Clinical Review & Education

JAMA Clinical Challenge

A 58-Year-Old Man With a Macerated Rash

of the Neck and Axilla
Christopher Haley, MD; Uyen Ngoc Mui, MD; Stephen K. Tyring, MD, PhD

Figure 1. Left, Rash of right axilla. Right, Rash of right lateral area of the neck with global view and close-up view (inset).

A 58-year-old overweight African American man presented with a 5-year history of a

slightly pruritic and painful rash of the right lateral area of the neck and right axilla. It was WHAT WOULD YOU DO NEXT?
worse during the summers, and blisters sometimes developed. Emollients were unhelpful.
The patient was otherwise healthy. His sister had diabetes mellitus and a similar rash in her A. Prescribe topical ketoconazole
axillae. The patient performed indoor manual labor as a maintenance engineer and had no
significant sun exposure. Physical examination revealed irregularly thickened skin of the
B. Obtain glycated hemoglobin
right axilla (Figure 1, left) and right lateral area of the neck (Figure 1, right) containing hyper-
(HbA1C) level
pigmentation, hypopigmentation, multiple acrochordons (skin tags), malodorous crust,
and areas of maceration and erosion. Further examination of the skin revealed pseudofol-
liculitis barbae in the submental and mandibular regions bilaterally. The nails, oral cavity, C. Prescribe a topical corticosteroid
and mucosal membranes appeared normal. A biopsy of right axillary skin was performed and a topical antimicrobial
(Figure 2).
D. Consult for surgical excision

Diagnosis
Hailey-Hailey disease (benign familial pemphigus)
What to Do Next
C. Prescribe a topical corticosteroid and a topical antimicrobial
Discussion
The key to the correct diagnosis is the presence of an intertriginous
rash with report of blistering, summertime exacerbation, and fam-
ily history of a similar rash. First-line treatment for Hailey-Hailey dis-
ease is topical and should include a topical corticosteroid with or with-
out a topical antimicrobial.1,2 Hailey-Hailey disease can have an
appearance similar to that of acanthosis nigricans in dark-skinned
patients, but acanthosis nigricans is typically asymptomatic and
unlikely to vary with season. A crusted rash with seasonal variation
could suggest seborrheic dermatitis or candidal intertrigo, which
can be treated with ketoconazole. Seborrheic dermatitis, however,
usually involves the face or scalp and worsens during winter. Lack
of satellite lesions makes candidal intertrigo unlikely.
Hailey-Hailey disease is a rare autosomal dominant acantholytic
disease with variable penetrance.3,4 The disease was first described in
1939bybrothersWilliamandHughHailey,whowerebothafflictedwith
the condition.3 Hailey-Hailey disease is often misdiagnosed and is part
of a broad differential diagnosis that includes common diseases such
as intertrigo, inverse psoriasis, seborrheic dermatitis, erythrasma, and
acanthosis nigricans, as well as rare diseases such as Darier disease,
Galli-Galli disease, and autoimmune pemphigus variants.3-5 Accurate
diagnosis and proper treatment are essential, because Hailey-Hailey

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Diagnosis of Hailey-Hailey disease is made clinically and can be

