Background

This blistering disease is autosomal dominantly inherited. It is characterized by crusted vesicles and bullae that often form circinate patches. With time and drying, deep fissures may form. The lesions characteristically involve the axillae, neck, inframammary area, groin, and perineum. Longitudinal white bands on the nails are characteristic. It is a chronic disease that recurs and remits.

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Benign familial pemphigus
AGE RANGE-MEDIAN	2-4th decades

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
HLA B16
Increased susceptibility to allegic contact dermatitis

 

PATHOGENESIS	CHARACTERIZATION
Autosomal dominant	Variable penetrance Chromosome 3q
Mechanism of acantholysis	Dissolution of desmosomal attachment plaque constituents desmoplakin 1 and 2 and plakoglobin which diffuse into the acantholytic cell cytoplasm
ATP2C1 GENE
Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, Healy E, Dissanayake M, Larregue M, Perrussel M, Lehrach H, Munro CS, Strachan T, Burge S, Hovnanian A, Monaco AP. Max-Planck-Institut fur Molekulare Genetik, D-14195 Berlin, Germany.	Hum Mol Genet 2000 Apr 12;9(7):1131-40 Abstract quote Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and non-conservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity.
Mutations of ATP2C1 in Japanese patients with Hailey-Hailey disease: intrafamilial and interfamilial phenotype variations and lack of correlation with mutation patterns. Ikeda S, Shigihara T, Mayuzumi N, Yu X, Ogawa H. Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan	J Invest Dermatol 2001 Dec;117(6):1654-6 Abstract quote We report herein mutations of ATP2C1 in 11 Japanese patients with Hailey-Hailey disease gene (including five previously reported) and compare the mutation pattern with clinical phenotypes. Patients with missense mutations and some of those with mutations causing premature termination showed erythema and erosions primarily at intertriginous areas. In two families with unique mutations, one with an in-frame three amino acid deletion plus an eight amino acid insertion and one with a two base pair deletion predicted to cause premature truncation, some affected individuals had unique clinical features -- generalization of Hailey-Hailey disease and generalized skin eruption resembling keratotic papules in Darier's disease -- but other affected individuals did not, suggesting the presence of severe intrafamilial phenotype variations. Our findings suggest that differences in clinical phenotypes are probably related to factors other than the type of causative mutation.
Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. Dobson-Stone C, Fairclough R, Dunne E, Brown J, Dissanayake M, Munro CS, Strachan T, Burge S, Sudbrak R, Monaco AP, Hovnanian A. The Wellcome Trust Center For Human Genetics, University of Oxford, UK.	J Invest Dermatol 2002 Feb;118(2):338-43 Abstract quote Hailey-Hailey disease is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Mutations in ATP2C1, the gene encoding a novel, P-type Ca2+-transport ATPase, were recently found to cause Hailey-Hailey disease. In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey-Hailey disease families and three sporadic cases with the disorder. We identified 22 different mutations, 18 of which have not previously been reported, in 25 probands. The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene. Six mutations were found in multiple families investigated here or in our previous study. Haplotype analysis revealed that two of these are recurrent mutations that have not been inherited from a common ancestor. Comparison between genotype and phenotype in 23 families failed to yield any clear correlation between the nature of the mutation and clinical features of Hailey-Hailey disease. The extensive interfamilial and intrafamilial phenotypic variability observed suggests that modifying genes and/or environmental factors may greatly influence the clinical features of this disease.
