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Importance: Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy., Objective: To investigate the molecular mechanism underlying the persistency of skin lesions in DD., Design, Setting, and Participants: In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism., Interventions or Exposures: Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD., Main Outcomes and Measures: Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD., Results: Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2)., Conclusions and Relevance: In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.

Background: Knowledge about the clinical features of Darier disease, an orphan autosomal-dominant genetic disorder, is sparse and has been evaluated only in few studies., Objectives: To investigate the clinical features of a large group of patients with Darier disease, and to explore for associations between disease characteristics and severity of the disease., Methods: Seventy-six individuals with Darier disease were evaluated utilizing a structured questionnaire-based interview, a physical examination, and a retrospective assessment of their medical records., Results: The most frequent locations of lesions were hands (99%) and fingernails (93%). Wart-like lesions on the hands were more visible after soaking them in water for 5 minutes, we therefore named this phenomenon the "wet hand sign". Oral involvement was found in 43% of patients, while 48% of women and 16% of men showed genital lesions. Patients with severe Darier disease had a tenfold greater risk of developing genital lesions than those with mild disease ( P = .01). Most patients (88%) in our study exhibited a combination of the four types of the disease patterns of distribution (flexural, seborrheic, nevoid, and acral)., Conclusions: Documentation of disease on the hands and fingernails provides a highly sensitive means to aid in the diagnosis of Darier disease. It is important to evaluate mucosal lesions including genital and oral mucosa.