Autosomal Recessive Dystrophic Epidermolysis Bullosa Research Articles

Estimated Spending on Beremagene Geperpavec for Dystrophic Epidermolysis Bullosa

New gene therapies can offer substantial benefits to patients, particularly those with rare diseases who have few therapeutic options. In May 2023, the US Food and Drug Administration (FDA) approved the first topical gene therapy, beremagene geperpavec (B-VEC), for treating both autosomal recessive and autosomal dominant dystrophic epidermolysis bullosa (DEB). However, FDA approval was based on limited data in patients with autosomal dominant disease, even though they comprise approximately 50% of all DEB cases. To estimate projected spending in the US on B-VEC therapy for treating autosomal recessive and autosomal dominant DEB. This economic evaluation used data from the National Epidermolysis Bullosa Registry to estimate the current population of US patients with autosomal dominant and autosomal recessive DEB, with the aim of estimating US spending on B-VEC therapy from an all-payers perspective during 1- and 3-year periods after FDA approval. A base-case cost of $300 000 per patient per year was assumed based on a report from the manufacturer (Krystal Biotech). Treatment with B-VEC. Estimated overall spending on B-VEC in the first year and over a 3-year period after FDA approval. Several prespecified sensitivity analyses with different assumptions about the eligible patient population and the cost of therapy were performed, and lifetime total costs of treatment per patient were estimated. The estimated number of US patients with DEB who were eligible for treatment with B-VEC in the first year after FDA approval was 894. The estimated total expenditure for B-VEC therapy was $268 million (range, $179 million-$357 million). Over a 3-year period, estimated spending was $805 million (range, $537 million-$1.1 billion). Estimated lifetime total costs per patient were $15 million (range, $10 million-$20 million) per patient with autosomal recessive DEB and $17 million (range, $11 million-$22 million) for patients with autosomal dominant DEB. Results of this economic evaluation suggest that the FDA's broad indication for the use of B-VEC in treating both autosomal recessive and autosomal dominant DEB will have significant implications for payers.

COL7A1 Homozygous Arg2471Ter Mutation Leads to the Severe Phenotype of Autosomal Recessive Dystrophic Epidermolysis Bullosa in the Fetus

Introduction: Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a rare disease with an early onset and severe phenotype. The pathogenic mechanism associated with mutations in the gene COL7A1 has been widely studied and many related cases have been reported, but prenatal cases are rare. Here, we report the prenatal diagnosis of a sporadic case of RDEB. Methods: In this study, the fetus with abnormal skin manifestations, which were determined during a prenatal ultrasound, was evaluated based on the ultrasound and autopsy findings and the results of molecular diagnostic analyses. Samples of the fetus and the parents were subjected to trio whole-exome sequencing, and in vitro functional analyses were conducted to analyze the pathogenicity of the detected mutation. Results: During the conventional prenatal ultrasound, the fetus showed abnormal epidermal lines on both lower limbs and the plantar skin as well as an interruption of the continuity of the lateral epidermal line below the ankle of the right lower limb. Gene testing revealed a homozygous nonsense mutation in COL7A1 (c.7411C>T, p.Arg2471Ter), which gave rise to RDEB in the fetus. Further, the results of the in vitro functional experiments confirmed that the mutation might lead to protein degradation. Conclusion: Most prenatal diagnoses of RDEB are the result of targeted molecular analyses carried out based on family history, and prenatal ultrasound reports of severe RDEB phenotypes are extremely rare. Our case suggests that the observation of abnormal epidermal lines should be given due consideration during prenatal diagnosis, as they may be a sign of possible epidermolysis bullosa.

Participatory co-design of patient-reported outcome indicators and N-of-1 evaluation of a dressing glove for Epidermolysis bullosa.

