Familial Benign Pemphigus (Hailey-Hailey Disease) 

Updated: Aug 20, 2020
Author: Thomas N Helm, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Familial benign pemphigus (Hailey-Hailey disease) originally was described by the Hailey brothers in 1939.[1] Familial benign pemphigus is a chronic autosomal dominant disorder with incomplete penetrance. Approximately two thirds of patients with familial benign pemphigus have a family history of the disorder. A history of multiple relapses and remissions is characteristic. Decreased numbers of desmosomes have been implicated in the pathogenesis of benign familial pemphigus. Therapeutic options are limited.

Medscape Drugs & Diseases articles on pemphigus include Pemphigus Erythematosus, Pemphigus Foliaceus, Pemphigus Herpetiformis, and Pemphigus Vulgaris.

Pathophysiology

Keratinocytes are held together through desmosomes and adherens junctions. These junctions consist of calcium-binding transmembrane glycoproteins, which contribute to cellular adhesion. Many hypotheses exist concerning the pathogenesis of familial benign pemphigus, but the cause remains uncertain. An overall defect in keratinocyte adhesion appears to be secondary to a primary defect in a calcium pump protein, ATP2C1.

ATP2C1 encodes the secretory pathway Ca2+/Mn2 ATPase (hSPCA1). Mutant proteins in familial benign pemphigus create a loss of sensitivity to Ca2+ and Mn2+ ion binding and transport. Low levels of Ca2+ within Golgi bodies impair protein processing. Gene expression may be affected in benign familial pemphigus, as may phosphorylation of adhesion molecules. Localized postzygotic mutation has caused segmental manifestations of familial benign pemphigus.[2, 3]

A 2009 study has shown that the calcium content of basal keratinocytes is lower than in normal skin and that transition of keratin 14 to 10 is abnormal.[4] . Study of familial and sporadic cases of familial benign pemphigus in the Chinese population has revealed a number of mutations scattered throughout the ATP2C1 gene.[5] At least 81 different mutations have been identified to date.

Etiology

Hailey-Hailey disease, or familial benign pemphigus, is hypothesized to result from a genetic defect in a calcium pump protein. The pump mutation is in ATP2C1, a gene localized on chromosome 3.[6] This gene defect is similar to the genetic defect in Darier disease, which also is a calcium pump defect, ATP2A2. The gene ATP2C1 encodes the human secretory pathway Ca++ -ATPase hSPCA1, which is dysfunctional and causes abnormal calcium release from the Golgi apparatus and endoplasmic reticulum. Acantholytic dermatosis of the crural folds may be a variant of Hailey-Hailey disease (familial benign pemphigus) and is also associated with ATP2C1 mutation.[7]

Pathways involved in PI3K-Akt signaling may play a role in the altered focal adhesion and extracellular matrix (ECM)‒receptor interactions noted in Hailey-Hailey disease.[8] Changes in protein digestion and absorption may impact microfibril-associated glycoprotein 4 and plakophilin.[8]

In addition to the primary gene defect in Hailey-Hailey disease (familial benign pemphigus), contributing factors are known that exacerbate the disease. These include heat, friction, and infection, resulting in separation of keratinocytes, especially in the intertriginous areas. Through ultrastructural studies of familial benign pemphigus lesions, characteristic changes in keratinocyte morphology have been described, including retracted tonofilaments, elongated membrane microvilli, and reduced numbers of desmosomes.

Epidemiology

Frequency

No precise data are available on the incidence of familial benign pemphigus.

Sex

Both sexes are affected equally by familial benign pemphigus.

Age

Familial benign pemphigus often manifests in the late teenage years or in adulthood (30s and 40s).

Prognosis

Familial benign pemphigus causes discomfort but is not life threatening. Benign familial pemphigus lesions often begin during the teenage years and manifest as itchy and malodorous plaques. Patients with familial benign pemphigus live long and productive lives. The skin disorder is more of a nuisance than a serious health threat. New treatment options are under study and offer hope for better treatments in the future.

Patient Education

Patients with familial benign pemphigus must be instructed to recognize flares in the disease promptly and to seek treatment for secondary infection before it becomes severe.

 

Presentation

History

A family history of benign familial pemphigus usually is present. Commonly, patients may not have symptoms until ages 30-49 years. Delayed diagnosis of familial benign pemphigus also is common, especially if the patient's lesions respond to topical corticosteroids, antibiotics, or antifungals.

Physical Examination

With familial benign pemphigus, vesicles and erythematous plaques with overlying crusts typically occur in the genital area, as well as the chest, neck, and axillary areas, as shown in the images below.

Right axilla with erosive erythematous plaques. Right axilla with erosive erythematous plaques.
Lumbar back with erythematous plaques with impetig Lumbar back with erythematous plaques with impetiginized crust.
Left axilla with tender erythematous plaques. Left axilla with tender erythematous plaques.
Eroded and crusted plaques in right groin at base Eroded and crusted plaques in right groin at base of penis.
Erythema of scrotum and erosive plaques in left gr Erythema of scrotum and erosive plaques in left groin (simulated intertrigo).
Central groin with yellow crust over cleaned plaqu Central groin with yellow crust over cleaned plaques.

