IAR Journal of Medical Sciences ISSN Online: 2708-3594 Frequency: Monthly Language: English Origin : Kenya Website : https://www.iarconsortium.org/journal-info/iarjms Case Report

Hailey-Hailey Disease: A Challenging Diagnosis in Biopsy Practice

Article History Abstract: Background: Hailey–Hailey disease (HHD) is a rare acantholytic genodermatosis. Establishing the diagnosis is often arduous and strictly depends Received: 25.10.2020 on adequate clinical history and histopathology results. Case Report: The Accepted: 29.11.2020 authors describes a 40-year-old woman, who periodically experienced skin Revision: 05.12.2020 erythemas in the axillae and groins, accompanied by intermittent inflammation, Published: 10.12.2020 secernation and purulent discharge. Last time, she presented with a demarcated erythematous plaque on the left submammary region. Histology revealed an Author Details extensive suprabasal acantholysis of the epidermis with intraepidermal vesicles Vladimír Bartoš*1, Karolína Vorčáková2 and and bullae formation. The widespread irregular acantholysis gave rise to the 3 Klaudia Péčová typical „dilapidated brick wall“ appearance. Adnexal structures were spared. Authors Affiliations The microscopic findings were characteristic for HHD, and even clinical symptomatology was highly suggestive for this disorder. Conclusion: Although 1Martin´s Biopsy Center, Ltd., Martin, Slovakia HHD exhibits a typical histomorphology, this is not pathognomonic for it. 2Clinic of Dermatovenerology, Jessenius Faculty Therefore, biopsy investigation alone may not be sufficient for the purpose of of Medicine in Martin, Slovakia making a definite diagnosis. HHD is a challenging diagnosis that always

3Dermatology Outpatient Department, Policlinic requires a comprehensive assessment of both, histopathologic and clinical findings. in Turčianske Teplice, Slovakia

Corresponding Author Keywords: Hailey-Hailey disease, Acantholysis, Dilapidated brick wall. Vladimír Bartoš How to Cite the Article INTRODUCTION Vladimír Bartoš, Karolína Vorčáková and Hailey–Hailey disease (HHD), also known as familial benign chronic Klaudia Péčová (2020); Hailey-Hailey Disease: A pemphigus, is a rare hereditary acantholytic skin disorder with an autosomal Challenging Diagnosis in Biopsy Practice. IAR J Med dominant mode of inheritance with complete penetrance, but a variable Sci, 1(7); 312-315. expressivity (Calonje, J.E. et al., 2020, Lagha, I.B. et al., 2020, Zhao, Q.F. et al., Copyright @ 2020: This is an open-access article 2017, Chiaravalloti, A.  Payette, M., 2014). In only about two-thirds of distributed under the terms of the Creative Commons Attribution license which permits unrestricted use, patients, however, is a family history obtained (Calonje, J.E. et al., 2020). The distribution, and reproduction in any medium for non first onset of disease generally occurs between 20 years and 40 years of age commercial use (NonCommercial, or CC-BY-NC) (Lagha, I.B. et al., 2020, Zhao, Q.F. et al., 2017). Classic clinical manifestation provided the original author and source are credited. is characterized by recurrent eruption of flaccid vesicles and blisters on erythematous skin, giving rise to erosions, fissures and secondary infection (Lagha, I.B. et al., 2020, Zhao, Q.F. et al., 2017, Chiaravalloti, A.  Payette, M., 2014, Bhavya Sri, K., 2019). The lesions are typically distributed symetrically in the intertriginous areas, mainly in the axillae, neck, inframammary folds, groin and perineum (Zhao, Q.F. et al., 2017, Chiaravalloti, A.  Payette, M., 2014). The natural progression of the disease is characterized by a chronic relapsing course with spontaneous remissions and multiple recurrences (Lagha, I.B. et al., 2020, Chiaravalloti, A.  Payette, M., 2014). Up to 80% of patients with HHD experience bacterial and fungal superinfections (Patel, V.M. et al., 2019). Therefore, controlling secondary infection is indispensable for treating this disease (Zhao, Q.F. et al., 2017). 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.

CASE REPORT

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

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Vladimír Bartoš, Karolína Vorčáková and Klaudia Péčová; IAR J Med Sci; Vol-1, Iss-7 (Dec, 2020): 312-315

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)

