Hailey-Hailey disease (benign familial pemphigus)
- Dean Morrell, MD
Dean Morrell, MD
- Associate Professor, Department of Dermatology
- University of North Carolina Chapel Hill
Hailey-Hailey disease (HHD) or "benign familial pemphigus" is a rare autosomal dominant disorder that affects the adhesion of epidermal keratinocytes. Initially described by the Hailey brothers in 1939 , this intraepidermal blistering disorder is a chronic condition with multiple recurrences and limited therapeutic options.
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of HHD. Darier disease, a condition that shares many clinical and pathological features with HHD, is discussed separately. (See "Darier disease".)
EPIDEMIOLOGY AND GENETICS
Hailey-Hailey disease (HHD) is a rare disorder. Its prevalence is unknown, since many patients lack an accurate diagnosis or do not seek treatment. The age of onset and clinical manifestations of HHD can vary widely within families, but presentation during childhood is uncommon . There is no apparent difference in prevalence among different ethnic groups.
Genetics — HHD (MIM #169600) is inherited in an autosomal dominant manner with complete penetrance and variable expressivity. Only two-thirds of patients have a family history of HHD; de novo mutations or lack of phenotypic expression in affected family members account for the absence of family history in the remainder. Interfamilial phenotypic variations and the lack of clear genotype-phenotype correlations indicate that environmental and/or other genetic factors may modify the clinical presentation.
Hailey-Hailey disease (HHD) is caused by loss-of-function mutations in the ATP2C1 gene at 3q22.1, which encodes the ATP-powered calcium pump protein hSPCA1that sequesters calcium into the Golgi apparatus . About 100 different mutations, distributed throughout the ATP2C1 gene, have been described in patients with HHD . These mutations, including nonsense, missense, frameshift, and splice-site mutations, are thought to lead to hSPCA1 haploinsufficiency.
- Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol 1939; 39:679.
- Xu Z, Zhang L, Xiao Y, et al. A case of Hailey-Hailey disease in an infant with a new ATP2C1 gene mutation. Pediatr Dermatol 2011; 28:165.
- Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet 2000; 24:61.
- Majore S, Biolcati G, Barboni L, et al. ATP2C1 gene mutation analysis in Italian patients with Hailey-Hailey disease. J Invest Dermatol 2005; 125:933.
- Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004; 114:1467.
- Hwang LY, Lee JB, Richard G, et al. Type 1 segmental manifestation of Hailey-Hailey disease. J Am Acad Dermatol 2003; 49:712.
- Manca S, Magrelli A, Cialfi S, et al. Oxidative stress activation of miR-125b is part of the molecular switch for Hailey-Hailey disease manifestation. Exp Dermatol 2011; 20:932.
- Cialfi S, Oliviero C, Ceccarelli S, et al. Complex multipathways alterations and oxidative stress are associated with Hailey-Hailey disease. Br J Dermatol 2010; 162:518.
- Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992; 126:275.
- Gisondi P, Sampogna F, Annessi G, et al. Severe impairment of quality of life in Hailey-Hailey disease. Acta Derm Venereol 2005; 85:132.
- Flint ID, Spencer DM, Wilkin JK. Eczema herpeticum in association with familial benign chronic pemphigus. J Am Acad Dermatol 1993; 28:257.
- Chen MY, Chiu HC, Su LH, et al. Presence of human papillomavirus type 6 DNA in the perineal verrucoid lesions of Hailey-Hailey disease. J Eur Acad Dermatol Venereol 2006; 20:1356.
- Chan CC, Thong HY, Chan YC, Liao YH. Human papillomavirus type 5 infection in a patient with Hailey-Hailey disease successfully treated with imiquimod. Br J Dermatol 2007; 156:579.
- Holst VA, Fair KP, Wilson BB, Patterson JW. Squamous cell carcinoma arising in Hailey-Hailey disease. J Am Acad Dermatol 2000; 43:368.
