A Case of Hailey–Hailey Disease in an Infant with a New ATP2C1 Gene Mutation

Abstract: Familial benign chronic pemphigus or Hailey–Hailey disease (OMIM 169600) is an autosomal‐dominant blistering disease. Here we present a rare case of familial benign chronic pemphigus in a Chinese infant. The 5‐month‐old proband, who showed diffusely distributed skin lesions, is the youngest patient of Hailey–Hailey disease ever reported. The detection of an ATP2C1 gene mutation in this infant confirmed the diagnosis. His mother carried the same mutation, but with no history of skin lesions.     

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.     

Successful treatment with narrow‐band UVB therapy for a case of generalized Hailey–Hailey disease with a novel splice‐site mutation in ATP2C1 gene

Hailey–Hailey disease (HHD) is a rare autosomal dominant disorder characterized by development of recurrent blisters, erosions, and crustations in the intertriginous areas. The treatment of HHD is often challenging, and various methods have been tried. We report here a case of a 45‐year‐old woman with a generalized form of HHD that was dramatically improved and well controlled by narrow‐band ultraviolet B phototherapy.     

Non‐cosmetic dermatological uses of botulinum neurotoxin

Botulinum neurotoxin (BoNT) is renowned for its inhibitory effects on the neuromuscular junction. The evidence for its use in cosmetic dermatology and in non‐dermatological indications is well established. We have systemically analysed the evidence for the non‐cosmetic dermatological uses of BoNT. This review presents the many small studies showing promising results for the use of BoNT in a multitude of dermatological diseases, including (but not limited to) hyperhidrosis, Darier's disease, Hailey–Hailey disease, pompholyx and hidradenitis suppurativa. There is, however, the need for larger, double‐blinded randomized control trials against established treatments to cement the evidence base underlying the use of BoNT in dermatology.     

Generalized Hailey–Hailey disease with flexural keratotic papules: An interesting presentation and remarkable response with minocycline

Hailey–Hailey disease is a hereditary blistering disorder characterized by episodic vesicles, pustules, erosions, and maceration mainly in intertriginous areas with generalized eruptions encountered rarely. We present a case of generalized HHD with keratotic papules over flexural areas along with its dermoscopic features; treated successfully with minocycline alone.     

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.

     

Use of low‐dose naltrexone in the treatment of severe Hailey–Hailey disease: One case report

Hailey–Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions, and macerated intertriginous skin. We present a 66‐year‐old woman with a personal 35‐year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone, and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25 mg nightly. Six weeks later, complete clearing was observed. At typical doses, naltrexone blocks μ and δ opiod receptors, thereby blocking the union of β ‐endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low‐dose naltrexone (LDN) may also exert an anti‐inflammatory action through its antagonist effect on toll‐like receptor 4 found on macrophages. We consider that LDN is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.     

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.     

Familial “benign” pemphigus? Erythroderma and fatal outcome

Hailey–Hailey disease, or familial benign pemphigus, is a rare bullous genodermatosis that usually presents with flaccid blisters, erosions, and maceration limited to flexural areas, resulting in increased morbidity and reduced quality of life for affected patients. The authors report an unusual case of generalized Hailey–Hailey disease with erythroderma and fatal outcome.     

Koebnerization of Hailey–Hailey disease into a cutaneous drug eruption of acute generalized exanthematous pustulosis associated with systemic symptoms

We describe a 65‐year‐old Caucasian female with well‐controlled Hailey–Hailey disease (HHD) who developed acute generalized exanthematous pustulosis (AGEP) with severe systemic symptoms. Despite sparing of the patient's intertriginous skin, histopathologic evidence of HHD was observed in all biopsies, suggestive of a unique koebernization phenomenon of HHD to areas of cutaneous drug eruption. While internal organ involvement is less commonly reported in AGEP, there are an increasing number of patients with signs and symptoms suggestive of an AGEP/drug reaction with eosinophilia and systemic symptoms (DRESS) spectrum of cutaneous drug disorders. Early diagnosis of patients with AGEP and systemic symptoms is critical so that these patients may receive prompt and aggressive systemic therapy to decrease the risk of end organ damage and improve overall morbidity and mortality.     

Papular acantholytic dyskeratosis of the vulva associated with familial Hailey–Hailey disease

Papular acantholytic dyskeratosis (PAD) of the vulva is a rare, chronic disorder first described in 1984. It presents in young women as white to skin‐coloured smooth papules over the vulva, which are persistent but asymptomatic. Histologically, there is hyperkeratosis and focal parakeratosis with acantholytic and dyskeratotic cells forming corps ronds and grains, placing PAD within Ackerman's spectrum of focal acantholytic dyskeratoses with Hailey–Hailey disease (HHD) and Darier disease. There have been 17 previous reports of PAD of the vulva, to our knowledge. Only one demonstrated a familial pattern, and none of the cases was associated with a family history of HHD. This is the first report of PAD and HHD in a single family, suggesting that PAD and HHD lie on a spectrum of disease and are genetically linked.     

A recurrent melanocytic nevus phenomenon in the setting of Hailey–Hailey disease

Atypical acquired melanocytic nevi in patients with epidermolysis bullosa (EB) have been referred to as EB nevi and are considered to be a type of recurrent nevus with atypical but distinctive histopathologic findings. Herein, we describe an atypical nevus in a patient with Hailey–Hailey disease with different histopathologic findings from EB nevi because of presumably different pathogenesis. It is important to be aware that the recurrent nevi phenomenon can be seen in acantholytic conditions as well as blistering disorders, given these lesions may clinically resemble melanoma.     

