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.

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.

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.

Patients with Darier Disease Exhibit Cognitive Impairment while Patients with Hailey-Hailey Disease Do Not: An Experimental, Matched Case-control Study.

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 Neuropsycho-logical 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 treat-ment, as such.

Regional Differences in the Permeability Barrier of the Skin-Implications in Acantholytic Skin Diseases.

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier's disease, and Hailey-Hailey disease).

An N-terminal Ca2+-binding motif regulates the secretory pathway Ca2+/Mn2+-transport ATPase SPCA1.

The Ca2+/Mn2+ transport ATPases 1a and 2 (SPCA1a/2) are closely related to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and are implicated in breast cancer and Hailey-Hailey skin disease. Here, we purified the human SPCA1a/2 isoforms from a yeast recombinant expression system and compared their biochemical properties after reconstitution. We observed that the purified SPCA1a displays a lower Ca2+ affinity and slightly lower Mn2+ affinity than SPCA2. Remarkably, the turnover rates of SPCA1a in the presence of Mn2+ and SPCA2 incubated with Ca2+ and Mn2+ were comparable, whereas the turnover rate of SPCA1a in Ca2+ was 2-fold higher. Moreover, we noted an unusual biphasic activation curve for the SPCA1a ATPase and autophosphorylation activity, not observed with SPCA2. We also found that the biphasic pattern and low apparent ion affinity of SPCA1a critically depends on ATP concentration. We further show that the specific properties of SPCA1a at least partially depend on an N-terminal EF-hand-like motif, which is present only in the SPCA1a isoform and absent in SPCA2. This motif binds Ca2+, and its mutation lowered the Ca2+ turnover rate relative to that of Mn2+, increased substrate affinity, and reduced the level of biphasic activation of SPCA1a. A biochemical analysis indicated that Ca2+ binding to the N-terminal EF-hand-like motif promotes the activity of SPCA1a by facilitating autophosphorylation. We propose that this regulation may be physiologically relevant in cells with a high Ca2+ load, such as mammary gland cells during lactation, or in cells with a low ATP content, such as keratinocytes.

An enhanced transcutaneous delivery of botulinum toxin for the treatment of Hailey-Hailey disease.

Successful treatment of Hailey-Hailey disease with intradermal botulinum toxin injections has been previously reported. The main disadvantages of this treatment are the excruciating pain and the risk of infections due to the numerous injections. We sought to evaluate the clinical effectiveness and safety profile of a novel approach using an energy-based device (Tixel, Novoxel, and Israel), followed by the topical application of botulinum toxin Type A for the treatment of Hailey-Hailey disease. A retrospective study of all cases of histologically diagnosed cases of Hailey-Hailey disease treated with Tixel device followed by topical application of botulinum toxin between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. The study included eight patients, of whom seven patients (87.5%) showed good or partial response. No systemic or local adverse effects were reported. There was no difference in effectivity between different body areas. Response to treatment ranged between patients with an average duration of 7.125 months after the second treatment. Tixel treatment followed by topical application of botulinum toxin can be considered in the treatment of Hailey-Hailey disease. This approach is less invasive, less painful, and yet effective as well as safe.

Vulvar Hailey-Hailey disease treated with low-dose naltrexone: case report and literature review.

PURPOSE: To report a case of vulvar familial benign pemphigus, or Hailey-Hailey disease, treated successfully with low-dose naltrexone and to review the current literature. METHODS: We report a case of a 71-year-old white woman with vulvar Hailey-Hailey disease recalcitrant to topical corticosteroids. After treatment with low-dose naltrexone, 3 mg nightly was initiated, the lesions began to heal and 5 months later her skin showed no lesions. A literature review on the use of low-dose naltrexone for Hailey-Hailey disease was performed. We searched the PubMed/MEDLINE databases for previous case reports using the key words ''Pemphigus, Benign Familial'' and ''naltrexone". RESULTS: We found 35 more cases of Hailey-Hailey disease treated with naltrexone, showing promising results, reported until January 2020, with no major adverse effects. CONCLUSION: Low-dose naltrexone may represent a cost-effective and successful treatment modality in nongeneralized Hailey-Hailey disease without serious adverse effects. Future prospective studies are needed to investigate this interesting therapeutic option.

Altered levels of focal adhesion and extracellular matrix-receptor interacting proteins were identified in Hailey-Hailey disease by quantitative iTRAQ proteome analysis.

Benign chronic familial pemphigus or Hailey-Hailey disease (HHD, OMIM 169600) is a rare, autosomal dominant blistering skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. To date, the proteomic changes in skin lesions from HHD patients has not been reported yet. In this study, a sample of skin lesions from HHD patients was collected for isobaric tags for relative and absolute quantitation to analyze proteome changes compared with unaffected individuals. The 134 differentially expressed proteins were assigned to at least one Gene Ontology term, and 123 annotated proteins with significant matches were assigned to 187 known metabolic or signaling pathways listed in the Kyoto Encyclopedia of Genes and Genomes. Most of the altered proteins in skin lesions of HHD patients were enriched in pathways involved in the PI3K-Akt signaling, focal adhesion, extracellular matrix (ECM)-receptor interaction, and protein digestion and absorption, such as collagen family members, microfibril-associated glycoprotein 4 and plakophilin. The changes of proteins related to cell adhesion, ECM-receptor interaction, and protein folding and glycosylation suggested that strategy targeted to alter cell junction and extracellular microenvironment might provide a potential treatment for HHD.

