Grover disease (transient and persistent acantholytic dermatosis)

INTRODUCTION — 

In 1970, Ralph Grover presented a series of six patients with a pruritic, papular, and/or papulovesicular rash upon the trunk that cleared within weeks [1]. Histopathologic analysis revealed a characteristic pattern of acantholysis (loss of cohesion between keratinocytes) within the epidermis, and Grover named the disease "transient acantholytic dermatosis." Subsequent reports described an often chronic course but essentially identical histologic findings, and the term "transient and persistent acantholytic dermatosis" was proposed [2,3]. However, the eponym "Grover disease" remains in wide use.

EPIDEMIOLOGY — 

The prevalence and incidence of Grover disease have not been firmly established. In a study from Switzerland, Grover disease was diagnosed in just 24 of more than 30,000 skin biopsies [4].

It is thought that Grover disease chiefly affects White adults in the fifth decade or later and appears to be approximately 1.6 to 2.1 times more common in males than in females [5,6]. Grover disease appears less common in individuals with darkly pigmented skin but has been reported [5].

ETIOLOGY — 

The etiology of Grover disease is unknown. Some cases have been associated with medications, such as sulfadoxine-pyrimethamine, ribavirin, anastrozole, interleukin (IL) 4, cetuximab, BRAF inhibitors (eg, vemurafenib, dabrafenib), and immune checkpoint inhibitors (eg, ipilimumab) [1,7-18]. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

One series of 300 patients with Grover disease reported an association with other coexisting dermatoses, including atopic dermatitis, contact dermatitis, and xerosis cutis [5]. Smaller series and case reports have detailed an association with pyoderma gangrenosum, bacterial infections, and viral infections, and malignancies were occasionally described [5,19-21].

Suspected triggers of disease activity include heat and sweating, sunlight, ionizing irradiation, end-stage kidney disease/hemodialysis, mechanical irritation or prolonged bedrest, and solid organ transplantation [21-24].

PATHOGENESIS — 

Although Grover disease may show histologic similarities to Darier disease, an autosomal dominant disorder associated with variants in the ATP2A2 gene, it does not appear to be caused by the same germline variants causing Darier disease [25]. However, in a series of 15 patients with Grover disease, damaging somatic single nucleotide variants in ATP2A2 could be detected in lesional skin but not in normal skin in the majority of patients [26]. (See "Darier disease", section on 'Pathogenesis'.)

Grover disease is frequently seen in association with increased sweating, whether caused by heat or bedrest. Some investigators believe the condition may be precipitated by occlusion of eccrine sweat glands, a process that may also lead to miliaria. In support of this hypothesis, one study used electron microscopy to identify occlusion of the acrosyringia (the coiled intraepidermal eccrine sweat ducts) in three patients whose disease had a definitive temporal relationship to increased perspiration [27]. However, occlusion of the eccrine ducts was noted in just 2 of 11 cases in a conflicting study [28]. It is unclear if this disparity can be attributed to differences in methodology or patient selection.

In contrast with an association with sweating, a review of biopsies at a dermatopathology center in New York City found that Grover disease was diagnosed four times more often in the winter months than in the summer months [6]. The authors suggested that Grover disease might be promoted when xerotic skin is exposed to cold, dry air.

CLINICAL FEATURES — 

In most cases, Grover disease affects the trunk, especially the central area of the chest and back. Typically, the eruption consists of intensely pruritic, erythematous papules (picture 1A and picture 1B). Keratotic papules, papulovesicles, vesicles, and papulosquamous plaques reminiscent of psoriasis or parapsoriasis have also been described [5]. The lesions of Grover disease are frequently eroded and crusted.

Truncal prominence is a common feature, although the limbs (particularly the proximal limbs) may be affected as well. Involvement of the face, palms, or soles is unlikely to occur [5]. Extensive disease or atypical presentations are more common in patients with a history of malignancy, recent chemotherapy, or recent transplant [29].

Often, the disease is first noticed after a period of fever or after a hospitalization with prolonged bedrest.

CLINICAL COURSE — 

The temporal course of the disease is highly variable. Patients may present with a self-limited eruption that resolves in two to four weeks; a waxing and waning course; or a persistent, recalcitrant pattern. In Colorado, a semiarid environment, it is not uncommon to see a flare in disease activity during the drier winter months.

DIAGNOSIS — 

The diagnosis of Grover disease is typically made on skin biopsy in the appropriate clinical setting, although the diagnosis can be made on clinical grounds in some patients. The key histopathologic feature of Grover disease is acantholysis (the dissociation of keratinocytes from one another in the epidermis) (picture 2) [19,30]. A number of histologic subtypes have been identified [30,31]. Different histologic subtypes may be observed within a single biopsy specimen.

No additional laboratory or imaging evaluation is generally needed for patients with histologically confirmed Grover disease and typical clinical presentation.

