Hailey-Hailey disease (benign familial pemphigus)

INTRODUCTION — Hailey-Hailey disease (HHD; MIM #169600), also called benign familial pemphigus or benign chronic pemphigus, is a rare, autosomal dominant disorder that affects the adhesion of epidermal keratinocytes. Initially described by the Hailey brothers in 1939 [1], this intraepidermal blistering disorder is characterized by painful blistering, erosions, maceration, and frequent secondary infection in the flexural areas (picture 1A). HHD is a chronic condition with multiple recurrences and limited therapeutic options.

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of HHD. Darier disease, a condition that shares many clinical and pathologic features with HHD, is discussed separately. (See "Darier disease".)

EPIDEMIOLOGY — Hailey-Hailey disease (HHD) is a rare disorder. Its prevalence is unknown since many patients lack an accurate diagnosis or do not seek treatment. The age of onset and clinical manifestations of HHD can vary widely within families. First onset after puberty is most common, but presentation during childhood may occur [2]. There is no apparent difference in prevalence among different ethnic groups.

PATHOGENESIS — Hailey-Hailey disease (HHD) is caused by loss-of-function variants in the ATP2C1 gene at 3q22.1, which encodes the adenosine triphosphate (ATP)-powered, magnesium-dependent calcium pump protein hSPCA1. Its function is to maintain normal intracellular concentrations of free calcium (Ca²⁺) by sequestering Ca²⁺ into the Golgi apparatus [3].

HHD is inherited in an autosomal dominant manner with complete penetrance and variable expressivity. Only two-thirds of patients have a family history of HHD; de novo mutations or reduced phenotypic expression in affected family members account for the absence of family history in the remainder. Interfamilial phenotypic variations and the lack of clear genotype-phenotype correlations indicate that environmental and/or other genetic factors may modify the clinical presentation.

Nearly 180 unique ATP2C1 variants have been reported in families or sporadic patients with HHD [4-6]. Missense, nonsense, frameshift, and splice-site variants have all been reported. ATP2C1 haploinsufficiency is thought to lead to reduced hSPCA1 activity.

Although the expression of ATP2C1 is ubiquitous, HHD is primarily localized to intertriginous areas. Segmental forms showing unilateral or linear distribution represent mosaicism, resulting from postzygotic variants in ATP2C1 (type 1 mosaicism) or postzygotic loss of heterozygosity (loss of the normal allele) combined with a germline pathogenic variant in ATP2C1 (type 2 mosaicism) [7-9].

Calcium homeostasis in keratinocytes is involved in epidermal differentiation, barrier repair, cell-cell adhesion, and keratinocyte motility. Although the precise mechanism is incompletely understood, the genetic defect results in altered cellular connections within desmosomes and adherens junctions of the epidermis (acantholysis), secondary to high cytosolic calcium levels.

However, other factors may have a role in the development of the clinical manifestations of HHD, including oxidative stress and microRNAs [10,11]. MicroRNAs are small, noncoding RNAs involved in post-transcriptional regulation of gene expression. The microRNA miR-125b, which regulates the expression of factors implicated in keratinocyte proliferation and differentiation, appears to be upregulated in keratinocytes from patients with HHD [10].

CLINICAL FEATURES

Typical presentation — The onset of Hailey-Hailey disease (HHD) typically occurs in the second and third decades of life. The clinical manifestations primarily involve the flexural areas in a symmetric fashion (groin, axillae, lateral neck, submammary region, and perineum). Mucosal involvement is rare.

Flaccid vesicles on erythematous to normal skin are the first manifestation and are often not noticed. Large, macerated, exudative plaques of superficial erosions with crusting are usually seen at the time of the diagnosis (picture 1A-D). Further progression to large, vegetative, malodorous plaques with painful fissures can occur. Flexural disease may be disabling, especially if the groin is involved.

Longitudinal, white bands of the nails have been described in approximately 70 percent of patients with HHD and can be a clue to the diagnosis [12].

Segmental or localized Hailey-Hailey disease — Localized or linear segmental forms of HHD, the latter also known as "relapsing linear acantholytic dermatosis," have been described [13-15]. They present as unilateral, linear, patchy, or otherwise localized lesions. Linear lesions are often distributed along the Blaschko lines, representing patterns of skin and appendage cell migration during embryogenesis. In very rare cases, segmental HHD lesions may appear at an early age in individuals who later develop typical, symmetrical, bilateral HHD lesions [7,14].