Mutation analysis of ATP2C1 gene in Taiwanese patients with Hailey-Hailey disease. Chao SC, Tsai YM, Yang MH. Department of Dermatology, College of Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Road, 704 Tainan, Taiwan.	Br J Dermatol 2002 Apr;146(4):595-600 Abstract quote Background Hailey-Hailey disease (HHD) is an autosomal dominant disorder with recurrent eruption of vesicles and bullae involving predominantly the neck, groin and axillary regions. Histopathology shows suprabasal cleavage in epidermal cells. Recent studies have revealed that HHD is caused by mutations in the ATP2C1 gene encoding a novel Ca2+ pump. Objectives To analyse the mutations of the ATP2C1 gene in Taiwanese patients with HHD. Methods In total, five familial and two sporadic cases of HHD were retrieved from the medical records. The diagnosis of HHD was made based on the characteristic clinical features and histopathological evidence. All 27 exons and flanking intron boundaries were amplified by polymerase chain reaction and products analysed by direct sequencing. Results We identified six novel mutations and one reported mutation: three deletion mutations (nt884-904del, 1459delCTCA, 1975delA), two non-sense mutations (R39X, R783X), one mis-sense mutation (A730T) and one splicing mutation (483 + 2T-->A). The non-sense mutation R39X had been reported previously; the other six mutations are novel mutations. Conclusions These results demonstrate that a spectrum of ATP2C1 gene mutations is present in Taiwanese HHD patients.
CADHERIN
Dissociation of intra- and extracellular domains of desmosomal cadherins and E-cadherin in Hailey-Hailey disease and Darier's disease. Hakuno M, Shimizu H, Akiyama M, Amagai M, Wahl JK, Wheelock MJ, Nishikawa T. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.	Br J Dermatol 2000 Apr;142(4):702-11 Abstract quote In order to clarify the pathomechanism of acantholysis in Hailey-Hailey disease (HHD) and Darier's disease (DD), the distribution of desmosomal and adherens junction-associated proteins was studied in the skin of patients with HHD (n = 4) and DD (n = 3). Domain-specific antibodies were used to determine the cellular localization of the desmosomal transmembrane glycoproteins (desmogleins 1 and 3 and desmocollin), desmosomal plaque proteins (desmoplakin, plakophilin and plakoglobin) and adherens junction-associated proteins (E-cadherin, alpha-catenin, beta-catenin and actin). A significant difference in staining patterns between intra- and extracellular domains of desmosomal cadherins and E-cadherin was demonstrated in acantholytic cells in both HHD and DD, but not in those in pemphigus vulgaris and pemphigus foliaceus samples used as controls. In acantholytic cells in HHD and DD, antibodies against attachment plaque proteins and intracellular epitopes of desmosomal cadherins exhibited diffuse cytoplasmic staining, whereas markedly reduced staining was observed with antibodies against extracellular epitopes of the desmogleins. Similarly, membrane staining of an intracellular epitope of E-cadherin was preserved, while immunoreactivity of an extracellular epitope of E-cadherin was destroyed. While the DD gene has been identified as ATP2A2, the gene for HHD has not been clarified. The dissociation of intra- and extracellular domains of desmosomal cadherin and E-cadherin is characteristic of the acantholytic cells in HHD and DD, and not of pemphigus. This common phenomenon in HHD and DD might be closely related to the pathophysiological mechanisms in both conditions.
Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darier’s disease Megumi Hakuno, etal.	Journal of Cutaneous Pathology 28 (6), 277-281 Abstract quote Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier’s disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases. Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299. Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.

