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.

Double-Blind, Placebo-Controlled Study of Onabotulinumtoxin A for the Treatment of Hailey-Hailey Disease.

BACKGROUND: Hailey-Hailey disease (HHD) can be treated with topical steroids, antibiotics, and invasive surgical procedures. Since sweating often exacerbates HHD lesions, the use of onabotulinumtoxin A could serve as an adjunctive treatment. OBJECTIVE: The goal of this study was to evaluate the safety and efficacy of onabotulinumtoxin A for the treatment of HHD. METHODS: A double-blind, placebo-controlled single center study was conducted. Six HHD patients who successfully completed this trial in addition to 1 patient who exited early are reported and discussed. Four of these patients received an initial injection of Btx-A and 3 received the placebo initially. RESULTS: All patients except 1 who received an initial or reinjection of Btx-A decreased 2 levels on a 4-point clinical severity scale at weeks 8 or 12 after treatment. Patient 6 received an initial placebo injection and maintained clearance for 6 months, while patients 5 and 7 did not have any improvement in their target lesions after a placebo injection. All patients who received a reinjection of Btx-A at the week 4 follow-up decreased by at least 1 level on the HHD severity scale. CONCLUSION: Btx-A is a safe treatment that is effective for most cases of HHD. The most severe cases of HHD may not respond to Btx-A as sole treatment. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.6857 Citation: Saal R, Oldfield C, Bota J, et al. Double-blind, placebo-controlled study of Onabotulinumtoxin A for the treatment of Hailey-Hailey disease. J Drugs Dermatol. 2023;22(4):339-343. doi:10.36849/JDD.6857.

Improvement of Hailey-Hailey Disease With Topical Cinacalcet, 3%, Ointment.

This case report describes a woman in her 50s with a large, crusted, erythematous plaque on the right chest that was consistent with a Hailey-Hailey disease flare.

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.

Rheumatoid arthritis and Hailey-Hailey disease treated with methotrexate.

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

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.

Sequential treatments of Hailey-Hailey disease with photodynamic therapy, botulinum toxin type A and dapsone: A case report.

Hailey-Hailey disease is a rare autosomal dominant chronic recalcitrant blistering genodermatosis involving the intertriginous areas. Therapeutic options are various, depending on the type and size of the lesion, and include topical and systemic corticosteroids, topical and systemic retinoids, and DMARDs, but the only true curative approach is represented by the destruction of the affected areas through different techniques like carbon dioxide laser, photodynamic therapy, electron beam radiotherapy, botulinum toxin type A. We report a case of Hailey-Hailey disease successfully treated with a consequential regimen of PDT, botulinum toxin type A and dapsone.

Necrotizing Fasciitis Associated with Hailey-Hailey Disease: A Rare Case.

Necrotizing fasciitis (NF) is a rare and life-threatening infection of soft tissue characterised by rapid and extensive destruction of the skin, subcutaneous fat, and fascia. Early diagnosis of NF is challenging, and it can be very difficult to distinguish NF from other infectious diseases of skin and subcutaneous tissue. Imaging studies and laboratory investigations are crucial diagnostic means for NF. We diagnosed a case of NF with multiple organ dysfunction and septic shock, and this is the first case of NF associated with Hailey-Hailey disease (HHD) to our knowledge. Clinicians should be alert to signs and symptoms of NF in HHD and other skin diseases with damaged skin barrier function such as pemphigus, pemphigoid, and all kinds of ulcers, especially in diabetic and immunosuppressed patients. Key Words: Necrotizing fasciitis, Genodermatosis, Hailey-Hailey disease.

Darier and Hailey-Hailey disease: update 2021.

The autosomal-dominant genodermatoses Darier disease and Hailey-Hailey disease present special challenges to dermatologists. Despite their similar pathogenesis featuring impaired adhesion of suprabasal keratinocytes as a result of defective ATPases in epidermal calcium channels, the two diseases differ considerably in clinical presentation and therapeutic options. Darier disease is characterized by reddish brown, keratotic papules in seborrheic and intertriginous areas, which may coalesce into extensive lesions. Individuals affected with Hailey-Hailey disease primarily develop intertriginous papulovesicles and small blisters, which often evolve into erythematous plaques with erosions and painful fissures. Quality of life is significantly reduced because of complaints (itch, burning sensation, pain), body malodor and chronicity. Therapeutic options remain limited. Antiseptics and intermittent topical corticosteroids are a cornerstone of therapy, and systemic anti-infective treatment is often required in cases of superinfection. Ablative surgical interventions such as dermabrasion and CO2 laser surgery can lead to long-term remissions in intertriginous Hailey-Hailey disease, while temporary relief may also be achieved by intralesional injections of botulinum toxin. Of the systemic medications available for Darier disease, acitretin, which is approved for this purpose, has the best supporting evidence. The efficacy of immunosuppressants and immune modulators is inconsistent. Low-dose naltrexone produces more satisfactory results in Hailey-Hailey than Darier disease. The present CME article summarizes current knowledge of the two dermatoses, taking recent developments into account.

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.