Purified Type I Collagen Wound Matrix Improves Chronic Wound Healing in Patients with Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa is a severe genetic blistering skin condition resulting in chronic wounds. Nonhealing wounds were treated over 8 weeks using a reconstituted natural purified type I collagen skin substitute. Chronic wounds were defined as nonhealing wounds present for longer than 6 months. For each patient, two chronic wounds were identified and randomized into a control or treatment group. Both groups received standard‐of‐care wound dressings. The treatment group received an additional type I collagen skin substitute. Wound size was measured at baseline and weeks 1, 4, and 8. Pain, pruritus, and burning and stinging were assessed. Wound cultures were obtained at baseline and thereafter as was considered clinically relevant. Ten subjects were enrolled; seven completed the study. Six subjects showed a positive response to the type I collagen skin substitute. Three subjects demonstrated full wound reepithelialization. Wounds treated using the collagen skin substitute showed statistically significantly greater improvement. Average scores for pruritus and pain decreased significantly. Reconstituted natural purified type I collagen skin substitutes improved the healing of chronic wounds and may be a valuable addition to the epidermolysis bullosa wound care arsenal.     

Molecular organization of the basement membrane zone

The dermal-epidermal basement membrane is a complex assembly of proteins that provide adhesion and regulate many important processes such as development, wound healing, and cancer progression. This contribution focuses on the structure and function of individual components of the basement membrane, how they assemble together, and how they participate in human tissues and diseases, with an emphasis on skin involvement. Understanding the composition and structure of the basement membrane provides insight into the pathophysiology of inherited blistering disorders, such as epidermolysis bullosa, and acquired bullous diseases, such as the pemphigoid group of autoimmune diseases and epidermolysis bullosa acquisita.     

Epidermolysis bullosa: new and emerging trends

Epidermolysis bullosa is a family of inherited blistering skin disorders characterized by blister formation in response to mechanical trauma. Major types of epidermolysis bullosa include epidermolysis bullosa simplex, hemidesmosomal epidermolysis bullosa, junctional epidermolysis bullosa, and dystrophic epidermolysis bullosa. Current treatment for epidermolysis bullosa consists of supportive care for skin and other organ systems and entails a combination of wound management, infection support for chronic wounds, surgical management as needed, nutritional support, and preventative screening for squamous cell carcinoma in recessive dystrophic epidermolysis bullosa. The regimen must be tailored specifically to the severity and extent of skin and systemic involvement in each case. Recent studies have identified specific protein and genetic abnormalities for most epidermolysis bullosa subtypes. These new advancements in the understanding of molecular pathophysiology have provided much of the basis for current efforts to develop effective gene and protein therapy for epidermolysis bullosa.     

Pain management of junctional epidermolysis bullosa in an 11-year-Old boy

Epidermolysis bullosa is a group of hereditary blistering disorders for which there is no definitive therapy. Wound care is an important component of management. Regular dressing changes are required to protect blistered and eroded skin, and to prevent secondary infection and sepsis. These dressing changes can be very painful for patients with extensive erosions. We report our experience of pain management in an 11-year-old boy with severe junctional epidermolysis bullosa. Amitryptiline and cognitive behavioral techniques were effective in relieving chronic pain and discomfort. Oral midazolam 0.33 mg/kg administered 20 minutes prior to baths and dressing changes substantially improved his tolerance of wound care.     

Inpatient management of children with recessive dystrophic epidermolysis bullosa: A review

Recessive dystrophic epidermolysis bullosa is a disorder marked by skin and mucosal blistering after minimal trauma. Even the most routine procedures in the hospital, if done incorrectly, can precipitate extensive skin loss, pain, and scarring. Most providers have little experience working with patients with this degree of skin fragility. When a person with recessive dystrophic epidermolysis bullosa is admitted to the hospital, there are multiple considerations to keep in mind while strategizing an effective care plan: avoidance of new blisters with a “hands‐off” approach; careful consideration of all indwelling devices; symptomatic management of pain, itch, and anxiety; coordination of dressing changes; aggressive treatment of skin infections; environmental and staffing considerations; and awareness of other chronic complications that affect care, such as anemia, malnutrition, and chronic pain. To minimize discomfort for patients with recessive dystrophic epidermolysis bullosa during the hospital stay, inpatient care teams should understand these considerations and modify the care plan accordingly. Prior preparation by the hospital facility and inpatient care team will facilitate the delivery of safe and effective care and greatly improve the overall patient experience.     

Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa

We report here on three patients suffering from recessive dystrophic epidermolysis bullosa and one suffering from generalized atrophic benign epidermolysis bullosa, all of whom developed cutaneous squamous cell carcinoma. Our observations and a review of the literature suggest that squamous cell carcinoma in generalized atrophic benign epidermolysis bullosa is very infrequent and has a better outcome compared to skin cancer in recessive dystrophic epidermolysis bullosa. These differences could be explained by the distinct pathophysiology and clinical course of each of these variants of epidermolysis bullosa. In contrast to UV-induced skin cancer, the tumours in epidermolysis bullosa develop on distal extremities at sites of chronic wound healing. The cases reported here underline the exceptional importance of early histopathological assessment of suspicious skin lesions in patients with epidermolysis bullosa.     

Ongoing blistering in a boy with congenital erosive and vesicular dermatosis healing with reticulated supple scarring

Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. A 9-year-old boy presented with a diagnosis of junctional epidermolysis bullosa, but displayed this characteristic scarring pattern and very mild ongoing blistering. In addition, he had severe chronic conjunctivitis due to cicatricial alopecia of the eyelashes and lacrimal duct obstruction. He had no evidence of enamel defects or other features of junctional epidermolysis bullosa. Ultrastructural analysis of his skin biopsy specimens showed a normal dermoepidermal junction. This characteristic scarring disorder may be associated with mild ongoing blistering and must be distinguished from other congenital blistering disorders.     

Evaluation of Wound Care Options in Patients with Recessive Dystrophic Epidermolysis Bullosa: A Costly Necessity

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder in which mutations in collagen VII, the main component of the anchoring fibril, lead to skin fragility and to the development of acute and chronic wounds. Wound care and dressing changes are an important part of the daily lives of individuals with RDEB. Ideal wound care should improve wound healing, minimize pain, and improve quality of life. The objective of the current study was to review wound care options that might be used in a patient with RDEB and calculate the cost of these various options based on publicly available pricing of wound care products. There is a wide range of costs for wound care options in patients with RDEB. For example, a 1‐day supply of dressing for a neonate boy with RDEB ranges from $10.64 for the least expensive option to $127.54 for the most expensive option. Wound care in patients with severe, generalized RDEB has not only a significant economic effect, but also directly affects quality of life in this patient population. Although randomized controlled trials evaluating different wound care products in patients with RDEB are lacking, small studies and expert opinion support the use of specialized nonadherent dressings that minimize skin trauma and promote wound healing. Until there is a cure, prospective studies are needed to assess pain, quality of life, and wound healing associated with the use of specialized wound care products for this life‐altering condition.     

Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.     

Amnia for intractable skin ulcers with recessive dystrophic epidermolysis bullosa: report of three cases

Recessive dystrophic epidermolysis bullosa (RDEB) is a disease characterized by recurrent blistering and chronic ulceration of the skin. In these patients, recurrent blisters frequently result in intractable skin ulcers due to impaired wound healing caused by mutations in the type VII collagen gene and malnutrition as well as by increased collagenase activity. To evaluate the efficacy of amnia for intractable ulcers in RDEB, we treated RDEB patients with amnia. The amniotic membrane was simply placed on the cleansed wound surface. The procedure was repeated once a week for up to 10 weeks. As a result, wound conditions improved remarkably after treatment with amnia for 2-10 weeks in all the patients, resulting in total re-epithelization of the ulcers. Amnia could be an effective therapy for intractable skin ulcers in RDEB patients, and should be considered as a re-emerging therapeutic option for the disease.     

