A Painful, Blistering, Malodorous Rash in a Woman’s Intertriginous Areas
Alexander K. C. Leung, MD, and Benjamin Barankin, MD
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: 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
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
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
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
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
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.
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.
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.
- Barde NG, Mishra DB, Ingole SO. Oral magnesium chloride: a novel approach in the management of Hailey-Hailey disease. Indian J Dermatol Venereol Leprol. 2017;83(2):259-262.
- Reyes MV, Halac S, Mainardi C, Kurpis M, Ruiz Lascano A. Familial benign pemphigus atypical localization. Dermatol Online J. 2016;22(4):12.
- Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Derm Syphilol. 1939;39(4):679-685.
- Li H, Chen L, Mei A, et al. Four novel ATP2C1 mutations in Chinese patients with Hailey-Hailey disease. J Dermatol. 2016;43(10):1197-1200.
- Yadav N, Madke B, Kar S, Prasad K, Gangane N. Hailey-Hailey disease. Indian Dermatol Online J. 2016;7(2):147-148.
- Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Hailey-Hailey disease: a fold (intertriginous) dermatosis. Clin Dermatol. 2015;33(4):452-455.
- Morrell D. Hailey-Hailey disease (benign familial pemphigus). UpToDate. http://www.uptodate.com/contents/hailey-hailey-disease-benign-familial-pemphigus. Updated September 6, 2016. Accessed July 10, 2017.
- Rao AG. Hailey-Hailey disease on sun-exposed areas. Indian J Dermatol. 2013;58(5):412.
- Alkhalifah A, Montaudié H, Lacour J-P, Lantéri-Minet M, Passeron T. Exacerbation of Hailey-Hailey disease by topiramate. J Eur Acad Dermatol Venereol. 2016;31(4):e185-e186.
- Falto-Aizpurua LA, Griffith RD, Yazdani Abyaneh MA, Nouri K. Laser therapy for the treatment of Hailey-Hailey disease: a systematic review with focus on carbon dioxide laser resurfacing. J Eur Acad Dermatol Venereol. 2015;29(6):1045-1052.
- Mauzo SH, Sulit DJ. Hailey-Hailey disease exacerbated by multiple pregnancies: case report and review of the literature. Dermatol Online J. 2014;20(10):10.
- Arora H, Bray FN, Cervantes J, Falto Aizpurua LA. Management of familial benign chronic pemphigus. Clin Cosmet Investig Dermatol. 2016;9:281-290.
- Farahnik B, Blattner CM, Mortazie MB, Perry BM, Lear W, Elston DM. Interventional treatments for Hailey-Hailey disease. J Am Acad Dermatol. 2017;76(3):551-558.e3.
- Ortiz AE, Zachary CB. Laser therapy for Hailey-Hailey disease: review of the literature and a case report. Dermatol Reports. 2011;3(2):e28.
- Bel B, Soudry-Faure A, Vabres P. Diagnostic value of nail examination in Hailey-Hailey disease. Eur J Dermatol. 2014;24(5):628-629.
- Kostaki D, Castillo JC, Ruzicka T, Sárdy M. Longitudinal leuconychia striata: is it a common sign in Hailey-Hailey and Darier disease? J Eur Acad Dermatol Venereol. 2014;28(1):126-127.
- Kelati A, Argenziano G, Mernissi FZ. Dermoscopic presentation of Hailey-Hailey disease. J Am Acad Dermatol. 2017;76(2S1):S31-S33.
- Leung AKC, Barankin B. Itchy, smelly lesions and streaked nails in a teenager (Darier disease). Consultant Pediatricians. 2014;13(3):118-121.
- Ruocco V, Ruocco E, Caccavale S, Gambardella A, Lo Schiavo A. Pemphigus vegetans of the folds (intertriginous areas). Clin Dermatol. 2015;33(4):471-476.
- Tchernev G, Cardoso JC. Familial benign chronic pemphigus (Hailey-Hailey disease): use of topical immunomodulators as a modern treatment option. Rev Med Chil. 2011;139(5):633-637.
- D’Errico A, Bonciani D, Bonciolini V, et al. Hailey-Hailey disease treated with methotrexate. J Dermatol Case Rep. 2012;6(2):49-51.
- 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.
- Hochwalt PC, Christensen KN, Cantwell SR, et al. Carbon dioxide laser treatment for Hailey-Hailey disease: a retrospective chart review with patient-reported outcomes. Int J Dermatol. 2015;54(11):1309-1314.
- 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.
- Flores-Terry MÁ, Cortina-de la Calle MP, López-Nieto M, Cruz-Conde de Boom R. Good response to doxycycline in Hailey-Hailey disease. Actas Dermosifiliogr. 2016;107(6):537-539.
- Le Saché-de Peufeilhoux L, Raynaud E, Bouchardeau A, Fraitag S, Bodemer C. Familial benign chronic pemphigus and doxycycline: a review of 6 cases. J Eur Acad Dermatol Venereol. 2014;28(3):370-373.
- Bagherani N, Smoller BR. The efficacy of botulinum toxin type A in the treatment of Hailey-Hailey disease. Dermatol Ther. 2016;29(6):394-395.
- Kaniszewska M, Rovner R, Arshanapalli A, Tung R. Oral glycopyrrolate for the treatment of Hailey-Hailey disease. JAMA Dermatol. 2015;151(3):328-329.
- White F, Shvartsbeyn M, Meehan SA, Urbanek RW. Benign familial pemphigus (Hailey-Hailey disease). Dermatol Online J. 2015;21(12):7.
- Sárdy M, Ruzicka T. Successful therapy of refractory Hailey-Hailey disease with oral alitretinoin. Br J Dermatol. 2014;170(1):209-211.
- Varada S, Ramirez-Fort MK, Argobi Y, Simkin AD. Remission of refractory benign familial chronic pemphigus (Hailey-Hailey disease) with the addition of systemic cyclosporine. J Cutan Med Surg. 2015;19(2):163-166.
- Hunt KM, Jensen JD, Walsh SB, et al. Successful treatment of refractory Hailey-Hailey disease with a 595-nm pulsed dye laser: a series of 7 cases. J Am Acad Dermatol. 2015;72(4):735-737.
- Lobato-Berezo A, Imbernón-Moya A, Aguilar-Martínez A. Refractory Hailey-Hailey disease that responded well to photodynamic therapy. Actas Dermosifiliogr. 2015;106(10):852-854.
- Yan XX, Tian HQ, Wang CL, Yang BQ, Wu WZ, Zhang FR. Successful treatment of Hailey-Hailey disease with aminolevulinic acid photodynamic therapy. Ann Dermatol. 2015;27(2):222-223.
- Son JH, Cho YS, Byun YS, Chung BY, Park CW, Kim HO. The effect of cryotherapy in Hailey-Hailey disease. Ann Dermatol. 2017;29(1):117-118.
- Jeon S-Y, Ha S-M, Ko D-Y, Song K-H, Kim K-H. Hailey-Hailey disease treated with topical tacalcitol. Ann Dermatol. 2013;25(3):389-390.
- Tang MBY, Tan EST. Hailey-Hailey disease: effective treatment with topical cadexomer iodine. J Dermatolog Treat. 2011;22(5):304-305.
- Biolcati G, Aurizi C, Barbieri L, Cialfi S, Screpanti I, Talora C. Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey-Hailey disease. Clin Exp Dermatol. 2014;39(2):168-175.