DERMATOLOGICA SINICA xxx (2016) 1e5

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Dermatologica Sinica
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ORIGINAL ARTICLE

HaileyeHailey disease: A review of clinical features in 26 cases with

special reference to the secondary infections and their control
Qiao-Feng Zhao, Toshio Hasegawa*, Etsuko Komiyama, Shigaku Ikeda
Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background/Objective: HaileyeHailey disease (HHD) is a rare autosomal dominant hereditary disorder
Received: Feb 15, 2016 that manifests with skin blisters. Controlling secondary infections is indispensable for this condition in
Revised: Jul 29, 2016 conjunction with treatment using anti-inflammatory drugs such as topical steroids. This study aimed to
Accepted: Aug 17, 2016
investigate the clinical features and secondary infections associated with HHD.
Methods: We retrospectively reviewed the records of 26 patients affected by HHD who visited our
Keywords:
hospital over a 10-year period. We explored the patients' age at onset, time from onset to diagnosis,
Candida albicans
affected sites, symptoms, secondary infections and their control, other treatment responses, and family
HaileyeHailey disease
secondary infection
history for HHD.
Staphylococcus aureus Results: The mean age at disease onset was 35 years. The average time from onset to diagnosis was
topical corticosteroids 7 years. The lesions were located at the neck, inframammary folds, axillae, groin, and perineum. Sec-
ondary infection accompanied HHD in 22 patients (85%); the most common infectious agents were
Staphylococcus aureus and Candida albicans. Our cases demonstrated that first-line treatment for HHD
was successful in most patients, which included topical corticosteroids in combination with topical or
oral antibiotics and/or antifungal agents.
Conclusion: Controlling the secondary infection is indispensable for treatment of skin lesions in HHD;
however, none of the treatment modalities prevented relapse after discontinuation of treatment.
Copyright © 2016, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
HaileyeHailey disease (HHD), which is also known as familial
benign chronic pemphigus, is a rare autosomal dominant heredi-
tary blistering skin disorder, which was first described by the
brothers Howard and Hugh Hailey in 1939.1 It is caused by het-
erozygous mutations in the ATP2C1 gene that encodes the secre-
tory pathway Ca2þ/Mn2þ ATP-ase protein (SPCA1) of the Golgi
apparatus, leading to alterations in Ca2þ-dependent intracellular
signaling and resulting in the loss of cellular adhesion in the
epidermis.2e4
Conflict of interest: The authors declare that they have no financial or non-
financial conflicts of interest related to the subject matter or materials discussed
in this article.
* Corresponding author. Department of Dermatology and Allergology, Juntendo
University Graduate School of Medicine, 2-1-1 Hongo, Bunkyou-ku, Tokyo 113-
8421, Japan.
E-mail address: t-hase@juntendo.ac.jp (T. Hasegawa).
The first onset of HHD generally occurs between 20 years and
40 years of age. HHD is clinically characterized by recurrent erup-
tion of blisters, erythema, and erosion in the friction areas, mainly
in the neck, axillae, submammary folds, groin, and perineum.
However, lesions also can occur in non-skin-fold areas. HHD can be
easily misdiagnosed because of its nonspecific, common symptoms,
such as erythema, erosion, blisters, itching, and pain. Various trig-
gers, including humidity, maceration, friction, trauma, and infec-
tion, are known to exacerbate dermatoses. Among these, secondary
infection is the most common deuteropathy in HHD. Thus, con-
trolling secondary infections is indispensable for treating HHD in
conjunction with the use of anti-inflammatory drugs such as
topical steroids.5 Anti-inflammatory drugs such as steroids and
tacrolimus are supposed to normalize HHD skin lesions by upre-
gulating ATP2C1 expression,6 although these drugs are thought to
be effective only when secondary infection is prevented. To
demonstrate that HHD is controllable, we report the results of a
clinical investigation of 26 patients with HHD, with special

