Darier Disease_0713 Derm Clinic 1
A black woman, aged 52 years, presented for follow-up of an eruption on the central chest, back, and scalp. Other than a history of depression, she was healthy. Family history was negative for first-degree relatives with similar skin findings.
Current medications included isotretinoin, fluocinolone acetonide oil, and fluoxetine. Physical exam was notable for greasy hyperpigmented and hyperkeratotic papules in a seborrheic distribution and for V-shaped notching of the fingernails with red and white longitudinal lines. Biopsy revealed acantholytic dyskeratosis, corps ronds, and corps grains.
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Darier disease, also known as keratosis follicularis, is an autosomal dominant disorder that typically affects the skin, nails, and mucous membranes. Men and women are affected equally. Although Darier disease is inherited in an autosomal dominant fashion, it is common for patients to deny a family history of the condition, likely due to variable expressivity of the gene mutation. Nearly 70% of patients with Darier disease present between age 6 years and age 20 years; however, the peak age of onset is during puberty.1
This genodermatosis is caused by a gene mutation in ATP2A2, which encodes for the protein product SERCA2, an endoplasmic reticulum calcium ATPase. Mutations of this gene result in the inadequate filling of endoplasmic reticulum calcium stores, causing a cascade of pathologic responses resulting in acantholysis and apoptosis. Recently, a novel missense mutation in the ATP2A2 gene that presents with late-onset Darier disease (the patient presented with symptoms that started at age 75 years) has been reported.2
Darier disease has a chronic course characterized by hyperkeratotic papules located in a seborrheic distribution, primarily on the chest, back, scalp, face, and lateral neck. Individual papules can coalesce into verrucous plaques. Rarely, papules may be intermixed with hypomelanotic macules or vesicles and bullae. These lesions are often malodorous, and pruritus is a common complaint. Other cutaneous findings include flat, skin-colored or brownish papules on the dorsal hands and feet, a symptom seen in approximately 50% of patients.
Nearly all patients present with papules on the palms and soles with keratin-filled depressions. Perhaps the most pathognomonic finding is longitudinal red and/or white lines with V-shaped notching at the distal nail plate. An infrequent manifestation of Darier disease is the presence of whitish papules in the oral mucosa, most commonly the palate. Rarely, Darier disease has been associated with extracutaneous involvement, namely the esophagus and eyes.3
UV irradiation, sweating, heat, and occlusion may exacerbate skin lesions associated with Darier disease, and lithium carbonate has been reported to worsen skin manifestations. Complications from Darier disease include secondary infections by yeast, dermatophytes, and bacteria. Painful swelling may be seen with salivary-gland obstruction if Darier disease involves the salivary ducts.
An association between Darier disease and such neuropsychiatric disorders as epilepsy, mental retardation, and schizoaffective disorders is being studied. Other rare complications include corneal ulcerations and staphylococcal endophthalmitis. There are a few case reports of cutaneous squamous cell carcinoma arising in patients with Darier disease.
There are currently three known subtypes of Darier disease. The acral hemorrhagic type presents with blue-black irregularly shaped macules on the palms, soles, and dorsal hands. Segmental type 1 presents with unilateral cutaneous lesions along Blaschko’s lines and results from genetic mosaicism caused by postzygotic somatic mutations.
Segmental type 2 is characterized by generalized Darier disease with a linear streak of increased severity. This type occurs in patients with a heterozygous germline mutation in addition to a somatic loss of heterozygosity of the wild-type allele in a segmental area.
A biopsy will demonstrate acantholysis with apoptotic keratinocytes, referred to as corps ronds and corps grains. Acantholysis is defined by keratinocytes that have lost intercellular adhesion. Corps ronds are enlarged apoptotic keratinocytes in the upper layer of the epidermis. Corps grains are small apoptotic keratinocytes in the stratum corneum. Although genetic testing is available, the diagnosis of Darier disease is often made on clinical grounds and confirmed by skin biopsy.
The differential diagnosis of Darier disease includes severe seborrheic dermatitis, Grover disease, and acrokeratosis verruciformis of Hopf. Seborrheic dermatitis can be distinguished from Darier disease by the absence of nail changes, keratotic papules on the palms, and mucosal changes.4 A skin biopsy would definitively distinguish between these two entities.
Grover disease most commonly affects middle-aged men. Although Grover disease tends to affect the chest and back as does Darier disease, this condition spares the scalp, palms, and soles. Another distinguishing feature of Grover disease is that the red-brown papules are discrete and do not coalesce into plaques as in Darier disease. It is difficult to distinguish Grover disease from Darier disease by skin biopsy, as acantholysis and apoptotic keratinocytes are seen in both.
Finally, acrokeratosis verruciformis of Hopf presents with flat-wartlike papules on the dorsal extremities, as seen in Darier disease. Some patients initially diagnosed with acrokeratosis verruciformis of Hopf later developed characteristic skin lesions and were subsequently diagnosed with Darier disease.
Persons with Darier disease are advised to wear lightweight clothes to minimize friction and sweating. Topical therapies may be initiated for mild disease. Topical corticosteroids may be effective in many patients. Corticosteroid potency is typically selected based on anatomic location. For example, a low-potency steroid (e.g., hydrocortisone 2.5% ointment or triamcinolone 0.1% cream) may be used sparingly on the face or intertriginous areas. A higher-potency steroid (e.g., triamcinolone 0.1% ointment or clobetasol 0.05% ointment) will typically be required on the trunk or extremities. To avoid such side effects as tachyphylaxis, cutaneous atrophy, or steroid acne, the patient should be placed on an intermittent schedule or alternating schedule with a steroid-sparing agent (e.g., tacrolimus 0.1% ointment [Protopic] or pimecrolimus 1% cream [Elidel]).
Antimicrobial cleansers may also be used, as patients are susceptible to secondary bacterial infections. Intralesional triamcinolone may be used alone or as adjunctive treatment for localized and/or refractory lesions.
Patients with generalized disease often require such systemic agents as retinoids. However, the efficacy of such retinoids as acitretin (Soriatane) or isotretinoin is not well established. Surgical therapies for refractory disease can be successful and include wide excision and grafting and superficial ablative techniques (CO2 laser, erbium:YAG laser).
In this case, acitretin 25 mg daily with topical corticosteroids was initiated. The patient showed no improvement following months of therapy, so acitretin was discontinued and isotretinoin initiated. Some improvement has been noted.
Audrey Chan, MD, is a second-year resident and Grace Sun, MD, is a third-year resident, both in the Department of Dermatology at Baylor College of Medicine in Houston.
- Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:791-796.
- Ueo D, Hamada T, Hashimoto T, et al. Late-onset Darier’s disease due to a novel missense mutation in the ATP2A2 gene: a different missense mutation affecting the same codon has been previously reported in acrokeratosis verruciformis. J Dermatol. 2013;40:280-281.
- Thiagarajan MK, Narasimhan M, Sankarasubramanian A. Darier disease with oral and esophageal involvement: a case report. Indian J Dent Res. 2011;22:843-846.
- Schwartz JL, Clinton TS. Darier’s disease misdiagnosed as severe seborrheic dermatitis. Mil Med. 2011;176:1457-1459.