A Painful, Blistering, Malodorous Rash in a Woman’s Intertriginous Areas

Authors:
Alexander K. C. Leung, MD, and Benjamin Barankin, MD

Citation:
Leung AKC, Barankin B. A painful, blistering, malodorous rash in a woman’s intertriginous areas. Consultant. 2017;57(9):545-548.

A 40-year-old woman presented with a rash in the axillae and inframammary folds that had been present on and off for approximately 10 years. The lesions would start as flaccid vesicles and bullae on an erythematous base and subsequently would rupture, resulting in erosions with formation of crusting plaques over time. The lesions were pruritic and painful and had a foul odor, especially during summer. The patient was obese but was otherwise in good health. Her 65-year-old father and 35-year-old sister had experienced similar lesions in the axillae and groins for years.

Physical examination revealed large, macerated, erythematous, scaly plaques with crusts, symmetrically distributed in the axillary and inframammary areas. She also had longitudinal white lines on her fingernails. The rest of the examination findings were unremarkable.

Results of a skin biopsy of the lesion showed intraepidermal vesiculation and loss of intercellular adhesion (acantholysis) between suprabasal keratinocytes, with direct immunofluorescence test results negative for antibodies.

Answer on next page

Answer: Hailey-Hailey disease

Hailey-Hailey disease, also known as benign familial pemphigus, is a rare genodermatosis. The disease is characterized histologically by suprabasal acantholysis and clinically by recurrent, fragile, vesicles/bullae and erosions in intertriginous areas.^1,2

The condition was first described in 1939 by brothers Howard Hailey, MD, and Hugh Hailey, MD, and the disease now bears their names.³

EPIDEMIOLOGY

It is estimated that the condition affects 1 in 50,000 persons in the general population.^4,5 Both sexes are equally affected. Typically, patients present between the second and fourth decade of life.^1,6 All ethnic and racial groups are at risk.⁶ Predisposing factors include UV radiation, heat, sweating, friction, and obesity.^7,8 The disease can also be precipitated by contact irritation, cutaneous infections, pregnancy, and medications (eg, nonsteroidal anti-inflammatory drugs, topiramate).^6,9-11

PATHOGENESIS

The disease is inherited as an autosomal dominant disorder with a high penetrance and variable expressivity.^1,7 Approximately two-thirds of patients with Hailey-Hailey disease have a family history of the disorder; one-third of cases are sporadic and attributable to a new mutation.^1,7

Hailey-Hailey disease is caused by loss of function mutations in ATP2C1, which is located on band 3q22.1.^4,7 The gene encodes a Golgi apparatus human secretory pathway calcium/manganese-adenosine triphosphatase (ATPase) protein 1 (hSPCA1).⁴ This calcium ATPase pump plays an essential role in intercellular calcium signaling and the sequestration of calcium within the Golgi apparatus of keratinocytes.¹² Mutations in ATP2C1 have been shown to cause severe disruption in calcium homeostasis, leading to depletion of calcium stores in the keratinocytes. Local calcium is essential in the production of desmosomes and adherens junctions, which help to hold keratinocytes together. Keratinocytes of affected individuals cannot stick tightly together, with resulting suprabasal acantholysis (epidermal blistering).¹² Oxidative stress of keratinocytes and upregulation of micro-RNA-125b in keratinocytes may also play a role.^6,7

HISTOPATHOLOGY

Histopathologic examination of the lesion shows epidermal hyperplasia and loss of intercellular adhesion (acantholysis) between suprabasal keratinocytes, giving the appearance of a “dilapidated brick wall” or a “row of tombstones” in the epidermis.^2,12,13 Suprabasal clefts and acantholytic vesicles/bullae may also been seen.⁷

CLINICAL MANIFESTATIONS

Clinically, Hailey-Hailey disease presents with flaccid vesicles/bullae on an erythematous base.¹² These vesicles/bullae rupture easily, resulting in macerated erosions, often coalescing into exudative, scaly, and crusting plaques.^7,12 Painful fissures and malodorous vegetations may be present.¹⁴ Burning and pruritus accompany the eruption. The Nikolsky sign is negative. Lesions tend to wax and wane and are more prominent in summer months.⁴

Sites of predilection include the intertriginous areas (particularly the axillary, inguinal, and inframammary folds and gluteal cleft), followed by, in decreasing frequency, the lateral neck, shoulders, chest, arms, and back.² Lesions are typically symmetric.^2,12 The palms and soles are characteristically spared.⁶ Longitudinal white lines on the nails have been described in approximately 60% to 70% of affected patients.^7,15,16

Rare clinical variants include unilateral lesion, segmental lesion, linear lesion, patchy lesion, atypical location (scalp), and mucosal involvement (conjunctiva, buccal mucosa, vaginal mucosa).^5,7,12

DIAGNOSIS

The diagnosis is based on the history (recurrent remissions and relapses, positive family history) and physical examination findings (typical distribution, characteristic clinical findings). Dermoscopy may aid in the diagnosis.¹⁷ A skin biopsy for histopathologic examination and direct immunofluorescence staining is generally recommended to confirm the diagnosis.⁷ The immunofluorescence test result for antibodies is negative.