In autosomal recessive dystrophic Epidermolysis bullosa, repeat blistering results in finger webbing and severe contractures of the hands. The aim of this study was to codesign patient-reported outcome indicators for hand therapy with patients, carers and clinicians, and use these to proof-of-concept test a novel dressing glove for recessive dystrophic Epidermolysis bullosa, with cost analysis. Qualitative interviews and focus groups with patients and carers generated content for the indicators. Validity and reliability were established through expert review, piloting and consensus between patients, carers and clinicians. The indicators were self-reported by patients before and while wearing the dressing glove in an N-of-1 study. Time for dressing changes and use of conventional products were also self-reported. A total of 11 indicators were initially generated from the thematic analysis. Expert review, piloting and consensus involved six patients, five carers and eight clinicians (total n=19). Participants agreed 14 indicators, covering hand skin condition (n=4), webbing between the digits (n=4), experiences of wearing and changing dressings (n=2), hand function (n=2), wrist function (n=1) and hand pain (n=1). In Phase 3, 12 patients scored indicators before wearing the gloves and four patients completed scoring while wearing the gloves. Statistically significant improvements between pre-glove and with-glove periods were found for most participants' experience scores. Skin appearance also improved for most participants. The indicators generated useful data, differentiation between scores and participants demonstrating proof-of-concept for patients with recessive dystrophic Epidermolysis bullosa who could wear the dressing gloves. The indicators are being used in routine practice, supporting clinical follow up, commercialisation and regulatory governance of the dressing glove.

Transplantation of autologous single hair units heals chronic wounds in autosomal recessive dystrophic epidermolysis bullosa: A proof-of-concept study

Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is characterized by recurrent mucocutaneous blistering with non-healing ulcers which are often complicated by squamous cell carcinoma (SCC). Despite having as high as 80% death rate from SCC, RDEB still does not have an effective treatment. We report on the efficacy of single follicular unit extract (FUE) grafting to heal chronic ulcers of intermediate RDEB in a 54-year-old woman with extensive chronic wounds covering around 30% of the body surface area. On Day 17 post first graft session, the area of treated ulcers on her right upper back was reduced by 80%. Immunofluorescence study revealed positive type VII collagen expression along the epidermal and follicular basement membrane zone in the donor and recipient sites. A few grafted follicles continued to grow hair on the recipient sites. A total of 360 FUEs were grafted in nine sessions over five years, resulting in healing of most treated ulcers and reduced significantly her time for daily wound dressing. Importantly, FUE grafting using patient's own scalp follicles does not require any laboratory manipulation. It is safe and easy to perform. Autologous follicular grafting appears efficacious for healing of recalcitrant wounds and provides an innovative solution for RDEB patients with such wounds.

Neonatal epidermolysis bullosa: lessons to learn about genetic counseling

Background Epidermolysis Bullosa (EB) is a heterogeneous group of congenital blistering diseases that usually presents in the neonatal period. EB is classified into three major categories, each with many subtypes based on the precise location at which separation or blistering occurs, namely epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB) and dystrophic epidermolysis bullosa (DEB).Methods We describe genetics of neonatal EB in Hong Kong.Results Two neonates of consanguineous Pakistani parents had the EB-Pyloric Atresia (EB-PA) variant. One had a 4 kb homozygous deletion of exon 19–25 of the ITGB4 gene, and the other with only a histopathological diagnosis. Both died of sepsis in infancy. Aberrant COL7A1 mutations in the dominant and recessive EB were described. Genetic analysis, together with histopathological classification is important to aid prognosis and counseling. JEB and EB-PA are associated with consanguinity and mortality during infancy. Morbidity and prognosis of the autosomal dominant DEB are optimistic. The autosomal recessive DEB is more severe, with neonatal onset and recurrent blistering. It is also associated with chronicity and malignant changes when the child reaches adulthood.Conclusion Exact genetic diagnosis aids in counseling of the family concerning the prognosis in the affected child and the risk of affected children in future pregnancies.

MANAGING ATOPIC DISEASE IN A PATIENT WITH EPIDERMOLYSIS BULLOSA

Introduction Managing atopic diseases, such as severe or refractory eczema, can be challenging in otherwise uncomplicated patients. Treating patients, especially young children, with additional chronic skin conditions presents unique challenges. Case Description A 20-month old male presents for evaluation of eczema and environmental allergies with underlying diagnosis of autosomal recessive dystrophic epidermolysis bullosa (DEB), pathogenic variants in COL7A1 gene. After diagnosis of DEB, eczematous lesions (confirmed by dermatologist as eczema) were noted around age 3 months. Initially a food trigger was suspected, but elimination diet did not resolve flares. Worsening eczema was noticed with environmental triggers at times of rhinitis and conjunctivitis symptoms and with weather changes. His skin care regimen is extensive and includes dressings on exposed skin below the neck for his DEB, with addition of topical tacrolimus, topical corticosteroids, oral antihistamines, and emollient use for his eczema, though he still flares. Discussion DEB is a skin and mucous membrane disorder leading to fragility, blistering, and scarring. Children with DEB are not at increased risk of atopic diseases, but they can coexist, which presents unique diagnostic and treatment challenges. With this patient, his atopy leads to significant discomfort and pruritus, with itching leading to blister formation and scarring. Patient had symptom improvement with addition of fexofenadine and montelukast, but topical regimens remain challenging due to his skin fragility. If feasible, future directions may include compassionate use of a biologic like dupilumab.

Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa simplex (DEB) is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB) is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES). Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa simplex (DEB) is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB) is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES). Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

The Frequency of Signs of Meibomian Gland Dysfunction in Children with Epidermolysis Bullosa

To determine the frequency of meibomian gland dysfunction (MGD) in children with epidermolysis bullosa (EB). Hospital-based cross-sectional study. One hundred five children with different forms of EB. Prospective ophthalmic examination of children with EB presenting over seventeen months including meibomian gland assessment using a recognized classification. Frequency of MGD. One hundred five children were recruited, 8.6% with junctional EB, 34.3% with simplex EB, 34.3% with autosomal recessive dystrophic EB, and 22.9% autosomal dominant dystrophic EB. Mean age was 7.42 years (range, 0.08-17.75 years). Ninety-two children (87.62%) demonstrated 1 or more features of MGD. Most children with EB exhibit signs of MGD. To the best of our knowledge, this is the first prospective ocular surface evaluation in children with EB to include lid margin evaluation using a recognized classification system. Our findings help explain some of the ocular surface anomalies seen in children with EB.

Induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of genetically inherited skin disorders affecting nearly 1 to 3 of every 100,000 live births and almost 500,000 individuals worldwide (1). Autosomal recessive dystrophic EB (RDEB) is an aggressive EB subtype (approximately 25% of EB cases), caused by COL7A1 gene mutation encoding type VII collagen and resulting in binding defect of epidermis to dermal tissue, excessive skin and mucosal fragility, blistering and scarring. Lesions occur below the basement membrane zone in the upper part of the dermis. Until today no definite therapy is available and patients suffering from RDEB are managed conservatively avoiding skin damage and aiming in improve quality of life and reducing the risk of developing complications, such as infection and malnutrition, or undergo surgical or minimal invasive palliative procedures (2,3). Current research strategies include protein, gene and molecular therapies (4-6). In their article “Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa” Sebastiano et al. propose an innovating cell therapy for RDEB treatment, by developing a state of the art protocol of genetically repaired induced pluripotent stem cells (iPSCs) as to generate sheets of normal skin tissue to treat affected skin areas (7). Moreover, as numerous stem cells are needed in order to cover the affected surface area, authors outline the necessity for creating personalized iPSCs banks as to provide a constant long-term iPSCs source.

Dilated cardiomyopathy associated with dystrophic epidermolysis bullosa: role of micronutrient deficiency?

Autosomal recessive dystrophic epidermolysis bullosa (DEB) is a chronic skin disorder characterized by widespread bullous formation, erosions, and scar formation. There have been reports of dilated cardiomyopathy and death in patients with DEB. The pathogenesis of cardiomyopathy in DEB remains uncertain, but some drugs, viral infections, iron loading, micronutrient deficiencies such as selenium and carnitine have been implicated. A 16-year-old boy who was followed-up from birth with the diagnosis of DEB presented with respiratory distress and heart failure symptoms of two-week history and early fatigue within the past year. Etiological evaluation showed a low plasma selenium level. Echocardiographic examination yielded the diagnosis of dilated cardiomyopathy. Findings of viral serology tests and metabolic screening were normal. Selenium replacement and anticongestive treatment were initiated, which led to partial improvement in cardiac functions. The authors draw attention to the possible role of micronutrient deficiency in the development of cardiomyopathy in patients with DEB.

The eye in epidermolysis bullosa

AIMSTo describe the ophthalmic findings in a large cohort of epidermolysis bullosa (EB) patients managed in one large specialist centre.METHODSA case note review of consecutive patients seen at Great Ormond...

