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Abstract

Darier’s disease is an autosomal dominant inherited skin disorder resulting from mutations in the ATP2A2 gene, which encodes SERCA2, an endoplasmic reticulum calcium ATPase. Darier’s disease classically manifests as confluent hyperkeratotic brown-to-red papules that manifest and follow a seborrheic distribution, which include the chest, neck, trunk, and face. Vesicular Darier’s disease is a rare variant of the disorder where patients develop numerous vesicles and bullae concurrently or independent of the more typical lesions found in Darier’s disease.

Keywords

Darier’s disease vesiculobullous disease

The current report outlines a 53-year-old female with a history of Darier’s disease presenting with a sudden onset of widespread pruritic papules and vesicles rapidly developing over her extremities and back. Patient was diagnosed with vesicular Darier’s disease, based on histology and ruling out a superimposed viral or bacterial infection.

Case report

A 53-year-old female with a history of Darier’s disease diagnosed at the age of 47 years presented with a sudden onset of widespread pruritic vesicles and papules over her extremities and back (Figures 1 and 2). The eruption had started on the back and rapidly spread to involve her trunk and extremities. Upon presentation, she was systemically in good health and otherwise recovering well 10 days post-operatively following a thyroid lobectomy for Grave’s disease. Physical examination revealed multiple pink-to-erythematous crusted papules, vesicles, and bullae with a few scattered pustules over the back, trunk, upper, and lower extremities. Physical examination also revealed characteristic nail changes for Darier’s disease in the form of longitudinal leukonychia and erythronychia and distal V-notching.

Figure 1.

Widespread pink-to-erythematous papules, vesicles, and bullae with a few scattered pustules over the trunk.

Figure 2.

Close-up of vesicles and crusted papules on the back.

Concomitant Kaposi varicelliform eruption was excluded with negative swabs for herpes simplex and varicella-zoster virus. Wound cultures of deroofed vesicles grew scant staph aureus likely from skin colonization. A skin biopsy of an intact vesicle was performed showing prominent lymphocytic infiltrate with acantholysis and dyskeratosis, and in the area of the vesicle formation, there was a suprabasilar split with scattered eosinophils and occasional dyskeratotic cells (Figure 3). These biopsy findings in conjunction with the patient’s past medical history and clinical presentation were in keeping with a vesiculobullous variant of Darier’s disease.

Figure 3.

(a) Low-power histologic image depicting prominent suprabasilar and intraepidermal vesicle with lymphocytic infiltrate acantholysis and dyskeratosis. Magnification 10× (b) High-power histologic image depicting suprabasilar and intraepidermal vesicle with dense dermal lympho-eosinophilic infiltrate. Magnification 40×.

Because of the acute onset of the blistering and the low suspicion of a superimposed immunobullous disease, a direct immunofluorescence biopsy was not performed.

Discussion

Darier’s disease is an autosomal dominant inherited skin disorder resulting from mutations in the ATP2A2 gene, which encodes SERCA2, an endoplasmic reticulum calcium ATPase.¹ Mutations of this ATPase are thought to result in dysfunctional junctional proteins, cell cycle regulation, and dyskeratosis and apoptosis of keratinocytes. Darier’s disease classically manifests as confluent hyperkeratotic brown-to-red papules in a seborrheic distribution involving the chest, neck, trunk, and face.¹ Characteristic nail abnormalities with Darier’s disease include distal V-shaped notching, subungual hyperkeratosis, and longitudinal erythronychia alternating with longitudinal leukonychia, which can help in making a clinical diagnosis.¹

Clinical variants of Darier’s disease include (1) vesiculobullous, (2) acral hemorrhagic, (3) hyperkeratotic/hypertrophic and keratoderma, (4) cornifying with cutaneous horns, (5) comedonal, (6) guttate hypopigmentation, and (7) linear/segmental occurring along Blaschko’s lines as a manifestation of type 1 or type 2 mosaicism.²

Vesicular Darier’s disease is a very rare variant of the disorder where patients develop numerous vesicles and bullae concurrently or independent of the more typical lesions found in Darier’s disease.³ Another rare variant of bullous Darier’s disease is a bullous hemorrhagic presentation.⁴

A comprehensive literature search was performed, which revealed a total of 26 case reports that described cases of vesicular Darier’s disease via search of title and/or abstract.^3–28 A list of 16 case reports that were accessible in English is summarized in Table 1.

Table 1.

Summary of the available current literature on vesicular Darier’s disease. Information collected includes study author and year, age, and sex, if the diagnosis of Darier’s disease was made prior to vesiculobullous eruption, distribution of lesions, postulated triggers, treatment options, and treatment outcome.