A novel splice-site mutation in the ATP2C1 gene of a Chinese family with Hailey-Hailey disease.

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is an autosomal dominant genodermatosis. It is characterized by erosions, blisters and erythematous plaques at sites of friction or intertriginous areas. The pathogenic gene of HHD has been revealed as the ATPase secretory pathway Ca2+ transporting 1 gene ( ATP2C1), which encodes the protein, secretory pathway Ca 2+/Mn 2+-ATPase 1 (SPCA1). ATP2C1 gene mutations are responsible for HHD by resulting in abnormal Ca 2+ homeostasis in the skin and giving rise to acantholysis, a characteristic pathology of HHD. In this study, a four-generation family containing three HHD sufferers was recruited. Direct sequencing of the ATP2C1 gene was performed in the proband and other available family members. Reverse-transcriptase polymerase chain reaction analysis was conducted to show the potential variant effect on ATP2C1 splicing. A novel heterozygous c.325-2A>G transition at the splice acceptor site of intron 4 in the ATP2C1 gene was identified, and it co-segregated with the disease in this family. The mutation resulted in exon 5 skipping and an in-frame deletion of 12 amino acids (p.Ala109_Gln120del) in SPCA1. This splice-site mutation may be responsible for HHD in this family. This study would further expand the mutation spectrum of the ATP2C1 gene and may be helpful in the genetic counseling and prenatal diagnosis of HHD.

The uses of naltrexone in dermatologic conditions.

BACKGROUND: Naltrexone in standard and reduced doses is efficacious in many inflammatory and acantholytic disorders. OBJECTIVE: We summarized the current data of naltrexone that are relevant to dermatologic practice. METHODS: An English language PubMed literature search was performed using the terms naltrexone, low-dose naltrexone, Hailey-Hailey, psoriasis, lichen planopilaris, alopecia, opioid, opioid receptor, treatment, dermatology, monitoring, side effect, skin, pruritus, cutaneous, acantholytic, and Darier. RESULTS: Opioid receptors are found throughout the skin and affect cell proliferation, migration, and adhesion. µ Opioid receptors have been found in all layers of the epidermis, while δ receptors are concentrated at cell junctions and can reduce desmoglein expression. Typical doses of naltrexone result in continuous binding to receptors. Low doses result in intermittent blockade with increased ligand and receptor expression, potentiating their effect. LIMITATIONS: Our review was restricted to the English language literature. CONCLUSION: Naltrexone affects inflammation, cell adhesion, and keratinocyte proliferation and migration. While low-dose naltrexone has demonstrated efficacy in treating patients with Hailey-Hailey disease, further dose-ranging studies are needed. Data suggest that naltrexone could be helpful in the treatment of pruritus and a variety of inflammatory and acantholytic skin diseases that are refractory to other treatments. At higher doses, liver function tests should be monitored on a periodic basis.

Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis.

BACKGROUND: Acantholysis can be seen in multiple skin diseases. Adnexal acantholysis has been regarded as a feature distinguishing pemphigus vulgaris (PV) from acantholytic conditions. METHODS: A retrospective review of the histopathologic features of diseases with acantholysis including PV, pemphigus foliaceus (PF), Hailey-Hailey disease (HHD), Darier disease (DD), Grover disease, and pityriasis rubra pilaris (PRP) was performed. RESULTS: Biopsies of PV (n = 49), HHD (n = 27), DD (n = 25), Grover disease (n = 65), and PRP (n = 33) showed suprabasilar acantholysis. Acantholysis was limited to the lower epidermis in PV and PRP, and involved all epidermal layers in HHD, DD, and Grover disease. Acantholysis in PF (n = 38) mainly involved the upper epidermis. Follicular acantholysis occurred more frequently in PV and PF (P < 0.0001). Eccrine acantholysis was found in PV (42%), HHD (18%), PF (13%), and DD (4%). Grover disease, DD, and HHD had greater dyskeratosis (P < 0.0001). Neutrophils were more common in PV, PF, and HHD, while eosinophils were more common in Grover disease and DD. A pattern termed acantholytic hypergranulosis occurred predominantly in PF. CONCLUSION: Adnexal acantholysis does not reliably distinguish PV from PF. The level of acantholysis, degree of dyskeratosis, and acantholytic hypergranulosis are distinguishing features between the two types of pemphigus and other acantholytic disorders.

Generalized Hailey-Hailey disease with flexural keratotic papules: An interesting presentation and remarkable response with minocycline.

Hailey-Hailey disease is a hereditary blistering disorder characterized by episodic vesicles, pustules, erosions, and maceration mainly in intertriginous areas with generalized eruptions encountered rarely. We present a case of generalized HHD with keratotic papules over flexural areas along with its dermoscopic features; treated successfully with minocycline alone.