DIFFERENTIAL DIAGNOSIS — 

Grover disease should be differentiated from other skin disorders histologically characterized by acantholysis. These include:

●Darier disease – Darier disease is a genodermatosis caused by mutations in the keratinocyte calcium transporter gene ATP2A2. It may demonstrate clinical and histologic similarities to Grover disease. Unlike Grover disease, Darier disease usually presents first during puberty; favors intertriginous areas; and is associated with concomitant nail changes, palmar pits, and mucosal manifestations (picture 3A-C). Darier disease is inherited in autosomal dominant fashion, and a family history of similar illness may suggest Darier disease rather than Grover disease. (See "Darier disease".)

●Hailey-Hailey disease – Hailey-Hailey disease is also an autosomal dominant condition. It is caused by a mutation in the ATP2C1 gene that encodes for a membrane-bound transporter protein present on keratinocytes. Hailey-Hailey disease is characterized by recurrent blisters and crusted, vegetating erosions in intertriginous areas (picture 4A-C). As with Darier disease, a positive family history suggests this inherited disorder rather than Grover disease. (See "Hailey-Hailey disease (benign familial pemphigus)".)

●Pemphigus – Pemphigus is an autoimmune bullous disorder that may be distinguished from Grover disease by positive direct immunofluorescence studies performed on involved skin (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

●Galli-Galli disease – Galli-Galli disease, the acantholytic variant of Dowling-Degos disease, is characterized by reticulated hyperpigmentation of major flexures and intertriginous areas [32]. (See "Congenital and inherited hyperpigmentation disorders", section on 'Dowling-Degos disease'.)

MANAGEMENT — 

There are no randomized clinical trials of therapies for Grover disease. Evidence for treatment comes from case series, case reports, and clinical experience.

Trigger avoidance and control of pruritus — Since heat and sweating may be triggers for Grover disease, patients should be advised to avoid activities that expose them to such triggers whenever possible [5,7,9]. Antihistamines may be helpful for symptomatic relief of itching [3]. Many dermatologists believe sedating antihistamines, if tolerated, possess superior antipruritic activity, although the evidence supporting this is limited. (See "Pruritus: Therapies for generalized pruritus", section on 'Role of antihistamines'.)

Our approach — For the treatment of Grover disease, we use a sequential approach that starts with safer, cheaper, and more readily available therapies. Patients for whom these therapies are ineffective can then undergo trials of second-line therapies.

●We suggest high-potency topical corticosteroids (table 1) as initial treatment for Grover disease. Topical corticosteroids are applied twice daily for two weeks. Moisturizers and emollients can be liberally used multiple times per day. Limited data suggest that topical corticosteroids improve the condition in approximately 50 to 70 percent of cases [4,33].

Patients whose disease does not respond to topical corticosteroids may benefit from a trial of topical vitamin D analog (eg, calcipotriene 0.005%) or calcipotriol-betamethasone twice daily for three to four weeks [34-37].

●For Grover disease that does not improve with topical treatment, second-line therapies include systemic corticosteroids (eg, prednisone 20 to 40 mg daily tapered over two to three weeks) or systemic retinoids (isotretinoin 40 mg daily for 2 to 12 weeks, taper to as little as 10 mg daily for prolonged control) [38-41].

Other therapies that have been anecdotally used in patients with Grover disease include:

●Dupilumab [42]

●Ultraviolet A1 (UVA1) phototherapy (may initially exacerbate disease before producing benefit) [43]

●Blue light phototherapy [44]

●Red light 5-aminolevulinic acid photodynamic therapy (ALA-PDT) [45]

●Etanercept [46]

PROGNOSIS — 

Although Grover disease is a benign condition, the associated pruritus may be severe and can have a significant impact on quality of life. The disease may resolve in weeks to months or be chronic and persistent. In persistent cases, pruritus may improve over time.

SUMMARY AND RECOMMENDATIONS

●Definition – Grover disease (transient and persistent acantholytic dermatosis) is an uncommon pruritic, papular, and/or papulovesicular rash that histologically shows a characteristic pattern of acantholysis (loss of cohesion between keratinocytes within the epidermis). The etiology is unknown, but there appears to be an association with heat and sweating. (See 'Introduction' above and 'Etiology' above.)

●Clinical presentation and course – Typically, the eruption consists of intensely pruritic, erythematous papules that, in most cases, affect the trunk, especially the central area of the chest and back (picture 1A-B). The course of the disease is highly variable. It may present with a self-limited eruption that resolves in two to four weeks; a waxing and waning course; or a persistent, recalcitrant course. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of Grover disease is made based on the clinical presentation and on the finding of acantholysis on a skin biopsy (picture 2). (See 'Diagnosis' above.)

●Management – There is limited evidence supporting topical or systemic therapies for Grover disease. We suggest high-potency topical corticosteroids and emollients as initial treatment (Grade 2C). Patients whose disease is not controlled with topical corticosteroids can be treated with a short course of systemic corticosteroids (eg, prednisone 20 to 40 mg daily tapered over two to three weeks) or systemic retinoids (isotretinoin 40 mg daily for 2 to 12 weeks). (See 'Management' above.)