Skip to main content

Darier’s Disease

Epidemiology, Pathophysiology, and Management

Abstract

Darier’s disease is a rare cutaneous disease with an autosomal dominant mode of inheritance. Greasy papules and plaques arise on the seborrheic areas and in the flexures and almost all patients have nail abnormalities. Acantholysis and dyskeratosis are the typical histological findings. The underlying defect is a result of mutations in the ATP2A2 gene on chromosome 12q23-24 that encodes for a sarco/endoplasmic reticulum calcium ATPase (SERCA 2). Acantholysis is thought to result from desmosome breakdown. Darier’s disease is an example of a dominantly inherited disease caused by haplo-insufficiency. Oral retinoids are the most effective treatment but their adverse effects are troublesome. Topical retinoids, topical corticosteroids, surgery, and laser surgery have their advocates but evidence for efficacy is sparse.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Table I
Fig. 5

References

  1. Darier J. Psorospermose folliculaire vegetante. Ann Dermatol Syphilol 1889; 10: 597–612

    Google Scholar 

  2. White JC. Acase of keratosis (ichthyosis) follicularis. J Cutan Genito-Urin Dis 1889; 7: 201–209

    Google Scholar 

  3. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet 1999; 21: 271–277

    PubMed  Article  CAS  Google Scholar 

  4. Svendson IB, Albrectsen B. The prevalence of dyskeratosis follicularis (Darier’s disease) in Denmark. Acta Derm Venereol 1959; 39: 256–259

    Google Scholar 

  5. Wilkinson JD, Marsden RA, Dawber RPR. Review of Darier’s disease in the Oxford region. Br J Dermatol 1977; 97 Suppl. 15: 15–16

    Article  Google Scholar 

  6. Munro CS. The phenotype of Darier’s disease: penetrance and expressivity in adults and children. Br J Dermatol 1992; 127: 126–130

    PubMed  Article  CAS  Google Scholar 

  7. Burge SM, Garrod DR. An immunohistological study of desmosomes in Darier’s disease and Hailey-Hailey disease. Br J Dermatol 1991; 124: 242–251

    PubMed  Article  CAS  Google Scholar 

  8. Burge SM, Cederholm-Williams SA, Garrod DR, et al. Cell adhesion in Hailey-Hailey disease and Darier’s disease:immunocytological and explant-tissue-culture studies. Br J Dermatol 1991; 125: 426–435

    PubMed  Article  CAS  Google Scholar 

  9. Sudbrak R, Brown J, Dobson-Brown C, et al. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca (2+) pump. Hum Mol Genet 2000; 9: 1131–1140

    PubMed  Article  CAS  Google Scholar 

  10. Zhao XS, Min Shin D, Liu LH, et al. Plasticity and adaption of Ca2+ signaling and Ca2+ dependent exocytosis in SERCA2+/- mice. EMBO J 2001; 20 (11): 2680–2689

    PubMed  Article  CAS  Google Scholar 

  11. Sakuntabhai A, Burge S, Monk S, et al. Spectrum of novel ATP2A2 mutations in patients with Darier’s disease. Hum Mol Genet 1999; 8 (9): 1611–1619

    PubMed  Article  CAS  Google Scholar 

  12. Ruiz-Perez VL, Carter SA, Healey E, et al. ATP2A2 mutations in Darier’s disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of class. Hum Mol Genet 1999; 8 (9): 1621–1630

    PubMed  Article  CAS  Google Scholar 

  13. Jacobsen NJO, Lyons I, Hoogendoorn B, et al. ATP2A2 mutations in Darier’s disease and their relationship to neuropsychiatric phenotypes. Hum Mol Genet 1999; 8 (9): 1631–1636

    PubMed  Article  CAS  Google Scholar 

  14. Sakuntabhai A, Dhitavat J, Burge S, et al. Mosaicism for ATP2A2 mutations causes segmental Darier’s disease. J Invest Dermatol 2000; 115: 1144–1147

    PubMed  Article  CAS  Google Scholar 

  15. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol 1992; 27 (1): 40–50

    PubMed  Article  CAS  Google Scholar 

  16. Coulson IH, Misch KJ. Haemorrhagic Darier’s disease. J Roy Soc Med 1989; 82: 365–366

    PubMed  CAS  Google Scholar 

  17. Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier’s disease. Br Dent J 1991; 171: 133–136

