Acute generalized Hailey–Hailey disease

T. A. Chave and A. Milligan

Department of Dermatology, Leicester Royal Infirmary, Leicester, UK

Summary A patient with extensive histologically proven Hailey–Hailey disease is described whose

initial clinical presentation was suggestive of erythema multiforme or toxic epidermal

necrolysis. This potentially misleading morphology of acute proven Hailey–Hailey

disease has not been described previously and may be a consequence of bacterial

infection exacerbating acantholysis.

Report

A 64-year-old Sri Lankan man presented with a 5-day

history of a progressive rash. This had initially devel-

oped on the neck and had spread gradually over the

trunk and limbs. He was systemically well and there had

been no preceding symptoms. He had glaucoma and

used timolol and fluorometholone eyedrops, but was on

no other regular medication. He had been seen in our

department in 1978 with biopsy proven Hailey-Hailey

disease (HHD) affecting his flexures, but was lost to

follow-up. Since then he had periodically used moder-

ately potent topical corticosteroids for his HHD with

good effect. He did not give a positive family history of

HHD.

On examination he had a widespread erythematous

blistering eruption, more pronounced centrally. On the

limbs there were targetoid lesions (Fig. 1), and on the

trunk areas of blistering and epidermal loss (Fig. 2).

The face, scalp and mucous membranes were spared.

Nikolsky’s sign could not be elicited. In addition to the

widespread rash he had well-demarcated fissured mal-

odorous plaques in his axillae and groins (Fig. 3),

typical of HHD. Based on these clinical appearances,

erythema multiforme (EM) with possible early progres-

sion towards toxic epidermal necrolysis was suspected.

He was admitted and biopsies were taken from an

EM-like targetoid lesion, an intact blistered area on the

abdomen and through the edge of an axillary plaque.

Histology of all three biopsies showed identical

features of extensive suprabasal acantholytic blisters

with epidermal oedema and focal infiltration by poly-

morphic neutrophils. There was no epidermal necrosis.

Gram stain revealed numerous bacteria at the skin

surface, but none were present in the areas of acantho-

lysis or in the focal areas of neutrophil aggregation.

Direct immunoflouresence of perilesional skin was

negative.

C-reactive protein was markedly elevated at

191 mg ⁄ L (normal range, 0–10 mg ⁄ L). Renal, liver

and haematological parameters were all within normal

limits. A skin swab taken from an unruptured bulla at

his initial presentation did not grow any organisms. A

repeat specimen taken on the ward grew both Staphy-

lococcus aureus and b-haemolytic group B Streptococcus.

On admission the patient was treated topically with

10% betadine in aqueous solution and mepitel� dress-

ings. Once the skin swab results were available he was

commenced on oral erythromycin 500 mg four times

per day for 7 days. The patient remained systemically

well throughout his admission and over a 10-day period

his rash resolved leaving classical HHD confined to the

axillae and groins, which he continues to have at

review.

HHD (benign familial chronic pemphigus) is an

uncommon autosomal dominant dermatosis, first des-

cribed in 1939.1 The genetic defect has recently been

characterized as mutation in the ATP2C1 gene on

chromosome 3q21, coding for an ATP-driven transmem-

brane calcium pump.2 In approximately 15% of cases a

positive family history cannot be elicited. This may be due

Correspondence: T. A. Chave, Department of Dermatology, Leicester Royal

Infirmary, Leicester, LE1 5WW, UK.

Tel.: +44 116 2541414. Fax: +44 116 2586792.

E-mail: toby@chave.fsbusiness.co.uk

Accepted for publication 28 January 2002

Clinical dermatology • Concise report

290 � 2002 Blackwell Science Ltd • Clinical and Experimental Dermatology, 27, 290–292

to sporadic gene mutation or because of unrecognized

mild disease affecting other family members.

Disease onset is typically in the third and fourth

decades. Flexural and intertriginous areas are affected

predominantly. Over 50% of affected women report

submammary involvement.3 Lesional morphology can

be varied. The distinctive clinical appearance of active

disease is of velvety hypertrophic fissured plaques, often

malodorous due to bacterial colonization. When less

florid, dry scaly eczematous patches or crusted erosions

can predominate, leading to frequent misdiagnosis as

eczema, or as bacterial or fungal infections. This

misdiagnosis is often compounded by a positive response

to topical corticosteroids combined with antibiotic or

antifungal agents. An interesting and potentially useful

clinical finding is longitudinal white bands found in the

nails in up to 70% of cases.3

The severity of HHD fluctuates over time, and tends to

improve as patients get older. Minor trauma is a

frequent precursor to the development of new lesions.