DIFFERENTIAL DIAGNOSIS

Hailey-Hailey disease should be differentiated from Darier disease. The skin changes of Darier disease are characterized by greasy, discrete, flat-topped, hyperkeratotic papules and plaques that occur in seborrheic areas such as the trunk, lateral sides of the neck, scalp, limbs, and forehead.¹⁸ The distribution is often symmetric. Lesions are itchy, yellow brown, brown, or skin-colored and feel like coarse sandpaper. Lesions may have a foul odor if secondary infection or colonization is present.

Pemphigus vegetans is an autoimmune blistering skin disorder that may mimic Hailey-Hailey disease. The condition is characterized by vegetating erosions, primarily in flexural areas.¹⁹ Direct immunofluorescence studies show immunoglobulin G and C3 complement deposits on the cell surface of keratinocytes.^19,20 Indirect immunofluorescence shows the presence of antidesmoglein 3 antibodies.²⁰ In contrast, Hailey-Hailey disease is not an autoimmune disease, and there are no autoantibodies.

Other differential diagnoses include intertrigo, seborrheic dermatitis, tinea corporis, tinea cruris, candidiasis, erythrasma, impetigo, inverse psoriasis, hidradenitis suppurativa, acanthosis nigricans, granular parakeratosis, extramammary Paget disease, and Galli-Galli disease.

COMPLICATIONS AND PROGNOSIS

The lesions usually heal without scarring,^4,11 but postinflammatory hyperpigmentation is common.^7,11 The hyperpigmentation, pruritus, irritation, pain, and malodor can have an adverse effect on the quality of life.^21-23 Secondary infection or colonization by bacteria (eg, Staphylococcus, Streptococcus) is common, followed by fungi (eg, dermatophytes, Candida), and viruses (herpes simplex).²⁰ Squamous cell carcinoma arising from Hailey-Hailey disease, although rare, has been reported.²⁴

The disease runs a chronic fluctuating course characterized by remissions and relapses throughout life.^1,11 While morbidity is significant, longevity is not affected.

MANAGEMENT

Currently, there is no known cure for this disease. Treatment is mainly symptomatic and can be used to control the underlying inflammation associated with the disease. The environment should be kept cool. Patients should be advised to wear comfortable, soft, breathable (eg, cotton), and loose clothing. Avoidance of direct sunlight and the use of sunscreens when outdoors can be helpful. Weight reduction should be advised for those who are overweight.

Intermittent use of moderate- to high-potency topical corticosteroids is often necessary in the treatment of inflamed lesions.⁷ Topical antibiotics (eg, mupirocin, clindamycin, gentamicin) should be used for secondary bacterial infection. Severe bacterial infection may require systemic antibiotics (eg, amoxicillin-clavulanate, cephalexin, ciprofloxacin, doxycycline).^25,26 Topical antifungal agents (eg, butenafine, ciclopirox, econazole, ketoconazole, miconazole, naftifine, terbinafine, tolnaftate) should be used in cases of superimposed fungal infection.

Topical calcineurin inhibitors such as tacrolimus and pimecrolimus are not as effective as potent topical corticosteroids in the treatment of this skin condition, although they can be considered in the long-term control of inflammation.^12,20 Other topical immunomodulators such as cyclosporine and 5-fluorouracil can also be used to mitigate the potential adverse effects of long-term corticosteroids but are also less effective.¹³

For patients with extensive and severe disease with associated significant hyperhidrosis, oral anticholinergics (eg, glycopyrrolate) and subcutaneous injections of botulinum toxin type A in the affected areas may be considered.^13,27-29

For those with severe and recalcitrant disease, oral retinoids (eg, acitretin, alitretinoin),³⁰ systemic immunosuppressants (eg, corticosteroids, methotrexate, cyclosporine),^21,31 ablative laser therapy (eg, carbon dioxide laser, erbium:yttrium-aluminum-garnet laser),^10,14,23,32 photodynamic therapy with 5-aminolevulinic acid,^33,34 and surgery (eg, dermabrasion, electrosurgery, excision and grafting)¹⁴ should be considered if the potential benefits of therapy outweigh risks.^12,13

Other therapies that have been used with variable success include cryosurgery,³⁵ topical tacalcitol and calcitriol,³⁶ topical cadexomer iodine,³⁷ oral magnesium chloride,¹ electron beam radiation therapy,²² and subcutaneous afamelanotide (a synthetic analogue of α-melanocyte-stimulating hormone).³⁸ Evidence of the efficacy and safety of various treatment modalities for Hailey-Hailey disease is limited to case reports and small case series. Future studies are warranted to assess their consistent efficacy and safety and to determine optimal treatment parameters. Affected patients may benefit from genetic counseling.

The patient in the case presented here was treated with betamethasone valerate-gentamicin cream, twice a day for 7 days, then once at night whenever necessary, along with a 6-week course of oral doxycycline, 100 mg once a day. At a 2-month follow-up visit, the area was well healed with no odor, no discomfort, and residual dyspigmentation. Genetic counseling was also offered. 

Alexander K. C. Leung, MD, is clinical professor of pediatrics at the University of Calgary and a pediatric consultant at the Alberta Children’s Hospital in Calgary, Alberta, Canada.

Benjamin Barankin, MD, is a dermatologist and the medical director and founder of the Toronto Dermatology Centre in Toronto, Ontario, Canada.

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