 

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Hyperkeratotic
Verrucous
Neurodermatitis
Papular
Relapsing linear acantholytic dermatosis	J Am Acad Dermatol 1995;33:920-922 Confined to a unilateral distribution following the lines of Blaschko

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Classically described as a dilapidated brick wall with full thickness acantholysis and downward proliferation of epidermal strands Rare corp ronds and corp grains Sparing of the adnexal structures
VARIANTS

 

SPECIAL STAINS/IMMUNOHISTOCHEMISTRY	CHARACTERIZATION
ELECTRON MICROSCOSCOPY
Internalization of gap junctions in benign familial pemphigus (Hailey-Hailey disease) and keratosis follicularis (Darier's disease). Haftek M, Kowalewski C, Mesnil M, Blaszczyk M, Schmitt D. INSERM U.346/CNRS 'Human Skin and Immunity', Hopital E.Herriot, 69437 Lyon cedex 03, France.	Br J Dermatol 1999 Aug;141(2):224-30 Abstract quote Hereditary skin disorders involving acantholysis, such as Hailey-Hailey disease and Darier's disease, have been genetically linked to distinct chromosomal parts which do not code for known structural proteins. Such evidence suggests that the genomic abnormalities underlying these dermatoses may concern functional/regulatory mechanisms of keratinocyte cohesion. Epidermal communication junctions (gap junctions) are responsible for direct coupling of cells and, thus, co-ordinate the behaviour of keratinocytes within the tissue. Consequently, they remain one of the potential, and poorly studied, elements in the pathogenesis of hereditary acantholytic diseases. We have investigated the distribution and fate of gap junctions during non-immune acantholysis, using fine immunolocalization methods at the light and electron microscopic levels. Our results demonstrate normal expression of epidermal gap junction proteins, connexins 26 and 43, in non-lesional skin of Hailey-Hailey and Darier's diseases. The gap junctions were not primarily dismantled during acantholysis, typical of both of the studied dermatoses, but underwent internalization and subsequent cytoplasmic dispersion in the portions of cells which were no longer attached to the rest of the tissue. In Darier's disease, perifollicular acantholysis did not specifically concern epithelium of appendages coexpressing connexin 26 in addition to connexin 43, further indicating that the observed changes in gap junction localization were secondary to the loss of cell-cell contact. We demonstrated that the sequence of changes was identical in both diseases and that the previously described putative differences were apparently related to the degree of acantholysis present in the studied biopsies. The fate of the junctional structures and proteins, documented in the present study, is most probably a form of recycling process also used by normal keratinocytes during organogenesis and tissue differentiation.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
GROVER'S DISEASE
Grover's disease: clinicopathologic review of 72 cases. Davis MD, Dinneen AM, Landa N, Gibson LE. Department of Dermatology, Mayo Clinic Rochester, MN 55905, USA.	Mayo Clin Proc 1999 Mar;74(3):229-34 Abstract quote OBJECTIVE: To report the clinicopathologic findings in patients with Grover's disease. MATERIAL AND METHODS: We reviewed the medical records and biopsy specimens from 72 patients with transient acantholytic dermatosis (Grover's disease) examined at Mayo Clinic Rochester. Hematoxylin-eosin-stained biopsy specimens (from all patients) were assessed. Immunohistochemistry stains BRST-2, CAM 5.2, and CD44 were used to stain eight specimens. Direct immunofluorescence reports were reviewed. Selected specimens were stained by indirect immunofluorescence to detect major basic protein. RESULTS: Of the 72 patients, 63 (88%) were men, and the mean age was 48 years (range, 31 to 85). Lesions were distributed mainly on the trunk (in 71 patients) and proximal extremities (in 25). Heat and sweating frequently were exacerbating factors. Fifteen patients (21%) were bedbound. Concurrent nondermatologic malignant disease was present in 18 patients (25%). Two patients (3%) had acquired immunodeficiency syndrome. Follow-up in 28 patients (mean, 38 months; range, 3 months to 7 years) revealed that the disease had recurred in 13, persisted in 3, and resolved in 12. Review of the biopsy specimens showed that acantholysis was pemphigus vulgaris-like in 40 patients (56%), Darier's disease-like in 16 (22%), spongiotic in 12 (17%), pemphigus foliaceus-like in 2 (3%), and Hailey-Hailey disease-like in 2 (3%). A perivascular lymphocytic infiltrate of varied intensity in 64 specimens (89%) was associated with eosinophils in 16 (22%). In nine biopsy specimens with dermal eosinophilia stained for major basic protein, varied dermal cellular and extracellular deposition of major basic protein was present. Results of direct immunofluorescence studies, performed in 17 cases, were negative or nonspecific. CD44 stained acantholytic areas in addition to sweat glands in two of eight specimens (25%). CONCLUSION: Further studies of the pathogenesis of Grover's disease are needed. The predisposing conditions, site of involvement, and relapsing nature of this disorder may implicate acrosyringeal dysfunction as the cause.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	J Cutan Pathol 1988;15:234-237 Squamous cell carcinomas have developed in lesions
Squamous cell carcinoma arising in Hailey-Hailey disease. Holst VA, Fair KP, Wilson BB, Patterson JW. Departments of Pathology and Dermatology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0214, USA.	J Am Acad Dermatol 2000 Aug;43(2 Pt 2):368-71 Abstract quote Hailey-Hailey disease is a recurrent, autosomal dominant vesiculobullous dermatotis with a predilection for intertrigenous areas. We report what we believe to be the first case of squamous cell carcinoma arising de novo in a skin lesion of Hailey-Hailey disease. The occurrence of malignant neoplasms arising in the skin lesions of Hailey-Hailey disease and other acantholytic dermatoses is reviewed.
