A worsening rash with a malodor


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The patient is a 19-year-old woman who presents with several years of a worsening rash. The rash appears as erythematous, hyperkeratotic thin plaques in a seborrheic distribution. The patient states that the rash is very irritating and sometimes pruritic. The patient’s main complaint is that the rash exudes a malodor. The patient states that her father has a similar rash that he chooses not to treat.

Darier disease, also known as keratosis follicularis or Darier-White disease, is a rare genodermatosis due to abnormal intracellular Ca2+ signaling, leading to acantholytic dyskeratosis. It is characterized by keratotic papules in a seborrheic distribution with characteristic nail findings.1,2 Studies have...

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Darier disease, also known as keratosis follicularis or Darier-White disease, is a rare genodermatosis due to abnormal intracellular Ca2+ signaling, leading to acantholytic dyskeratosis. It is characterized by keratotic papules in a seborrheic distribution with characteristic nail findings.1,2 Studies have estimated its prevalence at approximately 1 in 30,000 to 100,000 people.1 Darier disease is inherited in an autosomal dominant manner; however, sporadic mutations may account for as many as 40% to 50% of cases.3

The primary pathologic process is that of a mutated ATP2A2 gene long arm of chromosome 12 at 12q23-24.1.3 The ATP2A2 gene encodes SERCA2 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a calcium adenosine triphosphatase (ATPase) that is responsible for transporting Ca2+ from the cytosol into the endoplasmic reticulum.2 When this calcium ATPase is dysfunctional, Ca2+ accumulates in the cytosol, leading to the characteristic acantholysis and apoptosis seen in the disease. It is not exactly understood how this occurs, but it may be due to inhibited processing and trafficking of desmosomal proteins, such as desmoplakin, from the endoplasmic reticulum to the cell surface, or stress-induced apoptosis of keratinocytes secondary to calcium depletion.1,3

Clinical features typically appear in patients between 6 and 20 years of age (often around puberty), and may be varied. The predominant clinical finding is keratotic papules distributed symmetrically in a seborrheic distribution over the neck, shoulders, face, extremities, front of the chest, and midline of the back; it can also progress to include the buttocks and genitals.2 The papules are often initially skin colored, but mature into dark, crusted, greasy, vegetating plaques.2 Patients characteristically have notched (V-shaped knicks), subungual keratotic nails that contain longitudinal, alternating white and red streaks.1,2 Other clinical features include punctate palmoplantar keratosis, hypopigmented macules (especially in dark-skinned individuals), flat papules resembling flat warts, and small, white, mucosal papules.1,2

Exacerbating factors include heat, high humidity, sweat, ultraviolet light, pregnancy, surgery, bacterial colonization, and, in some cases, lithium carbonate.1 Itching and malodor are common complaints, especially if secondary infection is present. In certain cases, the disease and symptoms may lead to social isolation.

Neuropsychiatric disorders such as major depression, intellectual disability, epilepsy, and bipolar disorders have been associated with the disease.1 It is not known whether the ATP2A2 gene is primarily implicated in these disorders as well, if there are closely linked susceptibility genes, or if the relationship is not genetic. Social isolation may contribute to the social morbidity often observed in patients with Darier disease.

Darier disease is characterized histologically by acantholytic dyskeratosis.5 Acantholysis presents as suprabasilar clefting and is due to a loss of cell-to-cell adhesions. Dyskeratosis takes the form of corps ronds and grains, and is secondary to keratinocyte apoptosis. Corps ronds are round, pale to eosinophilic, dyskeratotic cells in the spinous or granular layer, which typically contain a perinuclear halo.5 Corps grains are flat, basophilic, dyskeratotic cells in the granular layer and stratum corneum.5 Hyperkeratosis and parakeratosis is also observed in the overlying stratum corneum.

The differential diagnosis includes Hailey-Hailey disease, acrokeratosis verruciformis of Hopf, Grover disease, seborrheic dermatitis, pemphigus vegetans, blastomycosis-like pyoderma, flat warts, acanthosis nigricans, and epidermodysplasia verruciformis.1,3 A personal and family history, in conjunction with results of a physical examination, is often highly suggestive of the diagnosis. A biopsy demonstrating acantholytic dyskeratosis further helps to make the correct diagnosis.

Hailey-Hailey disease, also caused by a defect in calcium signaling, may share similar features with Darier disease.1 However, its predominant feature of flaccid vesicles on erythematous skin with a predilection for the intertriginous areas, along with a histologically distinct pattern of acantholysis, can be used to make the distinction. Darier disease and acrokeratosis verruciformis of Hopf both feature flat-topped papules on the dorsal surface of the extensors.2 If the other features of Darier disease are absent, differentiation from acrokeratosis verruciformis of Hopf on clinical grounds may be impossible. Results of a biopsy readily distinguish the two, because acrokeratosis verruciformis of Hopf lacks acantholysis and dyskeratosis.1,2 Both entities share the same mutated gene, and some consider them to be related.1 Grover disease and seborrheic dermatitis are other considerations based on clinical features (Grover disease may even feature similar histology); however, there is no involvement of acral skin, the nails, or the oral mucosa in either of these diseases.

Treatment for Darier disease is symptomatic. Patients should be instructed to protect themselves from sun exposure and wear lightweight clothing to prevent exacerbations. Antimicrobial agents are used for bacterial colonization and keratolytic moisturizers for scaling.1,2 Topical retinoids and topical steroids can be used with some benefit in localized disease. Oral retinoids are effective, but often limited by side effects, and patients have a relapse after cessation.1,3 Surgical procedures, including dermabrasion, laser ablation, and excision and split-thickness grafting, can lead to long-term remission for recalcitrant hypertrophic lesions.1

The patient in this case was disturbed by her disease and was started on an oral retinoid for treatment. On follow-up the patient had significantly improved and was happy with the outcome of her treatment.

Jiating Jiang, BS, is a medical student at the Baylor College of Medicine, David Rizk, BS, is a medical student at the University of South Alabama, and Andrew Fischer MD, is a dermatology resident at Colorado University. 


  1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012.
  2. James WD, Berger TG, Elston DM, Neuhaus IM. Andrews’ Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.
  3. Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016;43:275-279.
  4. Wang Y, Bruce AT, Tu C, et al. Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytes. J Cell Sci. 2011;124:3568-3580.
  5. Elston D, Ferringer T, Ko CJ, Peckham S, High WA, DiCaudo DJ. Dermatopathology. Philadelphia, PA: Elsevier Saunders; 2014. 
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