These clinical phenotypes are considered mosaic forms of HHD, resulting from postzygotic variants in ATP2C1 or loss of heterozygosity at the ATP2C1 locus. (See 'Pathogenesis' above.)

Clinical course — HHD has a remitting and relapsing course with a substantial impact on quality of life [16]. When the inflammation remits and lesions heal, postinflammatory hyperpigmentation is a common sequela. Exacerbating factors include sweating, friction, ultraviolet radiation, and cutaneous infections [12].

Colonization and secondary infection with bacteria (Staphylococcus, Streptococcus) and fungi (dermatophytes, Candida) are common and a frequent cause of the persistence or exacerbation of lesions [17-19]. Vegetations and malodor are signs of bacterial or fungal overgrowth. Bacterial and fungal cultures should be performed during relapses to determine appropriate antibiotic or antifungal treatment.

Risk of squamous cell carcinoma — There are anecdotal reports of squamous cell carcinomas arising in vulvar and penile lesions of HHD [20-22]. However, it is unclear whether the chronic impairment of the epidermal barrier in HHD increases the risk of infection from oncogenic strains of human papillomavirus [23]. In a mouse model, ATP2C1 mutations induced the development of squamous cell tumors in the absence of skin manifestations of HHD [24]. Melanoma and other cancers have also been reported in patients with HHD [25].

DIAGNOSIS — The diagnosis of Hailey-Hailey disease (HHD) is suggested by the clinical finding of characteristic, macerated erosions limited to intertriginous areas without satellite lesions, especially if there is a history of similar clinical manifestations in other family members.

Skin biopsy and histopathology — A skin biopsy of lesional skin for routine histopathologic examination and direct immunofluorescence staining is needed to confirm the diagnosis.

Histopathologic findings include widespread loss of cohesion among suprabasal keratinocytes (acantholysis), resulting in suprabasal clefts and acantholytic vesicles and bullae. Areas of partial acantholysis form layers of intraepidermal and suprabasal, detached keratinocytes with the appearance of a "dilapidated brick wall" (picture 2). Dyskeratosis (abnormal keratinization) is usually mild.

The papillary dermis contains a sparse, perivascular, lymphocytic infiltrate with scattered eosinophils. Neutrophils may be seen in the vesicles and in the parakeratotic crust [26].

In contrast with autoimmune pemphigus, direct immunofluorescence is negative in HHD. (See 'Differential diagnosis' below and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

Molecular diagnosis — Molecular testing of peripheral blood DNA for variants in ATP2C1 that cause HHD is clinically available, although it is generally not required for the diagnosis. Referral for genetic services can help facilitate counseling, discussion of pros and cons of genetic testing, interpretation of the results, and implications for the family. The American College of Medical Genetics website can be searched by zip code or city and state to find local genetics services. (See 'Genetic counseling' below.)

DIFFERENTIAL DIAGNOSIS — Several dermatologic diseases may have clinical features and distribution similar to Hailey-Hailey disease (HHD) [27]:

●Darier disease – Flexural lesions of Darier disease are clinically difficult to differentiate from HHD. However, Darier disease is characterized by greasy, hyperkeratotic papules involving seborrheic areas (eg, scalp, ears, central chest, and upper back) and by a distinctive nail dystrophy (picture 3A-C). Histologically, acantholysis is more widespread in HHD than in Darier disease, whereas dyskeratosis (abnormal, premature keratinization of keratinocytes, which appear as "corps ronds" or "grains") predominates in Darier disease. (See "Darier disease".)

●Papular acantholytic dyskeratosis of the vulva – Papular acantholytic dyskeratosis (PAD) of the vulva is a rare, chronic disorder presenting in young adult and older females as small, pruritic papules over the vulva and inguinal folds. PAD is a noninherited disorder and is thought to be a mosaic form of Darier disease [28]. However, there are reports of familial cases of PAD, suggesting that PAD may be an allelic variant of HHD [29-31]. The histopathologic findings in PAD are characteristically a combination of those seen in both Darier disease and HHD (ie, suprabasal clefting and acantholysis, dyskeratotic cells resembling corps ronds and grains). (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

●Galli-Galli disease – Galli-Galli disease is a rare, autosomal dominant disorder considered an acantholytic variant of Dowling-Degos disease, a reticulated pigmentary disorder of the skin. Galli-Galli disease is caused by missense variants in the KRT5 gene and presents with reticulated hyperpigmentation and keratotic, papular lesions involving the major flexural areas. Histologically, there are elongated, finger-like strands of keratinocytes extending into the papillary dermis; hyperpigmentation of the rete ridges; multiple foci of acantholysis; and dyskeratotic cells. (See "Congenital and inherited hyperpigmentation disorders", section on 'Diffuse reticular hyperpigmentation'.)