Figure 2. Epidermal acantholysis causing separation of keratinocytes into
dilapidated brick wall appearance (hematoxylin-eosin, original magnification ×10).
disease profoundly affects quality of life4 and increases risk of bacte-
rial infection, fungal infection, and squamous cell carcinoma.2 The dis-
ease is caused by a mutation in the ATP2C1 gene, which encodes
a Ca+2/Mn+2 ATPase, hSPCA1, in the Golgi apparatus.1,3,6 hSPCA1 is pre-
sent throughout the body and is critical to keratinocyte function.3
Malfunction of hSPCA1 dysregulates calcium metabolism, which im-
pairs keratinocyte intercellular adherence and results in acantholysis,
which consists of epidermal cell separation.1,6,7
Hailey-Haileydiseasepresentsasachronicpainfulandpruriticrash
in flexural and intertriginous areas, with intermittent development of
blisters. Erosions and a malodorous crust may result after blisters
drain.1,3,4,6 The appearance of the rash is dependent on blister stage
and can vary widely, which can alter the differential diagnosis. The dis-
ease typically has no mucous membrane involvement,8 but fingernails
maydeveloplongitudinalwhitebands.1,6 Heat,sweat,friction,andtight
clothing often cause symptoms to worsen and the disease to progress,
making summertime exacerbations common.1,6 The disease is often
complicated by superimposed bacterial or fungal infections, which
can potentiate acantholysis.1 Rarely, fatal eczema herpeticum can also
occur if Hailey-Hailey disease becomes infected with herpes simplex
virus. Clinicians should consider herpes simplex testing in patients with
Hailey-Hailey disease and signs of systemic infection, vesiculopustu-
lar eruptions in the rash, or significant rash tenderness.9
confirmed histologically.4 Histopathologic examination reveals ac-
antholysis, which separates keratinocyte layers into a classic dilapi-
dated brick wall appearance (Figure 2).4 An overlying neutrophilic
crust is common.1 Dyskeratosis, or premature epithelial keratiniza-
tion, is usually mild, as opposed to Darier disease, in which dyskera-
tosis predominates over acantholysis.8 The dermis may be normal
or have mild lymphocytic perivascular inflammatory infiltrate.7 If
there is clinical concern for autoimmune pemphigus, immunofluo-
rescence can be performed.7
First-linetreatmentoptionsforHailey-Haileydiseaseincludetopi-
cal corticosteroids to reduce inflammation and topical antimicrobi-
als to treat infection.1,2 The disease occurs in intertriginous areas,
which are particularly susceptible to topical corticosteroid–induced
adverse effects such as skin atrophy, striae, telangiectasias, pur-
pura, and hypertrichosis. Use of topical corticosteroids should there-
fore be limited to acute exacerbations, while topical calcineurin in-
hibitors such as tacrolimus or pimecrolimus can be used for long-
term inflammation control.2 Topical antimicrobials should be used
in combination with topical corticosteroids if the rash exhibits signs
of infection such as a malodorous crust or if microbial colonization is
seen on histologic examination. Antimicrobial selection can include
antibiotics, antifungals, or both.1,2 Common options include topical
clindamycin, mupirocin, gentamicin, and ketoconazole.1,2 Lifestyle
modifications such as loose-fitting clothes, weight loss, periodic
chlorohexidine gluconate baths, and avoidance of humidity are
also helpful.2-4 Hailey-Hailey disease is often refractory to first-line
treatments.4 Second-line treatments with the best supporting
evidenceareoralantibiotics,surgicalexcisionwithskingrafting,botu-
linum toxin injections, CO2 laser, and dermabrasion.2,4 Other op-
tions for refractory disease include intralesional corticosteroids,
systemic antifungals, systemic corticosteroids, other systemic im-
munosuppressants, low-dose naltrexone, and oral retinoids.2,4,10
Patient Outcome
Biopsy confirmed the diagnosis of Hailey-Hailey disease, and the pa-
tient was treated with topical clindamycin (1% lotion) and triam-
cinolone (0.1% cream). At 1-month follow-up, the patient was asymp-
tomatic and the rash was nearly resolved. Postinflammatory
hyperpigmentation remained.

ARTICLE INFORMATION
Author Affiliations: Center for Clinical Studies,
Webster, Texas (Haley, Mui, Tyring); Department of
Dermatology, University of Texas Health Science
Center at Houston, Houston (Tyring).
Corresponding Author: Christopher Haley, MD,
Center for Clinical Studies, 451 N Texas Ave,
Webster, TX 77598 (chaley1029@gmail.com).
2. Arora H, Bray FN, Cervantes J, Falto Aizpurua LA. 8. Tomaszewska KA, Gerlicz-Kowalczuk Z, Kręgiel
Management of familial benign chronic pemphigus. M, et al. The coexistence of Darier’s disease and
Clin Cosmet Investig Dermatol. 2016;9:281-290. Hailey-Hailey disease symptoms. Postepy Dermatol
3. Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Alergol. 2017;34(2):180-183.
Hailey-Hailey disease: a fold (intertriginous) 9. de Aquino Paulo Filho T, deFreitas YK, da Nóbrega
dermatosis. Clin Dermatol. 2015;33(4):452-455. MT, et al. Hailey-Hailey disease associated with
4. Chiaravalloti A, Payette M. Hailey-Hailey disease herpetic eczema-the value of the Tzanck smear test.
and review of management. J Drugs Dermatol. Dermatol Pract Concept. 2014;4(4):29-31.

Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Additional Contributions: We thank the patient for
providing permission to share his information.
REFERENCES
1. Burge SM. Hailey-Hailey disease: the clinical
features, response to treatment and prognosis. Br J
Dermatol. 1992;126(3):275-282.
2014;13(10):1254-1257. 10. Ibrahim O, Hogan SR, Vij A, Fernandez AP.
5. Wolf R, Oumeish OY, Parish LC. Intertriginous Low-dose naltrexone treatment of familial benign
eruption. Clin Dermatol. 2011;29(2):173-179. pemphigus (Hailey-Hailey disease). JAMA Dermatol.
2017;153(10):1015-1017.
6. Missiaen L, Dode L, Vanoevelen J, Raeymaekers
L, Wuytack F. Calcium in the Golgi apparatus. Cell
Calcium. 2007;41(5):405-416.
7. Burge SM, Millard PR, Wojnarowska F.
Hailey-Hailey disease: a widespread abnormality of
cell adhesion. Br J Dermatol. 1991;124(4):329-332.

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