Hailey-Hailey Disease - Symptoms, Causes, Treatment | NORD (2024)

Disease Overview

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 change (variant or mutation) in the ATP2C1 gene. This gene creates a protein 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 an ATP2C1 gene variant. Hailey-Hailey disease was first described in the medical literature in 1939.

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Synonyms

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

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Signs & 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 people, 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.

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Causes

Hailey-Hailey disease is caused by a change (variant or 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, although recent studies suggest that Hailey-Hailey disease and the related diseases, Darier’s disease (see below) and Grover’s disease share defects in a central structural system of actin organization. The ATP2C1 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 a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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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.

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Disorders with Similar Symptoms

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 patients. Additional symptoms may be present in some people. 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 in an autosomal dominant pattern. (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.)

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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.

Molecular genetic testing for variants in the ATP2C1 gene is available to confirm the diagnosis.

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Standard Therapies

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. Fortunately, new options for therapy have been developed over the last few years.

Some therapies listed as investigational in the last version of this report are now accepted as standard therapy. Botulinum toxin (commonly used to reduce wrinkles) is also used as a therapy for individuals with Hailey-Hailey disease. Specifically, botulinum toxin therapy reduces sweating, which can trigger or worsen an outbreak, either alone or in conjunction with oral glycopyrrolate. Oral magnesium, with or without oral naltrexone, has been widely used for treatment, and may improve lesions in some patients.

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.

Other treatment is symptomatic and supportive.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

The revolution in immune modulating drugs has been extended to Hailey-Hailey disease. Dipilumab, which is a monoclonal antibody against IL-4, has shown some efficacy in treating patients with Hailey-Hailey disease in whom standard therapies have failed. Topical Janus kinase (JAK) inhibitors have also been proposed as therapies, although clinical studies for these agents have not yet been published. These drugs may be more useful in patients in whom skin inflammation is prominent, or patients in whom specific triggers that may induce inflammation cause lesions to occur. More research is necessary to determine the long-term safety and effectiveness of these drugs for the treatment of individuals with Hailey-Hailey disease.

Drug therapy that addresses abnormal calcium regulation has been tested. Golgi calcium concentrations are modified by a calcium receptor (CaSR) known to control calcium regulation in skin. Calcimimetics such as cinacalcet have been used to treat hyperparathyroidism, and this drug proved effective when compounded into a 3% topical petrolatum-based ointment.

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: [emailprotected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

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, UCSF Department of Dermatology
Service Chief, SFVAHCS, Department of Dermatology
Tel: 415-750-2091
Fax: 415-750-2106
Email: [emailprotected]

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References

JOURNAL ARTICLES
Aihie O, Dyer JA. JAK Inhibitors: A new weapon in the skin care providers’ arsenal. Mo Med. 2023; 120(1):45-8.

Dubin DP, Amir Y, Czernik A. Botulinum toxin and glycopyrrolate combination therapy for Hailey-Hailey disease. Cutis. 2023; 111(4):E28-E910.12788/cutis.0759

Edminister JR, Patel HA, Pixley JN, Huang WW, Jorizzo JL. Improvement of Hailey-Hailey disease with topical Cinacalcet, 3%, ointment. JAMA dermatology. 2023; 159(6):669-7110.1001/jamadermatol.2023.0435

Roth-Carter QR, Burks HE, Ren Z, et al. Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis. JCI Insight. 2023; 10.1172/jci.insight.168955

Alzahrani N, Grossman-Kranseler J, Swali R, et al. Hailey-Hailey disease treated with dupilumab: a case series. Br J Dermatol. 2021; 185(3):680-210.1111/bjd.20475

Alajmi A, Jfri A, Lovett A. Hailey-Hailey disease treated successfully with naltrexone and magnesium. JAAD Case Rep. 2019; 5(9):760-210.1016/j.jdcr.2019.06.022

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: July 7, 2022. https://emedicine.medscape.com/article/1063224-overview . Accessed Oct 25, 2023.

Lamb S. Benign Familial Pemphigus. DermNet NZ. June 2023. https://www.dermnetnz.org/systemic/familial-pemphigus.html Accessed Oct 25, 2023.

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