- Cockayne SE, Rassl DM, Thomas SE. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva. Br J Dermatol 2000; 142:540.
- Chun SI, Whang KC, Su WP. Squamous cell carcinoma arising in Hailey-Hailey disease. J Cutan Pathol 1988; 15:234.
- Ochiai T, Honda A, Morishima T, et al. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease. Br J Dermatol 1999; 140:509.
- Okunade GW, Miller ML, Azhar M, et al. Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. J Biol Chem 2007; 282:26517.
- Mohr MR, Erdag G, Shada AL, et al. Two patients with Hailey-Hailey disease, multiple primary melanomas, and other cancers. Arch Dermatol 2011; 147:211.
- Weedon D. Disorders of epidermal maturation and keratinization. In: Weedon's Skin Pathology, Third edition, David Weedon. (Ed), Elsevier Health, 2010.
- Wolf R, Oumeish OY, Parish LC. Intertriginous eruption. Clin Dermatol 2011; 29:173.
- Galimberti RL, Kowalczuk AM, Bianchi O, et al. Chronic benign familial pemphigus. Int J Dermatol 1988; 27:495.
- Ikeda S, Suga Y, Ogawa H. Successful management of Hailey-Hailey disease with potent topical steroid ointment. J Dermatol Sci 1993; 5:205.
- Rocha Paris F, Fidalgo A, Baptista J, et al. Topical tacrolimus in Hailey-Hailey disease. Int J Tissue React 2005; 27:151.
- Umar SA, Bhattacharjee P, Brodell RT. Treatment of Hailey-Hailey disease with tacrolimus ointment and clobetasol propionate foam. J Drugs Dermatol 2004; 3:200.
- Persić-Vojinović S, Milavec-Puretić V, Dobrić I, et al. Disseminated Hailey-Hailey disease treated with topical tacrolimus and oral erythromycin: Case report and review of the literature. Acta Dermatovenerol Croat 2006; 14:253.
- Rabeni EJ, Cunningham NM. Effective treatment of Hailey-Hailey disease with topical tacrolimus. J Am Acad Dermatol 2002; 47:797.
- Lapiere JC, Hirsh A, Gordon KB, et al. Botulinum toxin type A for the treatment of axillary Hailey-Hailey disease. Dermatol Surg 2000; 26:371.
- Bessa GR, Grazziotin TC, Manzoni AP, et al. Hailey-Hailey disease treatment with Botulinum toxin type A. An Bras Dermatol 2010; 85:717.
- Koeyers WJ, Van Der Geer S, Krekels G. Botulinum toxin type A as an adjuvant treatment modality for extensive Hailey-Hailey disease. J Dermatolog Treat 2008; 19:251.
- Bagherani N, Smoller BR. The efficacy of botulinum toxin type A in the treatment of Hailey-Hailey disease. Dermatol Ther 2016; 29:394.
- Bianchi L, Chimenti MS, Giunta A. Treatment of Hailey-Hailey disease with topical calcitriol. J Am Acad Dermatol 2004; 51:475.
- Dammak A, Camus M, Anyfantakis V, Guillet G. Successful treatment of Hailey-Hailey disease with topical 5-fluorouracil. Br J Dermatol 2009; 161:967.
- Berth-Jones J, Smith SG, Graham-Brown RA. Benign familial chronic pemphigus (Hailey-Hailey disease) responds to cyclosporin. Clin Exp Dermatol 1995; 20:70.
- Nanda A, Khawaja F, Harbi R, et al. Benign familial pemphigus (Hailey-Hailey disease) responsive to low dose cyclosporine. Indian J Dermatol Venereol Leprol 2010; 76:422.
- 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; 19:163.
- Fairris GM, White JE, Leppard BJ, Goodwin PG. Methotrexate for intractable benign familial chronic pemphigus. Br J Dermatol 1986; 115:640.
- Vilarinho C, Ventura F, Brito C. Methotrexate for refractory Hailey-Hailey disease. J Eur Acad Dermatol Venereol 2010; 24:106.