A 40-year-old woman was referred by her eosin (H&E) stained paraffin sections revealed an dermatologist to a surgeon in order to perform an extensive suprabasal acantholysis with intraepidermal incisional biopsy of the pathologic skin lesion. At that vesicles and bullae formation. The widespread irregular time, she presented with a 4x2-cm demarcated acantholysis at different levels of the epidermis gave erythematous plaque on the left submammary region. rise to the typical „dilapidated brick wall“ appearance The patient had undergone a long-term clinical follow- (Figure 1). Adnexal structures were spared. In some up and care at the dermatology outpatient department. areas, a dense accumulation of neutrophils inside the For the last 20 years, she periodically experienced skin intraepidermal clefts was visible (Figure 2). There was erythemas in the axillae and groins, that were focal dyskeratosis and parakeratosis (Figure 3). Dermis accompanied by intermittent inflammation, secernation showed mild to moderate chronic lymphocytic and purulent discharge. In addition, a psoriasiform skin inflammatory infiltrate with a few neutrophils and plaque on the right breast does also occur. The disease eosinophils. The pathologist denoted the had a chronic relapsing nature. Initially, the clinical histomorphologic findings to be typical for HHD. Yet diagnosis of hidradenitis supurrativa was considered. he stated, they must be judged in the contex of the The symptoms were treated by local patient's clinical symptomatology, which was also gentamicin/betamethasone application with good highly suggestive for this disorder. At the time of therapeutic response. Even the patient’s father writing this article, no further clinical information about manifested similar symptoms in the past. He suffered the patient was available. from macerated erythematous patches in both axillae that extended to the breast area on the right side. They ISCUSSION were suggestive of intertrigo and treated by local D application of cream containing hydrocortisone, HHD was first described in 1939 by two natamycin and neomycin. With regards to the clinical dermatologist Hailey brothers Hugh Edward and history, a diagnosis of HHD began to come into William Howard (Hailey, H.  Hailey, H., 1939). Later, consideration in the present woman. A surgical the disease was named after them. The incidence has diagnostic excision of the pathologic skin lesion under been estimated at 1/50,000 with equal predilection for the left breast was done and a biopsy sample was send males and females (Lagha, I.B. et al., 2020, for histopathological examination. Hematoxylin and Chiaravalloti, A.  Payette, M., 2014, Bhavya Sri, K.,

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Vladimír Bartoš, Karolína Vorčáková and Klaudia Péčová; IAR J Med Sci; Vol-1, Iss-7 (Dec, 2020): 312-315 2019). However, the actual prevalence is likely higher but they are well described in another papers (Calonje, due to mislabeling of the diagnosis because of its J.R. et al., 2020, Ho, J.  Bhawan, J., 2017, See, S.H.C., nonspecific symptoms, resemblance to other dermatoses et al., 2019). Among them, much attention has been and because many patients do not seek treatment for paid to the prototypical acantholytic (and dyskeratotic) milder variants (Chiaravalloti, A.  Payette, M., 2014, dermatoses including HHD, Darier’s disease (keratosis Bhavya Sri, K., 2019, Patel, V.M. et al., 2019). follicularis), Grover’s disease (transient acantholytic dermatosis), and pemphigus vulgaris (Ho, J.  Bhawan, HHD belongs to the group of acantholytic J., 2017). The histologic features of these conditions blistering genodermatosis (Calonje, J.E. et al., 2020). It show considerable overlap (Calonje, J.E. et al., 2020). is primarily an abnormality of cell adhesion (Calonje, The final diagnosis is therefore dependent on adequate J.E. et al., 2020, Lagha, I.B. et al., 2020). It results from clinical data and sometimes on the results of mutations in the ATP2C1 gene which encodes a protein immunofluorescence (Calonje, J.E. et al., 2020). As has SPCA1 (Secretory Pathway Calcium/manganese- already been mentioned, a characteristic pathologic ATPase) within the membrane of the Golgi apparatus finding of HHD is a suprabasal acantholysis of the (Zhao, Q.F. et al., 2017, Chiaravalloti, A.  Payette, M., whole epidermis, giving the classic description of the 2014, Bhavya Sri, K., 2019). Although the SPCA1 is „dilapidated brick wall“ (Calonje, J.E. et al., 2020). ubiquitous throughout the body, the human keratinocyte Adjacent epidermis is also disintegrated, but adnexal has been shown to be especially dependent on it for its structures are typically spared (Calonje, J.E. et al., calcium homeostasis compared with other human cells 2020). Dyskeratosis is less prominent and corps ronds (Chiaravalloti, A.  Payette, M., 2014). The alterations and grains are rare (Calonje, J.E. et al., 2020). In of the SPCA1 pathway lead to deregulation of the Ca2+- contrast, Darier’s disease tends to show more dependent intracellular signaling. This finally results in dyskeratosis and less acantholysis with involvement of impaired intercellular desmosome function and loss of adnexae and is associated with numerous corps ronds keratinocyte adhesion, leading to acantholysis of the and grains (Calonje, J.E. et al., 2020). Pemfigus suprabasal epidermis (Zhao, Q.F. et al., 2017, vulgaris is distinguished from HHD by the presence of Chiaravalloti, A.  Payette, M., 2014, Bhavya Sri, K., relatively intact epithelium in the adjacent epidermis 2019). and involvement of adnexal structures (Calonje, J.E. et al., 2020). In difficult cases, positive Acantholysis is a commonly encountered immunofluorescence staining supports a diagnosis of histological pattern in dermatopathological practice pemphigus (Calonje, J.E. et al., 2020). Instead of (Ho, J.  Bhawan, J., 2017). This term derives from the featuring specific histopathological changes, Grover’s Greek akantha - a thorn or pricle, and lysis - a loosening disease classically mimics all three diseases mentioned (Calonje, J.E. et al., 2020). It is defined by loss of above. In spite of similar histomorphology, however, it intercellular cohesion between keratinocytes, resulting is clinically quite easily differentiated from them. in cell separation and a rounded cellular outline (Ho, J. A summary of the most important clinicopathological  Bhawan, J., 2017). It may or may not be features of HHD, Darier’s disease, Grover’s disease and accompanied by clinically apparent blisters (Ho, J.  pemphigus vulgaris is illustrated in Table 1. In the Bhawan, J., 2017). There is a broad spectrum of present case, the spectrum of given findings was dermatoses exhibiting an acantholysis. Their detailed consistent with a diagnosis of HHD. description would go far beyond the scope of this article,

