Hailey-Hailey Disease Masquerading as Intertriginous Candidiasis for 10 Years Miguel Villacorta, DO, MPH,* Brittany P. Smirnov, DO,** Jennifer Moscoso Conde, DO,** Carlos H. Nousari, MD***

*Traditional Rotating Intern, PGY-1, Broward General Medical Center, Fort Lauderdale, FL **Dermatology Resident, PGY-3, Broward General Medical Center, Fort Lauderdale, FL ***Program Director, Dermatology Residency Program, Broward General Medical Center, Fort Lauderdale, FL

Abstract Hailey-Hailey disease (HHD) is a rare, autosomal-dominant genodermatosis that presents as erosive erythematous plaques commonly present with crusting, maceration and fissures in intertriginous locations. HHD may be difficult to distinguish from other intertriginous diseases. Additionally, bacterial or fungal infection can be superimposed on the affected areas, convoluting diagnosis and complicating management of the disease. Making a correct diagnosis and individualizing treatments are important to decrease patient morbidity and reduce complications. We present a patient with HHD that was misdiagnosed as intertriginous candidiasis for 10 years. The proper diagnosis was made after a thorough history was taken and a biopsy was performed. Clinical differences between diseases and common treatment modalities are discussed as well. We highlight the new treatment modalities to improve physician awareness of available interventions.

Introduction intergluteal and inguinal folds. The patient were positive for only light growth of Pseudomonas In 1939, the Hailey brothers were the first to reported waxing and waning of the eruption for aeruginosa. approximately 10 years, occasionally resolving describe Hailey-Hailey disease (HHD), or benign A complete blood count, comprehensive 1 entirely, but eventually recurring. Prior treatments familial pemphigus. Diagnosis of HHD can metabolic panel, and lipid panel were ordered in included betamethasone cream to affected areas, prove difficult, as it can present similarly to other preparation for possible soriatane treatment. She as well as oral and topical antibiotics, antifungals, intertriginous diseases and with a superimposed was prescribed oral fluconazole and doxycycline and topical corticosteroids for the treatment of infection. It is important for a clinician to be able in the interim. At the one-month follow up, the intertrigo and candidiasis. She originally denied a to distinguish HHD from other intertriginous patient stated that she noted some improvement family history of skin disorders or cancers. diseases. Herein, we describe a case of HHD with the medical regimen. Nystatin powder that had been misdiagnosed for 10 years as Physical examination revealed violaceous-to- and ciprofloxacin were added. Three months candidiasis. We focus on differentiating HHD brown hyperpigmented plaques with erosions later, active areas on the patient’s left axilla and from other diseases and summarize current and maceration located on her posterior neck, treatment modalities published in the literature. bilateral axillae, inframammary folds and groin, Figure 4 with scant surrounding satellite macules (Figures Case Report 1, 2, 3). Our patient did not exhibit longitudinal A 63-year old Haitian female with a past medical leukonychia. Following years of ineffective history of hypertension and diabetes presented treatment for intertriginous candidiasis, the with complaints of a painful, irritated rash on her patient presented to our clinic, and upon further posterior neck, bilateral axillary, inframammary, questioning, reported similar eruptions in three of her sisters, as well as her mother. Suspecting possible Hailey-Hailey disease, a 4-mm punch biopsy was performed in the left axilla. Histopathologic examination revealed a large focus of acantholytic dyskeratotic cells in a “dilapidated brick wall” pattern, with perinuclear eosinophilia (Figures 4, 5). PAS stain was negative for dermatophytes, and fungal and bacterial cultures performed at the time of biopsy