180-kDa bullous pemphigoid antigen defective generalized atrophic benign epidermolysis bullosa: report of four cases with an unusually mild phenotype

Generalized atrophic benign epidermolysis bullosa (GABEB) is a rare variant of non-lethal junctional epidermolysis bullosa characterized by generalized skin blistering healing with atrophy and by atrophic alopecia with onset in childhood. Other features include mild mucosal blistering, dental abnormalities and nail dystrophy. We report four additional cases of GABEB from two families originating from the same isolated village. The patients shared an unusually mild clinical phenotype with cutaneous blisters strictly limited to trauma sites and rare occurrence of oral mucosal lesions. Scalp, eyelash and eyebrow alopecia was present in only two cases. Immunofluorescence studies showed a markedly reduced expression of the 180-kDa bullous pemphigoid antigen (BP180), and northern analysis of cultured keratinocytes indicated that the gene encoding for BP180 is affected in these GABEB patients.     

The role of human skin collagenase in epidermolysis bullosa.

Human skin collagenase was quantitated by radioimmunoassay in 40 patients with various forms of epidermolysis bullosa to compare levels of the enzyme in blistered and clinically unaffected skin. Immunoreactive human skin collagenase was significantly elevated in the blistered skin of patients with both recessive and dominant forms of dystrophic epidermolysis bullosa (DEB). In addition, patients with generalized recessive DEB manifested a 4-fold increase in collagenase protein in normal-appearing skin, and patients with localized recessive DEB or epidermolysis bullosa letalis showed a 3-t to 3.5-fold elevation in the enzyme. However, patients with dominantly inherited DEB failed to displays a statistically significant increase in immunoreactive collagenase in nonblistered skin. Although it cannot be definitely stated whether the elevated collagenase content in the blistered skin represents a primary or secondary event, such as part of a wound healing response, the demonstration of markedly increased levels of collagenase in normal-appearing skin could, in part, provide an explanation at the molecular level for the formation of blisters in this disease.     

Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin

Genetic mutations in plectin, a cytoskeleton linker protein expressed in a large variety of tissues including skin, muscle, and nerves, cause epidermolysis bullosa simplex with muscular dystrophy, a recessive inherited disease characterized by blistering of the skin and late onset of muscular dystrophy, and Ogna epidermolysis bullosa simplex, a rare dominant inherited form of epidermolysis bullosa simplex with no muscular involvement. Here we report a novel homozygous genetic mutation (2727del14) in the plectin gene (PLEC1) associated with a lethal form of recessive inherited epidermolysis bullosa in a consanguineous family with three affected offspring. This new clinical variant of epidermolysis bullosa is characterized by general skin blistering, aplasia cutis of the limbs, developmental complications, and rapid demise after birth. Mutation 2727del14 is the first genetic defect described in PLEC1 that disrupts the plakin domain of plectin. The severe phenotype of the patients may be linked to the role of the N-terminal domain in the function of plectin and develops the understanding of the genotype-phenotype correlations in the genodermatoses affecting the dermal-epidermal junction.     

Epidermolysis bullosa acquisita and associated symptomatic esophageal webs

Epidermolysis bullosa acquisita (EBA) is a well-characterized, subepidermal blistering disorder associated with autoimmunity to type VII collagen, which is the collagen localized to anchoring fibrils within the dermoepidermal junction of skin. Although the full clinical spectrum of EBA is still being defined, it is known that the clinical features of EBA may be reminiscent of hereditary dystrophic epidermolysis bullosa, a scarring blistering disease of children that is commonly associated with esophageal stenosis. We describe a patient with EBA who had both an acral-predominant mechanobullous disease akin to dystrophic epidermolysis bullosa and an inflammatory, widespread bullous eruption reminiscent of bullous pemphigoid in association with esophageal webs and dysphagia. Although esophageal involvement is common in dystrophic epidermolysis bullosa, a review of the literature shows that this is the first bonafide case of EBA with symptomatic esophageal disease.     

