Continuing Education Activity

Darier disease, previously known as keratosis follicularis, is a rare autosomal dominant genodermatosis characterized by keratotic papules and longitudinal eyrthronychia; it is caused by mutations in the ATP2A2 gene, encoding a calcium pump within the endoplasmic reticulum. Notably, the condition showcases high penetrance but variable expressivity, emphasizing that while each individual inheriting the genotype manifests some form of the disease, its presentation and severity vary across affected persons. Due to its complex expressivity, this activity highlights the importance of recognizing Darier disease, irrespective of a negative familial background. 

Darier disease is exacerbated by sunlight, heat, infections, and friction. This activity reviews the clinical presentation encompassing multiple red or brown papules with hyperkeratosis, nail anomalies including longitudinal erythronychia, and mucosal changes typically surfacing around puberty and persisting throughout life. By exploring evaluation techniques and treatment modalities, this session empowers healthcare professionals to adopt a holistic approach, focusing on interdisciplinary collaboration to manage this dermatological disorder effectively. The interprofessional team's role in assessing, diagnosing, and coordinating care for Darier disease patients is underscored, recognizing the impact of external exposures and emphasizing tailored therapeutic strategies to improve patient outcomes and quality of life.

Objectives:

• Apply the pathophysiology when communicating with patients to explain the condition, treatment options, and long-term management strategies. 

• Identify characteristic skin lesions and nail abnormalities indicative of Darier disease through clinical examination and medical history assessment.

• Implement evidence-based management strategies, including topical and systemic therapies, to alleviate symptoms and minimize disease progression.

• Collaborate with dermatologists, genetic counselors, and support services to provide multidisciplinary care, addressing both the medical and psychosocial aspects of Darier Disease.

Introduction

Darier disease, previously known as keratosis follicularis, is a genodermatosis inherited in an autosomal dominant fashion.[1] This rare disease classically features multiple red or brown papules with hyperkeratosis, nail abnormalities (eg, longitudinal erythronychia), and mucosal changes that present initially around puberty and are exacerbated throughout the lifespan, usually with external exposures, such as sunlight.[2] The condition is found worldwide and classified with other acantholytic disorders, such as Hailey-Hailey disease and Grover disease.[3][1]

Etiology

Darier disease is caused by mutations in the ATP2A2 gene, which encodes a calcium pump in the endoplasmic reticulum.[1][4] The lack of a functional calcium ATPase pump ultimately leads to desmosomal breakdown, causing the classic acantholytic process.[5] Another hypothesis is that aggregates of the dysfunctional ATPase that are not degraded build up at toxic levels, leading to dyskeratotic acantholysis by causing stress to the endoplasmic reticulum.[6] 

The condition has a high penetrance but has variable expressivity, indicating that everyone who inherits the genotype will have some manifestation of the disease but that its severity and features will not be the same across all affected persons. Accordingly, 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, pyogenic infections, and friction or mechanical trauma can exacerbate the condition.[1][7]

Epidemiology

Darier disease is rare, with a prevalence of 1 case per 100,000 people, and affects men more frequently than women.[1] Likely due to dysregulation of calcium in the endoplasmic reticulum, patients with Darier disease have been shown to have an increased association with heart failure, though not with myocardial infarction.[8] They have also been shown to have an association with increased pancreatic beta-cell dysfunction, which may indicate a higher frequency or association of Darier disease in patients with diabetes.[9] In one Swedish study, Darier disease was also associated with intellectual disability. Another study showed that Darier disease may be associated with bipolar disorder.[10][11]

Pathophysiology

A mutation in the ATP2A2 gene causes Darier disease. This gene encodes a calcium pump in the endoplasmic reticulum called sarcoendoplasmic reticulum calcium ATPase (SERCA2).[4] This pump transports calcium from the cytosol to the inside of the endoplasmic reticulum, maintaining a high calcium concentration in the endoplasmic reticulum, where it is needed to process junctional proteins such as desmoplakins and desmogleins.[4] Impaired SERCA2 function leads to aberrant junctional protein processing and poor cohesion between keratinocytes. This impairment is believed to cause acantholysis, or loss of connection between keratinocytes, as seen in pathology.[4]

In addition to aberrant junctional protein processing, a decrease in calcium stores in the endoplasmic reticulum activates a cellular stress response.[12][4] The cellular stress response may explain 2 critical features of the disease: dyskeratosis seen in pathology and disease triggers.[6] On histology, Darier disease is characterized by corps ronds, which are rounded keratinocytes.[13] These keratinocytes likely represent dyskeratotic or apoptotic cells. This dyskeratosis/apoptosis is thought to result from the cellular stress response induced by depleted calcium stores in the endoplasmic reticulum.[4] This stress response could worsen due to triggers such as UV radiation and heat, leading to exacerbations of the disease.[14]

There are 2 segmentally distributed clinical variants in Darier disease since autosomal dominant disorders display 2 types of mosaicism.[15] A postzygotic mutation causes type 1 mosaicism, meaning that some cells have the change and others do not.[16] 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 patients with a prezygotic mutation. In this case, the disease originates with 1 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 2 mutations or 2 dominant alleles for the disease.[17] Patients with type 2 mosaicism have 2 types of cells: those with 1 mutation or dominant allele and those with 2.