    PubMed  Article  CAS  Google Scholar 

  18. Graham-Brown RAC, Mann BS, Downton D, et al. Darier’s disease with salivary gland obstruction. J Roy Soc Med 1983; 76: 609–611

    PubMed  CAS  Google Scholar 

  19. Venencie PY, Dusser A, Fabre M, et al. Maladie de Darier et encephalopathie evolutive: une observation familiale. Ann Pediatr 1996; 43: 713–715

    Google Scholar 

  20. Harris A, Burge SM, Dykes PJ, et al. Handicap in Darier’s disease and Hailey-Hailey disease. Br J Dermatol 1996; 135: 959–963

    PubMed  Article  CAS  Google Scholar 

  21. Telfer NR, Burge SM, Ryan TJ. Vesico-bullous Darier’s disease. Br J Dermatol 1990; 122: 831–834

    PubMed  Article  CAS  Google Scholar 

  22. Katta R, Reed J, Wolf JE. Cornifying Darier’s disease. Int J Dermatol 2000; 39: 844–845

    PubMed  Article  CAS  Google Scholar 

  23. Romano C, Massai L, Alessandrini C, et al. A case of acral Darier’s disease. Dermatology 1999; 199 (4): 365–368

    PubMed  Article  CAS  Google Scholar 

  24. Cianchini G, Colonna L, Camaioni D, et al. Acral Darier’s disease successfully treated with adapalene. Acta Derm Venereol 2001; 81 (1): 57–58

    PubMed  Article  CAS  Google Scholar 

  25. Foresman PL, Goldsmith LA, Gunn L, et al. Haemorrhagic Darier’s disease. Arch Dermatol 1993; 129: 511–512

    PubMed  Article  CAS  Google Scholar 

  26. McKenna KE, Walsh MY, Burrows D. Treatment of unilateral Darier’s disease with topical isotretinoin. Clin Exp Dermatol 1999; 24 (5): 425–427

    PubMed  Article  CAS  Google Scholar 

  27. Berth-Jones J, Hutchinson PE. Darier’s disease with perifollicular depigmentation. Br J Dermatol 1989; 120: 827–830

    PubMed  Article  CAS  Google Scholar 

  28. Peterson CM, Lesher JL, Sangueza OP. A unique variant of Darier’s disease. Int J Dermatol 2001; 40: 278–280

    PubMed  Article  CAS  Google Scholar 

  29. Cornelison RL, Smith EB, Knox JM. Guttate leukoderma in Darier’s disease. Arch Dermatol 1970; 102: 447–450

    PubMed  Article  CAS  Google Scholar 

  30. Burge S. Management of Darier’s disease. Clin Exp Dermatol 1999; 24 (2): 53–56

    PubMed  Article  CAS  Google Scholar 

  31. Milton GP, Peck GL, Fu JJ, et al. Exacerbation of Darier’s disease by lithium carbonate. J Am Acad Dermatol 1990; 23 (5): 926–928

    PubMed  Article  CAS  Google Scholar 

  32. Rubin MB. Lithium-induced Darier’s disease. J Am Acad Dermatol 1995; 32 (4): 674–675

    PubMed  Article  CAS  Google Scholar 

  33. Burge SM, Wilkinson JD, Miller AJ, et al. The efficacy of an aromatic retinoid, Tigason (etretinate), in the treatment of Darier’s disease. Br J Dermatol 1981; 104 (6): 675–679

    PubMed  Article  CAS  Google Scholar 

  34. Fulton JE, Gross PR, Cornelius CE, et al. Darier’s disease: treatment with topical vitamin A acid. Arch Dermatol 1968; 98 (4): 396–399

    PubMed  Article  Google Scholar 

  35. Burge SM, Buxton PK. Topical isotretinoin in Darier’s disease. Br J Dermatol 1995; 133 (6): 924–928

    PubMed  Article  CAS  Google Scholar 

  36. Steijlen PM, Reifenschweiler DOH, Ramaekers FCS, et al. Topical treatment of ichthyoses and Darier’s disease with 13-cis-retinoic acid: a clinical and immunohistological study. Arch Dermatol Res 1993; 285: 221–226

    PubMed  Article  CAS  Google Scholar 

  37. Steijlen PM, Happle R, van Muijen GNP, et al. Topical treatment with 13-cisretinoic acid improves Darier’s disease and induces the expression of a unique keratin pattern. Dermatologica 1991; 182: 178–183

