Hailey–Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare hereditary acantholytic skin disorder with an autosomal dominant mode of inheritance with complete penetrance, but a variable expressivity [1-4]. In only about two-thirds of patients, however, is a family history obtained [1]. The first onset of disease generally occurs between 20 years and 40 years of age [2,3]. Classic clinical manifestation is characterized by recurrent eruption of flaccid vesicles and blisters on erythematous skin, giving rise to erosions, fissures and secondary infection [2-5]. The lesions are typically distributed symmetrically in the intertriginous areas, mainly in the axillae, neck, inframammary folds, groin and perineum [3,4]. The natural progression of the disease is characterized by a chronic relapsing course with spontaneous remissions and multiple recurrences [2,4]. Up to 80% of patients with HHD experience bacterial and fungal superinfections [6]. Therefore, controlling secondary infection is indispensable for treating this disease [3]. Establishing a diagnosis of HHD is often arduous and strictly depends on adequate clinical history and histopathology results. Herein, a case of HHD in a young woman is described from a pathologist's perspective.

A 40-year-old woman was referred by her dermatologist to a surgeon in order to perform an incisional biopsy of the pathologic skin lesion. At that time, she presented with a 4×2cm demarcated erythematous plaque on the left sub-mammary region. The patient had undergone a long-term clinical follow-up and care at the dermatology outpatient department. For the last 20 years, she periodically experienced skin erythema in the axillae and groins, that were accompanied by intermittent inflammation, secernating and purulent discharge. In addition, a psoriasiform skin plaque on the right breast does also occur. The disease had a chronic relapsing nature. Initially, the clinical diagnosis of hidradenitis suppurative was considered. The symptoms were treated by local gentamicin/betamethasone application with good therapeutic response. Even the patient’s father manifested similar symptoms in the past. He suffered from macerated erythematous patches in both axillae that extended to the breast area on the right side. They were suggestive of intertrigo and treated by local application of cream containing hydrocortisone, natamycin and neomycin. With regards to the clinical history, a diagnosis of HHD began to come into consideration in the present woman. A surgical diagnostic excision of the pathologic skin lesion under the left breast was done and a biopsy sample was sent for histopathological examination. Haematoxylin and eosin (H&E) stained paraffin sections revealed an extensive supranasal acantholysis with intraepidermal vesicles and bullae formation. The widespread irregular acantholysis at different levels of the epidermis gave rise to the typical “dilapidated brick wall” appearance (Figure 1). Adnexal structures were spared. In some areas, a dense accumulation of neutrophils inside the intraepidermal clefts was visible (Figure 2). There was focal dyskeratosis and parakeratosis (Figure 3). Dermis showed mild to moderate chronic lymphocytic inflammatory infiltrate with a few neutrophils and eosinophils. The pathologist denoted the histomorphology findings to be typical for HHD. Yet he stated, they must be judged in the context of the patient's clinical symptomatology, which was also highly suggestive for this disorder. At the time of writing this article, no further clinical information about the patient was available.

Table 1: The most important clinicopathological features of HHD, Darier’s disease, Grover’s disease and pemphigus vulgaris [1]. 

Figure 1: Extensive suprabasal acantholysis showing a characteristic “dilapidated brick wall” appearance (H&E, 40x).

Figure 2: Massive acantholysis of the epidermis with a typically spared hair follicle (H&E, 60x).

Figure 3: Detail on acantholytic epidermis with dyskeratotic keratinocytes and parakeratosis (H&E, 80x).

HHD was first described in 1939 by two dermatologist Hailey brothers Hugh Edward and William Howard [7]. Later, the disease was named after them. The incidence has been estimated at 1/50,000 with equal predilection for males and females [2,4,5]. However, the actual prevalence is likely higher due to mislabelling of the diagnosis because of its nonspecific symptoms, resemblance to other dermatoses and because many patients do not seek treatment for milder variants [4-6].

HHD belongs to the group of acantholytic blistering genodermatosis [1]. It is primarily an abnormality of cell adhesion [1,2]. It results from mutations in the ATP2C1 gene which encodes a protein SPCA1 (Secretory Pathway Calcium/manganese-ATPase) within the membrane of the Golgi apparatus [4,5]. Although the SPCA1 is ubiquitous throughout the body, the human keratinocyte has been shown to be especially dependent on it for its calcium homeostasis compared with other human cells [4]. The alterations of the SPCA1 pathway led to deregulation of the Ca²⁺-dependent intracellular signalling. This finally results in impaired intercellular desmosome function and loss of keratinocyte adhesion, leading to acantholysis of the supranasal epidermis [3-5]. 

