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.

Hailey-Hailey disease: the role of azathioprine an immunomodulator.

Hailey-Hailey disease (HHD) is a rare autosomal dominant hereditary blistering and erosions disorder affecting the intertriginous regions of the body. There is still no treatment protocol for this disease thus clinicians are highly advised to draw up individualized treatment plan. In this case report, we discuss a case of HHD in a 58-year-old Chinese man who was successfully treated with azathioprine in Hubei province.

Treatment of Hailey-Hailey Disease With Low-Dose Naltrexone.

Importance: Hailey-Hailey disease is a severe genetic blistering disease of intertriginous skin locations that can lead to poor quality of life and increased morbidities. Multiple therapies are available with inconsistent outcomes and potentially severe adverse effects. Objective: To determine whether low-dose naltrexone is an effective treatment for Hailey-Hailey disease. Design, Setting, and Participants: This study was a case series performed at a dermatology outpatient clinic of 3 patients with severe Hailey-Hailey disease recalcitrant to at least 4 therapies. Interventions: Low-dose naltrexone, 3 mg nightly, titrated to 4.5 mg nightly in 2 patients. Main Outcomes and Measures: Reduction in size of lesions as well as subjective improvement of symptoms. Results: All 3 patients noted significant healing of erosions and plaques starting from the peripheral aspect within 1 to 2 weeks of treatment, and clinical resolution of lesions within 2 months. Discontinuation of low-dose naltrexone resulted in flaring of symptoms, which cleared within 2 to 3 days on rechallenge with low-dose naltrexone. Conclusions and Relevance: We present herein 3 cases of patients with severe Hailey-Hailey disease treated with low-dose naltrexone who achieved clinical resolution of symptoms. The success of these cases suggests low-dose naltrexone as a novel therapy for Hailey-Hailey disease. The possible mechanism may involve low-dose naltrexone influencing opioid or toll-like receptor signaling to improve calcium mobilization and improve keratinocyte differentiation and wound healing. Future studies are needed to clarify the mechanism and to define the role of low-dose naltrexone for treatment of Hailey-Hailey disease.

Low-Dose Naltrexone Treatment of Familial Benign Pemphigus (Hailey-Hailey Disease).

Importance: Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare and debilitating genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. Despite the reported therapeutic modalities, such as topical and systemic corticosteroids, systemic immunomodulators, topical and systemic retinoids, and laser, HHD can still be markedly difficult to control. Objective: To assess low-dose naltrexone hydrochloride in the treatment of recalcitrant HHD. Design, Setting, and Participants: In this case series, 3 patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic. Each patient was treated with low-dose naltrexone hydrochloride at a dosage of 1.5 to 3.0 mg per day. No laboratory monitoring was necessary. Clinical response (healing of erosions, improvement in erythema, and alleviation of pain), adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017. Main Outcomes and Measures: Objective clinical response as assessed by the treating dermatologist, subjective quality of life as reported by the patient, and recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. Results: The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded. Conclusions and Relevance: Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD.

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 and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca(2+) /Mn(2+) ATPase SPCA1 in cultured keratinocytes.

Mutations in the ATP2C1 gene encoding Ca(2+) /Mn(2+) ATPase SPCA1 cause Hailey-Hailey disease (HHD, OMIM 16960). HHD is characterized by epidermal acantholysis. We attempted to model HHD using normal keratinocytes, in which the SPCA1 mRNA was down-regulated with the small inhibitory RNA (siRNA) method. SiRNA inhibition significantly down-regulated the SPCA1 mRNA, as demonstrated by qPCR, and decreased the SPCA1 protein beyond detectable level, as shown by Western analysis. The expression of selected desmosomal, adherens and tight junction (TJ) proteins was then studied in the SPCA1-deficient and control keratinocytes cultured in low (0.06 mm) or high (1.2 mm) calcium concentration. The mRNA and protein levels of most TJ components were up-regulated in non-treated control keratinocyte cultures upon switch from low to high calcium concentration. In contrast, SPCA1-deficient keratinocytes displayed high levels of TJ proteins claudins 1 and 4 even in low calcium. ZO-1 did not, however, follow similar expression patterns. Protein levels of occludin, beta-catenin, E-cadherin, desmoplakin, desmogleins 1-3, desmocollin 2/desmocollin 3 and plakoglobin did not show marked changes in SPCA1-deficient keratinocytes. Indirect immunofluorescence labelling revealed delayed translocation of desmoplakin and desmoglein 3 in desmosomes and increased intracellular pools of TJ and desmosomal components in SPCA1-inhibited keratinocytes. The results show that SPCA1 regulates the levels of claudins 1 and 4, but does not affect desmosomal protein levels, indicating that TJ proteins are differently regulated. The results also suggest a potential role for claudins in HHD.

Golgi pH, its regulation and roles in human disease.

Most organelles within the exocytic and endocytic pathways typically acidify their interiors, a phenomenon that is known to be crucial for their optimal functioning in eukaryotic cells. This review highlights recent advances in our understanding of how Golgi acidity is maintained and regulated, and how its misregulation contributes to organelle dysfunction and disease. Both its biosynthetic products (glycans) and protein-sorting events are highly sensitive to changes in Golgi luminal pH and are affected in certain human disease states such as cancers and cutis laxa. Other potential disease states that are caused by, or are associated with, Golgi pH misregulation will also be discussed.

Detection and comparison of two types of ATP2C1 gene mutations in Chinese patients with Hailey-Hailey disease.

