Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Darier disease

Jonathan A Dyer, MD
Section Editor
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor
Rosamaria Corona, MD, DSc


Darier disease, also known as Darier-White disease or keratosis follicularis (MIM #1242000), is a rare autosomal dominant genodermatosis. It is characterized by a persistent eruption of greasy hyperkeratotic papules in seborrheic areas, nail abnormalities, 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.


Darier disease is caused by mutations in the ATP2A2 gene on 12q23-24.1 that encodes the sarcoplasmic/endoplasmic reticulum Ca2+-ATP isoform 2 protein (SERCA2), which is a calcium pump [4]. SERCA2 actively transports calcium ions from the cytosol into the lumen of the endoplasmic reticulum to maintain a low cytoplasmic Ca2+ level. One study showed that in Darier disease SERCA2-controlled Ca²+-dependent keratinocyte adhesion and differentiation is mediated by sphingolipid signaling [5]. In addition, keratinocytes in Darier disease display a constitutive endoplasmic reticulum stress response with immature adherens junctions and desmosomes, resulting in decreased strength of intercellular adhesion [6].

The molecular mechanisms by which specific ATP2A2 mutations alter the function of the SERCA2 protein and cause loss of desmosomal adhesion (acantholysis) and abnormal keratinization (dyskeratosis) are not known. In in vitro models, specific mutations of ATP2A2 induce defects in protein expression, ATP hydrolysis, calcium transport, and calcium binding and kinetics [7]. ATP2A2 mutations also have been associated with impaired synthesis, folding, or trafficking of desmosomal proteins and abnormal cytokeratin expression [8-10].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Mar 26, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  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. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol Med 2009; 1:268.
  12. Klausegger A, Nischler E, Wagner RN, et al. Seven novel mutations in the ATP2A2 gene of Austrian patients with Darier's disease. Arch Dermatol Res 2011; 303:371.
  13. 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; 150:652.
  14. Bchetnia M, Charfeddine C, Kassar S, et al. Clinical and mutational heterogeneity of Darier disease in Tunisian families. Arch Dermatol 2009; 145:654.
  15. 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.
  16. Munro CS. The phenotype of Darier's disease: penetrance and expressivity in adults and children. Br J Dermatol 1992; 127:126.
  17. 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.
  18. Gordon-Smith K, Jones LA, Burge SM, et al. The neuropsychiatric phenotype in Darier disease. Br J Dermatol 2010; 163:515.
  19. Dodiuk-Gad R, Lerner M, Breznitz Z, et al. Learning disabilities in Darier's disease patients. J Eur Acad Dermatol Venereol 2014; 28:314.
  20. 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.
  21. 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.
  22. 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.
  23. Jones I, Jacobsen N, Green EK, et al. Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease. Mol Psychiatry 2002; 7:424.
  24. 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.
  25. Telfer NR, Burge SM, Ryan TJ. Vesiculo-bullous Darier's disease. Br J Dermatol 1990; 122:831.
  26. Rongioletti F, Cestari R, Rebora A. Verrucous and malodorous vegetations on the legs. Darier's disease, cornifying type. Arch Dermatol 1992; 128:399, 402.
  27. Foresman PL, Goldsmith LA, Ginn L, Beck AL. Hemorrhagic Darier's disease. Arch Dermatol 1993; 129:511.
  28. Meziane M, Chraibi R, Kihel N, et al. Linear Darier disease. Dermatol Online J 2008; 14:11.
  29. Sanderson EA, Killoran CE, Pedvis-Leftick A, Wilkel CS. Localized Darier's disease in a Blaschkoid distribution: two cases of phenotypic mosaicism and a review of mosaic Darier's disease. J Dermatol 2007; 34:761.
  30. Otley CC, Momtaz K. Induction of Darier-White disease with UVB radiation in a clinically photo-insensitive patient. J Am Acad Dermatol 1996; 34:931.
  31. Okada E, Nagai Y, Motegi S, et al. Fatal case of Darier's disease with recurrent severe infections. Acta Derm Venereol 2009; 89:408.
  32. Woo SM, Won CH, Cho S. Darier's disease: variable clinical presentation and a fatal outcome. Clin Exp Dermatol 2009; 34:628.
  33. Haase O, Moser A, Rose C, et al. Generalized cowpox infection in a patient with Darier disease. Br J Dermatol 2011; 164:1116.
  34. 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.
  35. 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.
  36. Burkhart CG, Burkhart CN. Tazarotene gel for Darier's disease. J Am Acad Dermatol 1998; 38:1001.
  37. Oster-Schmidt C. The treatment of Darier's disease with topical tazarotene. Br J Dermatol 1999; 141:603.
  38. Dicken CH, Bauer EA, Hazen PG, et al. Isotretinoin treatment of Darier's disease. J Am Acad Dermatol 1982; 6:721.
  39. 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.
  40. Schmidt H, Ochsendorf FR, Wolter M, et al. Topical 5-fluorouracil in Darier disease. Br J Dermatol 2008; 158:1393.
  41. Yoon TY, Kim JW, Kim MK. Successful treatment of Darier disease with topical 5-fluorouracil. Br J Dermatol 2006; 154:1210.
  42. Le Bidre E, Delage M, Celerier P, et al. [Efficacy and risks of topical 5-fluorouracil in Darier's disease]. Ann Dermatol Venereol 2010; 137:455.
  43. 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.
  44. 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.
  45. 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.
  46. Suzuki K, Aoki M, Kawana S. Localized Darier's disease of the scalp: successful treatment with oral etretinate. Dermatology 2004; 208:83.
  47. 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.
  48. Letulé V, Herzinger T, Ruzicka T, Molin S. Treatment of Darier disease with oral alitretinoin. Clin Exp Dermatol 2013; 38:523.
  49. Barnstedt SE. [Successful treatment of Darier disease with oral alitretinoin]. Hautarzt 2012; 63:139.
  50. Wheeland RG, Gilmore WA. The surgical treatment of hypertrophic Darier's disease. J Dermatol Surg Oncol 1985; 11:420.
  51. Toombs EL, Peck GL. Electrosurgical treatment of etretinate-resistant Darier's disease. J Dermatol Surg Oncol 1989; 15:1277.
  52. 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.
  53. Brown VL, Kelly SE, Burge SM, Walker NP. Extensive recalcitrant Darier disease successfully treated with laser ablation. Br J Dermatol 2010; 162:227.
  54. 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.
  55. 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.
  56. Beier C, Kaufmann R. Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease. Arch Dermatol 1999; 135:423.
  57. 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.
  58. 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.
  59. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's disease with photodynamic therapy. Br J Dermatol 2003; 149:606.
  60. Avery HL, Hughes BR, Coley C, Cooper HL. Clinical improvement in Darier's disease with photodynamic therapy. Australas J Dermatol 2010; 51:32.
  61. 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.
  62. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997; 350:1143.