Hailey-Hailey disease successfully treated with vitamin D oral supplementation.

Hailey-Hailey disease (HHD) also known as familial benign chronic pemphigus is a rare autosomal dominant genodermatosis. HHD treatment is often not satisfactory and hence, various modalities of treatment have been tried. We describe the case of a 37-year-old woman with a 2 years history of macerated erythematous plaques along with erosions, fissures, and crusts located on axillae and submammary areas, successfully treated with only oral supplementation of vitamin D (800 I.U./die) for 3 months. We reported this case to suggest that oral vitamin D may be enumerated in the various treatments proposed for HHD so far due to its rapid efficacy on skin lesions and symptoms.

Hypotonic, Acidic Oxidizing Solution Containing Hypochlorous Acid (HClO) as a Potential Treatment of Hailey-Hailey Disease.

Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. Mutation of the Golgi Ca2+-ATPase ATP2C1 has been identified as having a causative role in Hailey-Hailey disease. HHD-derived keratinocytes have increased oxidative-stress that is associated with impaired proliferation and differentiation. Additionally, HHD is characterized by skin lesions that do not heal and by recurrent skin infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. Hypochlorous acid has been demonstrated in vitro and in vivo to possess properties that rescue both oxidative stress and altered wound repair process. Thus, we investigated the potential effects of a stabilized form of hypochlorous acid (APR-TD012) in an in vitro model of HHD. We found that treatment of ATP2C1-defective keratinocytes with APR-TD012 contributed to upregulation of Nrf2 (nuclear factor (erythroid-derived 2)-like 2). Additionally, APR TD012-treatment restored the defective proliferative capability of siATP2C1-treated keratinocytes. We also found that the APR-TD012 treatment might support wound healing process, due to its ability to modulate the expression of wound healing associated cytokines. These observations suggested that the APR-TD012 might be a potential therapeutic agent for HHD-lesions.

Dermoscopic and reflectance confocal microscopic presentation of Hailey-Hailey disease: A case series.

BACKGROUND/PURPOSE: Hailey-Hailey disease is a rare inherited acantholytic skin disorder characterized by heterogeneous clinical presentation. Its differential diagnosis might be wide, including other genodermatoses, inflammatory, and infectious skin diseases. Although histopathology remains as diagnostic gold standard, noninvasive techniques such as dermoscopy and reflectance confocal microscopy may assist clinical examination. Herein, we aim to further characterize the dermoscopic and reflectance confocal microscopic presentation of Hailey-Hailey disease with histologic correlation. METHODS: Eight patients with Hailey-Hailey disease were consecutively recruited. All patients were examined using dermoscopy and reflectance confocal microscopy. RESULTS: In all cases, dermoscopy enabled the visualization of polymorphous vessels, including glomerular and linear-looped vessels, within a pink-whitish background. Reflectance confocal microscopy revealed wide suprabasilar partial acantholysis and clefting, crusts, dilated papillae with tortuous vessels, and inflammatory cells. Dyskeratosis, uplocated papillae, and adnexal sparing were also observed. CONCLUSION: Although definite diagnosis was obtained by histopathology in all cases, dermoscopy and reflectance confocal microscopy allowed the identification of common features (even in cases with dissimilar clinical presentation) that may support an early diagnosis of Hailey-Hailey disease, and its differentiation from other more frequent skin disorders.

Segmental Hailey-Hailey disease of the vulva.

A female infant presented with an ulcerated lesion on the right side of the vulva. Histopathology showed a suprabasal acantholytic blister with intact papillae protruding into the blister cavity and a few dyskeratotic cells. There were no signs of injury on other locations. Family history was unremarkable. Our patient may have linear Hailey-Hailey disease of the vulva, most likely a case of type 1 mosaic.

A Case of Hailey-Hailey Disease Managed With Oral Magnesium Citrate and High-Dose Vitamin D3.

Hailey-Hailey disease, or benign familial pemphigus, is a rare blistering disease originally described in 1939. The disease is due to an autosomal dominant mutation in the ATP2C1 gene on chromosome 3, which encodes for an adenosine triphosphate-dependent calcium pump in the Golgi apparatus whose function is to maintain intercellular calcium homeostasis. Common treatments for Hailey-Hailey disease involve calcineurin inhibitors, topical corticosteroids, topical or systemic antibiotics, topical antifungals, ablative lasers, or botulin toxin. In this case report, we highlight a unique case of Hailey-Hailey disease that was resistant to many conventional therapies and ultimately managed with oral magnesium citrate and high-dose vitamin D3.

Afamelanotide in the Treatment of Dermatologic Disease

Afamelanotide, an α-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other treatments. Its efficacy has been demonstrated in several dermatologic conditions, including erythropoietic protoporphyria (EPP), solar urticaria, polymorphic light eruption (PMLE), vitiligo, acne, and Hailey-Hailey disease. Its relatively low risk side effect profile makes it an attractive treatment option and also paves the way for innovative use in other disorders.