ATP2C1 knockdown induces abnormal expressions of cytoskeletal and tight junction proteins mimicking Hailey-Hailey disease.

Background Hailey-Hailey disease (HHD) is a rare, autosomal dominant, hereditary skin disorder characterised by epidermal acantholysis. The HHD-associated gene ATPase calcium-transporting type 2C member 1 (ATP2C1) encodes the protein secretory pathway Ca2+ ATPase1 (SPCA1), playing a critical role in HHD pathogenesis. Aims We aimed to investigate the effect of ATP2C1 knockdown on keratinocytes that mimicked acantholysis in HHD. Methods Immunohistochemistry (IHC) was employed to evaluate the levels of cytoskeletal and tight junction proteins such as SPCA1, P-cofilin, F-actin, claudins, occludin, and zonula occludens 1 in the skin biopsies of patients with HHD. Subsequently, the expression of these proteins in cultured ATP2C1 knockdown keratinocytes was analysed using Western blotting and immunofluorescence. Furthermore, we assessed the proliferation, apoptosis, and intracellular Ca2+ concentrations in the ATP2C1-knocked keratinocytes. Results The results showed decreased levels of these proteins (SPCA1, P-cofilin, F-actin, claudins, occluding, and zonula occludens 1) in HHD skin lesions. Moreover, their levels decreased in human keratinocytes transfected with ATP2C1 short hairpin RNA, accompanied by morphological acantholysis. Furthermore, the proliferation and apoptosis of the keratinocytes, as well as intracellular calcium concentrations in these cells, were not affected. Limitations The limitations of this study are the absence of animal experiments and the failure to explore the relationship between skeletal and tight junction proteins. Conclusion The present study indicated that ATP2C1 inhibition led to abnormal levels of the cytoskeletal and tight junction proteins in the keratinocytes. Therefore, keratinocytes can mimic HHD-like acantholysis and serve as an in vitro model, helping develop treatment strategies against HHD.

A case report of Hailey-Hailey disease treated with fractional carbon dioxide laser.

Hailey-Hailey disease (HHD), or familial benign pemphigus, is a rare genetic condition characterized by recurrent blisters and erosions with a predilection for intertriginous areas. There is no specific treatment for HHD. Topical and systemic treatments tend to provide temporary remission. Alternative treatment (surgical interventions such as dermabrasion, excision, and laser) has been shown to prolong remission. Considering the risk of complications associated with surgical modalities, laser is often preferred as an alternative for patients failing to respond to first-line therapies. We report a case of recalcitrant HHD successfully treated with a fractional ablative CO2 laser procedure (wavelength of 10600 nm, power of 7-10 W, 2-3 passes) on a 35-year-old female. The patient has a 7-year history of therapy-resistant HHD. A 2-month followup showed substantially resolved lesions, with mild erythema and post-inflammatory hyperpigmentation in treated areas.

Dermoscopy as a Noninvasive Diagnostic Tool for Hailey-Hailey Disease and Darier Disease.

INTRODUCTION: Hailey-Hailey disease (HHD) and Darier disease (DD) are rare genetic disorders for which differential diagnosis, especially in less obvious cases, can be difficult. The diagnosis is based on the clinical picture and family history, and is confirmed by histopathologic examination. Dermoscopy is a noninvasive technique that is primarily used at the present time to diagnose skin cancers. However, in the past few years this technique has also been increasingly used as a noninvasive diagnostic tool of inflammatory skin diseases. The aim of the study was to evaluate whether dermoscopy is a useful noninvasive diagnostic tool for HHD and DD. METHODS: We performed an observational retrospective case series study involving 13 patients with HHD (n = 8) and DD (n = 5). The presence or absence of standardized dermoscopic features of inflammatory diseases (according to International Dermoscopy Society [IDS] guidelines) was assessed in these patients. RESULTS: The most distinctive feature of HHD was white clouds separated by pink furrows, visible in all cases (8/8; 100.0%). Another distinctive clue of HHD was the crumbled fabric pattern seen in six patients with HHD (6/8; 75.0%). These dermoscopic findings were not present in patients with DD. The most typical features of DD in the dermoscopic examination was star-like or oval-shaped yellow areas surrounded by whitish halo, visible in all patients (5/5; 100.0%). Another distinctive dermoscopic clue of DD was pinkish homogeneous structureless background, which was present in all patients (5/5, 100.0%). These latter two features were not observed in patients with HHD. CONCLUSION: Dermoscopy reveals distinctive features of HHD and DD, respectively. Therefore, we conclude that dermoscopy can be an excellent complementary noninvasive tool in the diagnostic process of patients with HHD and DD.