http://dx.doi.org/10.1016/j.dsi.2016.08.003
1027-8117/Copyright © 2016, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Zhao Q-F, et al., HaileyeHailey disease: A review of clinical features in 26 cases with special reference to the
secondary infections and their control, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/j.dsi.2016.08.003
2 Q.-F. Zhao et al. / Dermatologica Sinica xxx (2016) 1e5
reference to the importance of controlling secondary infections in
these patients.
Methods
We included patients diagnosed with HHD in our hospital in this
study. We retrospectively reviewed the records of all patients with
HHD collected through a 10-year period (from April 1, 2006 to
March 31, 2015). In addition to showing the characteristic appear-
ance of HHD, all the included patients fulfilled the following
criteria: (1) suprabasal acantholysis of epidermis proved by skin
biopsy; and (2) negative direct and indirect immunofluorescence
for antibodies, to rule out autoimmune disorders such as
pemphigus. All patients were examined for common collagen dis-
eases by routine hematological analysis and antibody testing, such
as antinuclear antibody tests. We examined the following charac-
teristics in all the patients: sex, age at onset, time from onset to
diagnosis, family history, symptoms, affected site, secondary
infection and its control, and other treatment responses for HHD.
Results
Patients
Twenty-six patients (22 men and 4 women, all Japanese) were
included in the present study. Tables 1 and 2 show the clinical
characteristics of the patients. Pathological examination revealed
epidermal acantholysis in all patients. The mean age at disease
onset was 35 years (range, 24e50 years); the mean age at diagnosis
was 42 years (range, 27e62 years); and the average time from onset
to diagnosis was 7 years (range, 0e37 years). Overall, 21 of 26 pa-
tients had a positive familial history for HHD; these details were not
available in the remaining five patients.
The main clinical manifestations were erythema, erosions,
crusts, blisters, pigmentation, and scale at friction sites, accompa-
nied by pain, itching, and malodor. All 26 patients had erythema, 16
had erosions, seven had crusts, six had scales, two had eczema,
three had blisters, and 14 complained of pain and itching. The le-
sions were located at the neck (7 patients), inframammary folds (1
patient), axillae (21 patients), groin (22 patients), and perineum (6
patients) (Table 1). Eight patients reported that their conditions
worsened in the summer because of heat and sweating.
Bacterial cultures were performed in 23 patients with signs of
local infection. Overall, 22 patients (85%) developed skin infections
caused by methicillin-sensitive Staphylococcus aureus (MSSA) (18
patients), Streptococcus spp. (7 patients), Pseudomonas aeruginosa
(3 patients), and Candida albicans (10 patients) (some patients
showed overlapping infections) (Tables 1 and 2). No resistant
strains were detected. Multiple infections, including bacterial and
fungal infections, were noted in 18 cases (Table 1).
Treatment
Twenty-two patients presented for regular follow-up, and their
treatment responses could therefore be assessed. Topical cortico-
steroids were applied as the first-line treatment for all patients.
Antibiotics were used in 14 patients with localized infection.
Among them, three patients were treated with topical antibiotics
(nadifloxacin, oxytetracycline, and clindamycin). Nine patients
were treated with a short course (within 2 weeks) of oral antibiotics
(cefdinir, cefcapene, levofloxacin, cefazolin, cefaclor, clari-
thromycin, or cefditoren). Seven patients were treated with a long
course (4 weeks or longer) of oral antibiotics (minocycline
100e400 mg/day). Topical antifungals were used in 21 patients
(ketoconazole, clotrimazole, lanoconazole, bifonazole, luliconazole,
Please cite this article in press as: Zhao Q-F, et al., HaileyeHailey disease: A review of clinical features in 26 cases with special reference to the
