Clinical Features Of Hailey-Hailey Disease (HHD)

Introduction

Hailey-Hailey disease, also known as Benign Familial Pemphigus, is a rare, genetic skin disorder, which was first described by the Hailey brothers in 1939.¹
It occurs due to a defect in the adhesion of keratin-producing cells (keratinocytes) in the skin, leading to blistering in skin folds such as underarms, sides and back of the neck, under the breasts, groin, and buttocks. 

Hailey-Hailey disease is also known as:

• Benign chronic familial pemphigus
• Benign familial pemphigus
• Familial benign chronic pemphigus

In this article, we’ll discuss the signs and symptoms of Hailey-Hailey disease, its causes, distribution, age of onset, diagnosis, other similar-looking diseases, and treatment. 

Importance of understanding clinical features 

Understanding the clinical features of Hailey-Hailey disease helps diagnose the condition accurately and timely. 

It helps manage the condition effectively if the patient is well aware and educated by the healthcare provider. 

It prevents worsening of the condition and maintains quality of life. -

The severity of symptoms of Hailey-Hailey disease varies from person to person. With thorough clinical knowledge:

• We can develop personalised treatment therapies
• Avoid unnecessary and harmful treatments
• Address emotional and mental impact on the patient

Etiology and Genetics 

Mutation in ATP2C1 gene 

ATP2C1 is a gene responsible for forming a protein that helps transport calcium ions in skin cells and maintains connections between them. A mutation (change or variation) in this gene disrupts the adherence of these cells.²  As a result, keratinocytes fail to stick to each other and form spaces between layers of skin. 

Autosomal dominant inheritance pattern

Hailey-Hailey disease is inherited in an autosomal dominant pattern, meaning a person affected with this condition has a 50% chance of passing it to their child. Hence, the patient may report multiple family members affected by the same skin condition. 

Onset and Epidemiology

Typical Age of Onset 

Hailey-Hailey disease usually affects people in their late adolescent years (18-24 years) or in their 30s or 40s. However, it may occur at any age and persist lifelong.³

Prevalence  

The number of people affected with Hailey-Hailey disease in a population is unknown because the cases are not reported or correctly diagnosed due to the rarity of the disease, limited data, and lack of documentation.⁴  But few sources estimate it to be around 1/50000, meaning that approximately 1 in 50000 people is affected by this condition.¹

However, the female-to-male ratio is 1, which means that the males and females are equally affected.¹

Predilection

A disease that occurs more frequently in a specific population is said to have a predilection for that group.. Hailey-Hailey disease shows no such predilection for any ethnic, geographical, or racial group.^1,4 

Primary Clinical Features

Skin Lesions 

Erythematous plaques, vesicles, and bullae 

The initial lesions appear as plaques, vesicles, or bullae on erythematous (red) to normal skin. These lesions may be localised or widespread.⁵ 

They follow a serpiginous pattern, meaning they slowly progress or creep from one place to another. These lesions do not usually leave scars.

Erosions, crusting, and fissures

Fluid-filled vesicles or blisters may rupture to macerate (look mashy in texture) or form crusts. A breakdown in the outer layer of skin or erosion can also be seen. 

A fissure is a deep crack that may develop on the reddish-colored plaques. 

Nails

Longitudinal Leukonychia

White vertical lines or bands in nails called Longitudinal Leukonychia may be seen in patients affected with HHD. These lines do not represent any serious threat but help diagnose the condition.⁶

Commonly Affected Areas  

Commonly affected areas are Intertriginous areas, where skin surfaces come into contact with each other by touching or rubbing. These areas include: 

• Armpits
• Sides and back of the neck
• Between the breasts
• Beneath the breasts
• Between stomach folds
• Inner thighs
• Pubic region
• Between genitals and anus
• Between buttocks
• Between fingers and toes

Flexural areas prone to friction and sweating 

Due to friction and sweating, there is an accumulation of moisture in flexural areas, which may lead to itching and a burning sensation. Hot weather may aggravate the condition.

