Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene.

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.

Parental mosaic cutaneous-gonadal GJB2 mutation: From epidermal nevus to inherited ichthyosis-deafness syndrome.

Ichthyosis and deafness syndrome is a group of devastating genodermatoses caused by heterozygous mutations in GJB2, encoding the gap junction protein connexin 26. These syndromes are characterized by severe skin disease, hearing loss, recurrent infections, and cutaneous neoplasms. Cutaneous somatic mutations in the same gene are associated with porokeratotic eccrine ostial dermal duct nevus. Here we report a family in which a parent presented with localized epidermal nevus and his child suffered with hystrix-like ichthyosis with deafness. Histologic examination of the parent's cutaneous lesion revealed verrucous epidermal nevus without features of porokeratotic eccrine ostial dermal duct nevus. Genetic analysis identified the same pathogenic variant, GJB2 c.148G>A (p.D50N), in DNA extracted from the parent's cutaneous lesion and the child's leukocytes, but not in the parent's leukocytes. This study expands the phenotypic heterogeneity of GJB2 mosaic variants in addition to porokeratotic eccrine ostial dermal duct nevus, and emphasizes the importance of molecular diagnosis of mosaic skin diseases considering the risk of severe inherited diseases in the offspring.