secondary infections and their control, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/j.dsi.2016.08.003
and liranaftate). In particular, ketoconazole was used in 10 patients.
Topical silver sulfadiazine cream was also used in eight patients. All
localized skin infections were well controlled by these treatments.
Bacterial culture was negative or white blood cell counts and C-
reactive protein levels were not high. Clinically, local tenderness,
localized warmth, and erosion symptoms were absent.
Apart from treatment with topical steroids and infection con-
trol, topical tacrolimus (2 patients), systemic steroids (prednisolone
5 mg/day, 1 patient), oral corticosteroideantihistamine combina-
tion (betamethasone 0.25 mg and dextrochlorpheniramine 2 mg, 3
patients 2 tablets/day and 3 patients 3 tablets/day, respectively),
topical retinoids (adapalene, 1 patient), systemic retinoids (etreti-
nate, 2 patients), and topical vitamin D3 (tacalcitol and max-
acalcitol, 2 patients) were used and provided some relief. Two
patients were successfully treated with CO2 laser, and one of these
patients was treated with a skin graft combined with dermabra-
sion. However, none of the treatment modalities prevented re-
lapses after discontinuation of treatment.
Representative case
The affected skin in the groin of Case 26 was successfully treated
with topical steroid and ketoconazole application (Figures 1A and
1B).
Discussion
In this study, we demonstrated that HHD is controllable when
secondary infection is prevented. Secondary infection accompanied
HHD in 22 of our patients (85%), which was a high rate. The primary
infectious agents were S. aureus and C. albicans; both of which are
often found in skin infections. The presence of dermatitis facilitated
bacterial invasion, and a humid environment was considered
favorable for fungal growth. Thus, the patients' symptoms were
aggravated in the summer season. Moreover, excess body weight
can favor friction and maceration. Infection with S. aureus and
C. albicans can induce the production of several cytokines, including
interleukin-6, from keratinocytes,7,8 and interleukin-6 can report-
edly prolong the duration of lesions or exacerbate skin lesions by
reducing ATP2C1 gene expression.8
The treatment of these 26 patients mainly included topical
corticosteroids, topical antifungals, and oral antibiotics. Twenty-
two patients showed improved re-epithelialization. In our pa-
tients, topical or oral antibiotics and/or antifungal agents controlled
most skin infections. Topical silver sulfadiazine, which is effective
for skin infections caused by Staphylococcus spp., Streptococcus spp.,
P. aeruginosa, and Candida spp., also was useful. The oral cortico-
steroideantihistamine combination (betamethasone 0.25 mg and
dextrochlorpheniramine 2 mg, 2 or 3 tablets/day) was helpful in six
patients, because of the inclusion of antihistamines, which
ameliorated itching. In patients with recalcitrant lesions, retinoids,
topical vitamin D3, and tacrolimus were also used. Two patients
were administered systemic retinoids; one of whom showed great
improvement. Ablation of the affected skin with a CO2 laser was
also performed. Furthermore, we treated a patient with refractory
lesions with a CO2 laser, with the lesions showing re-epithelization.
However, none of the treatments prevented relapse.
The mainstay of therapy for HHD comprises anti-infectious
agents, administered either topically or systemically, combined
with topical corticosteroids.6,9 Other treatment modalities, such as
topical tacrolimus ointment, dermabrasion, non-ablative lasers,
such as the long-pulsed alexandrite laser and dye laser, narrow-
band UV-B therapy, photodynamic therapy, and topical or sys-
temic retinoids, have been used to treat HHD.10e19 Some of these
treatments are considered to control ATP2C1 gene expression.6,9,20
 Q.-F. Zhao et al. / Dermatologica Sinica xxx (2016) 1e5 3