●Pemphigus – Vegetating, flexural lesions occur in pemphigus vegetans, an uncommon variant of pemphigus vulgaris (picture 4). A positive direct immunofluorescence confirms the diagnosis of pemphigus. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

●Seborrheic dermatitis – The involvement of intertriginous areas is possible in seborrheic dermatitis (picture 5A-B). However, erythematous plaques and/or yellowish, greasy scales are typically seen on the scalp, eyebrows, or nasolabial folds (picture 6A-C). (See "Seborrheic dermatitis in adolescents and adults".)

●Inverse psoriasis – Psoriasis of the intertriginous areas usually lacks scaling and may be difficult to differentiate from other causes of intertrigo (picture 7A-E). However, the presence of psoriatic plaques in nonflexural areas, involvement of the umbilicus, and pitting of nail plates allow for the correct diagnosis (picture 8A-B). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Inverse (intertriginous) psoriasis'.)

●Intertrigo – Erythematous, macerated plaques and erosions with peripheral scaling and satellite papulopustules are characteristic of candidal intertrigo (picture 9A-B). Tinea cruris usually presents with erythematous, scaling plaques with sharp margins, without vesicles or erosions and few satellite lesions (picture 10). Bacterial colonization, which is common in individuals with obesity, may cause maceration. (See "Intertrigo" and "Approach to the patient with an intertriginous skin disorder".)

●Erythrasma – Erythrasma is caused by the overgrowth of Corynebacterium minutissimum, a component of the normal skin flora. It presents with well-defined, erythematous/brown patches in the axillae, inframammary region, or groin (picture 11A-C). A coral-red fluorescence under Wood's lamp examination will confirm the diagnosis (picture 12). (See "Erythrasma".)

●Granular parakeratosis – Granular parakeratosis is a rare disorder characterized by hyperkeratotic, reddish-brown plaques occurring in intertriginous areas (picture 13). The diagnosis is based upon the histologic finding of keratohyalin granules within the corneocytes, resulting in a granular appearance of the stratum corneum. (See "Granular parakeratosis".)

MANAGEMENT — There is no specific therapy for Hailey-Hailey disease (HHD). The therapeutic approach to HHD involves the control of exacerbating factors, secondary infections, and cutaneous inflammation. Because of the rarity of the disease, evidence of efficacy for topical or systemic therapies is mainly based upon small observational studies, case reports, and clinical experience [32].

General measures — Since heat, moisture, and friction provoke cutaneous flares of HHD, all patients with HHD will benefit from measures aimed at reducing sweating, friction, and bacterial colonization in the involved areas:

●Reduction of body weight, if appropriate

●Use of lightweight, loose clothing

●Avoidance of very hot environments

●Use of absorbent pads in skin folds to reduce moisture

Open, crusted, macerated, and malodorous lesions can be treated with diluted bleach (0.5 cup or 120 mL of 6% bleach in a full bathtub of water [40 gallons or 150 L] or 1 tsp or 5 mL of bleach in one gallon of water [3.8 L]). This may be applied as baths, soaks, or compresses on a regular basis (eg, two to three times per week) to decrease staphylococcal carriage.

Alternatively, antibacterial washes, such as chlorhexidine gluconate 4% wash, may be used on a daily basis. Topical compresses of aluminum acetate solution at a 1:40 dilution, applied intermittently for 5 to 10 minutes, may also be beneficial for macerated lesions.

Bacterial and fungal cultures of the involved sites are useful to determine appropriate antibiotic or antifungal treatment.

Patients with mild disease

Topical therapies — For patients with mild disease, we suggest topical antimicrobials and topical corticosteroids or topical calcineurin inhibitors as first-line treatment. Topical therapies are aimed at controlling the overgrowth of microbial flora and reducing inflammation. The efficacy of these treatments has not been evaluated in clinical trials, and their use is mainly based on small observational studies and case reports and clinical experience [12,33]:

●Topical antibiotics − Clindamycin 1% lotion or cream, gentamicin 0.1% cream, or mupirocin 2% cream are applied to the affected areas two to four times per day for two to four weeks. In children, ointment preparations are generally better tolerated than lotions or creams.

Patients with frequent exacerbations due to heavy microbial colonization may need systemic treatment with oral antibiotics or antifungals, guided by the culture's results. (See 'Systemic therapies' below.)