Figure 5 Figure 2

Figure 1 Figure 3

Page 30 Hailey-Hailey Disease Masquerading as Intertriginous Candidiasis for 10 Years inframammary folds remained. Clobetasol Additionally, bacterial or fungal infection can be General measures should be considered for each was added to improve the persistent lesions. superimposed on the affected areas, convoluting patient, such as avoidance of hot and humid Unfortunately, one month later, there was no diagnosis and complicating management of weather, use of bleach or chlorhexidine baths, improvement with clobetasol. At this point the the disease. Longitudinal leukonychia has been weight loss, and use of lightweight, loose clothing patient had persistent lesions with only some described in approximately 70% of individuals such as cotton. The use of absorbent pads, barriers, minor improvement in her symptoms. Her with the disease and, if present, can aid in the and drying agents such as zinc oxide, petrolatum, prescriptions were adjusted to include fluconazole, diagnosis.3 aluminum sulfate, and talcum powder may be tacrolimus, clotrimazole and betamethasone. She used to keep skin dry and clean.15,16 Differential Diagnosis returned three months later with improvement First-line treatment should consist of a in her lesions. The lesions consisted of The clinical differential diagnosis of Hailey-Hailey disease includes candidiasis, inverse psoriasis, combination of topical antimicrobials and topical hyperpigmented patches and mild erythema steroids.3,17,18 Based on Level IIa and Level III on her bilateral axilla and inframammary folds intertrigo, tinea cruris, contact dermatitis, seborrheic dermatitis, hidradenitis suppurativa, evidence, clobetasol should be used for acute without any evidence of maceration. At this point 19 and erythrasma. Histologic differential diagnosis flares and topical tacrolimus for maintenance. the patient was only using nystatin powder and The topical antimicrobials that have shown includes other intraepidermal acantholytic the topical clotrimazole with betamethasone. some degree of success include clindamycin, processes such as pemphigus vulgaris, Darier’s gentamicin, mupirocin, and ketoconazole.3,17 As of her last visit, the patient has been following disease, and Grover’s disease. An extensive history with our clinic for nine months without any and physical examination along with a biopsy, Systemic therapy may be necessary if a patient additional flares in her disease. While her blood especially if little or no improvement is seen with fails the topical antimicrobial and topical steroid work for CBC, CMP, and lipid panel returned treatment, help to support the diagnosis (Table combination therapy. Doxycycline has been unremarkable, the patient has not been started 1). shown to be the most appropriate first-line oral on soriatane treatment since she had achieved antibiotic with Level IIa and Level III evidence.19 considerable improvement with her current A fungal infection, such as intertriginous candidiasis, may present clinically by the presence Second-line oral therapy includes erythromycin, medical regimen. She was advised to follow up in penicillin, and dapsone with limited Level III an additional four months and, if her symptoms of satellite lesions with peripheral papules and 9 studies. worsen, soriatane treatment would be considered. pustules. A potassium hydroxide stain will help to confirm the diagnosis, but care should be taken If a patient is refractory to therapy, additional as a superimposed fungal infection can lead to therapies include surgical excision and botulinum Discussion misdiagnosis by masking the underlying Hailey- toxin type A injections. These therapies have Level Hailey-Hailey disease (HHD), also known Hailey disease. IIA and Level III evidence and have had some as benign familial pemphigus, is a rare degree of success. Other treatment modalities genodermatosis first described by the Hailey Inverse psoriasis presents in intertriginous areas, include dermabrasion, NBUVB, and laser brothers in 1939.1 The disease is inherited in similarly to HHD. It presents as erythematous, therapy. These treatments have limited Level III an autosomal-dominant fashion with complete sharply demarcated, smooth, non-scaly, moist 10 evidence and have had limited success. Currently, penetrance but variable phenotypic expression. plaques with or without maceration and fissures. there is a Phase II trial in Italy studying the use It can also present as a de novo mutation.2 Typically, patients have a family history of of afamelanotide, an analog of alpha-melanocyte Affecting males and females equally, HHD psoriasis and psoriasiform lesions with evidence stimulating hormone (a-MSH), for the treatment typically presents in the second or third decade of typical psoriatic nail involvement, including 11 of HHD. of life, with an overall estimated incidence of 1 onycholysis and nail pitting. 3,4 in 50,000. The disease is caused by a mutation Intertrigo clinically appears very similar to of the ATP2C1 gene, which encodes the ATP- HHD, as erythematous plaques with maceration Conclusion Hailey-Hailey disease is a rare disease that may be powered calcium pump protein, hSPCA1, that and inflammation of the skin folds. These 5 difficult to distinguish from other intertriginous sequesters calcium into the Golgi apparatus. lesions are prone to bacterial or fungal infections diseases. HHD should be considered in patients The impaired calcium pump protein leads to such as candida. A Wood’s light can help to with recurrent flares of intertriginous lesions. lower calcium levels inside the Golgi apparatus, distinguish a pseudomonal infection from Diagnosis is more difficult if a superimposed causing impaired production of calcium-binding cutaneous erythrasma caused by C. minutissimum. bacterial and fungal infection is present. A transmembrane glycoproteins and subsequent Pseudomonas fluoresces green under Wood’s light, 6 biopsy and clinical features, such as longitudinal loss of cellular adhesion in the stratum spinosum. while C. minutissimum fluoresces as coral red 12 leukonychia, can help distinguish this disease. Histologically, the acantholysis is classically patches with well-defined borders. described as having a “dilapidated brick wall While there is no known cure, individualized appearance” with the retention of basilar layer Tinea corporis typically presents clinically by the treatments using a combination of antimicrobials adherence to the dermis.3 Other histologic appearance of a raised and annular active border and steroids are important to decrease patient features include suprabasal decomposition, of pustules or vesicles with either central scale morbidity, reduce flares, and limit complications. (in early lesions) or central clearing (in advanced intraepidermal bullae, epidermal hyperplasia, 13 parakeratosis, and lymphocytic infiltration..7 lesions). Tinea cruris may appear similar, as Direct immunofluorescence testing is negative.8 well-demarcated erythematous plaques with central clearing and elevated scaling borders that Hailey-Hailey disease presents as flaccid vesicles may be active with pustules or vesicles, and may or bullae in intertriginous locations such as the be confirmed by KOH examination.14 axilla, groin, gluteal cleft, and inframammary folds. These fragile vesicles are easily ruptured Treatment and are often absent on physical examination. HHD has no known cure, and treatment The remaining erosive erythematous plaques therapies are aimed at reducing exacerbations and commonly present with crusting, maceration increasing periods of remission. Many treatment and fissures. Patients can experience increases in modalities have been attempted, with most morbidity as affected areas can become painful, modalities demonstrating Level III evidence pruritic, and malodorous. The disease course in the literature. Some patients are refractory fluctuates between episodic remission and to treatment, thus individual therapy must be exacerbation aggravated by friction, heat, sweat, tailored to each patient (Table 2). tight clothing, increased weight, and infection.3 Villacorta, Smirnov, Conde, Nousari Page 31 Table 1. Clinical differentiation of intertriginous dermatitides Condition Clinical Differentiation - Intertriginous erosive erythematous plaques - Crusting, maceration, and fissures Hailey-Hailey Disease - 2nd or 3rd decade of life, waxing and waning symptoms - Longitudinal leukonychia - Satellite lesions with peripheral papules and pustules Intertriginous Candida - Well-demarcated, erythematous patches

