A 35-year-old woman is referred for evaluation and management of a rash involving both axillae. She reports recurring episodes of the same rash beginning in her early 20s. Lesions develop and involute spontaneously. Areas affected included the axillae, neck, and groin. Historically, outbreaks are more common and worse during the summer, and after vigorous exercise. Both her father and brother have the same problem; her brother saw a specialist, but forgot what he was told. Otherwise, she is healthy and taking no medications. Examination reveals moist, red, crusted, and malodorous plaques with fissures in both axillae.
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Hailey-Hailey disease (HHD), also referred to as familial benign chronic pemphigus, is a rare genodermatosis characterized by recurrent, scaly, and fissuring plaques of intertriginous areas. HHD was first described in 1939 by the Hailey brothers, William and Hugh, as a recurrent pruritic blistering eruption occurring on the necks of two different sets of brothers. Because the basic histologic changes were similar to pemphigus, they called this newly described condition familial benign chronic pemphigus.1 Eventually, Hailey and Hailey reported an additional 22 cases, in two different families, spanning four generations. To avoid confusion with the autoimmune form of pemphigus, this condition is usually referred to as HHD.
Inherited as an autosomal dominant trait, HHD has incomplete penetrance2,3; even affected individuals in the same family have varying degrees of severity. Although the actual prevalence is unknown, HHD is estimated to occur in 1 to 30,000 to 50,000 individuals.2,4 It is likely that many patients with HHD are undiagnosed or misdiagnosed. There appears to be no sex, racial, or ethnic predominance. For most individuals, lesions begin between the second to fourth decades of life and typically follow a relapsing and remissive cycle.
Although the specific genetic defect has not been isolated, data suggest that mutations in ATP2 C1, a calcium ion transporter on the Golgi apparatus within the keratinocyte, are responsible.2,5 An intact epidermis depends on calcium-mediated transcellular desmosomal structures to facilitate keratinocyte-keratinocyte adhesion. The genetic defects in HHD render the desmosome abnormal, resulting in epidermal fragility.
HHD is more common in intertriginous areas such as the neck, inframammary folds, and groin, likely due to repetitive trauma from friction. Outbreaks may be triggered, or be more symptomatic, following sweating related to exercise or excessive heat, or other minor traumas.2,3 Classic lesions are characterized by scaly, eroded, fissured plaques. In rare cases, providers see the early vesicular changes often described by patients.
Lesional characteristics of epidermal maceration and occlusion within the intertriginous areas predispose to secondary infection with bacteria and fungi. Although Staphylococcus aureus is the most common pathogen, both Streptococcus and Candida species are also frequently found.5,6 Because secondary infection slows wound healing and promotes odor, it must be addressed in the management of HHD.
Biopsy can show the classic acanthotic epidermis with suprabasal clefting and intraepidermal vesiculation, often described as a “dilapidated brick wall.”
The differential diagnosis of HHD includes disorders such as pemphigus vegetans, Darier disease, intertrigo, and herpes simplex virus infection.
Pemphigus vegetans, a chronic, vegetative variant of pemphigus vulgaris, is clinically and histologically comparable with HHD. However, the familial association and pathogenesis of HHD are unique and completely unrelated to autoimmune pemphigus. The presence of immunofluorescent staining of the skin biopsy, or measurement of circulating autoantibodies to desmoglein proteins, readily distinguishes pemphigus from HHD.
Darier disease is another autosomal dominant genodermatosis due to a calcium transporter defect, unique from that of HHD. Although lesion morphologies of these two conditions have some similarities, there are major clinical characteristics that are distinct. Typically, the onset of Darier disease is earlier than HDD. Whereas flexural involvement is characteristic for HHD, it is uncommon in Darier disease; instead, the head, neck, chest, and back are extensively affected. Moreover, histologic changes can definitively differentiate between the two conditions.
Intertrigo is a nondiscriminating term used to describe inflammation of the skin folds; it incorporates an assortment of different conditions that are typically classified as either infectious or noninfectious etiologies. Common infectious causes include fungal infections (mostly Candida species and dermatophytes), bacterial infections (mostly S aureus and Streptococcus species), and, occasionally, herpes simplex virus. Noninfectious causes of intertrigo include inverse psoriasis and seborrheic dermatitis. Microscopic analysis, cultures, and (if necessary) a biopsy assist in making the proper diagnosis and ultimately determine the cause of intertrigo, if present.
Various modalities have been used to treat HHD, including topical and systemic medications, phototherapy, and both surgical and laser procedures. The first step in therapy, however, is to reduce lesional inflammation and secondary infection, generally with topical corticosteroids, along with either topical or oral antimicrobial medications. In well-established lesions, steroid use should not be used as monotherapy, as it may exacerbate secondary infection. However, in a review of treatment management, 86% of patients found topical steroids beneficial and believed that, if applied early, they could potentially prevent an exacerbation.3
If topical therapies are ineffective, injection of botulinum toxin A (BTX-A) may prove beneficial. As a neurotoxin, BTX-A effectively blocks activation of eccrine sweat glands and decreases localized areas of sweating, a known trigger of HHD. Effective long-term remission has been reported with BTX-A.6 Glycopyrrolate, an oral antiadrenergic, may be similarly beneficial if used daily.
Treatment options to consider in recalcitrant disease include dermabrasion, CO2 laser therapy, systemic retinoids, methotrexate, afamelanotide, and lesional excision. These options should be performed or prescribed by only those familiar with the disease and the risks and benefits of these therapies.
Although HHD generally poses no risk of mortality, it negatively impacts the patient’s quality of life. Daily activities can be altered by lesional pain, and lesional unsightliness and odor can cause embarrassment and social ostracization. Although rare, a squamous cell carcinoma may develop within a chronic lesion, so patients should be examined on a regular basis.6 Fortuitously, HDD decreases in intensity and frequency as patients age.1,3
For the patient in this case, the diagnosis of HHD was confirmed by biopsy. Results of direct immunofluorescence were negative. The patient had complete resolution of her lesions with the use of topical fluocinonide, mupirocin, and nystatin creams.
Sarah Simpson is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.
- Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol Syphilol. 1939;39:679-685.
- Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Hailey-Hailey disease: A fold (intertriginous) dermatosis. Clin Dermatol. 2015;33:452-455.
- Burge SM. Hailey-Hailey disease: the clinical features, response to treatment, and prognosis. Br J Dermatol. 1992;126:275-282.
- Engin B, Kutlubay Z, Erkan E, Tüzün Y. Darier disease: A fold (intertriginous) dermatosis. Clin Dermatol. 2015;33:448-451.
- Cialfi S, Le Pera L, De Blasio C, et al. The loss of ATP2 C1 impairs the DNA damage response and induces altered skin homeostasis: consequences for epidermal biology in Hailey-Hailey disease. Sci Rep. 2016;6:31567.
- Arora H, Bray FN, Cervantes J, Falto Aizpurua LA. Management of familial benign chronic pemphigus. Clin Cosmet Investig Dermatol. 2016;14:281-290.