- Hunt MJ, Salisbury EL, Painter DM, Lee S. Vesiculobullous Hailey-Hailey disease: successful treatment with oral retinoids. Australas J Dermatol 1996; 37:196.
- Berger EM, Galadari HI, Gottlieb AB. Successful treatment of Hailey-Hailey disease with acitretin. J Drugs Dermatol 2007; 6:734.
- Kaniszewska M, Rovner R, Arshanapalli A, Tung R. Oral glycopyrrolate for the treatment of Hailey-Hailey disease. JAMA Dermatol 2015; 151:328.
- Menz P, Jackson IT, Connolly S. Surgical control of Hailey-Hailey disease. Br J Plast Surg 1987; 40:557.
- Aubert JP, Folchetti G, Berbis P, Magalon G. [Surgical treatment of Hailey-Hailey disease or benign chronic familial pemphigus. Apropos of a case of submammary localization]. Ann Chir Plast Esthet 1993; 38:568.
- Don PC, Carney PS, Lynch WS, et al. Carbon dioxide laserabrasion: a new approach to management of familial benign chronic pemphigus (Hailey-Hailey disease). J Dermatol Surg Oncol 1987; 13:1187.
- Kukova G, Homey B, Bruch-Gerharz D, Diedrichson E. [Familial benign chronic pemphigus (Hailey-Hailey disease): successful treatment with carbon dioxide laser]. Hautarzt 2011; 62:258.
- McElroy JA, Mehregan DA, Roenigk RK. Carbon dioxide laser vaporization of recalcitrant symptomatic plaques of Hailey-Hailey disease and Darier's disease. J Am Acad Dermatol 1990; 23:893.
- 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; 72:735.
- 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; 29:1045.
- Stolze I, Hamm H, Weyandt GH. Segmental multilayered argon plasma coagulation: effective therapy option for perianal and scrotal Hailey-Hailey disease. Colorectal Dis 2011; 13:802.
- Isbary G, Morfill G, Zimmermann J, et al. Cold atmospheric plasma: a successful treatment of lesions in Hailey-Hailey disease. Arch Dermatol 2011; 147:388.
- LeBlanc KG Jr, Wharton JB, Sheehan DJ. Refractory Hailey-Hailey disease successfully treated with sandpaper dermabrasion. Skinmed 2011; 9:263.
- Hamm H, Metze D, Bröcker EB. Hailey-Hailey disease. Eradication by dermabrasion. Arch Dermatol 1994; 130:1143.
- Kirtschig G, Gieler U, Happle R. Treatment of Hailey-Hailey disease by dermabrasion. J Am Acad Dermatol 1993; 28:784.
- Ruiz-Rodriguez R, Alvarez JG, Jaén P, et al. Photodynamic therapy with 5-aminolevulinic acid for recalcitrant familial benign pemphigus (Hailey-Hailey disease). J Am Acad Dermatol 2002; 47:740.
- Fernández Guarino M, Ryan AM, Harto A, et al. Experience with photodynamic therapy in Hailey-Hailey disease. J Dermatolog Treat 2008; 19:288.
- Lobato-Berezo A, Imbernón-Moya A, Aguilar-Martínez A. Refractory Hailey-Hailey Disease That Responded Well to Photodynamic Therapy. Actas Dermosifiliogr 2015; 106:852.
- Graham PM, Melkonian A, Fivenson D. Familial benign chronic pemphigus (Hailey-Hailey disease) treated with electron beam radiation. JAAD Case Rep 2016; 2:159.
- EPIDEMIOLOGY AND GENETICS
- CLINICAL PRESENTATION AND COURSE
- Clinical course
- Risk of squamous cell carcinoma
- Differential diagnosis
- General measures
- Topical therapies
- Systemic therapies
- Surgical or destructive therapies
- THERAPEUTIC APPROACH
- SUMMARY AND RECOMMENDATIONS