- + KOH Prep - Erythematous, sharply demarcated plaques - Smooth, moist, macerated, +/- fissures Inverse Psoriasis - Absent scales - + Nail involvement - Well-demarcated erythematous plaques Tinea Cruris - Central clearing and elevated scaling borders

- +/- Pustules or vesicles - Reddish-brown macules coalescing into patches - Well-defined borders Erythrasma - C. minutissimum - coral red fluorescence (Wood’s) - Pseudomonas - green fluorescence (Wood’s)

- Sharply marginated erythematous eruption Seborrheic Dermatitis - + Erosions and fissures - +/- Yellow greasy scales

Table 2. Treatment and management of Hailey-Hailey disease Individualized Combination Therapy Evidence Level Acute flare Clobetasol IIA, III Topical Steroids Maintenance Tacrolimus IIA, III plus Clindamycin Gentamicin First line: topical IIA, III Mupirocin Ketoconazole Antimicrobials Doxycycline IIA, III Dapsone Second line: systemic Erythromycin III Penicillin Refractory to Treatment Excision IIA, III Botulinum toxin A IIA, III Dermabrasion, NBUVB, Laser therapy III

General measures Bleach or chlorhexidine baths V Weight loss V Lightweight and loose clothing V Barrier and drying agents V Avoidance of hot and humid weather V

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