Inflamed, Hyperpigmented Axillary Plaque

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare genetic dermatosis that causes keratinocyte acantholysis and disruption of the desmosome-keratin complexes in the suprabasal layers of the epidermis.1 Howard and Hugh Hailey first characterized it in...

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Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare genetic dermatosis that causes keratinocyte acantholysis and disruption of the desmosome-keratin complexes in the suprabasal layers of the epidermis.¹ Howard and Hugh Hailey first characterized it in 1939 in their case study of 2 adult brothers with a unique blistering syndrome.² The disease is caused by an autosomal-dominant mutation in the ATP2C1 gene, which codes for a calcium ATPase that sequesters calcium in the Golgi apparatus and is highly expressed in epidermal keratinocytes.³ The dysregulation of intracellular calcium signaling is thought to affect the normal keratinocyte adhesion and lead to epidermal defects.

Clinically, HHD occurs as small vesicular lesions, erythematous scaly plaques and papules, or weeping and crusted erosions. Most commonly, these lesions affect the neck, groin, perineum, axillae, and other intertriginous regions of the skin. Other rare symptoms include involvement of the mouth, scalp, vulva, and esophagus, and linear white discoloration of the fingernails.⁴ The lesions may be painful or itchy, and symptoms are exacerbated or induced by heat, sweat, sun exposure, and friction.⁵ Thus, patients are often more symptomatic in the summer than in the winter and experience discomfort wearing tight clothing such as bras and shirt collars.¹ In addition, some female patients experience worsening of premenstrual symptoms.⁶ Secondary bacterial, viral, or fungal infections are also common in affected areas.⁷

Histology studies of HHD show widespread separation of the suprabasal layers, vesicle formation, and presence of acantholytic cells in the epidermis. Dyskeratosis may also be present. Involvement of the dermis is unusual, although signs of lymphocytic infiltration may be present. Ninety-eight mutations in ATP2C1 have been recorded in patients with HHD, and the gene locus is on chromosome 3q21-q24.⁶

The worldwide prevalence of HHD is unknown, although the disease affects men and women at equal rates. No observed difference in frequency by ethnic group is noted.⁸ The disease is fully penetrant in adults but has variable expressivity. The area of onset and affected regions are also variable among patients.¹ Patients with mild symptoms may show involvement only in the nails or may exhibit small skin lesions that resemble eczema. Other patients may have severe painful blistering that can inhibit normal physical activity, especially if it occurs in the groin.⁴ The lesions may have a foul odor and are susceptible to secondary infection, which can affect lifestyle negatively.⁹ Although rare, squamous cell carcinoma may arise from a skin lesion of HHD.¹⁰

Symptoms usually appear during early adulthood, between the ages of 20 and 40 years, although onset can occur from early adolescence to late-middle age. After age 50, many patients experience periods of remission and alleviation of symptoms. However, complete resolution is rare.

Because of the high variability of morphology, expressivity, and general phenotypic characteristics, HHD is often misdiagnosed. The differential diagnosis includes eczema, cutaneous infection, pemphigus vulgaris, and Darier disease. In fact, before the discovery of the mutationin the ATP2C1 gene, many believed that HHD was a vesicular variant of Darier disease, which is also an inherited dermatosis. However, HHD includes more widespread acantholysis and occurs later in life than Darier disease.¹ HHD is differentiated from pemphigus vulgaris because pemphigus vulgaris includes antidesmosomal autoantibodies, whereas HHD does not. Positive family history and a genetic test for the ATP2C1 mutation is the definitive way to diagnose HHD and differentiate it from these other conditions.³

There is no cure for HHD, and the chronic nature of the condition makes treatment challenging. However, several treatments are available, including topical creams, systemic treatments, light therapy, and surgery. In addition, the removal of triggers such as friction, heat, and sweat can help alleviate symptoms. It is important to note that most data about the efficacy of these treatments are based on case reports, not on results of controlled trials, and that the disease tends to wax and wane even without therapy.⁵

The goal of topical treatment is to modulate inflammation and protect against infections that may aggravate symptoms. Corticosteroid creams have been used in combination with topical antimicrobial agents with some success. However, the extended use of topical steroids may lead to skin atrophy, so this a short-term treatment. Long-term control of inflammation has been achieved with topical calcineurin inhibitors, although at least 2 case reports describe the worsening of lesions with this therapy. Other topical agents with reported success include calcitriol, cadexomer iodine powder, and 5-fluorouracil. Botulinum toxin type A injections are also effective for decreasing sudoresis and alleviating symptoms in intertriginous regions.⁵

When topical agents are ineffective or when lesions are widespread, systemic treatments may be more effective. These include oral antimicrobial, steroid, and retinoid medications. Other oral immunosuppressants, such as cyclosporine, may alleviate symptoms by decreasing levels of cytokines in the skin and regulating intracellular calcium levels.⁵ In patients with more severe cases of HHD, treatment with electron beam radiation therapy has shown variable levels of success.⁹ Finally, although surgical treatments such as dermabrasion and excision may lead to morbidity, they may be recommended for patients with debilitating disease.⁵

The patient underwent biopsy, which revealed suprabasal acantholysis. Treatment with topical hydrocortisone cream resulted in minor improvement. After discussion of the various treatment options, the patient opted for therapy with botulinum toxin type A injections and a topical calcineurin inhibitor. The reduction in axillary sweating and inflammation has resulted in significant improvement.

Ariella Noorily, BA, is a medical student and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston, Texas.

References

1. Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126(3):275-282.

2. Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol Syphilol. 1939;39(4):679-685.

3. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1):61-65.

4. Dobson-Stone C, Fairclough R, Dunne E, et al. Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. J Invest Dermatol. 2002;118(2):338-343.

5. Arora H, Bray FN, Cervantes J, Falto Aizpurua LA. Management of familial benign chronic pemphigus. Clin Cosmet Investig Dermatol. 2016;9:281-290.

6. Warycha M, Patel R, Meehan S, Merola JF. Familial benign chronic pemphigus (Hailey-Hailey disease). Dermatol Online J. 2009;15(8):15.

7. Zhao Q-F, Hasegawa T, Komiyama E, Ikeda S. Hailey-Hailey disease: a review of clinical features in 26 cases with special reference to the secondary infections and their control. Dermatologica Sinica. 2017;35:7-11.

8. Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Hailey-Hailey disease: a fold (intertriginous) dermatosis. Clin Dermatol. 2015;33(4):452-455.

9. Graham PM, Melkonian A, Fivenson D. Familial benign chronic pemphigus (Hailey-Hailey disease) treated with electron beam radiation. JAAD Case Rep. 2016;2(2):159-161.

10. Holst VA, Fair KP, Wilson BB, Patterson JW. Squamous cell carcinoma arising in Hailey-Hailey disease. J Am Acad Dermatol. 2000;43(2 Pt 2):368-371.