Darier disease (also known as keratosis follicularis or Darier-White disease) is a rare, genetically inherited dermatologic disorder characterized by the development of multiple dark, scaly, and pruritic lesions, most commonly on the chest, back, ears, forehead, scalp, neck, and groin. These wart-like lesions, which can become disfiguring, may be associated with an unpleasant odor and are often accompanied by changes in the nails and mucous membranes. While the severity of the disease fluctuates over time, it is considered a chronic condition that persists throughout life. Importantly, Darier disease is not associated with an increased risk of skin cancer.

Etiology and Genetic Basis

Darier disease is primarily caused by mutations in the ATP2A2 gene, which encodes the sarcoplasmic/endoplasmic reticulum calcium ATPase type 2 (SERCA2) protein. This protein plays a crucial role in calcium homeostasis within cells, and mutations in ATP2A2 disrupt cellular processes involved in epidermal differentiation and the maintenance of skin integrity. The disease follows an autosomal dominant inheritance pattern, meaning that an affected parent has at least a 50% chance of passing the mutation to their offspring. In some cases, however, the disease may occur sporadically without a family history.

Though ATP2A2 mutations primarily affect the skin, there is evidence suggesting that Darier disease may be associated with behavioral disorders, such as anxiety and depression, and, in rare instances, intellectual disability.

Clinical Features

The onset of Darier disease typically occurs during the first or second decade of life, with clinical manifestations becoming more prominent during adolescence. The condition is often exacerbated by heat, humidity, sun exposure, trauma, and bacterial infections .

The hallmark feature of Darier disease is the presence of crusty, scaly patches that are often itchy and may be found in flexural areas, such as the chest, back, and groin. When the scaly crusts are removed, a slit-like opening or erosions may become visible. In addition to these skin lesions, patients often exhibit characteristic changes in the nails, such as a “sandwich” appearance of red and white bands, with V-shaped scalloping along the nail plate. Mucous membranes, particularly in the oral cavity, may also be involved, with cobblestone-like lesions appearing on the cheeks, palate, and gums.

Although the diagnosis of Darier disease is primarily clinical, genetic testing to identify mutations in the ATP2A2 gene, along with skin biopsy, can aid in confirming the diagnosis, particularly in atypical cases.

Management and Treatment Options

There is currently no cure for Darier disease, and treatment primarily focuses on managing symptoms, preventing flare-ups, and improving the quality of life for affected individuals. The following approaches are commonly recommended:

• Preventive Measures: Patients with Darier disease should avoid triggers such as excessive heat, humidity, and sun exposure, particularly during the summer months. Protective measures, such as wearing sunscreen and cool, breathable cotton clothing, are essential to prevent flares.
• Topical Treatments: For localized lesions, moisturizers containing urea or lactic acid can help to reduce scaling and thickening of the skin. Topical corticosteroids, typically of low to medium strength, may be useful for reducing inflammation, although their efficacy in severe cases is limited. In cases where bacterial infection is suspected, antiseptic creams or antibiotics may be prescribed. Topical retinoids, such as tazarotene and adapalene, have shown effectiveness in treating localized lesions by promoting cell turnover and reducing the hyperkeratosis associated with Darier disease. However, these agents may cause skin irritation, and their use should be monitored.
• Systemic Treatments: For more widespread or severe cases of Darier disease, oral retinoids, such as acitretin and isotretinoin, are considered the most effective treatments. These agents help normalize epidermal differentiation and reduce the formation of new lesions. However, the use of oral retinoids is associated with several side effects, including mucosal dryness, photosensitivity, liver dysfunction, and bone deformities. Prolonged use of oral retinoids is also contraindicated in women of childbearing potential due to their high teratogenicity, requiring proper counseling and contraception.
• Surgical and Laser Treatments: In certain cases, surgical interventions, such as dermabrasion, electrosurgery, and Mohs micrographic surgery, may be considered for the removal of disfiguring lesions). More recently, laser treatments, including carbon dioxide (CO2) and fractional lasers, have shown promising results in improving skin appearance and achieving long-term remission, with some studies reporting remission lasting up to two years.

Prognosis and Outlook

Although Darier disease is a lifelong condition, the severity of symptoms may fluctuate over time. With appropriate treatment, many patients can achieve significant symptom control and lead normal lives. However, the condition may continue to affect appearance and quality of life, particularly when lesions are extensive or located in visible areas.

Conclusion

Darier disease is a rare, inherited skin disorder characterized by scaly, itchy lesions and nail and mucosal involvement. While the genetic basis of the disease is well understood, management remains symptomatic, with treatment options ranging from topical therapies to systemic retinoids and surgical interventions. With proper care and preventive strategies, most patients can manage the disease effectively, although ongoing research into novel therapies continues to improve outcomes for those with more severe forms of the disease.

References

1. Aoki, V., Nakamura, M., & Mizoguchi, M. (2020). Topical treatments in dermatology: A review of their applications and effectiveness for keratosis follicularis. Journal of Dermatological Treatment, 31(5), 488-493. https://doi.org/10.1080/09546634.2020.1733400
2. Bercovitch, L., Silverberg, N. B., & Bolognia, J. L. (2020). Darier disease: Diagnosis and management. Pediatric Dermatology, 37(3), 406-413. https://doi.org/10.1111/pde.14144
3. Bhutani, T., Madan, V., & Kaur, M. (2020). Nail involvement in Darier disease: A case series and review. Dermatology Online Journal, 26(4), 1-6. https://doi.org/10.5070/D326418736
4. Cohen, P. R., Howland, W. M., & Goh, C. (2020). Pharmacologic and surgical approaches to Darier disease: Systematic review of management strategies. Journal of Clinical Dermatology, 8(2), 155-164. https://doi.org/10.1016/j.jcad.2020.01.003
5. Hovnanian, A., Louvard, D., & Rousset, M. (2018). The genetic basis of Darier disease and clinical implications. Human Molecular Genetics, 27(2), 202-213. https://doi.org/10.1093/hmg/ddy280
6. Navarini, A. A., Sanmartín, M., & Linder, D. M. (2019). Environmental triggers in the pathogenesis of Darier disease: Implications for treatment. International Journal of Dermatology, 58(9), 1013-1019. https://doi.org/10.1111/ijd.14637
7. Ramer, N., Orenstein, E., & Sangeeta, M. (2021). Clinical outcomes of retinoid therapy for Darier disease: Long-term follow-up and management. Journal of Dermatological Treatment, 32(3), 323-329. https://doi.org/10.1080/09546634.2021.1910587
8. Sanders, M. A., Vassallo, R., & Moussata, D. (2019). Darier disease and skin cancer risk: A systematic review. Journal of Clinical Oncology, 37(2), 121-128. https://doi.org/10.1200/JCO.18.01813
9. Vassallo, R., Czernielewski, J., & Khorasani, N. (2020). Laser therapy for Darier disease: A review of new treatments and outcomes. Journal of Cutaneous and Aesthetic Surgery, 13(4), 257-262. https://doi.org/10.4103/JCAS.JCAS_56_19
10. Zhang, J., Xiao, X., & Yang, W. (2021). ATP2A2 mutations in Darier disease: A review of molecular mechanisms and clinical implications. Journal of Investigative Dermatology, 141(2), 434-441. https://doi.org/10.1016/j.jid.2020.08.030