Hailey-Hailey disease and Darier disease are rare genetic disorders, which are diagnosed based on the clinical picture and confirmed with skin biopsy. Dermoscopy is noninvasive diagnostic tool, which enables skin visualization at a 10-fold magnification. Currently, dermoscopy is mainly used to diagnose skin cancers. In the recent years, dermoscopy has been also increasingly used as a noninvasive diagnostic tool of inflammatory skin diseases. The aim of the study was to assess whether demoscopy may be a useful tool in diagnosing Hailey-Hailey disease and Darier disease. The study included thirteen patients: eight with Hailey-Hailey disease and five with Darier disease. The most typical dermoscopic feature of Hailey-Hailey disease was white clouds separated by pink furrows, which were visible in all cases. Another distinctive clue was crumbled fabric pattern seen in 75.0% of patients with Hailey-Hailey disease. These dermoscopic findings were not present in patients with Darier disease. In dermoscopic examination the most typical feature of Darier disease was star-like or oval-shaped yellow areas surrounded by whitish halo, visible in all patients. Also, pinkish homogeneous structureless background was present in all patients with Darier disease. These features were not observed in patients with Hailey-Hailey disease. Dermoscopy reveals characteristic features of Hailey-Hailey disease and Darier disease. Therefore, it can be an excellent complementary tool in the diagnostic process of patients with those diseases.

Hailey-Hailey disease successfully treated with photodynamic therapy: Case report.

Hailey-Hailey disease (HHD) is a rare genetic benign condition resulting in blisters predominantly on the skin folds. The inheritance is autosomal dominant with complete penetrance, but a variable expressivity in affected family members. It can be triggered by a vast variety of factors such as sweating, weight gain, infection, trauma, pregnancy, and ultraviolet radiation, but the major cause of the disease is a mutation in the ATP2C1 gene. The lesions are typically distributed symmetrically within intertriginous regions such as the retroarticular folds, axillae, inguinal, and perianal regions and presents as flaccid vesicles and blisters on erythematous skin, giving rise to erosions, fissures, and vegetations. There is no specific therapy for HHD. The therapeutic approach to HHD involves the control of exacerbating factors, secondary infections, and cutaneous inflammation. Because of the rarity of the disease, evidence of efficacy for topical or systemic therapies is mainly based on small observational studies, case reports, and clinical experience. We present a case of HHD successfully treated by photodynamic therapy (PDT) with a topical liposomal chlorin photosensitizer.

Acute generalized exanthematous pustulosis associated with clindamycin in a patient with Hailey-Hailey disease.

A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to her presentation, she was started on oral clindamycin for a tooth extraction procedure. Her physical examination shows diffuse erythema on the trunk and extremities with multiple nonfollicular pustules. A punch biopsy of her upper extremity revealed intraepidermal acantholysis, neutrophilic spongiosis, and subcorneal pustules. The perivascular and interstitial superficial dermal infiltrate is mixed and composed of predominantly neutrophils, with lymphocytes and rare eosinophils. These findings suggest a superimposed acute generalized exanthematous pustulosis (AGEP) in the background of HHD. AGEP is a potentially severe cutaneous condition characterized by the abrupt onset of numerous nonfollicular pustules in a background of pruritic edematous erythroderma. To date, only two case reports have described AGEP in patients with HHD. Early diagnosis of AGEP is essential to initiate prompt and aggressive systemic therapy, prompt medication cessation, close monitoring for end-organ damage, and improve overall morbidity and mortality.

Two Novel and a Recurrent ATP2C1 Mutations in Chinese Population with Hailey-Hailey Disease.

