Hailey-Hailey: The Great Imitator

Robert A. Norman, D.O., M.P.H., FAAIM; Joshua Dawalt, D.O.

Abstract
Hailey Hailey Disease, also known as Benign Familial Pemphigus, is a chronic, recurrent, autosomal dominant, blistering disease that may significantly affect quality of life.¹ The Hailey brothers first described it in 1939.

Case Report
A 47-year-old female with a thirteen year of disease "everywhere there is a crease" reported her disease started with a sore red rash under her armpits, under her breasts and around her groin and buttocks. When she is placed in a stressful situation or in humid, moist conditions she flares up with seeping crusted erosions causing her great discomfort and embarrassment. She also complains of premenstrual exacerbation. Her past medical history was significant for asthma, bronchitis and kidney stones. Her family history was negative for heart disease, diabetes, and skin cancer. She had a positive history for Hailey-Hailey on the paternal side of family (father and cousins). Her past treatment included ciprofloxin, triamcinolone acetonide, ketoconazole, ketoconazole shampoo, cyclopsorine (oral solution topically once daily), white vinegar, fluconazole, and laser therapy. She states only diphenydramine 50 mg three times per day and ciprofloxin help.

Discussion
Hailey Hailey Disease (H-H Dz) is not easily recognized, and in many cases is mistaken for something else. Because of the body regions where it is usually found, high friction areas such as armpits, under breasts, genitals, and inner thighs, it is commonly first mistaken for bacterial infection, chronic fungal infections, or in severe cases other bullous disorders like pemphigus Vulgaris.^2,3 An antimicrobial agent or topical corticosteroid (both of which are often used) will many times calm down a flare-up. But, if a correct diagnosis is not made and exacerbating factors are not recognized, recurrences occur. Therefore, it becomes important for the physician to at least recognize the existence of this disorder in the differential diagnosis. Once this has been done, the family physician will become a vital participant in helping to manage and control the disease, largely increasing the quality of life of each of these patients.

Certainly, H-H Dz is not a common disorder, affecting only one person in a million. But because this is an autosomal dominant disease, when it does affect the person it affects the entire family, often showing up intergenerationally, including siblings and extended family members. Due to the autosomal dominance, each child of an afflicted individual has a fifty percent chance of obtaining the disorder, and both sexes are affected equally with some evidence that there is partial penetration of the genetic disorder.

In trying to understand the genetic defect that causes H-H Dz, it is important to review the psychology of skin structure. There are three main layers of the skin. The three layers include the epidermis, which is the outermost layer; the dermis, which is the middle layer; and the subcutaneous layer, which is the bottom layer. The epidermis is made up of primarily keratinocytes, or epidermal cells, and is divided into four strata. From bottom to top, it includes the basal cell strata (stratum basalis); the spiny cell strata (stratum spinosum); the granular strata (stratum granulosum); and finally on the surface sits the cornified strata (strata corneum). Lying below the stratum basalis and above the dermis layer sits the basement membrane with the extremely important function of maintaining strength and structure to the skin, by attaching the basal cell layer to the dermis. Maintaining strength and structure is also performed by small attachments between the keratinocytes called desmosomal complexes. These complexes consist of the desmosome and the tonofilaments, both of which function to hold the keratinocytes together. It is in these demosomal complexes that the genetic defect of H-H Dz produces its affect.^4,6

Unlike the pemphigus disorders, for which H-H Dz is also often mistaken, the defect to the desmosomal proteins is not due to autoantibodies, but instead to a defect in the genetic coding of these proteins.⁷ It is this defect that is responsible for causing loss of cellular attachment among the keratinocytes and, thus, skin breakdown and bullous formation similar to pemphigus. The mutation is found in a gene on chromosome 3, and interestingly, researchers have recently found that this gene is responsible for making a calcium pump. It is thought that the calcium inside the cell signals the desmosomal complexes, or "sticky junctions;" to tell exactly how "sticky" they need to be. So in H-H Dz, where the pumps in many of the skin cells do not work, faulty signals are sent which decrease the cells' ability to hold together, called acantholysis.⁶ The skin breaks and becomes raw, forms blisters, allows for secondary infection, and presents as H-H Dz.

So, how does H-H Dz present, and how would a family doctor be able to recognize and treat the disorder? Usually, patients will present in the third or fourth decade with erythematous, localized patches or plaques of minute vesicles or bullae with crusted erosions especially in areas of moisture and friction such as the axilla, groin, or under breasts. Burning, pain and itching accompany the eruptions, and a malodorous seeping clear or pus-like fluid is many times present especially in a flare-up. In some patients, longitudinal white bands are found on the fingernails, and unlike other familial bullous disorders, mucosal involvement is very rare.^2,4,9

It usually starts out mild, and increases in severity as time passes, reaching a peak in the so-called flare-ups, thought by most to be a result of an overlying infection, which is either bacterial or funga.^l4 One of its other distinguishing characteristics is its recurrent nature. For much of the time it is either not present or mild, not causing the patient much discomfort; but, when external factors occur, such as seasonal changes, stress, or restrictive clothing, the flare that then occurs can be debilitating. Areas affected are primarily those subject to the most friction, which are usually those involved in motion, and this leads to pain during the activities of daily life. Finally, with the seeping of malodorous fluid occurring, great embarrassment afflicts many of these patients, which can significantly affect them socially.^2,4,8 If a suspicion is established with a family history, a biopsy is standard for making the diagnosis.