Hemidesmosomes Show Abnormal Association with the Keratin Filament Network in Junctional Forms of Epidermolysis Bullosa

Junctional epidermolysis bullosa is a group of hereditary bullous disorders resulting from defects in several hemidesmosome-anchoring filament components. Because hemidesmosomes are involved not only in keratinocyte-extracellular matrix adherence, but also in normal anchorage of keratin intermediate filaments to the basal keratinocyte membrane, we questioned whether this intracellular function of hemidesmosomes was also perturbed in junctional epidermolysis bullosa. We used quantitative electron microscopic methods to assess certain morphologic features of hemidesmosome-keratin intermediate filaments interactions in skin from normal subjects (n = 11) and from patients with different forms of junctional epidermolysis bullosa (n = 13). In addition, skin from patients with autosomal recessive epidermolysis bullosa simplex with plectin defects (n = 3) or with autosomal recessive dystrophic epidermolysis bullosa (n = 4) were included as controls. Values were expressed as a percentage of the total number of hemidesmosomes counted. In normal skin 83.3% +/- 3.3 (SEM) hemidesmosomes were associated with keratin intermediate filaments and 90.1% +/- 1.9 had inner plaques. In Herlitz junctional epidermolysis bullosa (laminin 5 abnormalities, n = 4) these values were reduced to 45.3% +/- 11.5 (p < 0.001; analysis of variance) and 50.3% +/- 12.8 (p < 0.001), respectively. In junctional epidermolysis bullosa with pyloric atresia (alpha6beta4 abnormalities, n = 3) the values were also reduced [41.8% +/- 7.0 (p < 0.001) and 44.5% +/- 5.7 (p < 0.001), respectively]. In the non-Herlitz group (laminin 5 mutations, n = 3) the counts were 66.7% +/- 7.1 (p > 0.05) and 70.5% +/- 8.5 (p < 0.05), and in skin from patients with bullous pemphigoid antigen 2 mutations (n = 3) the counts were 54.3% +/- 13.8 (p < 0.01) and 57.1% +/- 13.9 (p < 0.01). In epidermolysis bullosa simplex associated with plectin mutations the values were 31.9% +/- 8.9 (p < 0.001) for keratin intermediate filaments association and 39.9% +/- 7.1 (p < 0.001) for inner plaques. Findings in recessive dystrophic epidermolysis bullosa patients' skin were indistinguishable from normal control skin with inner plaques (90.5% +/- 2.5) and keratin intermediate filaments attachment (86.3% +/- 2.1). These findings suggest that the molecular abnormalities underlying different forms of junctional epidermolysis bullosa appear to affect certain critical intracellular functions of hemidesmosomes, such as the normal connections with keratin intermediate filaments. This may have important implications for the maintenance of basal keratinocyte integrity and resilience in junctional epidermolysis bullosa.

Fatal cardiomyopathy in dystrophic epidermolysis bullosa

Two unrelated children with autosomal recessive dystrophic epidermolysis bullosa (RDEB) developed fatal dilated cardiomyopathy. Both were malnourished and had severe growth problems. We believe that the most likely cause for the cardiomyopathy is a micronutrient deficiency, most probably selenium deficiency, since the serum selenium level was found to be reduced in the case in whom we measured this, and in 14 of 25 other children with dystrophic epidermolysis bullosa. Echocardiographic screening of 18 other patients revealed no evidence of cardiomyopathy. We recommend careful attention to nutrition, with prospective monitoring of vitamins and micronutrients including selenium and carnitine, and regular echocardiographic screening of patients with severe RDEB.

Anesthésie pour chirurgie de la main chez des patients atteints d'épidermolyse bulleuse

Epidermolysis bullosa is a rare genetic disease, characterized by the formation of bullae in the skin and squamous epithelium following minimal trauma. The majority of surgical indications specific to this disease concern autosomal recessive dystrophic epidermolysis bullosa (RDEB). Hand surgery is one of the fields of surgery involved. The cicatricial course of the lesions results in retraction and pseudosyndactylization of the fingers, sometimes leading to complete destruction of the hand. Since 1988, we have treated 23 patients, including 11 children under the age of 8 years and weighing less than 20 kg. 185 procedures were performed by two anaesthetists, using regional plexus blocks in 157 cases and general anaesthesia in only 28 cases. This series is comparable in number, to that reported by the London team, which prefers general anaesthesia. Regional anaesthesia has been previously used, but only following general anaesthetic induction. Our approach, based on the experience of a hand surgery center, is in marked opposition with this standard paediatric approach. Regional anaesthetic techniques, particularly in the upper limb, present many advantages in addition to their feasibility in small children: efficacy, simplicity, postoperative analgesia, and outpatient comfort. In the context of the specificities and difficulties encountered in the management of these patients suffering from epidermolysis bullosa, the authors demonstrate the value of first-line regional anaesthesia, even in very young children (less than 3 years). The presence of a parent in the operating room is a valuable aid, which is still insufficiently used, but which should be used with conviction for the benefit of all concerned.