Burning and itching accompany the eruption, and a malodorous drainage occurs in some cases as a result of secondary infection. Symptoms related to staphylococcal and candidal overgrowth are common in familial benign pemphigus. Multiple asymptomatic longitudinal white bands on the fingernails also have been described. Involvement of mucosa is rare. The characteristic clinical appearance of familial benign pemphigus, as well as biopsy findings, readily confirms the diagnosis.

Complications

Cellulitis, abscess formation, scarring, and depression concerning the chronic and refractory nature of the skin condition are possible complications of familial benign pemphigus.

Systemic corticosteroid therapy may result in the adverse effects of steroids, such as osteoporosis, cataracts, striae, ulcers, and others.

 

DDx

 

Workup

Laboratory Studies

Microscopic examination reveals intraepidermal and suprabasilar acantholysis, as shown in the image below. Elongated papillae (villi) extend into lacunae, and a single layer of basal cells lines the villi.

Acantholysis at all levels of the epidermis (hemat Acantholysis at all levels of the epidermis (hematoxylin and eosin stain, original magnification X20).

Many layers of detached keratinocytes (acantholysis) exist and appear similar to a dilapidated brick wall (clumped acantholytic cells have only a few intact intercellular bridges holding the keratinocytes together).

Unlike pemphigus vulgaris, direct immunofluorescence in familial benign pemphigus is negative. The Nikolsky sign is negative, and Tzanck preparation fails to reveal giant cells and syncytia formation characteristic of herpes virus infection.

Serologic studies for familial benign pemphigus fail to reveal circulating autoantibodies, unlike pemphigus vulgaris in which antibody titers correlate with disease activity.

Histologic Findings

Histologic findings in familial benign pemphigus are suprabasilar and widespread acantholysis.

 

Treatment

Medical Care

Familial benign pemphigus waxes and wanes in intensity. Soothing compresses (aluminum acetate 1:40 dilution) followed by intermittent use of mild corticosteroid preparations (class V or class VI corticosteroids) and topical antibiotics (clindamycin or erythromycin) result in transient improvement. More widespread flares of familial benign pemphigus may require systemic antibiotics to suppress protease activation and acantholysis. Erythromycin and tetracycline are favored. Bacterial culture and sensitivity can help guide appropriate therapy.

In patients with refractory cases of familial benign pemphigus (Hailey-Hailey disease), dapsone, systemic corticosteroids, methotrexate (MTX), retinoids (isotretinoin or acitretin),[9] and etretinate have been tried and have been reported to be of value in some anecdotal reports.

Most patients with familial benign pemphigus at the author's institution respond well to anti-infective therapy and short courses of corticosteroids, and other immunosuppressive agents have only rarely been helpful in the author's experience. Topical tacrolimus ointment has been a valuable addition to the treatment regimen and has been able to control familial benign pemphigus well, even without the adjunctive use of topical corticosteroids.

Most experts believe that the judicious use of topical corticosteroids should be first-line therapy and that topical calcineurin inhibitors can be a second-line option or used when significant amounts of topical corticosteroids are needed in sensitive body-fold areas.[10] The safety of long-term topical calcineurin inhibitor use for this purpose has not been established and close monitoring of patients is advised.

Topical tacrolimus ointment has been found to be helpful in familial benign pemphigus,[11] and photodynamic therapy with 5-aminolevulinic acid has been used for recalcitrant cases.[12]

Reports[13, 14, 15] indicate that low-dose botulinum toxin type A injection may be of benefit for familial benign pemphigus. Control of hyperhidrosis, which aggravates familial benign pemphigus (Hailey-Hailey disease), may be the mechanism for this off-label, novel approach. Remissions of up to at least 12 months have been achieved using only botulinum A toxin injection. Only a few isolated reports have been published,[13, 14] and further work is needed to explore the benefits of this off-label procedure.

Oral glycopyrrolate has also been used to treat familial benign pemphigus and is thought to work by controlling sweating. This systemic anticholinergic agent has a short half-life and is thought to have fewer central nervous system–related anticholinergic adverse effects when compared with other systemic anticholinergic agents.[16]

Isolated reports of oral acitretin[17] therapy or intramuscular alefacept[18] leading to improvement in familial benign pemphigus warrant further study. A recent report suggets that topical cadexomer iodine powder may be of value.[19] Also, a recent case report documented the success of narrow-band ultraviolet B phototherapy in a patient who was unimproved on various topical treatments, oral prednisone and etretinate.[20] A single case report of remission induced by multiple treatments of long-pulsed alexandrite laser brings additional promise of potential long-term control, though many more studies are needed.[21]

Topical tacrolimus and 50% zinc oxide paste may be of value.[22]

Oral tacrolimus along with intralesional botulinum toxin type A (100 U diluted with 5 mL of bacteriostatic saline per cm2) has also been of benefit in a 2015 report.[23]

Surgical Care

Dermabrasion, carbon dioxide laser ablation, and pulsed dye laser therapy have been tried in the treatment of familial benign pemphigus, with variable success.[24, 25, 26] Photodynamic therapy does not seem to be of value.[27]

Diet

To help minimize friction, it is recommended that patients with familial benign pemphigus maintain their weight at appropriate levels.

