Hailey-Hailey Research Articles

ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation.

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.

SPCA1 governs the stability of TMEM165 in Hailey-Hailey disease

TMEM165 is a Golgi protein whose deficiency causes a Congenital Disorder of Glycosylation (CDG). We have demonstrated that Mn2+ supplementation could suppress the glycosylation defects observed in TMEM165-deficient cells and that TMEM165 was a Mn2+-sensitive protein. In the Golgi, the other transmembrane protein capable to regulate Mn2+/Ca2+ homeostasis is SPCA1, encoded by the ATP2C1 gene. A loss of one copy of the ATP2C1 gene leads to Hailey-Hailey Disease (HHD), an acantholytic skin disorder in Humans. Our latest results suggest an unexpected functional link between SPCA1 and TMEM165. In order to clarify this link in case of partial SPCA1 deficiency, HHD fibroblasts were used to assess TMEM165 expression, subcellular localization and Mn2+-induced degradation. No differences were observed regarding TMEM165 expression and localization in HHD patients’ fibroblasts compared to control fibroblasts. Nevertheless, we demonstrated both for fibroblasts and keratinocytes that TMEM165 expression is more sensitive to MnCl2 exposure in HHD cells than in control cells. We linked, using ICP-MS and GPP130 as a Golgi Mn2+ sensor, this higher Mn2+-induced sensitivity to a cytosolic Mn accumulation in MnCl2 supplemented HHD fibroblasts. Altogether, these results link the function of SPCA1 to the stability of TMEM165 in a pathological context of Hailey-Hailey disease.

Exfoliative dermatitis causing diagnostic dilemma: Sibling provides the missing link

A 49-year-old male presented with erythroderma of 3-month duration with a flexural onset. No mucosal lesions were present, and skin biopsy showed features of acantholysis and suprabasal clefting. Direct immunofluorescence test was negative in repeated examinations. The patient was presumptively managed as pemphigus foliaceus with immunomodulators though the level of split was suprabasal rather than subcorneal, and the patient responded well to the treatment. However, his elder sister presented to the department with clinical and histopathological features of classical Hailey–Hailey disease (HHD) which resembled the pathological features found in the index case. This prompted us to review the diagnosis and retrospectively diagnose the index case as HHD presenting with erythroderma.

Medicaments and oral healthcare. Hyperpigmentation of oral soft tissues due to afamelanotide

The medicament afamelanotide is an analogue of endogenous ?-melanocyte-stimulating hormone. It promotes cutaneous pigmentation, providing protection from sunlight. In dermatology, afamelanotide seems to establish therapeutic results for polymorphic light eruption, solar urticaria, erythropoietic protoporphyria, Hailey-Hailey disease, vitiligo and acne vulgaris. Afamelanotide is available for non-medical use to realise quick and easy skin tanning. Adverse effects of afamelanotide mentioned in the scientific literature are development and aggravation of melanocytic naevi, degeneration of melanocytic naevi to melanomas, melanonychia, systemic toxicity, rhabdomyolysis, posterior reversible encephalopathy syndrome, priapism and hyperpigmentation of oral soft tissues. Furthermore, numerous adverse effects of afamelanotide have been reported to the Netherlands pharmacovigilance centre LAREB as well as numerous adverse effects due to overdosage of afamelanotide to the National Poisons Information Centre. Dentists should be alert to hyperpigmentation of oral soft tissues due to afamelanotide.

Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease

Hailey-Hailey disease (HHD) is a rare, late-onset autosomal dominant genodermatosis characterized by blisters, vesicular lesions, crusted erosions, and erythematous scaly plaques predominantly in intertriginous regions. HHD is caused by ATP2C1 mutations. About 180 distinct mutations have been identified so far; however, data of only few cases from Central Europe are available. The aim was to analyze the ATP2C1 gene in a cohort of Polish HHD patients. A group of 18 patients was enrolled in the study based on specific clinical symptoms. Mutations were detected using Sanger or next generation sequencing. In silico analysis was performed by prediction algorisms and dynamic structural modeling. In two cases, mRNA analysis was performed to confirm aberrant splicing. We detected 13 different mutations, including 8 novel, 2 recurrent (p.Gly850Ter and c.325-3 T > G), and 6 sporadic (c.423-1G > T, c.899 + 1G > A, p.Leu539Pro, p.Thr808TyrfsTer16, p.Gln855Arg and a complex allele: c.[1610C > G;1741 + 3A > G]). In silico analysis shows that all novel missense variants are pathogenic or likely pathogenic. We confirmed pathogenic status for two novel variants c.325-3 T > G and c.[1610C > G;1741 + 3A > G] by mRNA analysis. Our results broaden the knowledge about genetic heterogeneity in Central European patients with ATP2C1 mutations and also give further evidence that careful and multifactorial evaluation of variant pathogenicity status is essential.

