Benign Chronic Pemphigus

A number sign (#) is used with this entry because of evidence that Hailey-Hailey disease is caused by heterozygous mutation in the ATP2C1 gene (604384) on chromosome 3q22.


Hailey-Hailey disease, also known as benign chronic pemphigus, is a rare autosomal dominant cutaneous disorder that usually becomes manifest in the third or fourth decade of life with erythema, vesicles, and erosions involving the body folds, particularly the groin and axillary regions. Other sites of the body, such as the neck, perianal, and submammary regions, may likewise be affected (summary by Poblete-Gutierrez et al., 2004).

This disorder was first described by the dermatologist brothers Hailey and Hailey (1939).

Clinical Features

Loewenthal (1959) thought that pyogenic bacteria act as a precipitating factor. This possibility was supported by the beneficial effects of antibiotics, use of which has converted this condition into a relatively insignificant disorder. In 4 cases of 1 family, Burns et al. (1967) and Wilson et al. (1968) found Candida albicans in the lesions and found that the fungus would induce lesions in previously uninvolved skin.

Ultraviolet radiation, heat, sweating, and infection of the skin can provoke the abnormality. Malchus et al. (1986) claimed an increased frequency of HLA-B16. Lesions have been reported in a more generalized distribution on the skin (Marsch and Stuttgen, 1978) and even on mucosal surfaces, including those of the vagina, buccal mucosa, and esophagus (Burge, 1992; Wieselthier and Pincus, 1993). In addition, longitudinal white striae of the fingernails may be present. Onset usually is in the third to fourth decade but is delayed until after age 40 in approximately 12% of patients.

See also acrokeratosis verruciformis (101900) and Darier-White disease (124200).

Burge et al. (1991) demonstrated a widespread subclinical abnormality in keratinocyte adhesion in this disorder. They postulated defective adhesion junctions. In Darier disease, on the other hand, abnormal cell adhesion was demonstrable only in clinically involved skin. The studies were done with suction cups to induce blisters with a quantitative application of negative pressure.

Burge (1992) studied 58 patients. The disorder generally presented between the second and fourth decades but delay in diagnosis was common. Asymptomatic longitudinal white bands in the fingernails were found in 71% of 38 patients examined and was considered a helpful physical sign. The nail change had not previously been documented. The disorder is predominantly flexural. Friction and heat or sweating exacerbate the lesions and pain may limit physical activities.


The 58 patients studied by Burge (1992) were distributed in 31 families; 9 patients had no family history of Hailey-Hailey disease. The pedigree pattern was consistent with autosomal dominant inheritance.


By linkage analysis, Ikeda et al. (1994) mapped the locus for Hailey-Hailey disease to a region of chromosome 3q between D3S1589 and D3S1316. The maximum combined 2-point lod score in the 4 families studied was 14.60 at theta = 0.0 at the D3S1290 microsatellite repeat. The findings suggested the existence of a gene not previously known to be involved in keratinocyte cohesion at this site. A large number of other candidate genes thought to be important in adhesion in the epidermis had previously been excluded by linkage studies.

Richard et al. (1995) refined the localization of the HHD locus by linkage analysis in 6 German and Italian families using polymorphic microsatellite markers. No evidence of genetic heterogeneity was found. They observed complete cosegregation between HHD and D3S1587, with a maximum lod score of 4.54. Haplotype analyses allowed them to narrow the interval containing the HHD locus to 5 cM, flanked by D3S1589 and D3S1290. The approximate location was stated to be 3q21-q24.

Peluso et al. (1995) narrowed the HHD locus to a region flanked by D3S1589 and D3S1541. The centromeric end of a deletion observed in 1 affected family was located between these 2 markers.

Clinical Management

Izumi et al. (1971) found neomycin to be a precipitating factor in one of their patients. Berger and Lynch (1971) suggested that environmental conditions resulting in maceration and sweating could induce lesions on areas not limited to the neck, axilla, and groin. Reitamo et al. (1989) concluded that there is an increased frequency of contact allergies in patients with Hailey-Hailey disease. This fact may limit the use of a topical therapy with antibacterial or antimycotic agents. Mucosal involvement seems to be rare.

Burge (1992) assessed the prognosis in 27 patients and concluded that the long-term outlook is generally good; 17 patients had improved and the disease was static in 7 patients. Topical corticosteroids with or without added antibiotics were an effective treatment. Kartamaa and Reitamo (1992) obtained satisfactory therapeutic results with carbon dioxide laser vaporization.

Molecular Genetics

In 21 kindreds with HHD, Hu et al. (2000) identified mutations in the ATP2C1 gene (e.g., 604384.0001-604384.0003), which encodes the human homolog of an ATP-powered pump that sequesters calcium into the Golgi in yeast. Regulation of cytoplasmic calcium was impaired in cultured keratinocytes from HHD patients, and the normal epidermal calcium gradient was attenuated in vivo in HHD patients. Their findings not only provided an understanding of the molecular basis of HHD, but also underscored the importance of calcium control to the functioning of stratified squamous epithelia.

In a patient with unilateral segmental exacerbations of HHD, originally reported by Vakilzadeh and Kolde (1985), Poblete-Gutierrez et al. (2004) identified heterozygosity for a splice site mutation in exon 22 of the ATP2C1 gene (604384.0009). Haplotype analysis of the more severely affected segmental skin regions revealed consistent loss of the paternal wildtype allele, confirming the authors' hypothesis that such segmental exacerbations represent a form of mosaicism with hemizygosity for the mutation.