Although only 1 dominant allele is needed for the disease phenotype, 2 dominant alleles will lead to a more severe presentation in those cells. Clinically, these patients 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.[17] This condition is also called a loss of heterozygosity because patients were initially heterozygous for an autosomal dominant mutation and later had another mutation, making some cells homozygous for the autosomal dominant mutation. Darier disease has demonstrated 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.[18] Dyskeratosis is the premature keratinization of keratinocytes and is related to apoptosis. In Darier disease, this is seen as corps ronds.[1][7][1] Corps ronds are round keratinocytes with basophilic nuclei.[13] 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 red or brown hyperkeratotic papules and plaques.[19] These lesions develop in seborrheic and intertriginous areas.[1] The condition commonly starts on the upper trunk or neck.[20] The plaques can appear papillomatous or verrucous 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, along with nail fragility. The oral mucosa is involved in 50% of patients with Darier disease.[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.[21] Patients with Darier disease exhibit higher rates of depression and mood disorders.[22] Ocular findings can include blepharitis and dry eyes.[23]

Multiple variants of Darier disease can be distinguished by clinical features. The first variant is segmental, in which linear skin lesions may be present due to mosaicism of the ATP2A2 gene.[15] The acral hemorrhagic variant is uncommon and is thought to be related to trauma.[24][25] The acrokeratosis verruciformis of Hopf is thought to be a variant due to a slightly different missense mutation on the same gene; thus, this allelic variant is thought to include nail changes and palmoplantar pits, often in younger patients.[18][26]

Evaluation

Clinical and histopathologic correlation are used to diagnose Darier disease.[18] Family history may be helpful in the diagnosis; however, due to its variable expressivity, affected patients cannot always recall a family history of the illness.[27] Patients should be evaluated for any coexisting staphylococcal or herpetic lesions, as these lesions may complicate the presentation and may lead to significant morbidity or mortality.[28][29][30]

Treatment / Management

No apparent cure exists for Darier disease; however, there are ways to address symptoms and prevent triggers to prevent flares. 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.[31] In addition to keeping the skin cool, topical therapies may be helpful, particularly in addressing possible infections and hyperkeratosis.[32]

Keratolytic moisturizers containing lactic acid or urea can treat hyperkeratosis and scaling.[1] Topical corticosteroids may be used, as they are often used in many skin diseases, to help reduce the inflammation and irritation associated with the dyskeratotic areas. Topical corticosteroids may also aid in pruritus, although this observation is based mostly on clinical experience.[33] Topical retinoids can also improve hyperkeratosis by causing keratinocyte turnover, much like in other skin diseases.[34][24] Cleaning with antiseptic solutions can prevent infections.[35] Case reports describe topical 5-fluorouracil as an effective treatment.[1] 

Oral retinoids, such as acitretin, isotretinoin, and alitretinoin, also represent appropriate treatment options.[1][32][1][36] A new glucosylceramide synthase inhibitor, miglustat, which has been used to treat Gaucher disease and Niemann-Pick disease, has been developed and has been found to increase the adhesion strength of desmosomes in keratinocytes in patients with Darier disease, thus providing promise for a future treatment for this disease.[4][12][37] Other treatments can include topical calcineurin inhibitors, vitamin D analogues, naltrexone, laser treatment, and surgical excision of lesions.[34][38][39][40][41]

Differential Diagnosis

The differential diagnosis of Darier disease 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.[42] This histological differential diagnosis includes Hailey-Hailey disease, pemphigus vulgaris, and Grover disease.[1]

On histology, Darier disease and Hailey-Hailey disease both have some level of dyskeratosis, apoptosis, and acantholysis, although Darier disease usually shows more dyskeratosis. Hailey-Hailey disease is caused by a mutation in the ATP2C1 gene, which encodes a calcium pump in the Golgi apparatus.[43] Mutations in this gene lead to calcium depletion in the Golgi apparatus. This deficiency is thought to impair the processing of proteins essential to cell-cell adhesion.[43] 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 dyskeratosis is more pronounced in Darier disease. 

Prognosis

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

Complications

One serious complication for patients with Darier disease is susceptibility to serious bacterial and viral cutaneous infections, including human papillomavirus, herpes simplex virus, and poxvirus infections.

Deterrence and Patient Education

Environmental factors influence the appearance of plaques and papules in Darier disease. When exposed to heat and humidity, most patients experience increased lesions during summer. Exposure to ultraviolet light, friction (eg, tight-fitting clothing), minor injury or friction such as rubbing or scratching, and ingesting certain medications can also increase the appearance of lesions. Therefore, patients should receive counsel on these precipitating factors to practice appropriate preventative measures.

Enhancing Healthcare Team Outcomes

Darier disease is a rare genetic skin disorder without a cure. The disorder is treated symptomatically. The avoidance of triggers is paramount in preventing exacerbations of Darier disease. The primary care clinician, internist, dermatologist, nursing staff, genetic counselor, and pharmacist should function as an interprofessional team to educate the patient on avoiding triggers like 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 receive an offer for genetic counseling. Because the disorder has a profound effect on cosmesis, a mental health consult may be necessary to manage depression and anxiety.[44]