An elderly lady with multiple blisters all over the body: Hailey Hailey Disease

Hailey-Hailey disease (HHD) is an autosomal-dominant genodermatosis, associated with abnormal epithelial cell adhesion due to altered calcium metabolism. Clinical features involve painful red blisters, erosions, fissured and hypertrophic plaques predominantly in the intertriginous areas. Heat, friction, minor trauma, superimposed bacterial or viral infection can aggravate the condition. Here, we report a case of a 50-year old lady with no previous family history presented with severe attack of HHD since last 5 months. Histology showed acantholysis of keratinocytes resembling characteristic dilapidated brick wall appearance in the epidermis layer of skin which helped for the confirmed diagnosis.
 Bangladesh J Medicine Jan 2020; 31(1) : 29-32

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.

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.

New trends in botulinum toxin use in dermatology

Background: Recent studies have highlighted new botulinum neurotoxin (BoNT) applications in the field of dermatology. Objective: To review current knowledge of BoNT use in dermatology. Methods: The literature of the last 5 years has been reviewed. Results: We describe interesting protocols of BoNT treatment for hyperhidrosis (HH), hypertrophic scars and keloids, Raynaud phenomenon, facial flushing, oily skin, psoriasis, Hailey-Hailey disease, and cutaneous lesions like painful lesions and periorbital syringomas. Conclusions: Several skin conditions eligible for BoNT treatment have been described. After the wide application for HH treatment, scars as well as vascular and inflammatory skin disorders, oily skin and cutaneous lesions represent fields of application of BoNT.

Therapeutic effects of cyclosporine on Hailey-Hailey disease

Hailey-Hailey disease is an autosomal dominant hereditary skin disease. Severe cases are often difficult to treat. We report a recent case that was successfully treated using cyclosporine. The case is described from the aspects of treatment and gene mutation.

Hailey-Hailey Disease: An Update Review with a Focus on Treatment Data.

Hailey-Hailey disease is a rare blistering dermatosis first described in 1939 by the brothers Howard and Hugh Hailey. Its incidence is estimated at 1/50,000. The inheritance is autosomal dominant with complete penetrance, but a variable expressivity in affected family members. Clinically, Hailey-Hailey disease presents between the third and fourth decade as flaccid vesicles and blisters on erythematous skin, giving rise to erosions, fissures, and vegetations. Maceration and superinfections are frequent. The lesions are typically distributed symmetrically within intertriginous regions such as the retroauricular folds, lateral aspects of the neck, axillae, umbilicus, inguinal, and perianal regions. The disease is characterized by a chronic relapsing course with spontaneous remissions and multiple recurrences. Severe disease can be very frustrating and have a major psychological and social impact. Given the dearth of evidence-based guidelines and large clinical trials, the assessment of the efficacy and safety of treatments is difficult. Treatments include topical and systemic agents, and procedural therapy such as lasers and surgery. This review provides a systematic search of the literature with a focus on classical and emerging treatment options for Hailey-Hailey disease.

Characterization of Hailey-Hailey Disease-mutants in presence and absence of wild type SPCA1 using Saccharomyces cerevisiae as model organism

Hailey-Hailey disease is an autosomal genetic disease caused by mutations in one of the two ATP2C1 alleles encoding the secretory pathway Ca2+/Mn2+-ATPase, hSPCA1. The disease almost exclusively affects epidermis, where it mainly results in acantholysis of the suprabasal layers. The etiology of the disease is complex and not well understood. We applied a yeast based complementation system to characterize fourteen disease-causing ATP2C1 missense mutations in presence or absence of wild type ATP2C1 or ATP2A2, encoding SERCA2. In our yeast model system, mutations in ATP2C1 affected Mn2+ transport more than Ca2+ transport as twelve out of fourteen mutations were unable to complement Mn2+ sensitivity while thirteen out of fourteen to some extent complemented the high Ca2+requirement. Nine out of fourteen mutations conferred a cold sensitive complementation capacity. In absence of a wild type ATP2C1 allele, twelve out of fourteen mutations induced an unfolded protein response indicating that in vivo folding of hSPCA1 is sensitive to disease causing amino acid substitutions and four of the fourteen mutations caused the hSPCA1 protein to accumulate in the vacuolar membrane. Co-expression of either wild type ATP2C1 or ATP2A2 prevented induction of the unfolded protein response and hSPCA1 mis-localization.

Review of 52 cases with Hailey-Hailey disease identified 25 novel mutations in Chinese Han population.