Table 1 Patient characteristics and treatments.

No. Age at Time untill Affected site Secondary infection/Treatment/Control Other treatments/Response
onset/Sex diagnosis (years)

1 28/M 3 axilla, groin, Staphylococcus aureus (MSSA) /none/ topical steroid/improvement & recurrence
perineum controlled
2 44/M 0.4 axilla, groin, Staphylococcus aureus (MSSA), filamentous topical steroid, systemic steroid (prednisolone
perineum fungi/ketoconazole/controlled 5 mg/day), white petrolatum, antihistamine/
improvement topical steroid, systemic steroid
(prednisolone 5 mg/day), white petrolatum,
antihistamine/improvement
3 35/M 2 axilla, groin, Candida albicans, Staphylococcus aureus topical steroid, antihistamine, abrasion by CO2
perineum (MSSA), filamentous fungi/ketoconazole, laser, topical vitamin D3 analog, topical
minocycline, luliconazole, clotrimazole/ retinoid, systemic retinoid/improvement (CO2
controlled laser), no improvement (others)
4 32/M 1 axilla, groin, Staphylococcus aureus (MSSA), Candida topical steroid, antihistamine/improvement
perineum albicans/minocycline, clotrimazole/controlled
Staphylococcus aureus (MSSA), Candida
albicans/minocycline, clotrimazole/controlled
5 35/M 0 axilla, groin none/none/no follow-up no treatment/no follow up
6 26/M 1 axilla, groin none/none/no follow-up antihistamine, topical steroid/no follow-up
7 38/M 3 groin filamentous fungi/ketoconazole/controlled topical steroid, antihistamine, white
petrolatum/improvement
8 44/M 10 groin filamentous fungi/lanoconazole, cefdinir/ white petrolatum, topical steroid, zinc oxide
recurrent ointment, systemic retinoid, flavin adenine
dinucleotide/no improvement white
petrolatum, topical steroid, zinc oxide
ointment, systemic retinoid, flavin adenine
dinucleotide/no improvement
9 44/M 0.1 groin, perineum filamentous fungi/clotrimazole, bifonazole/ topical steroid/improvement & recurrence
controlled
10 40/M 14 axilla, groin Pseudomonas aeruginosa, Candida albicans/ topical steroid, systemic steroid and
clotrimazole, cefdinir, topical silver antihistamine/improvement
sulfadiazine/controlled
11 43/M 10 axilla, groin, Staphylococcus aureus (MSSA), Candida topical steroid, antihistamine/improvement
buttock albicans/clotrimazole, minocycline, cefdinir,
topical silver sulfadiazine/controlled
12 24/M 3 groin, crissum, Staphylococcus aureus (MSSA), Group G beta- topical steroid, antihistamine/improvement &
scrotum streptococcus, filamentous fungi/ketoconazole, recurrence
cefcapebe, topical silver sulfadiazine/controlled
13 26/M 4 axilla, groin, Staphylococcus aureus (MSSA), Pseudomonas topical steroid, tacrolimus, antihistamine,
perineum aeruginosa (group B), filamentous fungi/ calcium lactate 3 g/day, systemic steroid and
lanoconazole, minocycline, topical silver antihistamine/improvement & recurrence
sulfadiazine/contorolled
14 42/M 6 groin Staphylococcus aureus (MSSA), Group G beta- topical steroid, systemic steroid and
streptococcus, Candida albicans/minocycline, antihistamine, white petrolatum, topical
cefditoren, lanoconazole, levofloxacin, vitamin D3 compounds, antihistamine,
clotrimazole, topical silver sulfadiazine/ heparinoid cream/improvement & recurrence
controlled
15 25/F 37 axilla, groin, neck, Group B beta-streptococcus, Staphylococcus topical steroid, systemic steroid and
inframammary aureus (MSSA), Candida albicans, filamentous antihistamine, antihistamine, heparinoid
fungi, Herpes simplex/lanoconazole, cream/improvement & recurrence
ketoconazole, topical oxytetracycline,
minocycline, topical nadifloxacin, levofloxacin,
valaciclovir/controlled
16 50/M 10 axilla, groin, Alpha-streptococci, Staphylococcus aureus topical steroid, antihistamine, heparinoid
perianal, neck, (MSSA), Candida albicans, Herpes zoster, Herpes cream/improvement
lower leg simplex/luliconazole, clotrimazole, famciclovir,
valaciclovir/controlled
17 30/M 32 axilla, groin, neck, Staphylococcus aureus (MSSA), Candida topical steroid/improvement
poples albicans, Group B beta-streptococcus/topical
oxytetracycline, ketconazole, cefdinir/
controlled
18 20/M 7 axilla, groin Staphylococcus aureus (MSSA), Candida topical steroid/improvement
albicans/cefcapene, ketoconazole/controlled
19 26/M 10 axilla none/cefcapene/no follow-up topical steroid/no follow-up
20 30/F 0 axilla Staphytlococcus aureus (MSSA), filamentous topical steroid, heparinoid cream,
fungi/ketoconazole, lanoconazole, topicaal antihistamine/improvement
silver sulfadiazine/controlled
21 31/M 0 axilla, chelidon, Staphylococcus aureus (MSSA), filamentous topical steroid, heparinoid cream,
neck fungi/ketoconazole, topicaal silver sulfadiazine/ antihistamine/improvement
no follow-up
22 30/F 15 axilla, groin, neck Staphytlococcus aureus (MSSA), filamentous topical steroid, antihistamine, zinc oxide
fungi/lanoconazole/controlled ointment/improvement & recurrence
23 37/M 3 axila Staphylococcus aureus (MSSA), filamentous topical steroid, abrasion by CO2 laser,
fungi/cefazolin, topical clindamycin, bucladesine ointment, white petrolatum,
antihistamine, systemic steroid and
(continued on next page)

Please cite this article in press as: Zhao Q-F, et al., HaileyeHailey disease: A review of clinical features in 26 cases with special reference to the
secondary infections and their control, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/j.dsi.2016.08.003
4 Q.-F. Zhao et al. / Dermatologica Sinica xxx (2016) 1e5

Table 1 (continued )

