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Hailey-Hailey Disease

NORD is very grateful to 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.

Synonyms of Hailey-Hailey Disease

  • benign chronic familial pemphigus
  • benign chronic pemphigus
  • familial benign pemphigus
  • HHD

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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.

Symptoms

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.

Causes

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 pump in the cells. This protein pumps calcium 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.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders can be similar to those of Hailey-Hailey disease. Comparisons may be useful for a differential diagnosis.

Keratosis follicularis, also known as Darier’s disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions are progressive and may gradually grow bigger or spread. The nails and mucous membranes are also affected in many cases. Additional symptoms may be present in some cases. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited as an autosomal dominant trait. (For more information on this disorder, choose "keratosis follicularis" or Darier’s disease as your search term in the Rare Disease Database.)

Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. Autoimmune disorders occur when the body’s own immune system mistakenly attacks healthy tissue. Two main types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. Each type has subtypes. Additional disorders are sometimes classified as pemphigus including paraneoplastic pemphigus and pemphigus IgA. Some physicians consider these disorders similar, yet distinct, autoimmune blistering disorders with different clinical, immunological and microscopic tissue (histological) features. The symptoms and severity associated with the various forms of pemphigus vary. All forms of pemphigus are characterized by the development of blistering eruptions on the outer layer of the skin (epidermis). In pemphigus vulgaris, lesions also develop on the mucous membranes such as those lining the inside the mouth. Mucous membranes are the thin, moist coverings of many of the body’s internal surfaces. If left untreated, pemphigus can progress to cause life-threatening complications. The exact cause of pemphigus is unknown. (For more information on this disorder, choose "pemphigus" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

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 may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

In severe cases or cases that are resistant to traditional therapy (refractory Hailey-Hailey disease) additional medications have been tried including drugs that reduce sweating (astringents), vitamin A derivatives (retinoids) such as acitretin and etretinate, and drugs that suppress the immune system such as alefacept or tacrolimus. 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. 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: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

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: maurot@derm.ucsf.edu

Organizations related to Hailey-Hailey Disease

References

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). Emedicine. http://emedicine.medscape.com/article/1063224-overview. Updated March 26, 2012. Accessed July 30, 2012.

Lamb S. Hailey-Hailey disease. DermNet NZ. http://www.dermnetnz.org/systemic/familial-pemphigus.html. Last Updated November 15, 2011. Accessed July 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Benign Chronic Pemphigus; BCPM. Entry No: 169600. Last Edited April 1, 2005. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 30, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/08/02 00:00:00 GMT+0

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