Search

Glucagon-like peptide-1 (GLP-1) agonists are a class of medications indicated for type 2 diabetes and obesity that may play a role in the management of cutaneous disease, in part due to their anti-inflammatory effects. These molecules interact with cytokines critical to the development and persistence of skin disease, such as TNF-α, IL-23, IL-17 and IL-22. Correspondingly, immunologic pathways that are downregulated by GLP-1 agonists may serve as a target for various skin conditions that are worsened by inflammation. Furthermore, the known benefit of weight loss for certain skin conditions may be further potentiated by GLP-1 agonists. In this brief report, the authors describe multiple cases of patients with psoriasis, hidradenitis suppurativa, acanthosis nigricans, and Hailey-Hailey disease for which patients experienced improvement subsequent to treatment with GLP-1 therapy. These cases demonstrate the utility of GLP-1 agonists in treating dermatologic conditions that are refractory to other therapies and further highlight the potential of GLP-1 agonists in treating skin disease. [ABSTRACT FROM AUTHOR]

Introduction: Hailey-Hailey disease (HHD) is a rare inherited blistering skin disorder characterized by a chronic relapsing course. While it doesn't pose a serious threat to the patient's health, the quality of life can change. Unfortunately, there is currently no standard treatment for this condition. Objective: In this observational retrospective cohort study, our aim was to discover the demographic characteristics and treatment strategies for managing Hailey-Hailey disease. Methods: In this retrospective cohort study, we documented the demographic, clinical, and histopathological characteristics beside various treatment employed options of patients diagnosed with HHD at Razi Hospital over the past 14 years. Results: A total of 32 patients with HHD were enrolled in the study (15 male and 17 female). The mean age of patients was 50.41 ± 13.15 (22-77) years. The average age of disease onset was 37.31 ± 11.88 (15-60) years. Among the participants, 16 individuals (50%) affirm a positive family history of some kind of pemphigoid blisters. The most common site of disease activity was the inguinal area, observed in 14 patients (33.33%). Histopathological examination discovered the existence of suprabasal acantholysis in all of the specimens. Worthily, direct immunofluorescence analysis showed negative results in all skin biopsies. All patients received topical steroids and either topical or systemic antimicrobial agents. In cases of flares, systemic steroids were the most popular and favorable treatment choice during flares. Conclusion: Indeed, Hailey-Hailey disease, characterized by its chronic inflammatory and rare nature with a relapsing and remitting course, poses a significant challenge for dermatologists. The treatment of HHD has been less than satisfactory and it often presents a challenge and could be misdiagnosed. Among the available treatment options, topical steroids and antimicrobial agents are the most commonly administered therapies.

Background: Hailey-Hailey disease is a rare autosomal dominant genodermatosis whose cause is the ATP2C1 gene mutation. A prevalence of 1 in 50,000 cases is estimated and it manifests as grouped flaccid vesicles that break easily. The diagnosis is confirmed with the histopathological study creating an appearance called "dilapidated brick wall", identifying dyskeratosis in the form of round bodies and pimples. Treatment ranges from general measures to multiple pharmacological options, with topical corticosteroids being the most commonly used. Clinical case: Male patient diagnosed with Hailey-Hailey disease. On physical examination we observed a dermatosis disseminated to the neck, trunk, axillary and inguinal folds, and intergluteal region, unilateral, asymmetric with a polymorphous appearance, constitution due to exulceration, erythema, some pustules and flaccid vesicles that coalesced to form eczematous and hypertrophic plaques with the presence of fine scales on their surface, with a chronic evolution accompanied by pruritus. We also took the opportunity to review the most relevant information in the literature regarding Hailey-Hailey disease, especially focused on the therapeutic aspect. Conclusions: It is important to take into account that Hailey Hailey disease is a rare pathology, in order to make a differential diagnosis in daily clinical practice. [ABSTRACT FROM AUTHOR]

Abstract 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.

Deng Zhang,1 Zhen Xiao,2 Xiaoliang Ouyang,1 Xiuping Wang,1 Yunxia Zhu,1 Simin Yu,1 Chunming Li1 1Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Dermatology, Taiyuan Central Hospital, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Chunming Li, Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China, Tel/Fax +86 791 86278821, Email chunminglincu@163.comPurpose: 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.Keywords: Hailey–Hailey disease, novel mutation, ATP2C1, Chinese pedigree, Sanger sequencing

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.