Purpose: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominant inherited blistering dermatosis. Pathogenic variants in ATP2C1 have been associated with HHD since 2000. This study aimed to identify the mutations in the ATP2C1 gene in two Chinese pedigrees and two sporadic cases with HHD. Patients and Methods: Two Chinese pedigrees and two sporadic cases were included in this study. Whole-exome sequencing and Sanger sequencing were performed to detect the mutation of the ATP2C1 gene. Predictions of protein structure and function were performed using bioinformatics tools, including Mutation Taster, Polyphen-2, SIFT, and Swiss-Model. Results: In this study, we detected three heterozygous mutations, including novel compound mutations of (c.1840-4delA and c.1840_1844delGTTGC), splice site mutation of c.1570+3A>C, and a previously known nonsense mutation c.1402C>T in the ATP2C1 gene. Combined with our previous study, ten patients with c.1402C>T mutation in the ATP2C1 gene have been identified, and all these patients originated from Jiangxi Province. Conclusion: c.1402C>T mutation in the ATP2C1 gene was considered a regional highly prevalent mutation in the Chinese population with HHD. The results added new variants to the database of ATP2C1 mutations associated with HHD.

Loss of ATP2C1 function promotes trafficking and degradation of NOTCH1: Implications for Hailey-Hailey disease.

Hailey-Hailey disease (HHD) is a rare autosomal dominantly inherited disorder caused by mutations in the ATP2C1 gene that encodes an adenosine triphosphate (ATP)-powered calcium channel pump. HHD is characterized by impaired epidermal cell-to-cell adhesion and defective keratinocyte growth/differentiation. The mechanism by which mutant ATP2C1 causes HHD is unknown and current treatments for affected individuals do not address the underlying defects and are ineffective. Notch signalling is a direct determinant of keratinocyte growth and differentiation. We found that loss of ATP2C1 leads to impaired Notch1 signalling, thus deregulation of the Notch signalling response is therefore likely to contribute to HHD manifestation. NOTCH1 is a transmembrane receptor and upon ligand binding, the intracellular domain (NICD) translocates to the nucleus activating its target genes. In the context of HHD, we found that loss of ATP2C1 function promotes upregulation of the active NOTCH1 protein (NICD-Val1744). Here, deeply exploring this aspect, we observed that NOTCH1 activation is not associated with the transcriptional enhancement of its targets. Moreover, in agreement with these results, we found a cytoplasmic localization of NICD-Val1744. We have also observed that ATP2C1-loss is associated with the degradation of NICD-Val1744 through the lysosomal/proteasome pathway. These results show that ATP2C1-loss could promote a mechanism by which NOTCH1 is endocytosed and degraded by the cell membrane. The deregulation of this phenomenon, finely regulated in physiological conditions, could in HHD lead to the deregulation of NOTCH1 with alteration of skin homeostasis and disease manifestation.

Rheumatoid arthritis and Hailey-Hailey disease treated with methotrexate.

We report a rare case of long-standing Hailey-Hailey disease in a Caucasian Portuguese 69-year-old woman, recently diagnosed with rheumatoid arthritis. The patient's skin lesions remained active and exudative despite topical and oral treatments with corticosteroids, tetracyclines, antifungals, and oral treatment with azathioprine. After introduction of methotrexate for rheumatoid arthritis treatment, the skin lesions regressed, with significant impact on the patient's quality of life. This case report supports the clinical evidence of methotrexate's potential role in Hailey-Hailey disease treatment.

Lichenoid lesions around the anus: An unusual site of Hailey-Hailey disease.

The anal region is an unusual site of Hailey-Hailey disease. It manifests with lichenoid lesions with crusted erosions around the anus. It should be differentiated from condylomata acuminata, extramammary Paget disease, and bowenoid papulosis.

Necrotizing fasciitis following episiotomy in a woman with Hailey-Hailey disease: A case report.

A healthy 25-year-old primiparous woman had an uncomplicated pregnancy and spontaneous vaginal delivery with mediolateral episiotomy. Twenty-four hours postpartum, she developed increasing perineal pain and swelling. Initial examination showed a localized erythema and tissue oedema at the episiotomy site. The woman was admitted to hospital for management of the infected hematoma at the site of the episiotomy. Thereafter, she was started on intravenous antibiotics, and exploration under anaesthesia was planned. The woman's medical condition deteriorated rapidly, and necrotizing fasciitis (NF) was strongly suspected. Therefore, aggressive medical and surgical management was undertaken, including broader-spectrum antibiotics and multiple surgical debridement. A biopsy of the debrided tissue showed acantholysis and dyskeratosis, which are features of Hailey-Hailey disease of the skin (familial benign chronic pemphigus), a rare condition. The woman eventually had a V-Y advancement fascial flap and made a complete recovery. In this case report, the details of the development of NF in a woman who was found to have Hailey-Hailey disease are discussed.