Acantholysis is a commonly encountered histological pattern in dermatopathological practice [8]. This term derives from the Greek acantha - a thorn or price and lysis - a loosening [1]. It is defined by loss of intercellular cohesion between keratinocytes, resulting in cell separation and a rounded cellular outline [8]. It may or may not be accompanied by clinically apparent blisters [8]. There is a broad spectrum of dermatoses exhibiting an acantholysis. Their detailed description would go far beyond the scope of this article, but they are well described in another papers [1,8,9]. Among them, much attention has been paid to the prototypical acantholytic (and dyskeratotic) dermatoses including HHD, Darier’s disease (keratosis follicularis), Grover’s disease (transient acantholytic dermatosis) and pemphigus vulgaris [8]. The histologic features of these conditions show considerable overlap [1]. The final diagnosis is therefore dependent on adequate clinical data and sometimes on the results of immunofluorescence [1]. As has already been mentioned, a characteristic pathologic finding of HHD is a supranasal acantholysis of the whole epidermis, giving the classic description of the “dilapidated brick wall” [1]. Adjacent epidermis is also disintegrated, but adnexal structures are typically spared. Dyskeratosis is less prominent and corps rounds and grains are rare. In contrast, Darier’s disease tends to show more dyskeratosis and less acantholysis with involvement of adnexa and is associated with numerous corps rounds and grains. Pemphigus vulgaris is distinguished from HHD by the presence of relatively intact epithelium in the adjacent epidermis and involvement of adnexal structures. In difficult cases, positive immunofluorescence staining supports a diagnosis of pemphigus [1]. Instead of featuring specific histopathological changes, Grover’s disease classically mimics all three diseases mentioned above. In spite of similar histomorphology, however, it is clinically quite easily differentiated from them. A summary of the most important clinicopathological features of HHD, Darier’s disease, Grover’s disease and pemphigus vulgaris is illustrated in Table 1. In the present case, the spectrum of given findings was consistent with a diagnosis of HHD.

Hailey-Hailey disease is rarely encountered in dermatological practice. Although it exhibits a typical histomorphology, this is not pathognomonic for it. Therefore, biopsy investigation alone may not be sufficient for the purpose of making a definite diagnosis. Hailey-Hailey disease is a challenging diagnosis that always requires a comprehensive assessment of both, histopathologic and clinical findings.

1. Calonje, J.E. et al. McKee’s Pathology of the Skin: With Clinical Correlations. Vol. 1, 5th ed., Elsevier, 2020, pp. 171–200.

2. Lagha, I.B. et al. “Hailey-Hailey disease: An update review with a focus on treatment data.” American Journal of Clinical Dermatology, vol. 21, no. 1, 2020, pp. 49–68.

3. Zhao, Q.F. et al. “Hailey–Hailey disease: A review of clinical features in 26 cases with special reference to the secondary infections and their control.” Dermatologica Sinica, vol. 35, no. 1, 2017, pp. 7–11.

4. Chiaravalloti, A. and M. Payette. “Hailey-Hailey disease and review of management.” Journal of Drugs in Dermatology, vol. 13, no. 10, 2014, pp. 1254–1257.

5. Bhavya Sri, K. “A very brief overview of Hailey-Hailey disease with various available treatment options.” Journal of Clinical and Experimental Dermatology Research, vol. 10, no. 1, 2019, p. 477.

6. Patel, V.M. et al. “Hailey-Hailey disease: A diagnostic challenge.” Cutis, vol. 103, no. 3, 2019, pp. 157–159.

7. Hailey, H. and H. Hailey. “Familial benign chronic pemphigus: Report of 13 cases in four generations of a family and report of 9 additional cases in four generations of a family.” Archives of Dermatology and Syphilology, vol. 39, 1939, pp. 679–685.

8. Ho, J. and J. Bhawan. “Mimickers of classic acantholytic diseases.” Journal of Dermatology, vol. 44, no. 3, 2017, pp. 232–242.

9. See, S.H.C. et al. “Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis.” Journal of Cutaneous Pathology, vol. 46, no. 1, 2019, pp. 6–15.