The gene ATP2C1 is identified as the defective gene in Hailey-Hailey disease (HHD). The nonsense and missense are two common types of mutations and have, respectively, been detected in many HHD patients. The aims of our study were to identify the pathogenic ATP2C1 abnormality in Chinese HHD patients, and to compare nonsense and missense mutations in vivo to provide further understanding of the molecular and the physiological basis of HHD. The nucleotide sequencing of the ATP2C1 gene was performed in HHD patients, unaffected family members and 100 unrelated individuals. Meanwhile, we detected and analyzed the clinical manifestations, the expression of ATP2C1 mRNA and hSPCA1 protein in the two types of mutations. Three heterozygous mutations were identified, including a previously reported nonsense mutation (R799X), two novel missense mutations (D644G) and (R417K). The results of comparisons between two types of mutations showed that the common clinical features, the similarly low-level expressions of ATP2C1 mRNA and hSPCA1 protein, but the ATP2C1 mRNA expression of nonsense mutation was lower than missense mutation and even less than half the level of normal people. Our findings expand the known spectrum of ATP2C1 mutations in HHD. We supported the haploinsufficiency theory as prevalent mechanism in both types of mutations, and believed that the differences of ATP2C1 mRNA expressions in peripheral blood may relate with the type of mutation and reflect the state of illness of patients.

Are patients with Darier and Haily-Haily diseases susceptible to Alzheimer's disease? A theory based on abnormal intraneuronal Ca2+ homeostasis.

Calcium is one of the most important intracellular messengers in human brain. Studies show that there is a relationship between altered Ca2+-homeostasis, especially elevation of intracellular calcium, and formation of the hallmark pathological lesions of Alzheimer's disease. Additionally, Ca2+ is crucial for normal function of the skin, and an abnormal rise in intracellular Ca2+ can consequently lead to the development of two skin disorders: Darier and Hailey-Hailey diseases. As these mutated genes are also highly expressed in the brain and these patients are reported to experience some neuropsychiatric problems, we have hypothesized that patients with these dermatologic diseases may be more prone to the development of Alzheimer's disease. Further investigation may give us clues to find novel therapeutic targets and agents for modulation of intracellular calcium in neurons.

Diseases involving the Golgi calcium pump.

Secretory-pathway Ca2(+)-transport ATPases (SPCA) provide the Golgi apparatus with Ca2+ and Mn2+ needed for the normal functioning of this organelle. Loss of one functional copy of the human SPCA1 gene (ATP2C1) causes Hailey-Hailey disease, a rare skin disorder characterized by recurrent blisters and erosions in the flexural areas. Here, we will review the properties and functional role of the SPCAs. The relationship between Hailey-Hailey disease and its defective gene (ATP2C1) will be adressed as well.

Topical tacrolimus in Hailey-Hailey disease.

Hailey-Hailey disease, or familial benign chronic pemphigus, is a rare relapsing-remitting autosomal-dominant epidermal blistering disease. It preferentially affects females and is characterized by recurrent vesicles and erosions in the intertriginous areas. There are several topical corticosteroid therapeutic options, which are often limited in their use by their secondary effects and localization of the lesions. We report a case of a 60-year-old woman with Hailey-Hailey disease involving axillary, groin, cervical, antecubital, inframammary and abdominal folds. She was treated with 0.1% tacrolimus ointment, applied twice daily, with clinical improvement in 2 weeks and total remission in 4 weeks. She remains asymptomatic after a 10-month follow-up period.

Placas eritematosas erosivas en caras laterales del cuello, axilas e ingles / Erythematous-erosive plaques on the sides of the neck, axillae and groins

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Diagnóstico y tratamiento enzimático sustitutivo de la enfermedad de Fabry / Diagnosis and enzyme replacement therapy of Fabry´s disease

Las manifestaciones cutáneas de la enfermedad de Fabry tienen un papel importante para el diagnóstico precoz de la enfermedad. Con la introducción de terapias de sustitución enzimática pueden tener una relevancia aún mayor.Se describe un caso en el que la presencia de dolores lancinantes en los dedos de las manos tras el ejercicio y de angioqueratomas difusos sugirieron el diagnóstico, posteriormente confirmado mediante estudio enzimático y genético. En este caso, el tratamiento sustitutivo con alfa-galactosidasa es de utilidad para el paciente (AU)

Functional expression of heterologous proteins in yeast: insights into Ca2+ signaling and Ca2+-transporting ATPases.

The baker's yeast Saccharomyces cerevisiae is a well-developed, versatile, and widely used model organism. It offers a compact and fully sequenced genome, tractable genetics, simple and inexpensive culturing conditions, and, importantly, a conservation of basic cellular machinery and signal transducing pathways with higher eukaryotes. In this review, we describe recent technical advances in the heterologous expression of proteins in yeast and illustrate their application to the study of the Ca(2+) homeostasis machinery, with particular emphasis on Ca(2+)-transporting ATPases. Putative Ca(2+)-ATPases in the newly sequenced genomes of organisms such as parasites, plants, and vertebrates have been investigated by functional complementation of an engineered yeast strain lacking endogenous Ca(2+) pumps. High-throughput screens of mutant phenotypes to identify side chains critical for ion transport and selectivity have facilitated structure-function analysis, and genomewide approaches may be used to dissect cellular pathways involved in Ca(2+) transport and trafficking. The utility of the yeast system is demonstrated by rapid advances in the study of the emerging family of Golgi/secretory pathway Ca(2+),Mn(2+)-ATPases (SPCA). Functional expression of human SPCA1 in yeast has provided insight into the physiology, novel biochemical characteristics, and subcellular localization of this pump. Haploinsufficiency of SPCA1 leads to Hailey-Hailey disease (HDD), a debilitating blistering disorder of the skin. Missense mutations, identified in patients with HHD, may be conveniently assessed in yeast for loss-of-function phenotypes associated with the disease.