    PubMed  Article  CAS  Google Scholar 

  38. Hofmann B, Stege H, Bruch-Gerharz D, et al. Ichthyosen: alternative indikation fur den Einsatz von tazaroten (Zorac®). Z Hautkr 1997; 10: 767–769

    Google Scholar 

  39. Micali G, Nasca MR. Tazarotene gel in childhood Darier disease. Pediatr Dermatol 1999; 16 (3): 243–244

    PubMed  CAS  Google Scholar 

  40. Burkhart CG, Burkhart CN. Tazarotene gel for Darier’s disease. J Am Acad Dermatol 1998; 38 (6): 1001–1002

    PubMed  Article  CAS  Google Scholar 

  41. Oster-Schmidt C. The treatment of Darier’s disease with topical tazarotene. Br J Dermatol 1999; 141 (3): 603–604

    PubMed  Article  CAS  Google Scholar 

  42. English JC, Browne J, Halbach DP. Effective treatment of localised Darier’s disease with adapelene 0.1 % gel. Cutis 1999; 63 (4): 227–230

    PubMed  Google Scholar 

  43. Clucas A, Verschoore M, Sorba V, et al. Adapalene 0.1 % gel is better tolerated than isotretinoin 0.0 25% gel in acne patients. J Am Acad Dermatol 1997; 36: S116–S118

    PubMed  Article  CAS  Google Scholar 

  44. Knulst AC, Baart de la Faille H, Van Vloten WA. Topical 5-fluorouracil in the treatment of Darier’s disease. Br J Dermatol 1995; 133 (3): 463–466

    PubMed  Article  CAS  Google Scholar 

  45. Bamshad J, Hilton PE. Darier’s disease: treatment with 5-fluorouracil. Cutis 1971; 8: 555–556

    Google Scholar 

  46. Kragballe K, Steijlen PM, Ibsen HH, et al. Efficacy, tolerability, and safety of calcipotriol ointment in disorders of keratinization: results of a randomised, double-blind, vehicle-controlled, right/left comparative study. Arch Dermatol 1995; 131 (5): 556–560

    PubMed  Article  CAS  Google Scholar 

  47. Peck SM, Chargrin L, Sobotka H. Keratosis follicularis (Darier’s disease): a vitamin A deficiency disease. Arch Dermatol Syph 1941; 43: 223–229

    Article  CAS  Google Scholar 

  48. Peck SM, Glick AW, Sobotka H. Vitamin A studies in keratosis follicularis (Darier’s disease). Arch Dermatol Syph 1943; 48: 17–31

    Article  Google Scholar 

  49. Wilson D, Kay V, Charig M, et al. Skeletal hyperostosis and extraosseous calcification in patients receiving long-term etretinate. Br J Dermatol 1988; 119: 597–607

    PubMed  Article  CAS  Google Scholar 

  50. Burge SM, Wilkinson JD. The use of Tigason (etretinate) in Darier’s disease. In: Cunliffe WJ, Miller AJ, editors. Retinoid therapy. Lancaster: MTP Press Ltd, 1984: 61–62

    Chapter  Google Scholar 

  51. Van Dooren-Greebe RJ, van der Kerkhof PCM, Happle R. Acitretin monotherapy in Darier’s disease. Br J Dermatol 1989; 121: 375–379

    PubMed  Article  Google Scholar 

  52. Lauharanta J, Kanerva L, Turjanmaa K, et al. Clinical and ultrastructural effects of acitretin in Darier’s disease. Acta Derm Venereol 1988; 68 (6): 492–498

    PubMed  CAS  Google Scholar 

  53. Christopherson J, Geiger JM, Danneskiold-Samsoe P. A double-blind comparison of acitretin and etretinate in the treatment of Darier’s disease. Acta Derm Venereol 1992; 72: 150–152

    Google Scholar 

  54. Bleiker TO, Bourke JF, Graham-Brown RA, et al. Etretinate may work where acitretin fails. Br J Dermatol 1997; 136: 368–370

    Google Scholar 

  55. Gilgor RS, Chiaramonti A, Goldsmith LA, et al. Evaluation of 13-cis-retinoic acid in lamellar ichthyosis, pityriasis rubra pilaris and Darier’s disease. Cutis 1980; 25: 380–385

