Hailey-Hailey Disease is Associated with Diabetes: A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis.

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.

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.

Two sporadic cases of childhood-onset Hailey-Hailey disease with superimposed mosaicism.

A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.

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.

Interleukin-17A immune pattern across genetic acantholytic and blistering disorders.

There is a high therapeutic need in acantholytic and blistering genodermatoses. Cutaneous inflammation is a reasonable therapeutic target, although the patterns are not yet fully elucidated. Here we investigated by immunohistochemistry whether interleukin (IL)-17A is expressed in the inflammatory infiltrate in 34 patients with Hailey-Hailey disease, Darier disease, and junctional and dystrophic epidermolysis bullosa. There was a 5-7-fold increase in the number of IL-17A-positive cells in all patients' samples as compared with normal skin. IL-17A cells were present in epidermal acantholytic areas and dermal inflammatory infiltrates in Hailey-Hailey and Darier disease. In epidermolysis bullosa samples, positive cells were present at the dermoepidermal junction zone. The IL-17A inflammatory pattern was validated by observing upregulation of downstream genes/proteins, S100A7, S100A8 and S100A9 (S100 calcium-binding proteins). These results suggest that IL-17A contributes to skin inflammation and could be a therapeutic target during inflammatory flares in these disorders.

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

Subcellular compartmentalization of STIM1 for the distinction of Darier disease from Hailey-Hailey disease.

BACKGROUND AND OBJECTIVES: Darier disease (DD) and Hailey-Hailey disease (HHD) are rare disorders caused by mutations in the ATPase, Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2) and ATPase Ca2+ Transporting Type 2C, Member 1 (ATP2C1) gene, respectively, which lead to a disturbance of calcium metabolism in keratinocytes. Clinically, this is reflected by an impairment of keratinization. Histologically, acantholysis with variable degrees of dyskeratosis and parakeratosis is observed. Both diseases can usually be differentiated clinically, histopathologically and genetically. However, their routine distinction might be challenging since some patients do not harbor ATP2A2 or ATP2C1 mutations. To solve this diagnostic challenge, we studied the differential expression of two proteins of store-operated calcium entry (SOCE), stromal interaction molecule 1 (STIM1) and calcium release-activated calcium modulator 1 (ORAI1), by immunohistochemistry. PATIENTS AND METHODS: Five individuals with ambiguous diagnostic findings and eight controls with an unambiguous diagnosis were studied clinically, histologically, genetically, and by immunohistochemistry for STIM1 and ORAI1. RESULTS: DD patients consistently showed a cytoplasmic STIM1 expression while patients with HHD revealed a membrane-associated staining pattern. In contrast, ORAI1 did not show a differential expression pattern. CONCLUSIONS: Our data suggest subcellular compartmentalization of STIM1 as novel biomarker for the distinction of the two disorders.

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.

Two cases of Hailey-Hailey disease effectively treated with apremilast and a review of reported cases.

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.

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.

Whole exome sequencing improves mutation detection in Hailey-Hailey disease.

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.

Generalized Hailey-Hailey disease: Novel splice-site mutations of ATP2C1 gene in Chinese population and a literature review.

BACKGROUND: Hailey-Hailey disease (HHD; OMIM: 169600) is an autosomal dominate genodermatosis, characterized by recurrent blisters and erosions clinically and remarkable acantholysis pathologically. The underlying pathogenic factor is the mutation of ATP2C1 gene (OMIM: 604384), which encodes secretory pathway Ca2+ /Mn2+ -ATPase (SPCA1). Skin folds are the predilection site of HHD. Atypical cases with a generalized pattern have rarely been reported, making it prone to misdiagnosis. METHODS: In this study, we presented three Chinese pedigrees of Hailey-Hailey disease with generalized skin lesions. ATP2C1 mutations were screened by DNA sequencing and their transcripts were further confirmed by minigene assay. We also performed a literature review of previously published generalized HHD over past two decades together with our cases. RESULTS: Three splice-site mutations were identified: c.2487+1G>A, c.2126+1G>A, and c.1891-2A>G, which resulted in an exon 25-truncated transcript, two exon 22-truncated transcripts, and two exon 21-truncated transcripts, respectively. The c.2487+1G>A and the c.1891-2A>G mutations are novel mutations which have not been reported before. No clustered mutations of ATP2C1 gene were found in generalized HHD patients in literature along with our novel mutations. CONCLUSION: We found no hot spot mutations in ATP2C1 correlated with the generalized pattern of HHD. Our study expanded the spectrum of ATP2C1 mutations, which would be useful for disease diagnosis and genetic counseling.

Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease.

BACKGROUND: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKII proteins in the skin lesions of HHD patients. METHODS: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. RESULTS: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKII levels. CONCLUSION: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKII levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

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.