Are You Confident of the Diagnosis?
Darier’s disease is a rare autosomal dominant disease with up to 95% penetrance but variable phenotypic expression even between family members. Some cases of Darier’s can be attributed to random new mutations in the absence of a familial history of the disease.
It is characterized as a disorder of keratinization and a loss of intercellular adhesion, which leads to skin lesions, nail changes, and oral mucosal involvement.
Characteristic findings on physical examination
The skin lesions are greasy, hyperkeratotic, firm, brown, crusted, and malodorous papules (Figure 1). These predominate in the seborrheic areas including the forehead, scalp, scalp margins, nasolabial folds, ears, chest and back. About 80% of patients have mild flexural involvement and up to 95% of patients have involvement of the hands including punctate keratoses and palmar pits. The nail abnormalities are longitudinal red and white lines, longitudial ridges and splitting, subungual hyperkeratosis, and V-shaped nicks at nail edges.
Mucosal involvement occurs in about 15% of patients and produces white papules with central depressions. The most frequent complaints of patients with Darier’s are itch, pain, and odor, which may worsen in the summer due to heat, sweating, and UV exposure.
Expected results of diagnostic studies
Skin biopsy of a representative lesion coupled with the clinical history and clinical findings is sufficient to provide an accurate diagnosis in almost all cases. The characteristic histologic feature is that of focal acantholytic dyskeratosis (Figure 2). Occasionally, direct immunofluorescence testing is required to exclude primary blistering diseases.
Some cases of Darier’s share clinical features with acrokeratosis verruciformis of Hopf, which has a more limited distribution, mainly limited to the extremities, while Darier’s is located on the trunk, scalp, and face. Additionally, acrokeratosis verruciformis lacks acantholysis, a distinguishing pathologic feature of Darier’s. Several patients with acrokeratosis verruciformis of Hopf have been found to harbor mutations in the ATP2A2 gene, suggesting some cases may actually be a localized form of Darier’s disease.
Who is at Risk for Developing this Disease?
Prevalence of Darier’s ranges from 1/100,000 in Denmark to 1/55,000 in England. It has an estimated incidence of 4 per million per 10 years with equal incidence in men and women. Although the disease is rare, it infrequently skips a generation due to its autosomal dominant pattern of inheritance. Onset is usually between ages 11 and 20; however, it has been shown that Darier’s may manifest itself as early as age 4, but rarely presents after age 40. Patients expressing “late onset” possibly had milder, unrecognized clinical characteristics earlier in life.
What is the Cause of the Disease?
Mutations in the gene ATP2A2 on chromosome 12q23-24, which codes for sarco-endoplasmic reticulum Ca2+ ATPase, leads to both acantholysis and apoptosis. Defects in Ca2+ sequestration from the cytosol into the lumen of ER damages the normal processing of junctional-adhesion proteins such as impaired synthesis, maturation, or function of the desmosomes in epithelial cells.
The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model. The investigators found that the resultant transfected cells showed defects in ATP2A2 protein expression, ATP hydrolysis, calcium transport and calcium binding. Thus diverse biochemical mechanisms are responsible for altered protein function.
Systemic Implications and Complications
While unproven, there is speculation involving a relationship between Darier’s and various psychological disorders. The malodor and disfiguring appearance of the papules can be distressing and lead to social isolation, especially during adolescence in severe cases. This may be responsible for the reports of depression and various psychiatric disorders in some patients with Darier’s disease. A susceptibility locus for bipolar disease co-segregates with the Darier’s disease region.
Patients with herpes simplex infections are at risk for the development of eczema herpeticum
Although rare, squamous cell carcinomas may complicate Darier’s disease, both cutaneously and on the oral mucosa.
Vitamin A acid (retinoic acid)
Isotretinoin (not available in the United States)
–Corticosteroids: There is no evidence-based documentation, but their use is widespread by practitioners especially in the case of retinoid-induced cutaneous irritation.