●Topical antifungals − Ketoconazole 2% cream or another azole cream may be helpful for patients with fungal colonization. Antifungal creams are applied twice daily for two to four weeks.

●Topical corticosteroids − Short courses of moderate- to high-potency topical corticosteroids (groups 3 and 4 (table 1)) may be used in conjunction with topical antimicrobials to treat episodes of exacerbation. Topical corticosteroids are applied twice a day for five to seven days.

●Topical calcineurin inhibitors − Tacrolimus ointment may be an alternative to topical corticosteroids for long-term control of inflammation. Tacrolimus 0.1% ointment is applied twice a day until resolution of the lesions.

There are isolated reports of successful treatment with topical calcipotriol [34-36], topical fluorouracil [37], and topical cinacalcet [38].

Patients with severe disease

Intralesional botulinum toxin type A — For patients with extensive or severe disease, intermittent injections of botulinum toxin aimed at reducing sweating and maceration can be an adjunct to topical antimicrobial and anti-inflammatory therapies. Botulinum toxin type A is injected into the axillae or inguinal folds with the same technique used in the treatment of hyperhidrosis [39-43] (see "Primary focal hyperhidrosis", section on 'Botulinum toxin'):

●In a series of six cases, botulin toxin 500 units was injected into the axillae or inguinal folds, following the technique used in the treatment of hyperhidrosis [41]. There were no flares four months after treatment in one patient and no flares at two months in two additional cases.

●In an open-label study, 30 patients (26 with HHD and 4 with Darier disease) received intradermal injections of botulinum toxin (50 units per 100 cm², up to a total of 200 units) in selected areas of moderate to severe disease [44]. Of the 26 patients with HHD, 15 (58 percent) showed a sustained improvement at six months, whereas 11 experienced a relapse (9 at one month).

Systemic therapies — Intermittent courses of oral antibiotics are occasionally used to control episodes of increased disease activity. The choice of antibiotic is determined by the patient's culture results. Some advocate use of tetracyclines because of their additional anti-inflammatory effect [45].

Other systemic therapies anecdotally reported as beneficial include cyclosporin 2.5 to 3.5 mg/kg per day [46-48]; methotrexate 15 mg/week [49,50]; acitretin 25 mg/day [51,52]; alitretinoin [53]; glycopyrrolate 1 mg/day [54]; oral tacrolimus [55]; afamelanotide 16 mg in a sustained-release, resorbable implant formulation [56]; oral vitamin D supplementation [57]; dupilumab 300 mg subcutaneously every other week [58,59]; apremilast [60,61]; and ocrelizumab [62].

Surgical or destructive therapies — Surgical and destructive methods have been used in a few patients with recalcitrant HHD and include [63]:

●Surgical excision [64,65]

●Carbon dioxide laser or 595 nm pulsed dye laser ablation [66-71]

●Argon plasma coagulation [72]

●Cold atmospheric plasma [73]

●Dermabrasion [74-76]

●Photodynamic therapy [77-80]

●Electron beam radiation [81,82]

●Superficial radiation therapy [83]

Drawbacks of surgical and destructive therapies include long healing time; pain; scarring; and uncertain, long-term benefit.

Emerging medical therapies — Serendipitous, patient-reported observations have drawn attention to two promising therapies for HHD: oral magnesium chloride supplementation and low-dose oral naltrexone. Although promising, the efficacy of these treatments needs to be confirmed in additional studies before they can be recommended for the treatment of severe, recalcitrant HHD:

●Magnesium chloride – In three patients, magnesium chloride taken once daily as an oral solution containing approximately 300 mg of elemental magnesium induced a rapid improvement in HHD lesions, with nearly complete resolution in four weeks [84,85]. No adverse effects were reported. In one patient, the electrolyte serum levels, including calcemia and magnesemia, were normal after 12 months of continued treatment [85].

Although the mechanism of action of magnesium chloride supplementation in HHD has not been clarified, one hypothesis is that it may affect the altered intracellular calcium homeostasis in HHD keratinocytes.

●Naltrexone – Naltrexone, an opioid antagonist used in the treatment of alcohol and opioid dependence, has been found to be effective in inducing the resolution of HHD lesions in some patients [86-91]. The mechanism of action of naltrexone in HHD is unclear. One hypothesis is that its effect may be due to its anti-inflammatory properties, as well as to some influence on intracellular calcium homeostasis:

•In one report, three patients with recalcitrant HHD were treated with low-dose naltrexone hydrochloride given orally at a dose of 1.5 to 3 mg per day after stopping all other topical or systemic therapies [87]. All three patients achieved an 80 to 90 percent clinical improvement, defined as resolution of erosions, improvement in erythema, and decrease in tenderness and discomfort, after three to four months of treatment with naltrexone.