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. Plain Language Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Peiyao Li1,2 &ast;, Jialin Qi3 &ast;, Baishun Zhou,1 Ting Ding,4 Juan Long,5 Heng Xiao1 1Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Endocrinology, Yiyang Central Hospital, Yiyang, People’s Republic of China; 5Department of Dermatology, Hunan Children’s Hospital, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heng Xiao, Department of Pathology, School of Medicine, Hunan Normal University, 371 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86-731-88912501, Email emmaxiao1988@hotmail.comBackground: 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.Keywords: ATPase secretory pathway Ca2+ transporting 1, Hailey–Hailey disease, pathogenesis, secretory pathway Ca2+/Mn2+-ATPase 1

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 treatment tends 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 seven-year history of therapy-resistant HHD. A 2-month follow-up showed substantially resolved lesions, with mild erythema and post-inflammatory hyperpigmentation in treated areas.

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background A 60-year-old woman received a diagnosis of Hailey-Hailey disease (HHD) and underwent a trial of electronbeam radiation therapy (EBRT) to treat her lesions. Discussion HHD is an acantholytic skin disorder that can be inherited in an autosomal dominant manner or can result from a new mutation. Although the therapy successfully eliminated the existing lesions, new lesions developed subsequently in other areas of her body. EBRT was continued as needed, allowing the patient to remain in remission for 30 months to date. Conclusion EBRT might be an effective treatment for HHD, with the potential for long-term remission in certain patients. [ABSTRACT FROM AUTHOR]

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disorder of keratinocyte adhesion. It occurs due to mutations in ATP2C1, a gene on chromosome 3q21-24 which encodes human secretory pathway Ca2+/Mn2+ ATPase isoform 1, a calcium pump on the Golgi apparatus membrane. Recently, there has been a focus on certain pro-inflammatory cytokines such as IL-6 and IL-8 which play a role in HHD. Various triggers include excessive heat, menstruation, pregnancy, sweating, friction, exposure to sunlight and superficial infections. The therapy of the disorder is better understood by the varied pathogenetic steps and we aimed to comprehensively search for the various medical therapies used in HHD and align them with the existing knowledge on the pathogenesis and delineate them according to their major mode of action.

Hailey-Hailey disease is an autosomal dominant disorder caused by a mutation in the ATP2C1 gene and characterized by recurrent blisters, erosions, and crust in intertriginous areas. Currently, there are no curative treatments for Hailey-Hailey disease, and therapeutic strategies are focused on controlling skin microbial colonization, infection, and inflammation. Recent efforts have aimed to find therapies that target the biochemical pathway involved in the pathogenesis of this disease. Several case reports indicate the use of different biological agents to achieve long-term remission in patients with recalcitrant Hailey-Hailey disease. Tumor necrosis factor-alpha inhibitors have been used to treat and maintain remission in recalcitrant Hailey-Hailey disease patients, but additional reporting and studies are required. In this case series, we report three cases of recalcitrant Hailey-Hailey disease whose lesions were successfully controlled with adalimumab., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alicea-Negrón et al.)

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.

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.

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. [ABSTRACT FROM AUTHOR]

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a rare inherited acantholytic dermatosis. It is an autosomal dominant disease affecting the intertriginous areas. HHD has been characterized by flaccid blisters, erosions, and macerations that are limited to flexural (friction-prone) areas. The painful blisters and erosions significantly decrease patients’ quality of life. There are multiple types of therapy related to this disorder. Many of the studies have suggested benefits from steroid therapy in addition to oral antibiotics.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hailey–Hailey disease (HHD) is a rare autosomal-dominant blistering disorder characterized by recurrent vesicular and erosive lesions at intertriginous sites. We described a 24-year-old male who presented with multiple bright red verrucous papules in his mons pubis, bilateral groins, scrotum, perineum, and crissum, clinically resembling condyloma acuminatum. The histopathology showed extensive acantholysis with the characteristic appearance of a dilapidated brick-wall. The mutation analysis revealed a novel splice-site mutation in the ATP2C1 gene. The patient was definitely diagnosed with HHD. The antibacterial treatments resulted in a dramatic improvement. Our findings help to broaden the understanding of clinical manifestations of HHD and improve the clinical diagnosis and treatment of this disease. [ABSTRACT FROM AUTHOR]

