Darier disease

A punch biopsy confirmed the diagnosis of Darier disease (also known as dyskeratosis follicularis). First described in 1899, Darier disease is a genetic disorder of the skin characterized by keratotic red-brown warty papules and plaques. The lesions develop in childhood or early adolescence, and the peak age of onset is around the time of puberty. Flares of the disease may occur in summertime or following UV-light exposure. The papules often appear to be centered on hair follicles but are not restricted to follicular units. Characteristically, the lesions recreate a “seborrheic” distribution, commonly occurring on the chest, scalp, and lateral neck. The flexural surfaces (especially the axillae, groin, and inframammary folds) are also frequently involved. Additionally, most patients develop hyperkeratotic papules and pits on the palms. Other cutaneous features of Darier disease include hypopigmented macules and flat-topped brown papules that clinically resemble flat warts on the dorsal hands. Whitish papules may be seen on the palatal and buccal mucosa of the oropharynx. Rarely, these papules may be seen on other mucosal surfaces, including the anus.

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The nails are often abnormal in patients with Darier disease. Nails feature bands of red and white (longitudinal erythronychia) and characteristic V-shaped notches at the distal edge of the nail plate. The nail plate is often short and broad. Patients oftentimes complain of pruritus and an offensive odor. Superinfection with bacteria, yeast, and fungi may occur. Less frequently, Darier disease may be complicated by widespread herpes simplex virus infection, as occurs in children with atopic dermatitis. No specific dysfunction of the immune system has been identified in patients with Darier disease; rather, the propensity for superinfection is likely secondary to chronic disruption of the skin barrier.

Men and women are equally affected by Darier disease. Although the condition is inherited in an autosomal dominant fashion, many sporadic cases represent new mutations. Darier disease is thought to be penetrant in virtually all carriers of the mutation, although the severity of disease may vary from patient to patient and within kindreds.

Additionally, genetic mosaicism and post-zygotic mutation may lead to segmental variants of Darier disease. In segmental Darier disease, the cutaneous findings are restricted to linear developmental zones known as the lines of Blaschko. The mutation is not passed along to offspring unless the gonads are also involved.

Darier disease is caused by a mutation in ATP2A2, a gene that encodes a calcium transporter in the endoplasmic reticulum. This transporter is essential to the processing of cell-to-cell adhesion molecules. The mutation causes dyscohesion of skin cells. Without the cohesive mortar holding together the cells of the epidermis, acantholysis ensues. Dysfunction of the calcium transporter also leads to apoptosis or cell death.1 Both of these features are readily apparent on histopathologic examination of skin biopsies in Darier disease. On routinely stained histologic specimens of Darier disease, the dominant finding is focal acantholytic dyskeratosis, a term that implies the presence of both acantholysis (lack of cellular cohesion) and dyskeratosis (apoptosis or individual cell death). While biopsy findings may be quite characteristic, the diagnosis ultimately requires clinicopathologic correlation since other diseases may show focal acantholytic dyskeratosis.

The clinical differential diagnosis for Darier disease is relatively limited. Similar findings may be seen in seborrheic dermatitis, Hailey-Hailey disease, and Grover’s disease. Seborrheic dermatitis affects many of the same body regions as does Darier disease but does not usually lead to hyperkeratosis. Additionally, nail dystrophy is absent in seborrheic dermatitis. Hailey-Hailey disease predominates in the axillae and is characterized by erosions and fissures. Grover’s disease is a scaly papular eruption of the trunk with no associated nail or mucosal disease.

Topical retinoids are the mainstay of treatment in mild cases, and antiseptic washes will minimize bacterial colonization and resultant odors. Tretinoin cream may be combined with mid-potency topical steroids to reduce the irritation inherent in chronic application of retinoids. In more severe cases, oral retinoids (acitretin or isotretinoin) can be very effective treatment but must be used cautiously due to the potential for side effects. Both isotretinoin and acitretin are teratogenic. Other potential side effects of oral retinoids include hypertri­glyceridemia, cheilitis, hepatitis, myalgia/arthralgia, and headache. In selected cases, surgical ablation of affected areas may provide an effective alternative. Specifically, erbium:YAG or CO2 laser ablation has been reported to lead to long-term remission.

The patient described in this case has used oral retinoids but stopped after he was not able to tolerate the side effects of cheilitis and dyslipidemia. He currently manages his disease symptomatically with topical steroids and rigorous antibacterial hygiene.

Dr. Vandergriff is a dermatology resident at The University of Texas Southwestern Medical Center in Dallas. The author has no relationships to disclose relating to the content of this article.

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1. Dhitavat J, Fairclough RJ, Hovnanian A, Burge SM. Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease. Br J Dermatol. 2004;150:821-828.