    PubMed  CAS  Google Scholar 

  56. Peck GL, Yoder FW, Olsen TG. Treatment of Darier’s disease, lamellar ichthyosis, pityriasis rubra pilaris, cystic acne and basal cell carcinoma with oral 13-cis retinoic acid. Dermatologica 1978; 157: 1211–1214

    Article  Google Scholar 

  57. Dicken CH, Bauer EA, Hazen PG, et al. Isotretinoin treatment of Darier’s disease. J Am Acad Dermatol 1982; 6 (4): 721–726

    PubMed  Article  CAS  Google Scholar 

  58. Speight EL. Vesicobullous Darier’s disease responsive to oral prednisolone steroids. Br J Dermatol 1998; 139 (5): 934–935

    PubMed  Article  CAS  Google Scholar 

  59. Gordon PM, Shahidullah H, Humphreys F, et al. Systemic steroids and eczematised Darier’s disease [letter]. Br J Dermatol 1995; 133: 492

    PubMed  Article  CAS  Google Scholar 

  60. Shahidullah. H, Humphreys F, Beveridge GW. Darier’s disease: severe eczematization successfully treated with cyclosporin. Br J Dermatol 1994; 131 (5): 713–716

    PubMed  Article  CAS  Google Scholar 

  61. Larbre B, Nicolas JF, Frappaz A, et al. Cyclosporine et maladie de Darier. Ann Dermatol Venereol 1993; 120 (4): 310–311

    PubMed  CAS  Google Scholar 

  62. Oostenbrink JH, Cohen EB, Steijlen PM, et al. Oral contraceptives in the treatment of Darier-White disease: a case report and review of the literature. Clin Exp Dermatol 1996; 21 (6): 442–444

    PubMed  Article  CAS  Google Scholar 

  63. Epsy PD, Stone S, Jolly HW. Hormonal dependency in Darier’s disease. Cutis 1976; 17: 315–320

    Google Scholar 

  64. du Plessis PJ, Jacyk WK. Essential fatty acids in the treatment of Darier’s disease. J Dermatol Treat 1998; 9: 97–101

    Article  Google Scholar 

  65. Toombs EL, Peck GL. Electrosurgical treatment of etretinate-resistant Darier’s disease. J Dermatol Surg Oncol 1989; 15 (12): 1277–1280

    PubMed  CAS  Google Scholar 

  66. Zachariae H. Dermabrasion in Darier’s disease. Acta Derm Venereol 1979; 59 (2): 184–185

    PubMed  CAS  Google Scholar 

  67. Zachariae H. Dermabrasion of Hailey-Hailey disease and Darier’s disease [letter]. J Am Acad Dermatol 1992; 27: 136

    PubMed  Article  CAS  Google Scholar 

  68. Cohen KI, Kraemen KH, Peck GL. Cornifying Darier’s disease — a unique variant II: surgical treatment. Arch Dermatol 1976; 112 (4): 504–506

    PubMed  Article  CAS  Google Scholar 

  69. Wheeland RG, Gilmore WA. The surgical treatment of hypertrophic Darier’s disease. J Dermatol Surg Oncol 1985; 11 (4): 420–423

    PubMed  CAS  Google Scholar 

  70. Dellon AL, Chretien PB, Peck GL. Successful treatment of Darier’s disease by partial-thickness removal of skin. Plast Reconstr Surg 1977; 59 (6): 823–830

    PubMed  Article  CAS  Google Scholar 

  71. McFadden JP, Mayou BJ, Griffiths WAD. Darier’s disease of the groin treated by surgery [letter]. Br J Dermatol 1991; 125: 52

    Article  Google Scholar 

  72. Beier C, Kaufmann R. Efficacy of erbium: YAG:laser ablation in Darier disease and Hailey-Hailey disease. Arch Dermatol 1999; 135 (4): 423–427

    PubMed  Article  CAS  Google Scholar 

  73. 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 (5): 893–897

    PubMed  Article  CAS  Google Scholar 

  74. Calderon MJ, Landa N, Gardeazabal J, et al. Combined retinoid plus surgical treatment of hypertrophic Darier’s disease. J Eur Acad Dermatol Venereol 1993; 2: 242–244

    Article  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susan M. Cooper.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cooper, S.M., Burge, S.M. Darier’s Disease. Am J Clin Dermatol 4, 97–105 (2003). https://doi.org/10.2165/00128071-200304020-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00128071-200304020-00003

Keywords

  • Retinoid
  • Isotretinoin
  • Etretinate
  • Calcipotriol
  • Acitretin