–Vitamin D analogues calcipotriol in European Union (calcipotriene in United States) / Calcitriol
Calcipotriene was noted to cause intolerable skin irritation or worsening of Darier’s in 8 of 12 patients in a randomized, controlled trial.
A new vitamin D derivative, calcitriol, has recently been approved in the United States. At this time, there is no specific data on its use in patients with Darier’s, but it causes less skin irritation than calcipotriene, and we have used it successfully in some patients.
Etretinate (not available in the United States)
–Oral contraceptive for women with premenstrual exacerbation
–Laser: CO2 laser, erbium:YAG laser
–Split-thickness skin grafting
–Botulinum toxin type A
–Cool cotton clothing
–Emollients: urea or ammoniated lactate based (if tolerable)
–Sun blocks when sun exposure is likely
Optimal Therapeutic Approach for this Disease
Physical treatments listed above are most effective in controlling irritation. Additionally, daily use of antimicrobial cleansers can help prevent bacterial colonization leading to malodor.
Topical retinoids are primarily for mild or generalized forms of Darier’s but are also used as adjunctive therapy for more extensive disease. Since irritation is frequent, it is recommended that treatment be applied on alternate days. If treatment is well tolerated, attempt to increase treatment to once daily.
Combination therapy with mid-potency topical corticosteroids can help reduce irritation from retinoids. Vitamin A acid is known to cause the most irritation compared with tretinoin, adapalene, and tazarotene. Typically we start with tretinoin 0.025% in the cream base every 3 days and slowly increase the frequency of application. Tazarotene may be more effective but it may be slightly more irritating. We also prefer the cream base. Koebnerization of Darier’s lesions has been reported due to irritancy caused by any topical agent, which is the rationale to start with less frequent applications.
Oral retinoids have been shown to be very effective in patients with generalized to severe cases of Darier’s as they reduce hyperkeratosis and flatten greasy papules. They have, however, a high rate of mild dose-related adverse effects that cause many patients to discontinue use. Dose-related adverse effects include drying and soreness of mucosal surfaces, nosebleeds, fragility of skin, pruritus, as well as elevated triglycerides and cholesterol. Additionally, it is important to be aware of possible diffuse skeletal hyperostosis and extraosseous calcification although clinically significant bony issues are unusual.
Systemic retinoid use is indicated for widespread disease and in cases where quality of life is adversely impacted by malodor or psychosocial consequences of appearance. Dose adjustment of the oral retinoid therapy will usually permit treatment with continued clinical benefit and tolerable mucocutaneous side effects. Currently, acitretin is the most popular oral retinoid as etretinate is no longer available in the United States.
For women, pregnancy must be avoided during treatment with systemic retinoids, and two forms of birth control are recommended. Also, it is suggested that pregnancy be avoided for 3 years following conclusion of acitretin therapy. Isotretinoin is recommended for women of child-bearing age due to the shorter half-life and 30-day restriction to avoid conception after treatment is discontinued.
As with topical retinoid therapy, the key to successful therapy is to start at low doses and slowly increase as tolerated. Typically we start with acitretin in a dose of 0.3 to 0.5mg/kg every other day (example 25mg every other day for a 70 kg patient). If the patient is a woman of child-bearing potential we suggest isotretinoin in a similar dose of 0.3 to 0.5mg/kg every other day. Dose adjustments based on clinical progress and tolerability are made monthly until an ideal level is achieved.
Oral contraceptive pills are mainly used for contraceptive purposes but can also help in women who experience menstrual-related flares. There seems to be no reported difference in types and concentrations.
Topical 5-Fluorouracil (1%) is effective as adjunctive therapy in therapy-resistant Darier’s patients already receiving oral retinoids. This therapy is difficult to use and often not tolerated by patients due to the significant local irritation.