Hailey‐Hailey disease (HHD) is an autosomal dominant genetic disease caused by a mutation of the ATP2C1 gene. Corticosteroids, antibiotics or cyclosporine have been administered to reduce inflammation and prevent flare‐ups, but the efficacy is not always sufficient. We herein report two cases of HHD effectively treated with apremilast and review the previous literature. Patient 1 was a 28‐year‐old male and patient 2 was a 35‐year‐old female. Both patients were diagnosed with HHD based on histological and genetic analyses. Both patients were treated with oral antibiotics or topical corticosteroids, but their symptoms were refractory, therefore apremilast was administered to both patients. Two weeks later, the skin lesion of both patients was improved. No adverse reaction was observed except for mild headache in patient 2. There have been 13 reported cases of HHD treated with apremilast, including our cases. Eight cases showed a good response to apremilast, whereas five cases showed no response. There seems to be no association between the disease severity and efficacy of apremilast, although the reason remains unknown. Interestingly, an early improvement of the HHD lesion was observed in all good response cases. Although digestive symptoms, headache, and myalgia were observed as adverse events, the treatment was well‐tolerated. The accumulation of a greater number of similar cases and further research will be required. We hypothesize that apremilast may be a useful therapeutic option for skin lesions of HHD. [ABSTRACT FROM AUTHOR]

Hailey–Hailey disease (HHD) is a rare autosomal-dominant blistering disorder characterized by recurrent vesicular and erosive lesions at intertriginous sites. We described a 24-year-old male who presented with multiple bright red verrucous papules in his mons pubis, bilateral groins, scrotum, perineum, and crissum, clinically resembling condyloma acuminatum. The histopathology showed extensive acantholysis with the characteristic appearance of a dilapidated brick-wall. The mutation analysis revealed a novel splice-site mutation in the ATP2C1 gene. The patient was definitely diagnosed with HHD. The antibacterial treatments resulted in a dramatic improvement. Our findings help to broaden the understanding of clinical manifestations of HHD and improve the clinical diagnosis and treatment of this disease.

Competing Interests: Dr Tjahjono has served as a consultant for Bristol Myers Squibb. Dr Silverberg is an advisor, speaker, or consultant for AbbVie, Asana Biosciences, Dermavant, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, Menlo Therapeutics, Novartis, Pfizer, Realm Pharma, and Regeneron-Sanofi; and also a researcher for GlaxoSmithKline. Author Garg has no conflicts of interest to declare.

Darier's disease (DD) is a rare autosomal dominant genetic disorder caused by a mutation in ATP2A2, which encodes calcium (Ca 2+ ) ATPase pumps in the endoplasmic reticulum. In this report, we present the first documented case in Japan successfully treated with apremilast. An 18-year-old female presented with red or brown hyperkeratotic papules and plaques on her head, neck, and chest. Histopathological examination revealed a hyperkeratotic, acanthotic epidermis, along with suprabasal acantholysis characterized by corps ronds and grains. Exome sequencing of DNA from peripheral blood mononuclear cells identified a missense mutation in ATP2A2. Based on the above results, we diagnosed her with DD despite the absence of a family history. Given the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, in treating Hailey-Hailey disease (HHD), a genetically related disorder involving ATPases in epidermal calcium channels, we opted for apremilast therapy. Eight weeks post-initiation, significant improvement was observed in the patient's skin lesions on the head, neck, and chest. In this paper, we discuss the successful treatment of DD and HHD cases with apremilast, providing insights into its therapeutic potential, and offer a comprehensive review., (© 2024 Japanese Dermatological Association.)

This report presents two cases of patients with long-standing, treatment-resistant Hailey-Hailey disease (HHD) who experienced significant symptom relief through a combination therapy of oral naltrexone and dupilumab injections. The therapeutic potential of targeting the Th2 pathway and Ca 2+ signaling with dupilumab in managing HHD manifestations is highlighted. The findings suggest that Th2 blockade with dupilumab, in conjunction with naltrexone, effectively controls recalcitrant HHD, indicating a role of cytokine response in altering disease pathogenesis. This case contributes to the growing body of literature on biologic treatments for HHD and suggests avenues for further research in HHD management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Santoso et al.)

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.

