NORD gratefully acknowledges Theodora Mauro, MD, Professor in Residence and Vice-Chair, Dermatology Department, University of California, San Francisco and Dermatology Service Chief, San Francisco Veterans Hospital, for assistance in the preparation of this report.
The symptoms and severity of Hailey-Hailey disease varies from one person to another, even among members of the same family. In most cases, there is a family history of the disorder.
Hailey-Hailey usually first appears as an erosive, blistering skin rash, most often affecting the armpits, neck, chest and groin. The lesions may develop a yellow crusty overlying layer. In many cases, the rash may itch or cause a burning sensation. The lesions can separate leaving painful, cracked skin. Secondary infection of the skin lesions can also occur and may cause an unpleasant odor.
The skin lesions that characterize Hailey-Hailey disease are generally relapsing and remitting, which means that they go away on their own but recur periodically. The length of an outbreak and the time between the lesions going away and a recurrence varies. When the lesions heal, they generally do not leave scars. The skin lesions are worsened by friction, heat, injury and sun exposure.
Hailey-Hailey disease can occur randomly due to a spontaneous genetic change (i.e., new mutation) in the ATP2C1 gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that the ATP2C1 gene is located on the long arm (q) of chromosome 3 (3q-21-q24). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q21-q24” refers to bands 21-24 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The ATP2C1 gene contains instructions for creating (encoding) a protein that acts as a calcium and magnesium pump in the cells. This protein pumps calcium or magnesium ions into a specialized organelle in the cell known as the Golgi apparatus. Calcium ions play an essential role in cell-to-cell adhesion and, when the calcium pump does not function properly, the affected cells will not stick together, damaging the skin (acantholysis). The exact process by which loss or improper function of the protein product of the ATP2C1 gene causes Hailey-Hailey disease is not fully understood. The protein is most active in keratinocytes, the main cell type of the outermost layer of skin (epidermis). Failure of keratinocytes to stick together results in the blistering seen in the disease.
Hailey-Hailey disease affects males and females in equal numbers. According to one estimate, the disorder affects 1 in 50,000 people in the general population. Hailey-Hailey disease often goes misdiagnosed or undiagnosed, making it difficult to determine its true frequency in the general population.
Although Hailey-Hailey disease usually becomes apparent around puberty, some cases do not develop until the third or fourth decade. Hailey-Hailey disease was first described in the medical literature in 1939.
A diagnosis of Hailey-Hailey disease is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests including the surgical removal and microscopic examination (biopsy) of affected skin tissue. A biopsy may reveal abnormal formation of keratin tissue (keratinization) and failure of cell-to-cell adhesion (acantholysis). Blood tests in individuals with Hailey-Hailey disease will fail to detect antibodies, which rules out autoimmune disorders such as pemphigus.
The treatment of Hailey-Hailey disease is directed toward the specific symptoms that are apparent in each individual. Specific therapies depend upon several factors including the extent and severity of the disease and an individual’s age and general health.
Individuals with Hailey-Hailey disease are encouraged to avoid “triggers” such as sunburn, sweating and friction and to keep affected areas dry. For some individuals, sunscreen, loose clothing, moisturizing creams and avoiding excessive heat may help prevent outbreaks.
Cool compresses, dressings, mild corticosteroid creams and topical antibiotics may be effective in treating mild cases. More serious cases may require systemic antibiotics or stronger corticosteroid creams. Long-term corticosteroid therapy is not recommended because it can further weaken damaged skin over time.
Drugs that fight bacterial, fungal or viral infections are also commonly used to treat or prevent secondary infection sometimes associated with Hailey-Hailey disease.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
More recent therapies have tried to improve HHD by shutting down sweat glands. In particular, Botulinum toxin (commonly used to reduce wrinkles) also is used as a therapy for individuals with Hailey-Hailey disease. Specifically, botulinum toxin therapy reduces sweating, which can trigger or worsen an outbreak. Finally, oral glycopyyrolate has been reported to help HHD by reducing sweating. For patients in whom sweating is a major trigger, these therapies may improve HHD.
In severe cases or cases that are resistant to traditional therapy (refractory Hailey-Hailey disease) additional medications have been tried including vitamin A derivatives (retinoids) such as acitretin and etretinate, drugs that suppress the immune system such as alefacept or tacrolimus, and oral magnesium chloride to help the ion pump work better. Use of agents that reduce oxidative stress, such as the subcutaneous administration of the melanocortin analogue Nle4-D-Phe7-alpha MSH, also have been reported to improve the skin lesions of HHD. More research is necessary to determine the long-term safety and effectiveness of such drugs for the treatment of individuals with Hailey-Hailey disease.
Controlled surgical sanding (dermabrasion) and surgical excision of affected skin have also been used to treat some affected individuals. The use of lasers to disintegrate affected skin has been tried for some individuals with Hailey-Hailey disease. More research is necessary to determine the long-term safety and effectiveness of such procedures for the treatment of Hailey-Hailey disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Hailey-Hailey disease:
Theodora Mauro, MD
Professor in Residence and Vice-Chairman, UCSF Department of Dermatology
Service Chief, SFVAMC Department of Dermatology
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;19:251-254.
Hurd DS, Johnston C, Bevins A. A case report of Hailey-Hailey disease treated with alefacept (Amevive). Br J Dermatol. 2008;158:399-401.
Szigeti R, Kellermayer R. Autosomal dominant calcium ATPase disorders. J Invest Dermatol. 2006;126:2370-2376.
Majore S, Biolcati G, Barboni L, et al. ATP2C1 gene mutation analysis in Italian patients with Hailey-Hailey disease. J Invest Dermatol. 2005;125:933-935.
Helm TN, Lee TC. Familial Benign Pemphigus (Hailey-Hailey Disease).Medscape. http://emedicine.medscape.com/article/1063224-overview Updated: Apr 9, 2015. Accessed May 27, 2015.
Lamb S. Hailey-Hailey disease. DermNet NZ. http://www.dermnetnz.org/systemic/familial-pemphigus.html Last modified Dec 15, 2014. Accessed May 27, 2015.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Benign Chronic Pemphigus; BCPM. Entry No: 169600. Last Edited 03/02/2015. Available at: http://omim.org/entry/169600 Accessed May 27, 2015.
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