Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

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.

Afecciones perianales no infecciosas, no neoplásicas, del adulto / Noninfectious, non-neoplasic adult perianal affections

Las enfermedades perianales del adulto, de carácter no infeccioso y no neoplásico, son un motivo de consulta poco frecuente. Se caracterizan por la variedad de su etiología y de su sintomatología clínica, y plantean dificultad en el diagnóstico y en la terapéutica. El objetivo del presente trabajo es abordar una patología que plantea la necesidad de una intervención interdisciplinaria. Se incluyen consideraciones anatomopatológicas, clínicas y terapéuticas. (AU)

Noninfectious, non- neoplasic perianal affections are uncommon diseases. They are characterized by the variety of the etiology and clinical symptomatology, posing difficulty in diagnosis and therapeutics. The objective of this paper is to address a pathology that raises the need for interdisciplinary intervention anatomopathological, clinical and therapeutic considerations are included. (AU)

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.

Tratamiento de la enfermedad de Hailey-Hailey generalizada con fototerapia UVB de banda estrecha / Narrowband UV-B Phototherapy in the Treatment of Generalized Hailey-Hailey Disease

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Yeast-Based Screen to Identify Natural Compounds with a Potential Therapeutic Effect in Hailey-Hailey Disease.

The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD.

Interventional treatments for Hailey-Hailey disease.

Hailey-Hailey disease or familial benign chronic pemphigus is a rare blistering dermatosis that is characterized by recurrent erythematous plaques with a predilection for the skin folds. For extensive Hailey-Hailey disease that is recalcitrant to conventional therapy, laser ablation, photodynamic therapy, electron beam radiotherapy, botulinum toxin type A, dermabrasion, glycopyrrolate, and afamelanotide have been reported as useful treatments, but comparative trials are lacking. This review discusses the various treatment modalities for Hailey-Hailey disease and a summary of the evidence for the most recommended treatments.

Enfermedad de Hailey- Hailey: reporte de casos entre los años 2001 y 2016 en un hospital universitario y revisión de la literatura / Hailey-Hailey disease: case report among the years 2001 and 2016 in a university hospital and review of the literature

Introducción: La enfermedad de Hailey-Hailey (pénfigo crónico familiar benigno) es una dermatosis ampollar, de evolución crónica, recidivante, autosómica dominante, de penetrancia y expresividad variables, localizada predominantemente en los pliegues. Métodos: Se realizó una revisión de la base de datos del Servicio Anatomía Patológica del Hospital Clínico Universidad de Chile (HCUCH) entre los años 2001 y 2016 y se complementaron con los antecedentes clínicos extraídos de las fichas clínicas. Resultados: Se obtuvo un total de 6 casos ilustrativos de la patología en estudio. Discusión y conclusiones: La enfermedad de Hailey-Hailey es una genodermatosis poco frecuente cuyo diagnóstico y tratamiento constituyen un desafío para el dermatólogo.

Background: The Hailey-Hailey disease (familial benign chronic pemphigus) is a bullous dermatosis, with chronic and recurrent evolution, autosomal dominant with variable penetrance and expressivity, localized predominantly in the folds. Methods: A review of the database of the Anatomic Pathology Service of the Hospital Clínico Universidad de Chile (HCUCH) between 2001 and 2016 was carried out and supplemented with the clinical history extracted from the clinical records. Results: A total of 6 illustrative cases of the pathology under study were obtained. Discussion and conclusions: Hailey-Hailey's disease is a rare genodermatosis whose diagnosis and treatment is a challenge for the dermatologist.

Enfermedad de Hailey-Hailey recalcitrante con buena respuesta a terapia fotodinámica / Refractory Hailey-Hailey Disease That Responded Well to Photodynamic Therapy

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Hailey-Hailey disease: A fold (intertriginous) dermatosis.

Hailey-Hailey disease, also called benign familial pemphigus, is a late-onset blistering disorder that affects the flexures. There are typically painful erosions and cracks in affected areas. Lesions generally begin between 20 and 40 years of age. In two third of all cases, positive family history is detected. In pathogenesis, there is a defect in keratinocyte adhesion due to ATP2 C1 gene mutation. The result of the desmosomal decomposition is acantholysis. Menstruation, pregnancy, skin infections, physical trauma, excessive sweating and exposure to ultraviolet radiation are important triggering factors. Histopathologic changes are suprabasal acantholysis and formation of intraepidermal bullae. In the epidermis, a partial acantholysis that looks like broken bricks is observed.

Hailey-Hailey disease and review of management.