Hailey-Hailey disease (HHD) is a rare autosomal dominant inherited keratosis caused by mutations in ATP2C1. The aim of our study was to identify and analyze the features of the mutations in HHD. We examined 52 Chinese Han cases which were diagnosed as HHD based on their clinical and histological findings. Genomic DNA polymerase chain reaction and direct sequencing of ATP2C1 were performed from peripheral blood samples of the patients and 100 unrelated healthy controls. Twenty-five novel mutations and 14 recurrent mutations were identified, including 11 (28.2%) missense mutations, nine (23.1%) frame-shift deletion mutations, eight (20.5%) nonsense mutations, seven (17.9%) splicing mutations and four (10.3%) frame-shift insertion mutations. Together with ours, all 209 mutations showed a uniform distribution without hotspots or clusters. In addition, there is no specific genotype-phenotype correlation in HHD. Our findings update the spectrum of mutations in ATP2C1.

Recalcitrant Hailey-Hailey disease treated with low-dose naltrexone

Recalcitrant Hailey-Hailey disease treated with low-dose naltrexone

Variable response of Hailey-Hailey disease to naltrexone: A case series

Variable response of Hailey-Hailey disease to naltrexone: A case series

Management of Hailey-Hailey disease with Castellani’s paint

Management of Hailey-Hailey disease with Castellani’s paint

GOUGEROT-HAILEY-HAILEY’S FAMILIAL BENIGN CHRONIC PEMPHIGUS: A CASE REPORT

The review of the literature on epidemiology, pathogenesis, diagnosis and treatment methods for chronic familial benign pemphigus Gougerot-Haley-Haley, as well as a clinical case of a patient with this disease with family history are presented. The manifestation of the disease occurred at the age of 24, after childbirth. Later there were numerous relapses. Remission was quickly achieved after treatment with antibiotics and oxygen-ozone therapy. In recent years, there has been an increase in the frequency of exacerbations of the disease, and a decrease in treatment effectiveness.

The Use of Naltrexone in Dermatology. Current Evidence and Future Directions.

Naltrexone is a competitive opioid receptor antagonist approved as supportive treatment in alcohol dependence and opioid addiction. At a dose of 50-100 mg daily, naltrexone is used off-label in dermatology for the treatment of trichotillomania and different types of pruritus. At a dose as low as 1- 5 mg per day, naltrexone demonstrates immunomodulatory action i.e. modulates Toll-like receptors signaling, decreases release of proinflammatory cytokines (tumor necrosis factor, interleukin-6, interleukin- 12), inhibits T lymphocyte proliferation, down-regulates the expression of chemokine receptors and adhesion molecules. The efficacy of standard and low doses of naltrexone in a variety of dermatological disorders has been reported. These include diseases such as familial benign chronic pemphigus (Hailey-Hailey disease), dermatomyositis, systemic sclerosis, psoriasis and lichen planopilaris. Optimistic preliminary findings, low cost of therapy and good tolerance make naltrexone a promising alternative therapy or adjunct drug in dermatology.

Linear IgA bullous disease presenting as a Hailey-Hailey disease associated with Hashimoto thyroiditis: a case report

Linear IgA bullous disease presenting as a Hailey-Hailey disease associated with Hashimoto thyroiditis: a case report

Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Exocytic and endocytic compartments each have their own unique luminal ion and pH environment that is important for their normal functioning. A failure to maintain this environment – the loss of homeostasis – is not uncommon. In the worst case, all the main Golgi functions, including glycosylation, membrane trafficking and protein sorting, can be perturbed. Several factors contribute to Golgi homeostasis. These include not only ions such as H+, Ca2+, Mg2+, Mn2+, but also Golgi redox state and nitric oxide (NO) levels, both of which are dependent on the oxygen levels in the cells. Changes to any one of these factors have consequences on Golgi functions, the nature of which can be dissimilar or similar depending upon the defects themselves. For example, altered Golgi pH homeostasis gives rise to Cutis laxa disease, in which glycosylation and membrane trafficking are both affected, while altered Ca2+ homeostasis due to the mutated SCPA1 gene in Hailey–Hailey disease, perturbs various protein sorting, proteolytic cleavage and membrane trafficking events in the Golgi. This review gives an overview of the molecular machineries involved in the maintenance of Golgi ion, pH and redox homeostasis, followed by a discussion of the organelle dysfunction and disease that frequently result from their breakdown. Congenital disorders of glycosylation (CDGs) are discussed only when they contribute directly to Golgi pH, ion or redox homeostasis. Current evidence emphasizes that, rather than being mere supporting factors, Golgi pH, ion and redox homeostasis are in fact key players that orchestrate and maintain all Golgi functions.