Applying sunscreen regularly, wearing soft loose cotton clothes, and staying indoors in fans and air conditioning may help curb the harshness of the weather.³

Pattern and Progression 

Symmetrical distribution 

The lesions appear in a bilaterally symmetrical fashion, i.e. uniform appearance on both sides simultaneously.² This occurs largely due to the disease’s predilection for intertriginous areas, which are located symmetrically on the body and uniform expression of the mutated gene in the entire body. 

Chronic and recurrent nature with exacerbations and remissions

Once affected by Hailey-Hailey disease, it persists for a lifelong period. It tends to come and go without scarring.⁷ The person affected with this condition may notice periods of improvement in signs (remission) followed by periods of recurrence (relapse).⁷

Secondary Clinical Features

Pruritus and Pain 

Intense itching (pruritus), burning sensation, and pain due to skin lesions are major concerns of the patient. 

Secondary infections 

Secondary infections such as bacterial, fungal, and viral infections are quite common due to the tendency of flexural areas to accumulate sweat. 

Bacterial infections such as Staphylococcal aureus and Streptococcus pyogenes release toxins that may aggravate blistering and exacerbate the condition.¹

Fungal infections such as Candida species and viral infections such as herpes simplex (HSV), human papillomavirus (HPV), and pox virus require prompt anti-microbial action. 

HHD cases unresponsive to treatment (recalcitrant) are often associated with HSV infection.

Secondary infections can exacerbate the existing lesions by delaying healing and altering the appearance of the lesions. The lesion may appear redder, warmer to touch, and more swollen. This may also create diagnostic confusion and lead to misdiagnosis by the clinician.

Malodour and pigmentation 

Heavy body malodour (unpleasant odour) due to sweat and secondary infections impacts the quality of life of the people affected by this condition. It causes social embarrassment and distress.

Keeping the skin dry and sweat-free and applying topical antibiotics and antifungal creams can help reduce malodour and secondary infections.

In some instances, the healed lesions may result in a darker (hyperpigmentation) or lighter (hypopigmentation) colour than the surrounding skin, leading to uneven skin tone. 

Diagnostic Criteria and Workup

Clinical Diagnosis 

Clinically, Hailey-Hailey disease is diagnosed by physical examination of the lesions and thorough patient history, particularly family history, due to its autosomal inheritance. 

Histopathological Examination 

Biopsy

A confirmatory diagnosis is done by biopsy. It examines the tissue structure under the microscope for characteristic features at the cellular level. 

In the case of a confirmed diagnosis, the biopsy report reveals ‘suprabasal acantholysis’ and a ‘dilapidated brick wall’ appearance. 

Direct Immunofluorescence test (DIF)

Direct Immunofluorescence is a laboratory test that uses antibodies to detect antigens in cells or tissues. It helps detect immune-mediated diseases. Since HHD is a genetic disorder, DIF is negative. 

Genetic Testing 

Molecular analysis (a group of tests done to analyze certain genes, proteins, and other molecules) to identify a mutation in the ATP2C1 gene can be done to confirm the diagnosis. 

Genetic testing is not routinely performed but may be used to confirm the diagnosis after clinical examination or when histopathological examination is not evident. 

Differential Diagnosis

Pemphigus Vulgaris  

Hailey-Hailey disease or Familial Benign Chronic Pemphigus is often confused with a variant of Pemphigus due to its name. 

Pemphigus is a broad term for auto-immune skin disorder, i.e. a condition in which the body’s immune system attacks its own healthy cells instead of foreign invaders (such as bacteria, viruses, etc). Hailey-Hailey disease is a genetic disorder due to a mutation in the ATP2C1 gene. 

The clinical appearance of both diseases is similar in painful and itchy rashes, fluid-filled blisters, and fissures. However, it varies on the tissue (histological) level when seen under a microscope. 

HHD shows a dilapidated brick wall appearance, whereas Pemphigus vulgaris shows a tombstone appearance of cells.

To differentiate HHD from Pemphigus Vulgaris, a lab test called Direct Immunofluorescence (DIF) is performed, which is negative for Hailey-Hailey disease since it is a genetic disease, not autoimmune. 

An interesting case from the Journal of American Academy of Dermatology (JAAD) shows a 61-year-old female patient presenting with painful and pruritic rashes on the neck, scalp, chest, back, underarms, and groin. She gave a family history of multiple members affected with the same condition. Although the clinical features were consistent with Hailey-Hailey disease, the biopsy and tissue examination confirmed Pemphigus vulgaris. 

