Darier disease is a rare autosomal-dominant genodermatosis caused by the mutation of the ATP2A2 gene, at the locus 12q23q24.1, which encodes SERCA2, an ATPase responsible for regulating calcium-dependent signaling. The classic manifestations, which usually appear in the second or third decades of life, include wart-like and keratotic papules located mainly in seborrheic areas of the scalp, face, and trunk, as well as characteristic nail changes (fragility, fragmentation, and longitudinal ridging with red and white streaks). On rare occasions, the disease can also compromise other organs. Various phenotypic presentations have been described, including acral hemorrhagic Darier disease. This variant is very rare—approximately 20 cases have been reported—and is characterized by lesions on acral sites. We report 3 new cases of acral hemorrhagic Darier disease and review the literature.

Case description 1: A 50-year-old man with no past medical history of interest presented with lesions on the hands that had first appeared several years earlier. The lesions were triggered by trauma and worsened in the summer. Physical examination revealed hemorrhagic macules, papules, and vesicles on the back of the hands, the palms, and the wrists (Fig. 1). The lesions were intermixed with multiple firm keratotic papules that were the color of normal skin or slightly erythematous, as well as nail changes. On the dorsum of the feet and the lateral region of the soles, pebbly papules were present but no hemorrhagic lesions were observed. No lesions were found on the mucosas or other sites. A biopsy revealed suprabasal acantholysis with dyskeratosis and intraepidermal hemorrhagic vesicles (lacunae) (Fig. 2). During the most intense flares, the patient developed multiple hemorrhagic blisters as well as classic Darier disease lesions on the chest and face. Acitretin (25mg/d) was prescribed for use during the most intense flares and partial response was achieved.

Figure 1.

A and B, Macules, papules, and a hemorrhagic blister on the back of hands, the palms, and the wrists.

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Figure 2.

A and B, Suprabasal acantholysis with intraepidermal hemorrhagic lacunae.

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Case description 2: A 28-year-old woman—the daughter of the patient in case 1—reported the appearance of hemorrhagic papules and vesicles on her hands since childhood. The lesions were triggered by minor trauma, worsened in the winter, and improved in the summer. Physical examination revealed hemorrhagic vesicles and blisters on the back of the hands (Fig. 3A) and the palms, as well as hyperkeratotic papules and nail changes. On the feet, only hyperkeratotic papules were present; no hemorrhagic lesions were observed. No other cutaneous or mucosal lesions were present. The main histopathologic findings were suprabasal acantholysis, dyskeratosis, and hemorrhagic vesicles. Treatment with topical retinoids (tretinoin 0.05%) and, for more severe flares, isotretinoin (20mg/d) achieved partial improvement.

Figure 3.

A, Hemorrhagic papules and vesicles on the dorsum of the fingers (case 2). B, Dermoscopic image of a lesion showing signs of bleeding.

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Case description 3: A 60-year-old woman presented with nail changes triggered by trauma that had first appeared 12 years earlier. Physical examination revealed confluent hyperkeratotic papules on the back of the hands and the palms, as well as longitudinal ridging of the nails. A month later, the patient presented with new papules and hemorrhagic vesicles on the back of his hands; no lesions were observed at other sites. Biopsy of a lesion revealed acantholytic cells and dyskeratosis with intraepidermal hemorrhagic vesicles. The patient said her brother had similar lesions. Because the lesions had little effect on her quality of life, the patient refused treatment and only took measures to avoid known trigger factors.

Segmental and unilateral clinical presentations of Darier disease have been reported, as well as rarer forms such as bullous, hemorrhagic, comedonal, and hypertrophic Darier disease.1 In patients with classic Darier disease, there have been reports of pitting or hyperkeratotic papules resembling acrokeratosis verruciformis of Hopf at acral sites. Acral hemorrhagic Darier disease was first described in 1964 by Jones in a report of 4 cases; 2 of the patients were members of the same family.2 Clinically, this entity is characterized by the appearance of hemorrhagic macules, papules, and vesicles and, in more intense flares, blisters at acral sites.3,4 These patients can present classic Darier disease lesions either concomitantly or during different flares5 and they may have family members or descendants with the same condition or a different phenotypic manifestation of Darier disease. Histopathologically, acral hemorrhagic Darier disease is characterized by the presence of red blood cells4 in intraepidermal vesicles and the presence of acantholytic and dyskeratotic cells.3 About 20 cases have been reported to date, although in the series by Burge et al. the acral hemorrhagic variant accounted for 6% of all cases of Darier disease.6 Acral hemorrhagic Darier disease is more common in women7 and the mean age of onset is comparable to that of classic Darier disease.4 In some of the reported cases of acral hemorrhagic Darier disease, a mutation was found in exon 15 of the ATP2A2 gene. This mutation is not found consistently in all cases, reflecting the variability of clinical manifestations and the lack of genotype/phenotype consistency in Darier disease8; this could be due to the interaction of multiple genetic and/or environmental factors. The skin can generally compensate for the lack of SERCA2 protein from an altered allele through an increase in normal allele expression or other mechanisms such as secretory pathway Ca2+/Mn2+ ATPase isoform 1 (SPCA1) in the Golgi apparatus. However, certain external factors, such as UV-B radiation and frictional trauma, can alter the balance by decreasing ATP2A2 expression or increasing the SERCA2 requirement until the protein reaches a critical level.9

Trigger factors for acral hemorrhagic Darier disease include local trauma4 and the summer months. These factors were seen in cases 1 and 3; in the former, they were even seen in association with a flare of classic Darier disease manifestations. In case 2, the opposite occurred, with the lesions worsening in the winter.

Differential diagnosis includes multiple entities, such as cutaneous vasculitis, acral lesions of bacterial endocarditis, gonococcal sepsis, and parvovirus infection,5 as well as petechial-purpuric lesions of dermatitis herpetiformis.10,11

Corticosteroids and topical and oral retinoids have been used to treat acral hemorrhagic Darier disease,7 although the results have been contradictory.12 The lesions tend to resolve spontaneously when aggravating factors are avoided,4 but treatment usually helps to improve symptoms.

In 2 of our patients, partial and transient improvement was observed after treatment with oral retinoids. This finding contrasts with a previous report of a patient with classic Darier disease who received treatment with acitretin and subsequently developed hemorrhagic palmoplantar lesions, which disappeared after the drug was withdrawn,12 and another report in which the appearance of acral hemorrhagic Darier disease was associated with the use of etretinate.13 In cases in which acral hemorrhagic Darier disease may have appeared following administration of oral retinoids, an increase in vascular endothelial permeability induced by the drug's activation of vascular endothelial growth factor has been suggested as a possible mechanism.12

In conclusion, we report 3 new cases of acral hemorrhagic Darier disease (Table 1) in order to increase knowledge about this entity and favor early diagnosis, given the characteristic and reproducible clinical-pathological picture presented by this rare variant of Darier disease. We also show the possible usefulness of oral retinoids in the treatment of this entity.