As if recognizing the disorder is not difficult enough, finding the right treatment can be as strenuous. There is no one specific method or modality in doing so, and unfortunately, refractory cases occur, making it even more frustrating. But on the other hand, many cases are manageable on an outpatient basis, making the primary care physician a vital aspect to their management. Discussions with H-H Dz patients show that it is important to find the regime that works best for each patient.¹⁰ To help in making this easier, it is useful to break down each case into maintenance therapy, therapy for flare- ups, and refractory therapy.

In maintenance therapy, improving overall quality of life and preventing flare-ups are the emphasis. First, and most important, a healthy weight, which will help in minimizing friction and moisture on certain regions of the body, should be emphasized. Instructing patients to use cool compresses and dressings, as well as keeping the body parts as dry as possible by using a hair dryer following a bath should also be stressed.^7,10 Simple preventive acts in general hygiene and toiletry can make a lot of difference, which includes certain bathing accessories. Many over-the-counter remedies includ- ing Tea-Tree Oil, Oilatum Plus, and oatmeal products such as Aveeno Colloidal Oatmeal have been recommended by H-H Dz sufferers as being especially soothing and important in keeping the skin supple.¹⁰

It has also been recommended by other sufferers to use an astringent, a drying agent used in management of hyperhidrosis.^4,10 Again there are several over-the-counter choices, including Aluminum chloride (Drysol) or Mitchum Clear Gel (that is sold as an antibacterial deodorant) that may be applied to affected regions each night for a week and then on an as needed basis works well. The latter uses a triple nozzle top and ejects the gel by a turn screw in the base, thus minimizing any possible cross infection from using a roll on top. Finally, the recognition that secondary bacterial or fungal infections can cause flare-ups is important. If caught early, a flare-up can thus be prevented.^2,4,8

Flare-ups are common to all H-H Dz sufferers, and instructing the patient to be aware of this becomes necessary.⁴ When a flare-up does occur, the physician should first question whether an external factor such as weather changes, stress, or restrictive clothing is the partial cause.^2,4 Working on changing or at least trying to avoid these factors can help tremendously, and might allow other treatments to be saved for later. The understanding that infection, maceration, and friction induce a cascade of inflammation responsible for the flare-up is the next step.¹¹ It is in this understanding that physicians have found that these flare-ups often respond to antimicrobials and corticosteroids.

For some cases, a topical antibiotic cream such as clindamycin or erythromycin used twice a day will be a first and only line of treatment. Combining this with intermittent use of a mild to moderate topical corticosteroid, also twice a day, may also work. For some widespread flares a systemic antibiotic may be required. In this case erythromycin 500mg twice a day, clindamycin 300mg four times a day, or tetracycline 500mg four times a day are all options. A bacterial culture and sensitivity can then provide the much needed additional information for gearing further treatment, and in many cases a fungal swab may be needed to determine if there is also a secondary fungal infection which would then require an anti-fungal agent such as ketoconazole cream two percent applied once or twice a day for two to six weeks. Once the flare-up is diminished with the above protocols, maintenance therapy with an oral antibiotic such as erythromycin 250mg once daily can be very beneficial in helping to prevent the next flare-up.^{1, 2,4,8,10}

In refractory cases, the aim is at stopping the inflammatory response of T lymphocytes and cytokine transcription, both of which have recently been found to be increased in severe H-H Dz. Such modalities able to do this include immuno-suppresants, oral corticosteroids, and occasionally, a retinoid such as isotretinoin.^2,4 Among the immunomodulators shown to have a strong effect in refractory cases, topical Tacrolimus(FK506) 0.1 percent ointment applied twice daily has been shown to have significant reduction in the extent of disease with minimal discernible side effects.¹¹ Oral methotrexate 5mg once per week has also been shown to improve refractory cases, but, with hepatic and renal function being a concern in patients using this, it should only be used as one of the last resorts.¹⁰

Oral corticosteroids and isotretinoin use are also last resorts. With oral corticosteroids, rebound flare-ups are common once the medication is discontinued emphasizing that these should only be used in severe cases on a short-term basis.⁴ With isotretinoin, used in this case for its ability to inhibit sebaceous gland function allowing for dryer skin, side effects such as liver toxicity and possible teratogenicity not to mention the cost of therapy also make it a last resort. Finally, other modalities such as carbon dioxide laser therapy, dermabrasion, PUVA, oral and topical cyclosporine, oophorectomy, and photodynamic therapy with topical 5-aminolevulinic acid with subsequent irradiation therapy have all been used in the most refractory cases. Definitive care has been shown for each of these modalities, but with scarring to afflicted regions a potential risk they are only reserved for the most unmanageable cases.^1,4,8,12-17

As can be seen from above, the variety of treatments and modalities are vast. It is important from a patient's perspective to know both the type of treatment and the etiology of their problem. To those suffering from H-H Dz, it is imperative that physicians, including family doctors, be at least aware of its existence. This will allow for an earlier diagnosis, and result in an earlier treatment regime that can greatly improve the patient's quality of life, which is the goal of every physician.

© 2004 American Association of Physician Specialists, Inc.

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