Study author and year	Age and sex	Diagnosis of Darier’s disease made prior to vesiculobullous eruption	Distribution of lesions	Postulated triggers	Treatment options	Treatment outcome
Pels 1939⁵	40M	21 years prior	Abdomen, groin, flexural elbows, upper trunk	Worsened with certain foods including candy, oranges, and tomatoes	Intravenous arsenical preparation and intramuscular bismuth	No improvement in skin disease
Reiss 1947⁶	43M	10 years prior	Generalized	—	(A) Tartar emetic, (B) 1% penicillin, (C) chlorarsen, (D) 50% glucose solution, (E) insulin, (F) parathormone, (G) desoxycortisone acetate 20% ointment	No benefit in A–G. Optimum improvement with vitamin C 1000 mg
Finnerud 1950⁷	40M	8 years prior	Neck, shoulders, trunk, axillae, upper extremities	Summer	—	—
Niordson 1965¹²	42F	35 years prior	Face, body, and extremities	Onset at ovulation, disappeared at menstruation, and week before delivery	—	—
Reed 1969¹⁶	34F	—	Photo-exposed sites	Summer	—	—
Hori 1982³	50F	Since early childhood	Inner aspects of lower extremities	Summer/sun, surgery for ovarian cancer	—	—
Telfer 1990²⁰	49M	De novo	Hands, forearms, and wrists	2 days post-operative surgical drainage of submandibular abscess, possibly etretinate	Clobetasol propionate 0.05% ointment	Gradual improvement after 4 weeks
Colver 1992²¹	49F	—	Sun exposure	Local streptococcal infection, possibly etretinate	—	—
Speight 1998²²	58F	—	Trunk and extremities	Hip joint prosthesis surgery	Methylprednisolone 40 mg po daily	Rapid resolution
Mei 2000²³	71M	At least 50–60 years prior	Neckline, sternum, groin, axillary folds, buttocks, and scalp	Sun	Methylprednisolone therapy 0.2 mg/kg/day	Resolved over the course of 3 weeks
Kakar 2007²⁴	45F	2 years prior	Neck and antecubital fossae	—	Oral steroids	Almost complete resolution
Khaled 2011²⁵	51F	—	Axillary and inguinal areas	—	Topical antimicrobials	Complete healing of the lesions
Khaled 2011²⁵	25F	—	Axillary and infra-mammary folds	Heat, sweat, and friction	Topical retinoid	Partial clearance
Sanchez-Salaz 2011⁴	48M	4 month	Trunk, neck, and extremities	—	Antihistamines, 5-fluorouracil 1% cream, topical tazarotene cream	Minimal improvement
Klimas 2016²⁶	50M	—	Chest, cervical and axillary folds, back, groin, lower extremities, hands, and feet	Sodium hypochlorite baths, oral cefalexin, febrile event	Prednisone 40 mg po daily, triamcinolone 0.1% ointment BID	Resolved over the course of 8 days
Wang 2019²⁷	55F	Several years prior	Trunk, extremities	—	Cetirizine 40 mg po daily over 4 weeks	Symptomatic control with cetirizine
Ashbaugh 2021²⁸	55F	30 years prior	Dorsal feet and digits, intramammary folds, axilla, medial thigh, and legs	Stress and illness	Oral retinoid	—
Current Study	53F	6 years prior	Extremities, trunk, and back	Thyroid lobectomy	Betamethasone valerate 0.1% ointment	Lesions improved after 2 weeks

The vesicular variant of Darier’s disease was first mentioned by Pels and colleagues in 1939, first reported in a case of a 40-year-old male with a 20 -year history of Darier’s disease who presented on follow-up with newly developing vesicular lesions over abdomen, groin, flexural elbows, and upper trunk.⁵

Triggers for the formation of the vesicular variant of Darier’s disease include stress and illness,²⁸ bacterial infection, surgery,²⁰ and possibly medications such as etretinate.²⁰ Etretinate, an oral retinoid that was used to treat Darier’s disease but is no longer available on the market, may predispose patients to developing vesicular lesions as this medication has been found to inhibit desmosome production and contribute to skin fragility.²⁰ The mechanism by which vesicular Darier’s disease manifests is not completely known but it can be hypothesized that dysfunction in desmosomal activity may play a role. Eosinophils may promote the development and production of this rare variant of disease via major basic protein, which disrupts desmosomes leading to an intraepidermal split.²⁷ Further supporting this, is symptomatic control with oral cetirizine, which has been shown to attenuate eosinophil migration into the skin, in a case of biopsy-proven vesiculobullous Darier’s with intravesicular eosinophils.²⁷

Treatments that have resulted in favorable responses include oral vitamin C, topical corticosteroids, oral/intravenous corticosteroids, topical antimicrobials, and cetirizine for symptom control. In the current reported case, the lesions improved after 2 weeks of applying a mid-potency corticosteroid (betamethasone valerate 0.1% ointment) twice daily to all affected areas.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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