Case report: Difference in outcomes between two cases of Hailey-Hailey disease treated with apremilast.

Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis clinically characterized by recurrent erythematous plaques and erosions mainly on the intertriginous regions. Although HHD seriously affects quality of life, conventional treatments often fail to provide long-term relief for most patients. The effectiveness of apremilast, a phosphodiesterase-4 inhibitor, against severe HHD was first reported in 2018, and after further testing, this agent is currently expected to be established as an efficacious and safe therapeutic option. Here we report two cases of HHD treated with apremilast which showed opposite outcomes. Although the case with extremely severe symptoms showed remarkable and long-lasting improvement with apremilast used after acute treatment with oral corticosteroid, the other case, with milder symptoms treated only with apremilast, showed no improvement. Our transcriptome analysis using skin samples collected prior to apremilast administration revealed the involvement of the NF-κB signaling pathway, which is related to the responses to bacteria and other organisms. However, this pathway was more strongly activated in case 2 than in case 1, suggesting that the steroid treatment preceding apremilast may have been effective and supportive in the apremilast-responding case. One of the two cases highlights the potential of apremilast as a treatment option for HHD, but the other underlines the difficulties in managing HHD and the complexity of the disease background. The accumulation of cases and larger clinical studies are expected to precisely evaluate the safety and efficacy of apremilast, and the potential for therapies in combination with conventional treatments.

The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey-Hailey Disease.

Background: Hailey-Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD. Methods: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant. Results: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi. Conclusion: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.

Two novel mutations in the ATP2C1 gene found in Japanese patients with Hailey-Hailey disease.

Hailey-Hailey disease (HHD) is an autosomal dominant genodermatosis and the defective gene in HHD is ATP2C1, which encodes secretory pathway Ca2+ /Mn2+ ATPase type 1 (SPCA1). Here we report four Japanese HHD patients showing three kinds of mutations with premature termination codons in the ATP2C1 gene, including two novel ones. Patient 1 was a 39-year-old man with a novel heterozygous mutation, c.664dup in exon 8 (p.N215Kfs*26). Patient 2 was a 33-year-old man (the younger brother of patient 1) with the same mutation as patient 1. Patient 3 was a 55-year-old man with a previously reported heterozygous mutation, c.519dup in exon 7 (p.R174Tfs*4). Patient 4 was a 33-year-old woman with a novel heterozygous mutation, c.2640del in exon 27 (p.L881Ffs*10). The clinical characteristics of our four cases varied in disease severity and the response to treatment. The present cases enrich the database of mutational analysis for HHD.

Weak immunohistochemical expression of galectin-3 near blisters in Hailey-Hailey disease.

BACKGROUND: Hailey-Hailey disease (HHD) is an uncommon hereditary and benign skin condition characterized by blisters and erosions on intertriginous areas. It is related to a mutation of the ATP2C1 gene, which encodes a Ca2+ pump. It is characterized by multiple foci of skin acantholysis in the epidermis, with dyskeratosis and suprabasilar clefting. Galectin-3 is a beta-galactoside-binding protein that has an essential role in cell-to-cell and cell-to-matrix adhesion. We assessed galectin-3 immunohistochemical expression in HHD to explore its impact on the pathogenesis of this hereditary blistering disorder. METHOD: In a retrospective study, seven specimens from seven patients diagnosed with HHD were stained with antibodies to galectin-3. We evaluated the nuclear and cytoplasmic expression of galectin-3, as well as the staining intensity around blisters and distant normal skin. RESULTS: We observed a significant decrease in cytoplasmic and nuclear expression of galectin-3 as well as stain intensity around blisters compared with distant normal skin. CONCLUSIONS: While the acantholysis process in HHD is related to abnormality in cadherin expression caused by altered Ca2+ pump concentration, lower expression of galectin-3 may cause the extension of blisters by initiating cell-to-cell disassembly in the epidermis.