Darier Disease

Harmon, R. M., Ayers, J. L., McCarthy, E. F., Kowalczyk, A. P., Green, K. J., & Simpson, C. L. (2025). Pumping the Breaks on Acantholytic Skin Disorders: Targeting Calcium Pumps, Desmosomes, and Downstream Signaling in Darier, Hailey-Hailey, and Grover Disease. The Journal of investigative dermatology, 145(3), 494–508. https://doi.org/10.1016/j.jid.2024.06.1289

Pathology:

Darier disease (DD), also known as dyskeratosis follicularis, is an inherited disease that is autosomal dominant, meaning one mutant allele is sufficient for the disease to be manifested. The number of alleles may also dictate the severity the disease, with patients with 2 mutant alleles having a more severe clinical presentation. About 1 in 30,000 to 1 in 100,000 people are diagnosed with DD, and the onset of the disease is generally observed in adolescence or early adulthood. The gene associated with DD is the ATP2A2 gene, which encodes for the SERCA2 protein. SERCA2 is a calcium (Ca²⁺) pump in the endoplasmic reticulum of the cell that is highly expressed in keratinocytes and is responsible for regulating calcium levels in these cells. Genetic mutations impacting the function of the SERCA2 protein may impeded proper cell to cell interactions, which in the skin are critical to maintaining the structure of the skin barrier. Ca²⁺ has a role in dictating cell differentiation in the skin, allowing cells to properly transition across the layer of the skin. The impact on the structure of the skin can be seen in Figure 1., where DD patients have disrupted cell layers in comparison to healthy control patients. In addition to impeding proper cell adhesion, altered function of the SERCA2 protein can also lead to cell stress from improper folding of proteins, which then leads to cell death, ultimately impacting the skin structure as well.  

Figure 1. H&E staining of skin biopsies from healthy control (left) and DD (right) patients. Figure adapted from Zaver, S. A., Sarkar, M. K., Egolf, S., Zou, J., Tiwaa, A., Capell, B. C., Gudjonsson, J. E., & Simpson, C. L. (2023). Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease. JCI insight, 8(18), e170739. https://doi.org/10.1172/jci.insight.170739

Clinical manifestations:

Patients with DD, may exhibit greasy skin, papules or plaques which may be hyperkeratotic. Some of the anatomical areas most affected are the trunk, neck, face, axillary folds, inguinal folds, submammary areas, and other regions which have sebaceous glands. The lesions on the skin may be accompanied by itching, burning, pain, and body odor, all of which impact patients daily. DD is manifested differently across patients and with its rarity there is not currently a scoring method for assessing disease severity. In addition to the manifestations on the skin, patients also experience systemic symptoms. SERCA2 is also expressed in cell types in the brain, highlighting potential impacts of ATP2A2 mutations having repercussions manifested as neuropsychiatric disorders. Comorbidities of DD with psychiatric conditions, such as epileptsy, bipolar disorder and depression, have been observed. Additionally, the pain of the clinical manifestations, and accounting how the severity of the disease may create difficulties in day to day activities, also increase the risk of depression disorders in DD patients.

Treatments:

The most common therapeutic treatment for DD utilizes topical corticosteroids and systemic retinoids. Due to the mechanical stress on the lesions, there is an increased risk of secondary infections, which are then treated by topical antibiotics and antifungals. The use of systemic retinoids results in a variety of side effects, limiting their use for disease management and highlighting the need for alternative therapies. While not an autoimmune disease, some patients exhibit increased infiltration of Th17 cells that contribute to the inflammation experienced in DD, which has suggested Th17 cells, and the inflammatory cytokines they produce, as a possible therapeutic targets.

References:

Ettinger, M., Kimeswenger, S., Deli, I., Traxler, J., Altrichter, S., Noack, P., Wikstrom, J. D., Guenova, E., & Hoetzenecker, W. (2025). Darier disease: Current insights and challenges in pathogenesis and management. Journal of the European Academy of Dermatology and Venereology : JEADV, 39(5), 942–951. https://doi.org/10.1111/jdv.20448

Moschella, B., Busciglio, S., Ambrosini, E., Cesarini, S., Caramanna, L., Zanelli, S., Cannizzaro, I. R., Luberto, A., Taiani, A., Treccani, M., De Sensi, E., Caggiati, P., Azzoni, C., Bottarelli, L., Lorusso, B., Lagrasta, C. A. M., Montanaro, A., Pagliaro, L., Zamponi, R., Gherli, A., … Percesepe, A. (2025). Genetics of Darier's Disease: New Insights into Pathogenic Mechanisms. Genes, 16(6), 619. https://doi.org/10.3390/genes16060619

Schmieder, S. J., Sathe, N. C., & Rosario-Collazo, J. A. (2023). Darier Disease. In StatPearls. StatPearls Publishing.

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