IMPORTANCE: Hailey-Hailey disease, or familial benign chronic pemphigus, is a rare genodermatosis that can be challenging for both patients and dermatologists as the disease can significantly impact patients' quality of life and is often difficult to control. In recalcitrant cases, multiple treatment modalities are often needed to obtain benefit. Unfortunately, most of the available evidence pertaining to treatment is scattered across case reports and retrospective analyses. OBJECTIVE: To review successful treatments of Hailey-Hailey, synthesize the evidence, and provide recommendations for therapy. FINDINGS: The best evidence exists for treatment with topical steroids and topical antimicrobials. Refractory disease has shown the most benefit with addition of oral antibiotics, excisional procedures and botulinum toxin A. Other therapies are described but with much less supporting evidence. CONCLUSIONS: Herein we review the literature to identify successful treatments for Hailey-Hailey disease. We have outlined the treatments with the most evidence. The difficult nature of treating this disease requires that clinicians approach each patient differently. The literature shows that no one regiment works for all patients.

Pénfigo benigno familiar / Pemphigus benign familial

El pénfigo benigno familiar o enfermedad de Hailey-Hailey es una genodermatosis ampollar, de evolución crónica, recidivante y de etiología desconocida. Se observa con mayor frecuencia en las áreas de pliegues. Las lesiones se caracterizan por ser ampollares, con contenido seroso que evolucionan a costras. En la histología se evidencia acantólisis suprabasal y separación de los queratinocitos por destrucción de los desmosomas. No hay un tratamiento específico. Se presentan dos casos para el aporte del conocimiento de esta enfermedad.

The pemphigus benign familial or Hailey-Hailey disease is genodermatosis a blistering, chronic evolution, ethology recurrent and unknown. Seen most commonly in the areas of folds. The lesions are characterized by bullous serous content evolve at scabs. Histology in suprabasal acantholysis evidence and separation of keratinocytes by destruction of desmosomes. There is no specific treatment. Below are two cases for the contribution of knowledge of this disease.

Enfermedad de Hailey-Hailey y tacrolimus: reporte de caso / Hailey-Hailey disease and tacrolimus: case report

La enfermedad de Hailey-Hailey es una enfermedad ampollar poco frecuente y recurrente. Existen múltiples terapéuticas para esta patología, siendo agentes de primera línea los antibióticos, corticoides y antifúngicos tópicos y orales. Se describe el caso de una mujer de 37 años de edad, que presenta placas erosivas y verrugosas en zonas intertriginosas de 15 años de evolución; con buena respuesta terapéutica a tacrolimus 0,1%.

The Haiiey-Hailey disease is a rare disease and recurrent blistering, There are many therapies for this condition, with first-line agents antibiotics, corticosteroids and topical and oral antifungal. We describe the case of a 37 year old having erosive and warty plaques in intertriginous areas 15 years of evolution, with good therapeutic response to tacrolimus 0,1%.

Tratamiento de la enfermedad de Hailey-Hailey con láser de dióxido de carbono: tratamiento en 8 pacientes / Carbon Dioxide Laser Treatment in Hailey-Hailey Disease: A Series of 8 Patients

Introducción y objetivos: La enfermedad de Hailey-Hailey (EHH) o pénfigo familiar benigno es un rara genodermatosis ampollosa con herencia autosómica dominante. Cursa con erosiones cutáneas, localizadas principalmente en los grandes pliegues, que se sobreinfectan y pueden ser muy dolorosas e incapacitantes para los pacientes. Es una afección difícil de tratar, y aunque se han usado múltiples tratamientos tópicos y sistémicos para controlar los brotes de la enfermedad, ninguno de ellos consigue remisiones a medio-largo plazo. Pacientes y método: Realizamos un estudio retrospectivo de una serie de 8 casos de EHH tratados con láser CO2 en nuestro centro desde 1999 a 2011. Los pacientes tratados tenían una media de edad de 50,7 años, siendo 4 de ellos hombres y 4 mujeres. El seguimiento de los pacientes osciló entre uno y 12 años. Resultados: De los 8 pacientes tratados 6 obtuvieron unos resultados satisfactorios (4 pacientes con mejoría clínica>75% y 2 pacientes entre 50-75%). Esta eficacia se mantuvo a lo largo del tiempo. Los peores resultados se observaron en los pacientes tratados con potencias más bajas. Las zonas con recidiva de la enfermedad después del tratamiento se trataron con una segunda sesión de láser con buena respuesta. No observamos efectos adversos, salvo ligeros cambios texturales y de la pigmentación. Conclusiones: El láser de CO2 es un tratamiento eficaz y seguro a medio-largo plazo en los casos de EHH sintomáticos y refractarios a tratamientos convencionales (AU)

