Keratosis Follicularis (Darier Disease)

Article Author:
Shawn Schmieder
Article Editor:
Juan Rosario-Collazo
Updated:
10/27/2018 12:31:40 PM
PubMed Link:
Keratosis Follicularis (Darier Disease)

Introduction

Darier disease, also known as keratosis follicularis, is a genodermatosis that is inherited in an autosomal dominant fashion.[1] The disease classically features keratotic papules and longitudinal eyrthronychia. It is rare and distributed worldwide.[1]

Etiology

Mutations in the ATP2A2 gene cause Darier disease.[1] This gene encodes a calcium pump in the endoplasmic reticulum.[2] The condition has a high penetrance but has variable expressivity. That means that every person that inherits the genotype will have some manifestation of the disease, but its severity and features will not be the same across all affected persons. Because of this, patients with the disease cannot always recall a family history. Thus, it is important not to exclude Darier disease based solely on a negative family history of the disease. Sunlight, heat, infections, and friction can exacerbate the condition.[1]

Epidemiology

Darier disease is rare, with a prevalence of 1:100,000.[1] The disease affects men more frequently than women.[1]

Pathophysiology

A mutation in the ATP2A2 gene causes Darier disease. This gene encodes a calcium pump in the endoplasmic reticulum called SERCA2.[2] This pump transports calcium from the cytosol to the inside of the endoplasmic reticulum, maintaining a high calcium concentration in the endoplasmic reticulum.[2] High levels of calcium in the endoplasmic reticulum are needed to process junctional proteins such as desmoplakin and desmogleins.[2] Impaired SERCA2 function leads to aberrant junctional protein processing and subsequent poor cohesion between keratinocytes. This impairment is believed to cause the acantholysis, or loss of connection between keratinocytes, seen on pathology.[2]

In addition to aberrant junctional protein processing, a decrease in calcium stores in the endoplasmic reticulum activates a cellular stress response. The cellular stress response may explain two critical features of the disease: dyskeratosis seen on pathology and disease triggers. On histology, Darier disease is characterized by corps ronds, which are rounded keratinocytes. These keratinocytes likely represent dyskeratotic and/or apoptotic cells. This dyskeratosis/apoptosis is thought to be the result of the cellular stress response induced by depleted calcium stores in the endoplasmic reticulum.[2] This stress response could worsen due to triggers such as UV radiation and heat, leading to exacerbations of the disease.

Expanding on this concept can help differentiate the pathogenesis and histopathology of Darier disease from those of a related entity, Hailey-Hailey disease. On histology, both conditions have some level of dyskeratosis/apoptosis and acantholysis. Darier disease usually shows more dyskeratosis than Hailey-Hailey disease. Hailey-Hailey disease is caused by a mutation in the ATP2C1 gene, which encodes a calcium pump in the Golgi apparatus.[3] Mutations in this gene lead to a depletion of calcium in the Golgi apparatus. This deficiency is thought to impair the processing of proteins essential to cell-cell adhesion.[3] However, calcium depletion in the Golgi apparatus does not seem to elicit the same cellular stress response as that of calcium depletion in the endoplasmic reticulum, as seen in Darier disease. This difference could account for the fact that although both Darier disease and Hailey-Hailey disease feature acantholysis and dyskeratosis, the dykeratosis is more pronounced in Darier disease. 

There are two segmentally distributed clinical variants in Darier disease. To understand these variants, one must first understand mosaicism. Autosomal dominant disorders display two types of mosaicism. A postzygotic mutation causes type 1 mosaicism, meaning that some cells have the change and others do not. In dermatology, type 1 mosaicism presents with areas of diseased skin intermixed with areas of healthy skin reflecting the cells with and without the mutation, respectively. The affected skin often follows lines of Blaschko reflecting an embryonic migration of skin cells. Type 2 mosaicism arises from a postzygotic mutation in a patient that already has a "prezygotic" mutation. This patient starts out with one mutation, or disease allele, in all cells. Then another mutation happens farther into the cell division process that only some of the cells will have. These cells will have two mutations or two dominant alleles for the disease.[4] This patient has two types of cells: those with one mutation or dominant allele, and those with two. Although only one dominant allele is needed for the disease phenotype, two dominant alleles will lead to a more severe presentation in those cells. Clinically, this patient will have linear segments of increased disease severity in a background of already diseased skin. The areas of increased severity often follow the lines of Blaschko.[4] This condition is also called a loss of heterozygosity because the patient was initially heterozygous for an autosomal dominant mutation and later had another mutation, making some cells homozygous for the autosomal dominant mutation. Darier disease has been reported to demonstrate both type 1 and type 2 mosaicism, giving rise to segmental type 1 and segmental type 2 variants of Darier disease, respectively.[1]

Histopathology

Dyskeratosis and acantholysis on histopathology characterize Darier disease. Dyskeratosis is premature keratinization of keratinocytes and is related to apoptosis. In Darier disease this is seen as corps ronds.[1]Corps ronds are round keratinocytes with basophilic nuclei. Acantholysis means a loss of adhesion between cells. This loss can be seen as lacunae in the keratinocytes above the basal layer. In addition to these findings, the epidermis shows hyperkeratosis.[1]

History and Physical

The skin manifestations of Darier disease consist of hyperkeratotic papules and plaques. These lesions develop in seborrheic and intertriginous areas.[1] The condition commonly starts on the upper trunk or neck.[5] The plaques can appear papillomatous or verrucoid and can manifest painful fissures. It is common for these lesions to develop a secondary infection.[1] Wounds in the intertriginous areas can become malodorous, which can be very distressing for the patient. Sun exposure, friction, heat, and sweat can exacerbate the disease.[1]

Nail findings include red and white lines oriented longitudinally over the nail. Patients can also have V-shaped notches at the distal end of the nail plate as well as nail fragility. In 50% of patients with Darier disease, the oral mucosa is involved.[1] The oral lesions consist of white or red firm papules. The papules may form crusts or ulcerations but are usually asymptomatic.[1] Neurologic abnormalities such as epilepsy and intellectual disability have been described in association with Darier disease. Patients with Darier disease exhibit higher rates of depression and mood disorders.[6]

Evaluation

Clinical and histopathologic correlation diagnose Darier disease. Family history may be helpful in the diagnosis. However, due to its variable expressivity, affected patients are not always able to recall a family history of the illness.

Treatment / Management

The avoidance of triggers is paramount in preventing exacerbations of Darier disease. Triggers can include sunlight, heat, occlusive clothing, and friction.[1] Patients should avoid sun exposure, wear loose clothing, use sunscreen, and employ proper hygiene practices. As Darier disease is inherited in an autosomal dominant fashion, patients should be offered genetic counseling.

Keratolytic moisturizers containing lactic acid or urea can treat the hyperkeratosis/scale.[1] Topical retinoids can also improve the hyperkeratosis. Cleaning with antiseptic solutions can prevent infections. Case reports describe topical 5-fluorouracil as an effective treatment.[1] Oral retinoids also represent an appropriate treatment option.[1]

Differential Diagnosis

The differential diagnosis includes acanthosis nigricans, confluent and reticulated papillomatosis, seborrheic dermatitis, and acrokeratosis verruciformis of Hopf.[1] Acrokeratosis verruciformis of Hopf presents with flesh-colored flat papules on the distal extremities. The disease shares the same mutation as Darier disease.[7]

This histological differential diagnosis includes Hailey-Hailey disease, pemphigus vulgaris, and Grover disease.[1]

Prognosis

The disease persists for life in a relapsing-remitting manner. Avoiding triggers and using the appropriate treatments can allow for at least partial control of the disease.