BACKGROUND: Benign familial pemphigus is a rare benign genodermatosis caused by mutations in the ATP2C1 gene. It is characterized by affecting areas of folds, with presentation of outbreaks of vesicles and blisters. Its pathogenesis is unclear. The diagnosis is clinical; however, a histopathological study is performed to corroborate it. Currently there is no specific treatment, and it depends on the evolution of each individual; however, the first treatment is corticosteroids and topical antibiotics. CLINICAL CASE: A 15-year-old male patient with a maternal branch family history of bullous dermatosis, who presented plaques with multiple papular-like lesions, hyperpigmented, dark brown, pruritic in the armpits and groin. The histopathological study confirmed Hailey-Hailey disease, starting treatment with naltrexone with a favorable evolution. CONCLUSIONS: Hailey-Hailey disease is a little-known condition that affects the quality of life of patients, so it is important to know about this disease to make the correct diagnosis and avoid the prescription of inappropriate drugs that can delay diagnosis or aggravate dermatosis. [ABSTRACT FROM AUTHOR]

Darier disease and Hailey-Hailey disease are severe, monogenetic dermatological disorders with mutations affecting all cells, making them liable to exhibit extra-dermal symptoms. The aim of this study is to assess broad cognitive function in individuals with these diseases, using an experimental, case-control set-up comparing cognition in patients with that in healthy controls matched for age, sex and level of education. Cognition was assessed with the Cambridge Neuropsycho­logical Test Automated Battery. Patients with Darier disease (n = 29) performed significantly poorer on 5 of the 10 key cognitive measurements, while patients with Hailey-Hailey disease (n = 25) did not perform differently from controls. The main conclusion is that patients with Darier disease exhibit significant impairment in cognitive function, which reinforces the view that Darier disease should be regarded as a disorder affecting multiple organs, and should therefore be given medical consideration, and possibly treat­ment, as such.

Hailey–Hailey disease (HHD) is an autosomal dominant monogenic disease that is defective in the ATP2C1 gene. In previous studies, Sanger sequencing was the main method applied to detect mutations in HHD patients, and no mutations in the ATP2C1 gene were found in 12–55% of those reported. The aim of our study was to carry out whole exome sequencing (WES) for the HHD patients in whom efforts to identify mutations by Sanger sequencing had failed, and to find a new pathogenic gene. WES was performed using genomic DNA from 13 HHD patients and 364 in‐house healthy controls. Potential pathogenic mutations were subsequently validated by Sanger sequencing. As a result, eight mutations in the ATP2C1 gene were identified using WES. In the remaining five patients, we found one mutation in the ATP2A2 gene which was the causal gene of Darier's disease. Four patients had no detectable mutations in ATP2C1 and the other ATPase genes. Together with our previous study in 2019, the total mutation rate was calculated to be 47/52 (90.4%). These findings demonstrate that WES is capable of improving the mutation detection sensitivity in HHD compared with Sanger sequencing. [ABSTRACT FROM AUTHOR]

Darier disease and Hailey-Hailey disease are severe, monogenetic dermatological disorders with mutations affecting all cells, making them liable to exhibit extradermal symptoms. The aim of this study is to assess broad cognitive function in individuals with these diseases, using an experimental, case-control set-up comparing cognition in patients with that in healthy controls matched for age, sex and level of education. Cognition was assessed with the Cambridge Neuropsychological Test Automated Battery. Patients with Darier disease (n = 29) performed significantly poorer on 5 of the 10 key cognitive measurements, while patients with Hailey-Hailey disease (n = 25) did not perform differently from controls. The main conclusion is that patients with Darier disease exhibit significant impairment in cognitive function, which reinforces the view that Darier disease should be regarded as a disorder affecting multiple organs, and should therefore be given medical consideration, and possibly treatment, as such. [ABSTRACT FROM AUTHOR]

Recent anecdotal evidence suggests that oral low-dose naltrexone (LDN) is effective for Hailey–Hailey disease (HHD) but suffers the limitation of immediate relapse following cessation of the medication. With lack of safety data on long-term administration of LDN, we explored the utility of a topical diphenhydramine/ketamine (DK) cream in maintaining the remission achieved with LDN. A 42-year-old male with treatment-refractory HHD remitted with 5 mg naltrexone/day but relapsed on stopping the drug. Symptoms abated after restarting LDN. The impact of regular twice-a-day application of a specially formulated DK cream containing diphenhydramine (2% w/w) and ketamine (1% w/w) over the affected areas on maintenance of remission was explored till the next relapse. Our approach enabled dose reduction of naltrexone to 3 mg/day without loss of treatment benefit. After 3-month overlap of naltrexone and DK cream, withdrawal of naltrexone maintained remission with only the topical regime with no adverse effects till 4 months of follow-up. The use of topical agents with anti-inflammatory, antipruritic, antinociceptive, and naltrexone-mimicking properties merits exploration as an option to provide short but significant period of naltrexone-free maintenance of remission to patients with HHD.

Copyright of Médicas UIS is the property of Universidad Industrial de Santander and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)