Non-Herlitz junctional epidermolysis bullosa without hair involvement associated with BP180 deficiency

Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous recessively inherited blistering disease of the skin and mucous membranes due to impaired epithelial adhesion. In particular, defective expression of the 180-kD bullous pemphigoid antigen (BP180) has been correlated to a non-lethal (non-Herlitz) form of JEB, generalized atrophic benign epidermolysis bullosa (GABEB), characterized by widespread skin blistering healing with atrophy and by atrophic alopecia with onset in childhood. We report the case of a 33-year-old man suffering from a generalized blistering skin disorder since birth. He also presented nail dystrophy and tooth abnormalities. Mucosal involvement was limited to gingival erosion. Alopecia was absent and body, axillary and pubic hair were normal. Immunofluorescence analysis showed a markedly reduced expression of BP180, electron microscopy studies evidenced hypoplastic hemidesmosomes and Northern blot analysis confirmed a striking decrease in the amount of BP180 mRNA. The clinical features of our patient confirm that BP180 deficiency usually results in a non-Herlitz JEB form. However, the degree of skin, mucous membranes and hair involvement appears more variable and less typical than originally described for GABEB.     

Burnlike scars: A sign suggestive of KLHL24‐related epidermolysis bullosa simplex

Epidermolysis bullosa simplex is a group of inherited disorders with allelic and locus heterogeneity in which skin fragility and blistering within the skin occur. Mutations in KRT5 and KRT14 underlie the majority of reported cases. Mutations in KLHL24, a gene that encodes KLHL24 protein, have been reported recently to cause a generalized subtype of epidermolysis bullosa simplex, presumably by increasing the degradation of keratin 14. We describe a case of KLHL24‐related epidermolysis bullosa simplex and highlight the burn‐like pattern of scars.     

Common Wound Colonizers in Patients with Epidermolysis Bullosa

Abstract:  One of the major morbidities of patients with epidermolysis bullosa is the tendency to develop chronic wounds, which predisposes them to multiple complications including life-threatening infections, failure to thrive, and squamous cell carcinomas. Chronic wounds frequently become colonized with bacteria, and we sought to identify the most common microorganisms isolated on cultures from patients with epidermolysis bullosa. We conducted a retrospective review of positive wound, nasal, and blood cultures, including bacterial, fungal and viral, in 30 patients with epidermolysis bullosa. Staphylococcus sp., Streptococcus sp., diptheroids, Pseudomonas aeruginosa , and Candida sp. were the most commonly isolated microorganisms in wound cultures from our epidermolysis bullosa patients. Two patients had viral cultures that grew herpes simplex virus type-1. Bacterial colonization of chronic wounds can lead to infections and may also impact wound healing. Results from this study provide data on which to base empiric antibiotic choice in patients with epidermolysis bullosa when needed and may be useful in planning strategies for decolonization and improved wound healing in this population.     

Protease inhibitor therapy for recessive dystrophic epidermolysis bullosa. In vitro effect and clinical trial with camostat mesylate

Recently we reported that a kind of serine protease, SH protease, and collagenase might be involved in blister formation and, furthermore, that the cooperative action of these three proteases was essential for blister formation in recessive dystrophic epidermolysis bullosa. In this study we examined the inhibitory effect of clinically usable serine protease inhibitors for blister formation in organ culture and in clinical trials of recessive dystrophic epidermolysis bullosa patients. Camostat mesylate, a synthetic serine protease inhibitor that is available for the treatment of chronic pancreatitis, demonstrated a striking effect of inhibiting blistering in organ culture of normal human skin with recessive dystrophic epidermolysis bullosa blister fluids. Subsequently we administered camostat mesylate by topical application to four patients with recessive dystrophic epidermolysis bullosa to assess its ability to reduce blistering. Therapeutic response was favorable; a significant effect in decreasing the number of blisters was observed in three of four patients. These findings actually supported the hypothesis that a kind of serine protease had a close relationship with blistering in recessive dystrophic epidermolysis bullosa and that therapy with a clinically usable protease inhibitor was useful for the treatment of this disease.     

Dystrophic epidermolysis bullosa inversa: a case report

The inverse form of recessive dystrophic epidermolysis bullosa is a rare genodermatosis characterized by a smouldering course of integumental blistering with improvement of lesions in adulthood, preferential localizations of lesions in flexural areas, severe oral and esophageal mucosal involvement and nail dystrophy. We describe a 41-year-old patient showing all the typical features of this form of epidermolysis bullosa. Ultrastructural findings in specimens obtained from perilesional and healthy skin were similar to those usually observed in the Hallopeau-Siemens form of epidermolysis bullosa. The patient has been treated with phenytoin for a period of 9 months with considerable improvement of the skin manifestations.