TREATMENT
DERMABRASION
Type 2 segmental manifestation of Hailey-Hailey disease: poor therapeutic response to dermabrasion is due to severe involvement of adnexal structures. Konig A, Horster S, Vakilzadeh F, Happle R. Department of Dermatology, Philipp University, Deutschhausstrasse 9, D-35033 Marburg, Germany.	Eur J Dermatol 2000 Jun;10(4):265-8 Abstract quote In autosomal dominant skin conditions, two different types of segmental manifestation can be distinguished. Type 1 represents heterozygosity for a postzygotic mutation, resulting in a degree of severity similar to that of the nonmosaic phenotype. Type 2 reflects loss of heterozygosity and shows an excessively pronounced involvement superimposed on the ordinary nonsegmental phenotype. We describe the clinical, histopathological and therapeutic aspects of the first case of type 2 segmental manifestation of Hailey-Hailey disease (HHD). A 24-year-old woman with a family history of HHD comprising four generations, presented with lesions of erythema and blistering arranged in a unilateral pattern following the lines of Blaschko. The disorder was first noted at the age of 3 months. At the age of 24 years, additional scattered symmetrical lesions involving the axillary and inguinal folds were noted. Histopathological examination of the severely involved linear skin areas revealed pronounced acantholysis within the deep adnexal structures, whereas clinically unaffected skin showed the typical histopathological features of the heterozygous phenotype with suprabasal clefting and acantholysis sparing the adnexae. Dermabrasion was performed in the areas of segmental involvement. During a follow-up period of one year, no recurrence was noted, but 18 months after dermabrasion a recurrence was present in the left submammary and left perianal regions. This therapeutic resistance to dermabrasion may be explained by the presence of acantholysis within the adnexal structures of the skin as found in type 2 segmental HHD.
LASER
Benign familial pemphigus (Hailey-Hailey disease). Treatment with the pulsed carbon dioxide laser. Touma DJ, Krauss M, Feingold DS, Kaminer MS. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.	Dermatol Surg 1998 Dec;24(12):1411-4 Abstract quote BACKGROUND: Benign familial pemphigus (BFP) is a chronic blistering disease with significant morbidity. Surgical methods are often needed to control flares in difficult cases. OBJECTIVE: To describe the response of BFP to vaporization with a pulsed carbon dioxide (CO2) laser. METHODS: A 38-year-old woman with chest and axillary involvement unresponsive to conventional therapy was treated with the UltraPulse 5000 Laser (Coherent Medical Group, Palo Alto, CA). After active sites of BFP showed good response to treatment, we treated uninvolved skin of the left axilla to assess the efficacy of prophylactic therapy. RESULTS: Treatment of affected areas, except biopsy sites, resulted in clearing of active lesions after 1-2 weeks. We noted striking sparing of the treated areas from developing subsequent disease. The region that was later treated prophylactically has shown minor, asymptomatic recurrence of BFP in less than 5% of the area treated over an 18-month follow-up period. CONCLUSION: The pulsed carbon dioxide laser is a useful modality in treatment of BFP. In our patient, prophylactic treatment led to near complete eradication of disease in the treated area. A controlled, larger study is needed to confirm our results, and to determine optimal laser parameters. Long-term effects and duration of remission remain to be determined.
Treatment of Hailey-Hailey disease (or benign familial pemphigus) using short pulsed and short dwell time carbon dioxide lasers. Christian MM, Moy RL. West Los Angeles Veterans Medical Center, Los Angeles, CA 90024, USA.	Dermatol Surg 1999 Aug;25(8):661-3 Abstract quote BACKGROUND: Surgical intervention of Hailey-Hailey disease (HHD) may be required to achieve prolonged remission or cure. Excisional surgery, dermabrasion, and continuous carbon dioxide (CO2) laser therapies have been utilized with success, though patients may experience considerable morbidity. OBJECTIVE: To evaluate the use of short pulsed and short dwell time CO2 lasers in the treatment of HHD. METHOD: Case report and review of the relevant literature. RESULTS: A 26-year-old woman with refractory axillary HHD was initially treated with a short dwell time CO2 laser. The right axilla was treated with two passes at a fluence of 25 J/cm2, and the left axilla with three passes at 28 J/cm2. Three years later, several foci within each axilla that periodically blistered were further treated with two passes of a short pulsed CO2 laser at a fluence of 15 J/cm2. At a 3.5-year follow-up, the patient reported continued resolution of her left axilla but disease persistence in her right axilla. CONCLUSION: HHD can be effectively treated with a short dwell time CO2 laser if appropriate laser parameters are used.
PHOTODYNAMIC THERAPY
Photodynamic therapy with 5-aminolevulinic acid for recalcitrant familial benign pemphigus (Hailey-Hailey disease). Ruiz-Rodriguez R, Alvarez JG, Jaen P, Acevedo A, Cordoba S. Departments of Dermatology and Pathology, Clinica Ruber, Madrid, and the Department of Dermatology, Hospital Universitario de Guadalajara	J Am Acad Dermatol 2002 Nov;47(5):740-2 Abstract quote Familial benign pemphigus is a chronic, recurrent, autosomal dominant blistering disease that may significantly affect quality of life. Surgical methods are often needed to control flares in difficult cases. We describe the use of photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) followed by irradiation with incoherent light (ALA-PDT) in 2 patients with chronic, recalcitrant familial benign pemphigus.

Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

Skin Rashes

Last Updated 11/16/2002

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