Although none of the following techniques have been assessed in controlled trials, surgical treatment is supported after the failure of other forms of treatment based on individual case reports. Dermabrasion down to and including the papillary dermis resulted in disease-free skin for up to two and a half years. Additionally, CO2 and erbium:YAG lasers both yielded good results, but erbium:YAG lasers may present an advantage over CO2 lasers in the prevention of scarring or keloid formation and the complete resolution of lesions and itch.
Sharp debridement and split-thickness skin grafting are also possible treatments for long-term remission.
Before undergoing any of these therapies, it is important to undergo a test patch trial to gauge a patient’s response. Botulinum toxin type A has been reported to be useful in a single report of localized disease.
Long-term monitoring is important for patients with Darier’s given the chronic and unremitting nature of the disease. Patients receiving long- or short-term oral retinoid therapy require monitoring of the expected mucocutaneous side effects and periodic screening for hepatic and lipid abnormalities. As stated, female patients of child-bearing age receiving oral retinoids require two forms of birth control. Also, topical corticosteroid therapy requires monitoring for long-term adverse effects such as atrophy particularly on the face and skinfold areas.
Many of the topical therapies such as retinoids, vitamin D analogues, and 5-fluorouracil can produce cutaneous irritation, and this needs to be followed to avoid worsening of the condition and secondary infections.
Unusual Clinical Scenarios to Consider in Patient Management
There can be clinical situations where there is limited phenotypic expression of the disease. Where this is primarily acrokeratotic, confusion with acrokeratosis verruciformis of Hopf can emerge. The importance of pathologic assessment of the lesions for characteristic acantholytic and dyskeratotic features is critical to differentiate these two entities.
Vesiculobullous forms of Darier’s can be difficult to distinguish clinically from superficial forms of pemphigus. Direct immunofluorescence testing and family history are important in these cases. Intertriginous Darier’s disease shares a positive family history, clinical features, and distribution with benign familial pemphigus (ie, Hailey-Hailey Disease), but can usually be distingushed histopathologically.
A significant complication associated with Darier’s is an increased susceptibility to cutaneous bacterial and viral infections, in particular staphylococcal, herpes simplex virus and poxvirus infections. It is crucial to have a heightened clinical suspicion and to perform the appropriate diagnostic tests if an infection is suspected. The early institution of antibacterial or antiviral therapy will decrease chance of serious infection.
Unusual clinical variants of Darier’s disease include hemorrhagic and vesiculobullous presentations.
What is the Evidence?
Burge, SM, Wilkinson, JD. ” Darier-White disease: A review of the clinical features in 163 patients”. J Am Acad Dermatol. vol. 27. 1992. pp. 40-50. (Review article with large series of 163 patients with comprehensive assessment of clinical features.)
Cooper, SM, Burge, SM. “Darier's disease: epidemiology, pathophysiology and management”. Am J Clin Dermatol. vol. 4. 2003. pp. 97-105. (Review article with detailed discussion of treatment options.)
Hohl, D, Mauro, T. “Darier disease and Hailey-Hailey disease”. Dermatology. 2008. pp. 823-35. (Textbook chapter outlines history, clinical features, differential diagnosis, and molecular pathogenesis.)
Leinonen, PT, Myllylä, RM, Hägg, PM, Tuukkanen, J, Koivunen, J, Peltonen, S. “Keratinocytes cultured from patients with Hailey-Hailey disease and Darier disease display distinct patterns of calcium regulation”. Br J Dermatol. vol. 153. 2005. pp. 113-7. (Cultured keratinocytes reveal defects of calcium metabolism specific to Darier's disease and differential pattern from Hailey-Hailey, another genetic acantolytic disorder.)
Ringpfeil, F, Raus, A, DiGiovanna, JJ, Korge, B, Harth, W, Mazzanti, C. “Darier disease – novel mutations in ATP2A2 and genotype-phenotype correlation”. Exper Dermatol. vol. 10. 2001. pp. 19-27. (Defines genoptypic abnormalities in keratinocyte calcium transport and helps to explain variable phenotypic manifestations.)
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