Genetic diagnosis of Hailey–Hailey disease in two Chinese families: novel mutations in the ATP2C1 gene

Hailey–Hailey disease (HHD; OMIM 169600), is an autosomal dominantly inherited disorder characterized by suprabasal cell separation of the epidermis. Mutations in ATP2C1, which encodes the human secretory pathway Ca²⁺/ Mn² ± ATPase protein 1 (hSPCA1), have been identified as the pathogenic gene of HHD without evidence of genetic heterogeneity. In this study, the ATP2C1 gene was screened in two typical Chinese pedigrees with HHD, and two specific novel mutations of the ATP2CL gene were identified. Family 1 had a 16‐base deletion mutation c.1068–1083del16 and family 2 had a substitution mutation c.1982T>G (p.Met661Arg). DNA sequencing of the three descendants of the probands revealed that they all had the normal genotype, indicating that there had been no transmission of the mutation.     

Acantholytic dermatosis of the vagina: the diagnostic challenge of acantholytic disease in the genital region

We report the case of a 24‐year‐old woman with an 8‐month history of deep pelvic pain and postcoital bleeding. Examination revealed desquamation of the vaginal epithelium with tender fissured plaques in the vagina, initially thought to be vaginal intraepithelial neoplasia. Histology showed squamous mucosa with suprabasal acantholysis and hyperkeratosis, and no evidence of viral infection, dysplasia or malignancy. These findings were consistent with acantholytic dermatosis (AD), a rare lesion that resembles Hailey–Hailey and Darier disease histopathologically, but can be distinguished on a clinical basis. Vulval cases of AD are well recognized, but to our knowledge, this is the first reported case involving the vaginal epithelium alone.     

Laser therapy for the treatment of Hailey–Hailey disease: a systematic review with focus on carbon dioxide laser resurfacing

Benign familial chronic pemphigus, or Hailey–Hailey disease (HHD), is a recurrent bullous dermatitis that tends to have a chronic course with frequent relapses. Long‐term treatment options include surgery with skin grafting or dermabrasion. Both are highly invasive and carry significant risks and complications. More recently, ‘laser‐abrasion’ has been described as a less invasive option with a better side‐effect profile. In this article, we systematically review the safety and efficacy of carbon dioxide laser therapy as a long‐term treatment option for HHD, as well as provide a review of other lasers that have been reported with this goal. A total of 23 patients who had been treated with a carbon dioxide laser were identified. After treatment, 10 patients (43%) had had no recurrence, 10 (43%) had greater than 50% improvement, 2 (8%) had less than 50% improvement and 1 (4%) patient had no improvement at all (follow‐up period ranged from 4 to 144 months). Laser parameter variability was wide and adverse effects were minimal, including dyspigmentation and scarring. Reviewed evidence indicates this therapy offers a safe, effective treatment alternative for HHD with minimal risk of side‐effects. Larger, well‐designed studies are necessary to determine the optimal treatment parameters.     

Four novel ATP2C1 mutations in Chinese patients with Hailey–Hailey disease

Hailey–Hailey disease (HHD) is a kind of autosomal dominant dermatosis. The ATP2C1 gene has been identified as the pathogenic gene of HHD since 2000. In this study, direct DNA sequencing was used to identify ATP2C1 gene mutations in four Chinese families and two sporadic cases with HHD. The entire coding and flanking intronic sequences of ATP2C1 were screened for mutations and five heterozygous mutations of the ATP2C1 gene were detected in the four pedigrees and two sporadic cases with HHD. Four of them were novel, including three frame‐shift mutations (c.1330delC, c.888_889insT, c.478_479insA) and one nonsense mutation (c.1720C>T). These data added new variants to the database of ATP2C1 mutations associated with HHD.     

Hailey‐Hailey disease successfully treated with vitamin D oral supplementation

Hailey‐Hailey disease (HHD) also known as familial benign chronic pemphigus is a rare autosomal dominant genodermatosis. HHD treatment is often not satisfactory and hence, various modalities of treatment have been tried. We describe the case of a 37‐year‐old woman with a 2 years history of macerated erythematous plaques along with erosions, fissures, and crusts located on axillae and submammary areas, successfully treated with only oral supplementation of vitamin D (800 I.U./die) for 3 months. We reported this case to suggest that oral vitamin D may be enumerated in the various treatments proposed for HHD so far due to its rapid efficacy on skin lesions and symptoms.     

The non‐neuronal and nonmuscular effects of botulinum toxin: a graceful opportunity for a deadly molecule to treat a disease in the skin and beyond

Botulinum neurotoxins (BoNT) are proteins produced by Clostridium botulinum bacteria. There are different subtypes of these toxins, named from A to G. The A, B, and E subtypes cause botulism in humans, which is a potentially fatal disease. However, recently types of BoNT have been developed into injectable treatments used to relax facial muscles and therefore reduce wrinkles (for which it is often known by the brand name ‘Botox’). In addition to the well‐known cosmetic effects, types A and B have been used as treatments in various medical conditions, mainly related to muscle relaxation. This review, from the U.S, outlines the many treatments that involve use of BoNT, including skin disorders such as hyperhidrosis, Hailey‐Hailey disease, Darier disease, inversed psoriasis and Raynaud phenomenon. Experimental studies have demonstrated that BoNT/A may be able to help wound healing, decrease thicknesses of certain scars, and even reduce acne.