No. Age at Time untill Affected site Secondary infection/Treatment/Control Other treatments/Response
onset/Sex diagnosis (years)

clarithromycin, clotrimazole, lanoconazole, antihistamine, Zinc oxide ointment, tacrolimus,

cefaclor/controlled heparinoid cream, skin grafting combined with
abrasion/improvement & recurrence
24 45/M 5 axilla, groin, none/none/no follow-up topical steroid/no follow-up
hypogastrium,
buttock
25 34/M 10 axilla, groin, neck, Staphylococcus aureus (MSSA), Pseudomonas topical steroid, antihistamine, heparinoid
dorsum aeruginosa, Group B beta-streptococcus, cream/improvement & recurrence
Candida albicans/ketoconazole, liranaftate/
controlled
26 46/F 0 groin, neck, axilla, Staphylococcus aureus (MSSA), Microaerophilic topical steroid, azulene cream, antihistamine,
wrist, buttock Streptococcus, filamentous fungi/ketoconazole, systemic steroid and antihistamine/
levofloxacin, clotrimazole, minocycline, topical improvement & recurrence
silver sulfadiazine/controlled

Our study demonstrated that first-line treatment for HHD was

It has also been reported that botulinum toxin, which causes the successful in most of the patients, which included topical cortico-
degradation of proteins required for the release of acetylcholine steroids in combination with topical or oral antibiotics and/or
and stimulation of perspiration, is effective in treating HHD by antifungal agents. MSSA, C. albicans, and other filamentous fungi
decreasing sweat secretion.21 Lower moisture levels are considered are the most common pathogenic organisms in HHD patients.
to decrease microorganism colonization as well as friction. Simi- Topical silver sulfadiazine is useful because of its effectiveness
larly, oral glycopyrrolate e a systemic anticholinergic that inhibits against MSSA and C. albicans. Ketoconazole, lanoconazole, and
the sympathetic stimulation of eccrine sweat glands by blocking minocycline are also often used for treating secondary infections in
the M3 muscarinic receptors in glandular tissue e has been shown HHD. Overall, the control of secondary infections is indispensable
to be effective for maintenance therapy in patients with HHD.22 in treating HHD and is not difficult. However, more aggressive
However, treatment efficacy is difficult to evaluate in HHD therapeutic approaches, such as gene therapy, that will prevent
because the effect of individual treatments is difficult to assess, recurrence of lesions in HHD patients are highly desirable.
given that most patients are simultaneously treated with multiple
treatment modalities. Thus far, no controlled studies have been
published for the various treatment modalities available for HHD. It
has been reported that although corticosteroids achieve good ef-
fects as first-line drugs, they do not prevent lesion recurrence;
similar to our findings.
The diagnosis of HHD is often delayed. In our patients, the
average time from disease onset to diagnosis was 7 years. We
observed a male predominance for HHD in our series. The lesion
morphology was variable, and itching, pain, and malodor were
observed frequently among our patients. No patient presented with
lesions affecting the mucous membranes.

Table 2 Summary of clinical characteristics.

Patients 26
Sex (patients)
Male 22
Female 4
Onset age (years) 24-50 (mean 35)
Onset to diagnosis time (years) 0-37 (mean 7)
Family history
Positive 21
not available 5
Secondary infection rate 85%
Staphylococcus aureus (MSSA) 18
Streptococcus 7
Pseudomonas aeruginosa 3
Candida albicans 10
Treatment
Antibacterial 14
Antifungal 21
Topical steroid 26
Systemic steroid 7
Topical tacrolimus 2
Topical retinoid (adapalene) 1
Systemic retinoid (etretinate) 2
Topical vitamin D3 2
Figure 1 Clinical findings (Case 26). (A) Erosive, blistering erythema in the groin. (B)
Carbon dioxide laser 2
Appearance of the lesion after treatment with topical steroid and ketoconazole. Erosive
Skin grafting 1
erythema has disappeared.

Please cite this article in press as: Zhao Q-F, et al., HaileyeHailey disease: A review of clinical features in 26 cases with special reference to the
secondary infections and their control, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/j.dsi.2016.08.003
 Q.-F. Zhao et al. / Dermatologica Sinica xxx (2016) 1e5 5

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Please cite this article in press as: Zhao Q-F, et al., HaileyeHailey disease: A review of clinical features in 26 cases with special reference to the
secondary infections and their control, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/j.dsi.2016.08.003