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Last updated:
July 27, 2018
Years published: 2009, 2012, 2015, 2018
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.
Summary
Hailey-Hailey disease is a rare genetic disorder that is characterized by blisters and erosions most often affecting the neck, armpits, skin folds and genitals. The lesions may come and go and usually heal without scarring. Sunlight, heat, sweating and friction often aggravate the disorder. The symptoms of Hailey-Hailey disease occur because of the failure of skin cells to stick together resulting in the breakdown of affected skin layers. Hailey-Hailey disease occurs due to a mutation in a specific gene that creates a protein that is essential for the proper health of skin. The disorder becomes apparent after puberty, usually by the third or fourth decade, but symptoms can develop at any age.
Introduction
Hailey-Hailey disease is also known as familial benign pemphigus, which has created significant confusion in the medical literature. Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. The symptoms and skin damage of pemphigus and Hailey-Hailey disease are similar. However, pemphigus is an autoimmune disorder, a disorder that occurs when the body’s own immune system mistakenly attacks healthy tissue. Hailey-Hailey disease is not an autoimmune disorder and there are no autoantibodies. Hailey-Hailey disease is a distinct genetic disorder caused by a gene mutation.
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 is caused by a genetic change (mutation) in the ATP2C1 gene. 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 follows an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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.
Molecular genetic testing for mutations in the ATP2C1 gene is available to confirm the diagnosis.
Treatment
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 is recommended 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
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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
Tel: 415-750-2091
Fax: 415-750-2106
Email: [email protected]
JOURNAL ARTICLES
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.
INTERNET
Helm TN, Lee TC. Familial Benign Pemphigus (Hailey-Hailey Disease).Medscape. Updated: Jan 23, 2017. http://emedicine.medscape.com/article/1063224-overview . Accessed July 26, 2018.
Lamb S. Benign Familial Pemphigus. DermNet NZ. September 2016. http://www.dermnetnz.org/systemic/familial-pemphigus.html Accessed July 26, 2018.
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 July 26, 2018.
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