Introduction and objectives: Hailey-Hailey disease (HHD), or benign familial pemphigus, is arare autosomal dominant genodermatosis characterized by the formation of blisters. Eruptionsare usually located in large skin folds, and when blisters become infected the condition can bevery painful and disabling. HHD is difficult to treat. Many topical and systemic treatments have been used to bring exacerbations under control, but none have achieved medium- to long-term remission. Patients and methods: Retrospective study of 8 patients with HHD treated with carbon dioxide laser therapy in our hospital between 1999 and 2011. The patients’ mean age was 50.7 years. The 4 men and 4 women were followed for between 1 and 12 years. Results: Satisfactory outcomes were achieved for 6 of the patients. Clinical improvement was observed in more than 75% of the affected area in 4 patients and in 50% to 75% of the area in 2 patients. The effect of treatments was maintained over time. The poorest outcomes were observed in patients treated at lower potencies. When blistering recurred after treatment, a second laser session achieved a good response. We observed no adverse events other than slight changes in skin texture and pigmentation. Conclusions: Carbon dioxide laser therapy was safe and effective in producing medium- to long-term improvement in HHD symptoms that were refractory to conventional treatments (AU)

Refractory Hailey-Hailey disease successfully treated with sandpaper dermabrasion.

A 53-year-old woman presented with a 20-year history of pruritic dermatitis on the groin, axillae, inframammary folds, posterior aspect of the neck, and popliteal fossae. She was referred to our clinic by an outside facility after results from a punch biopsy diagnosed Hailey-Hailey disease (HHD). The patient had previously attempted treatment with many traditional noninvasive options with no success. Topical treatment modalities included corticosteroids, immunomodulators, antifungals, retinoids, and antibiotic preparations. Intralesional corticosteroids, as well as botulinum toxin and carbon dioxide laser, were also unsuccessful. Failed systemic treatment modalities included antibiotics, antihistamines, prednisone, azathioprine, mycophenolate mofetil, acitretin, isotretinoin, adalimumab, and etanercept. Of note, cyclosporine was successful in clearing the cutaneous involvement in our patient, but elevation ofcreatinine and exacerbated hypertension precluded continued use. The decision was made to treat the patient by dermabrasion with sandpaper. The patient was prepped in a sterile fashion, and a field block with 1% lidocaine with epinephrine was performed. This was followed by abrasion down to the superficial dermis with 3M Sandblaster fine sandpaper (3M, St. Paul, MN) and hyfrecation between rounds ofdermabrasion. The treated areas were then covered with petrolatum and sterile gauze, and antibiotics and pain medication were prescribed. This treatment was initially performed on the patient's posterior aspect of the neck and later to the bilateral popliteal fossae and axillae. Three months post-treatment, desirable functional and cosmetic results of the treated areas had been achieved (Figure 1 and Figure 2). While no recurrence of clinically active HHD has been seen in the dermabraded areas of the neck and popliteal fossae, the patient continues to have active disease in the axillae despite sandpaper dermabrasion. To quantify our results, we performed two biopsies in the dermabraded sites of the popliteal fossae as healing occurred: a shave biopsy from an obviously active area, and a punch biopsy from a peripheral inactive border. The biopsy from the active area showed diffuse epidermal acantholysis similar to that seen in untreated HHD, while the healing periphery showed only scattered acantholytic areas and a sparse perivascular infiltrate-a marked improvement from the untreated areas.

Enfermedad de Hailey-Hailey / Hailey-Hailey´s disease

La enfermedad de Hailey-Hailey es una genodermatosis rara, producida por mutaciones en el gen ATP2C1. Se caracteriza por afectar áreas de pliegues, simulando intertrigos de diversas etiologías, lo que genera un retraso en su diagnóstico y tratamiento. Debido a su carácter crónico y a los síntomas que ocasiona, como dolor y fetidez, suele afectar la calidad de vida de los pacientes. Se han propuesto numerosos tratamientos tópicos, físicos y sistémicos. Hasta la fecha no existen modalidades terapéuticas que sean totalmente efectivas, si bien el láser de dióxido de carbono (CO2) ha logrado remisiones prolongadas.

Hailey-Hailey’s disease is a rare hereditary disease caused by ATP2C1-gene mutations. Itaffect the folds, simulating intertrigo of various etiologies, leading to a delay in diagnosisand treatment. Its chronic nature, and symptoms such as pain and bad odour, affects thequality of life of patients.Numerous topical, physical an systemic treatments have been proposed. To date there are nofully effective treatment modalities, although CO2 LASER has achieved prolonged remissions.