(Read more at: https://www.jaad.org/article/S0190-9622(17)31072-1/abstract)

Inverse Psoriasis 

Inverse psoriasis is another auto-immune disorder that affects areas of friction like the armpits, under the breasts, and groin. 

It occurs as smooth, red, and shiny patches without blisters and erosions.

Darier Disease 

Darier disease is a genetic disorder caused by a mutation in the ATP2A2 gene. 

While HHD shows blistering in skin folds, Darier disease usually shows small, sandpaper-like papules that may turn into larger cauliflower-like warty lesions. 

It is more commonly seen in seborrheic (oily) areas such as the scalp, forehead, and sides of the nose.

Darier disease also shows nail abnormalities like V-shaped notches, red and white streaks, and small pits. 

Complications

Long-term non-healing lesions 

The lesions of Hailey-Hailey disease are chronic and recurring. Small or mild to moderate lesions take a few weeks to heal. In contrast, severe lesions may take up to months to heal. The process of healing can be emotionally and mentally draining for the person affected by HHD.

Cosmetic and functional concerns 

The visible skin lesions with redness, crusting, and fluid can be aesthetically unpleasant. In the case of large lesions, scarring may be seen. 

Such appearance may have a psychological impact on the person with HHD. It may give rise to self-consciousness, embarrassment, social withdrawal, and isolation. 

Functionally, a person may find it difficult to perform daily activities such as walking, sitting, lifting, and exercising due to pain and itching. The discomfort leads to reduced mobility. 

This may also pose challenges in social interaction and occupational activities. 

Risk of Skin Cancer 

The most dangerous complication of Hailey-Hailey disease is the potential for long-standing (chronic) lesions to develop into a Squamous Cell Carcinoma (SCC), which is the second most common type of skin cancer. 

Management Strategies

General Principles 

A few simple steps and lifestyle modifications can help manage the condition effectively. To avoid friction and sweating in the skin folds, the following general measures can be taken:

• Wearing lightweight, loose clothes and undergarments
• Avoiding sun exposure
• Applying sunscreen regularly
• Maintaining personal hygiene and cleanliness
• Bathing with non-soap-based surfactants and dilute bleach
• Losing excess weight 
• Educating patients and creating awareness about triggers and conditions
• Attending counseling and joining support groups

Topical Therapies  

Certain topical agents, such as antiseptics, topical corticosteroids, and topical antibiotics like clindamycin and gentamicin creams, are effective in soothing the lesions. 

Applying wet compresses with 1:40 diluted aluminum acetate followed by a topical corticosteroid is effective for mild lesions. According to a study of 58 patients, approximately 86% showed a good response to topical corticosteroid treatment.⁸

For long-term cases, topical calcineurin inhibitors such as Tacrolimus and pimecrolimus can be used.

Recently, low-dose Botulinum Toxin A injections have been introduced to reduce sweat. It can be given alone or along with oral glycopyrrolate.⁷

Systemic treatments 

Oral corticosteroids such as prednisolone and other immunosuppressants such as methotrexate, cyclosporine, and azathioprine are used to treat severe cases. 

Corticosteroids are not used for the long term because they may weaken the damaged skin.⁷

Oral retinoids may be used when antibiotics do not show much improvement. 

Surgical Interventions  

Various surgical options include excision, laser therapy, photodynamic therapy, dermabrasion, and skin grafting. Recurring and difficult-to-treat cases are usually treated surgically. 

Summary

Hailey-Hailey disease is a rare genetic skin disorder due to a mutation in the ATP2C1 gene. It shows painful itchy blistering in skin folds. It persists for a lifelong duration. But it can be managed by avoiding triggers, maintaining good hygiene, and moisturizing. Medically, topical corticosteroids, topical and oral antibiotics, and antifungal creams can be used. Surgical intervention is done in severe cases. With psychological support and help, the people affected by this condition can lead a better quality of life. Ongoing research focused on the genetic and molecular basis of the disease, developing new and improved treatment strategies, and creating more awareness about the disease can help manage Hailey-Hailey disease more effectively in the near future.