In patients with HHD, even clinically uninvolved skin

will develop subrabasal acantholysis with suction,4

which may explain this Koebner-like response. Heat,

stress and sunlight can also exacerbate the disease.

The role of infection in HHD has been controversial

since, soon after it’s original description, pyogenic cocci

and Candida albicans were cultured from unruptured

vesicles.5 It is thought, however, that most organisms

isolated from active HHD lesions represent secondary

colonization rather than primary infection. Biopsy-

proven HHD has been demonstrated following the

application of Staphylococcus aureus and Candida albicans

to the skin,6,7 and the frequent response of HHD to

antimicrobial preparations also supports a contributory

role for infective agents. Widespread skin involvement

by herpes simplex virus in patients with underlying

HHD has been reported,8–10 but whether the virus

actually induces lesions of HHD remains unclear.

Most of the few reports of extensive biopsy-proven

HHD in the literature appear to be a Koebner-like

response, following insults such as drug eruptions11 or

scabies.12 Erythrodermic histologically proven HHD has

been reported,13 without an obvious precipitant.

Our patient is interesting in that although initial

swabs from an unbroken vesicle did not grow any

organisms, subsequent swabs taken 3 days later grew

both Staphylococcus aureus and b-haemolytic Strepto-

coccus, and there was rapid improvement following the

instigation of antibiotic therapy. This suggests that

although infection may not have initiated the exacer-

bation of HHD, it’s presence may have potentiated

Figure 2 Close-up of blistering and desquamation on abdomen.

Figure 1 Annular lesions on left arm, some showing targetoid

appearance.

Acute generalized HHD • T. A. Chave and A. Milligan

� 2002 Blackwell Science Ltd • Clinical and Experimental Dermatology, 27, 290–292 291

ongoing acantholysis. His clinical presentation is also

unusual, and to the best of our knowledge, HHD

bearing a clinical resemblance to lesions of erythema

multiforme or toxic epidermal necrolysis has not been

described previously.

References

1 Hailey H. Familial benign chronic pemphigus. Arch Der-

matol Syphilol 1939; 39: 679–85.

2 Hu Z, Bonifas JM, Beech J et al. Mutations in ATP2C1,

encoding a calcium pump, cause Hailey–Hailey disease.

Nature Genet 2000; 24: 61–5.

3 Burge SM. Hailey–Hailey disease: the clinical features,

response to treatment and prognosis. Br J Dermatol 1992;

126: 275–82.

4 Burge SM, Millard PR, Wojnarowska F. Hailey–Hailey

disease: a widespread abnormality of cell adhesion. Br J

Dermatol 1991; 124: 329–32.

5 Ayres S Jr, Anderson NP. Recurrent herpetiform dermatitis

repens. Arch Dermatol Syphilol 1939; 40: 402–13.

6 Loewenthal LJA. Familial benign chronic pemphigus. The

role of pyogenic bacteria. Arch Dermatol 1959; 80:

318–26.

7 Burns RA, Reed WB, Swatek FE, Omieczynski DT. Familial

benign chronic pemphigus. Induction of lesions by Candida

albicans. Arch Dermatol 1967; 96: 254–8.

8 Ogilvie M, Kesseler M, Leppard B et al. Herpes simplex

infections in pemphigus: an indication for urgent viral

studies and specific antiviral therapy. Br J Dermatol 1983;

109: 611–3.

9 Zaim MT, Bickers DR. Herpes simplex associated with

Hailey–Hailey disease. J Am Acad Dermatol 1987; 17:

701–2.

10 Flint ID, Spencer DM, Wilkin JK. Eczema herpeticum in

association with familial benign chronic pemphigus. J Am

Acad Dermatol 1993; 28: 257–9.

11 Meffert JL, Davis BM, Campbell JC. Bullous drug eruption to

griseofulvin in a man with Hailey–Hailey disease. Cutis

1995; 56: 279–80.

12 Gerdsen R, Hartyl C, Christ S et al. Hailey–Hailey disease:

exacerbation by scabies. Br J Dermatol 2001; 144: 211.

13 Marsch WCh, Stuttgen G. Generalised Hailey–Hailey dis-

ease. Br J Dermatol 1978; 99: 553–9.

Figure 3 Fissured vegetating axillary plaque.

Acute generalized HHD • T. A. Chave and A. Milligan

292 � 2002 Blackwell Science Ltd • Clinical and Experimental Dermatology, 27, 290–292