Darier’s disease (DD), also known as Keratosis Follicularis or Darier-White disease, is a rare disorder of keratinization. The disease is caused by a loss-of-function mutation in the ATP2A2 gene on chromosome 12q23-24 that encodes the sarco/endoplasmic reticulum calcium ATPase (SERCA2). This loss of function leads to a disruption of Ca2+ homeostasis within the keratinocytes,specifically depletion of Ca2+ stores in endoplasmic reticulum. Ultimately, the mutation leads to impaired cell-to-cell adhesion with the common histological findings of suprabasal acantholysis and dyskeratosis of cells in the epidermis [
A 34-year-old woman with type 2 skin presented to clinic for evaluation of a lesion in the left popliteal fossa that had been present for approximately 1.5 years and frequently bled.
Past medical history was significant for DD which was diagnosed at 12 years of age. This was initially localized to the left side of the body but over the previous ten years had gradually become bilateral. She managed her disease with only emollients and sun protection but as a teenager had tried topical steroids, topical retinoids, and a short course of accutane. She was otherwise well and not on any medication. She denied a past history of excess sun exposure or blistering burns. Neither of her two children or parents were affected by DD.
Examination revealed hundreds of erythematous to light brown scaly 2-3 mm diameter papules involving the head and neck, trunk, and extremities. These formed large linear plaques which were more prominent on the left half of the body and followed Blaschko lines (Figures
Posterior lower limbs demonstrating segmental linear plaques of warty papules on a background of less prominent hyperkeratotic papules and plaques.
Left lateral upper limb demonstrating diffuse hyperkeratotic papules and plaques.
Left thumbnail demonstrating longitudinal erythronychia and distal nicking of the nail plate.
An erythematous shiny telangiectatic papule measuring 7 mm in diameter was noted within a linear collection of papules in the left popliteal fossa (Figure
Left popliteal fossa demonstrating a shiny telangiectatic papule within a linear collection of keratotic papules in the left popliteal fossa.
Histopathology of papule in left popliteal fossa consistent with nodular basal cell carcinoma.
Histopathology demonstrating characteristic Darier’s pathology of suprabasal acantholysis and dyskeratosis.
Histopathology demonstrating nodular basal cell carcinoma surrounded by characteristic suprabasal acantholysis and dyskeratosis seen in Darier’s disease.
We present a case of DD with well-defined segmental involvement superimposed on a milder, diffuse manifestation. The DD case is unusual due to both the distribution of the disease as well as the presence of basal cell carcinoma (BCC).
Over 50 cases of segmental DD have been reported in the last 100 years and have been variably referred to as localized, zosteriform, linear, segmental, or unilateral. In 1997, Happle proposed a categorization of mosaic forms of autosomal dominant skin disorders [
Summary of the literature search of type 2 segmental cases.
Chester and Brown [ | Esche et al. [ | Happle et al. [ |
Itin et al. [ |
Itin and-Happl [ | Yusuf et al. [ | de la Torre Fraga [ | Rodríguez-Pazos et al. [ | Presented | |
---|---|---|---|---|---|---|---|---|---|
Age | 25 | 53 | 45 | 52 | 17 | 12 | 24 | 50 | 34 |
Sex | Female | Male | Male | Female | Male | Male | Female | Male | Female |
Side of involvement and areas of segmental distribution | Right side involving: Shoulder, chest, abdomen, retroauricular, and intraauricular | Face and trunk | Left side involving: retroauricular, scapular, pectoralis major, and lumbar regions | Right side | Twin spot | N/A | N/A | Twin spot phenomenon | Left side involving: head, neck, trunk, and extremities |
Additionally, this case is unusual due to the presence of BCC in an area receiving minimal sun exposure. Given the patient’s young age and the lack of significant risk factors for non-melanoma skin cancer (NMSC), the development of BCC is unusual and raises suspicion of a link between DD and cutaneous malignancy. A literature review was undertaken to identify any association between DD and BCC or any other cutaneous malignancy. The review revealed that NMSC occurring in DD has rarely been described. Since 1981, 13 cases of NMSC in patients with DD have been reported: 7 squamous cell carcinomas (SCC), 5 BCC, and 1 adenexal tumor. Of the 5 cases of BCC, 2 of the cases had previously received grenz-ray therapy and/or superficial radiotherapy [
Summary of the literature review of DD cases with BCC.
Case 1 [ | Case 2 [ | Case 3 [ | Case 4 [ | Case 5 [ | Case 6 | Average Presentation | |
---|---|---|---|---|---|---|---|
Age | 42 | 38 | 47 | 48 | 36 | 34 | 55 |
Sex | Male | Male | Male | Male | Female | Female | M2.1 : F1 |
Tumor and Site | (a) BCC Leg | (a) BCC left lower eyelid | (a) BCC cheek | (a) BCC ear | BCC cheek | BCC popliteal fossa | 70% head |
While no molecular link between DD and BCC has been described, the imbalance of cellular survival and apoptosis due to the DD mutation or other genodermatosis may contribute to the presentation. Darier’s disease is caused by a loss-of-function mutation in the ATP2A2 that leads to a disruption of Ca2+ homeostasis within the keratinocytes. A decreased SERCA activity leads to an upregulation of the transient receptor potential canonical 1 Ca channel that increases cell proliferation and resistance to apoptosis [
Although the literature is scarce and our understanding of the relationship between carcinomas and DD is developing, the case presented illustrates a possible association between DD and BCC.
Dr. Lynne Robertson and Dr. Maxwell B. Sauder had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Robertson and Sauder, acquisition of data: Robertson and Sauder, analysis and interpretation of data: Robertson and Sauder, drafting of the manuscript: Robertson and Sauder, critical revision of the manuscript for important intellectual content: Robertson and Sauder, and study supervision: Robertson.
Special thanks to Dr. M. Trotter for providing the histopathology pictures.