. Avery HL, Hughes BR, Coley C, Cooper HL. Clinical improvement in Darier's disease with photodynamic therapy. Australas J Dermatol 2010; 51:32.
  87. Loureiro KD, Kao KK, Jones KL, et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Am J Med Genet A 2005; 136:117.
  88. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997; 350:1143.