Table 1: The most important clinicopathological features of HHD, Darier’s disease, Grover’s disease, and pemphigus vulgaris. (compilated from ref. Calonje, J.E. et al., 2020). Hailey-Hailey disease  usually in the second to fourth decade, improves with age  typically on the intertriginous areas (axillae, groin, inframammary, perianal)  relapsing-remitting clinical course, no sex predilection  less dyskeratosis, more acantholysis with „dilapidated brick wall“ pattern  adnexal structures are sparsed, adjacent epidermis is disintegrated  corps ronds and grains are rare  direct immunofluorescence is negative

Darier disease  usually in the first or second decade  typically on the seborrheic areas (scalp, forehead, nasolabial folds, upper chest, back)  long-term disease with very rare spontaneous remissions, no sex predilection  less acantholysis, more dyskeratosis  adnexal structures are involved, adjacent epidermis is intact  corps ronds and grains are numerous  direct immunofluorescence is negative

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Vladimír Bartoš, Karolína Vorčáková and Klaudia Péčová; IAR J Med Sci; Vol-1, Iss-7 (Dec, 2020): 312-315 Pemphigus vulgaris  predominantly in the middle age (inset typically at 40-60 years of age)  usually affects oral mucosa, only rarely confined to the skin  skin manifestation most often on the scalp, face, axillae, and groins  long-term disease, no sex predilection  adnexal structures are involved, adjacent epidermis is intact  corps ronds and grains absent  direct immunofluorescence is positive Grover disease  usually in the middle age and elderly  predilection for the chest, back, and thighs  the disease is usually transient with a predilection for the winter months  males are more affected than females (M/F ratio 3:1)  the lesions may histologically mimic any of them and can only be distinguish by Immunofluorescence

ONCLUSION cases in 4 generations of a family. Arch Dermatol C Syphilol, 39, 679-685. Hailey-Hailey disease is rarely encountered in dermatological practice. Although it exhibits a typical 5. Ho, J.,  Bhawan, J. (2017). Mimickers of classic histomorphology, this is not pathognomonic for it. acantholytic diseases. J Dermatol, 44(3), 232-242. Therefore, biopsy investigation alone may not be 6. Lagha, I.B., Ashack, K.,  Khachemoune, A. sufficient for the purpose of making a definite (2020). Hailey-Hailey disease: An update review diagnosis. Hailey-Hailey disease is a challenging with a focus on treatment data. Am J Clin diagnosis that always requires a comprehensive Dermatol, 21(1), 49-68. assessment of both, histopathologic and clinical 7. Patel, V.M., Rubins, S., Schwartz, R.A., Septe, M., findings.  Rubins, A. (2019). Hailey-Hailey disease: A diagnostic challenge. Cutis, 103(3), 157-159. REFERENCES 8. See, S.H.C., Peternel, S., Adams, D.,  North, J.P. (2019). Distinguishing histopathologic features of 1. Bhavya Sri, K. (2019). A very brief overview of acantholytic dermatoses and the pattern of Hailey-Hailey disease with various available acantholytic hypergranulosis. J Cutan Pathol, 46(1), treatment options. J Clin Exp Dermatol Res, 10(1), 6-15. 477. 9. Zhao, Q.F., Hasegawa, T., Komiyama, E.,  Ikeda, 2. Calonje, J.E., Brenn, T., Lazar. A.,  Billings, S.D. S. (2017). Hailey–Hailey disease: A review of (2020). McKee's pathology of the skin: with clinical features in 26 cases with special reference clinical correlations. Volume one. 5th edition. to the secondary infections and their control. Elsevier, p. 171-200. Dermatologica Sinica, 35(1), 7-11. 3. Chiaravalloti, A.,  Payette, M. (2014). Hailey- Hailey disease and review of management. J Drugs Dermatol, 13(10), 1254-1257. 4. Hailey, H.,  Hailey, H. (1939). Familial benign chronic pemphigus. Report of 13 cases in four generations of a family and report of 9 additional

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