Activity

Instruct patients with familial benign pemphigus (Hailey-Hailey disease) to select cool and comfortable clothing that reduces heat, moisture, and friction. Patients should avoid fabrics or clothing styles that rub or irritate affected areas. Washing new shirts may soften the collars. In some cases, pain may limit physical activities.

Prevention

Maintaining a healthy weight and keeping the body folds cool and dry as much as possible help prevent flares of familial benign pemphigus.

Long-Term Monitoring

Almost all patients with familial benign pemphigus can be treated successfully on an outpatient basis, but many patients may need to be excused temporarily from manual labor so that affected body folds can heal promptly under treatment.

Familial benign pemphigus patients require regular evaluation to be sure that secondary infection is brought under control and that the adverse effects of topical corticosteroids (eg, cutaneous atrophy) are avoided.

Individuals who receive intermittent courses of systemic corticosteroids should be evaluated for possible decrease in bone density and should be instructed regarding diet and therapy that may maintain bone density.

One report describes squamous cell carcinoma arising in the setting of familial benign pemphigus. Biopsy specimens should be taken from any suspicious infiltrated areas.

 

Medication

Medication Summary

The goals of pharmacotherapy in familial benign pemphigus are to reduce morbidity and to prevent complications. Reportedly,[13, 14] off-label use of low-dose botulinum toxin type A injection may be of benefit to control hyperhidrosis, which aggravates familial benign pemphigus. Etretinate (Tegison), which is not available in the United States, is a retinoic acid analog that is used only after other medicines have been tried and failed.

Immunosuppressants

Class Summary

Immunosuppressants are used in refractory cases. They ameliorate symptoms of inflammation (eg, pain, swelling, stiffness). Use of systemic immunosuppressive therapy for familial benign pemphigus is controversial. No large-scale studies offer a clear evidence-based approach to immunosuppressive therapy in the management of familial benign pemphigus. Because adverse effects can be severe and even fatal at times, such therapies must be initiated cautiously and with adequate informed consent.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is a glucocorticoid (adrenocortical steroid) that is absorbed easily into the GI tract. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Triamcinolone topical (Kenalog, Oralone, Triderm, Zytopic)

Triamcinolone treats inflammatory dermatosis that is responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. Use 0.1% cream.

Retinoid-like Agents

Class Summary

Retinoid-like agents inhibit sebaceous gland function and modify keratinization.

Isotretinoin (Amnesteem, Claravis, Sotret)

Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization. Isotretinoin is used to treat severe cystic acne.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Acitretin (Soriatane)

Acitretin is a retinoic acid analog, similar to etretinate and isotretinoin. Etretinate is primary metabolite and has demonstrated clinical effects close to those seen with etretinate. Its mechanism of action is unknown.

Antibiotics, Other

Class Summary

Antibiotics are used to eliminate microorganisms. Use these agents for possible secondary bacterial infections. Also, some antimicrobials have immunomodulatory effects.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest. Erythromycin is used for the treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine the proper dosage. When twice-daily dosing is desired, half the total daily dose may be taken every 12 hours. For more severe infections, double the dose.

Clindamycin hydrochloride (Cleocin)

Clindamycin is a lincosamide used for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.

Dapsone

Dapsone is bactericidal and bacteriostatic against mycobacteria; its mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth. Its anti-inflammatory mechanism of action most likely relates to the inhibition of neutrophils through the suppression of the halide-myeloperoxidase system.

Tetracycline

Tetracycline treats gram-positive and gram-negative organisms, as well as mycoplasmal, chlamydial, and rickettsial infections. It inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).

Clindamycin phosphate solution 10 mg/mL (Cleocin T, Evoclin, Clindagel, ClindaMax)

Clindamycin is a lincosamide used for the treatment of serious skin and soft-tissue staphylococcal infections when taken systemically. It is useful in the treatment of acne when applied topically. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.

Ketoconazole topical (Extina, Xolegel)

Ketoconazole is an imidazole that inhibits the synthesis of ergosterol, thereby affecting cell membrane integrity and resulting in fungal cell death.

Astringents

Class Summary

Astringents are drying agents used in the management of hyperhidrosis.

Aluminum chloride topical (Drysol, Certain Dri, Hypercare, Xerac)

This agent is aluminum chloride hexahydrate 20% in absolute alcohol. Its antiperspirant mechanism of action is not known, although the creation of aluminum-containing casts within the sweat duct has been postulated.

Aluminum acetate solution

Dissolve aluminum acetate tablets in water to attain a 1:20 solution. It has a drying effect on vesicular or wet dermatoses.