•In another report, three patients older than 50 years with longstanding HHD were treated with oral naltrexone 3 mg and up to 4.5 mg per day [86]. Erosions began to heal from the periphery within one to two weeks of starting treatment and were completely resolved at four months. No major adverse effects were reported with low-dose naltrexone. Minor adverse effects included headache, gastrointestinal symptoms, and vivid dreams. In both reports, discontinuing low-dose naltrexone resulted in a relapse of HHD within a few days, which resolved within a week of restarting therapy.

•In another report of three patients, complete resolution was achieved in one patient taking oral naltrexone 4.5 mg per day after 18 months of continued treatment. A rapid, complete resolution occurred in one patient after a two-month treatment with a higher dose of naltrexone (12.5 mg per day), whereas no response was observed in another patient treated with naltrexone 50 mg per day for concurrent brachioradialis pruritus [88].

•In a Spanish series of 14 patients (12 with moderate or severe disease) treated with low-dose naltrexone and followed up for a median of 34 weeks, six patients showed no improvement, six patients had an initial improvement but relapsed, and only two patients showed a sustained response [89].

•In two case reports, combination treatment with low-dose naltrexone and oral magnesium resulted in substantial improvement of longstanding and recalcitrant HHD [92,93].

GENETIC COUNSELING — For patients with Hailey-Hailey disease (HHD), offering referral for genetics services to discuss inheritance pattern, recurrence risk, pros and cons of genetic testing, and reproductive options (eg, preimplantation genetic testing) is appropriate. (See 'Molecular diagnosis' above.)

Because HHD is an autosomal dominant disorder, an affected person will have up to a one in two chance of having a child who is also affected. Prenatal diagnosis is possible for future children in a family when the causative mutation in a parent is known.

PROGNOSIS — Hailey-Hailey disease (HHD) has a chronic, relapsing, and remitting course. The long-term benefits of medical and/or surgical approaches to HHD are uncertain, and recurrence is common. Patients with HHD have a normal life expectancy, although with significantly impaired quality of life.

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Hailey-Hailey disease (HHD), also called benign familial pemphigus, is a rare, autosomal dominant genodermatosis caused by variants in the ATP2C1 gene, encoding an adenosine triphosphate (ATP)-powered calcium pump, which result in altered intercellular connections (acantholysis) in the epidermis. (See 'Pathogenesis' above.)

●Clinical presentation – HHD typically presents in the second or third decades of life with blistering, erosions, maceration, and frequent secondary infection in the flexural areas (picture 1A-D). HHD has a remitting and relapsing course; exacerbating factors include sweating, friction, ultraviolet radiation, and infection. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of HHD is suggested by the clinical findings. A skin biopsy for histopathologic examination and direct immunofluorescence staining is needed to confirm the diagnosis and rule out other dermatoses with similar clinical findings and lesion distribution. Molecular testing of peripheral blood cells for causative DNA mutations in the ATP2C1 gene is clinically available. (See 'Diagnosis' above and 'Molecular diagnosis' above.)

●Management – There is no specific therapy for HHD. Its management involves the control of exacerbating factors, secondary infections, and cutaneous inflammation (see 'Management' above):

•For patients with mild disease, we suggest topical antimicrobials and topical corticosteroids or topical calcineurin inhibitors as first-line therapy (Grade 2C). Topical antibiotics, such as clindamycin 1% lotion or cream, gentamicin 0.1% cream, or mupirocin 2% cream, are applied two to four times per day for two to four weeks. Short courses (five to seven days) of moderate- to high-potency topical corticosteroids (groups 3 and 4 (table 1)) may be used in conjunction with topical antimicrobials to treat episodes of exacerbations. (See 'Patients with mild disease' above.)

•For patients with extensive or severe disease, we suggest intermittent injections of botulinum toxin (Grade 2C). Botulin toxin reduces sweating and maceration and may be added to topical antimicrobial and anti-inflammatory therapies. For the rare cases of severe and recalcitrant disease, oral cyclosporine, methotrexate, acitretin, or alitretinoin (not available in the United States) are options to be tried prior to destructive approaches with laser and/or surgery. (See 'Patients with severe disease' above and 'Surgical or destructive therapies' above.)