Oral involvement of recessive dystrophic epidermolysis bullosa inversa

The inversa subtype of autosomal recessive dystrophic epidermolysis bullosa (EBDR-I) is a rare variant characterized by lesions involving primarily the flexural areas of the body. The purpose of this investigation was to characterize the oral manifestations of this unusual dermatologic condition. Ten individuals having EBDR-I were evaluated and compared with an age and sex-matched population of unaffected individuals that served as controls. The diagnosis of EBDR-I was confirmed by skin biopsy that demonstrated tissue separation below the lamina densa and the clinical presentation of blister formation that typically localized to flexural areas. There was clinical variability in the severity and distribution of skin involvement; however, none of the affected individuals demonstrated pronounced digital webbing, severe generalized blistering or growth retardation characteristic of the Hallopeau-Siemens form of EBDR. Oral involvement was seen in all cases with ankyloglossia, loss of tongue papillae and obliteration of the oral vestibule between the lips and gingiva being typical. The oral opening was significantly reduced in older EBDR-I individuals compared with matched controls, confirming that acquired microstomia is a characteristic of EBDR-I. The teeth were not clinically abnormal or malformed and showed no evidence of generalized enamel hypoplasia. Despite this, the prevalence of dental caries in EBDR-I individuals was significantly higher than the control group. The inversa form of EBDR presents with oral findings that are similar but generally milder than those seen in the Hallopeau-Siemens variant of EBDR.

Epidermolysis bullosa: Recent advances in understanding pathogenetic mechanisms

Epidermolysis bullosa (EB) is a group of mechanobullous diseases of the skin and mucous membranes characterized by the development of blisters and erosions following minor trauma. Hereditary EB exists in four major patterns: (1) intraepidermal blistering in autosomal dominant EB simplex; (2) junctional blistering in autosomal recessive junctional EB; (3) dermal blistering in autosomal dominant dystrophic EB; and (4) dermal blistering in autosomal recessive dystrophic EB. Electron microscopic examination of the skin is the current standard for diagnosis, although a number of immunologic reagents have been developed that are diagnostic tools and probes to pathogenesis. Particularly important are the antibody probes that have been developed for use in junctional and dystrophic forms of EB, since several of the monoclonal antibody preparations also confer at least some information about the likely genetic pattern and prognosis. Antibody preparations have also been used to screen complementary DNA (cDNA) expression libraries for clones representing candidate genes in EB. In EB simplex, mutations in the keratin 14 gene have been discovered. Since keratin 14 combines with keratin 5 to form a heterodimer, the existence of these mutations results in poor keratin filament formation in vitro. In recessive junctional EB, antibody staining patterns suggest involvement of the proteins of the anchoring filaments, such as BM-800/nicein. A partial cDNA clone representing one of the subunits of BM-800/nicein has been developed, and this protein represents an isoform of laminin, suggesting the existence of a family of laminin-like molecules that are important for adhesion of epidermis in the basement membrane zone of the skin. In dominant dystrophic and recessive dystrophic EB, often there are decreased numbers and abnormal appearance of the anchoring fibrils suggesting involvement of type VII collagen. Genetic linkage has been established to the type VII collagen gene in dominant dystrophic EB families. In recessive dystrophic EB, abnormalities in anchoring fibrils may be due to mutation(s) in the type VII collagen gene and/or due to excessive degradation by increased amounts of collagenase. Spontaneous, transgenic, and xenograft models of EB exist. Among the spontaneous models is recessive dystrophic EB in white alpine sheep, which show no staining for type VII collagen in the skin. A new xenograft model of recessive dystrophic EB has also been developed using EB skin grafted onto severe combined immunodeficient mice. A transgenic model has been developed for the herpetiform type of EB simplex resulting from the insertion of a truncated form of the keratin 14 gene.

Intraepidermal collagen type VII in dystrophic epidermolysis bullosa: report of five new cases

The presence of intraepidermal collagen type VII has recently been used to define a subgroup of patients with mild dystrophic epidermolysis bullosa (DEB). This subgroup demonstrates virtual resolution of blistering during infancy despite often severe neonatal blistering. Using the antibody LH7.2, we have detected intraepidermal collagen type VII in five cases with DEB. These represent a much wider spectrum of clinical features and of intraepidermal and basement membrane zone (BMZ) staining patterns. Only one of our cases had features consistent with reported cases. Sequential skin biopsies from this case showed a marked change towards normal within 6 months of birth, paralleling the clinical improvement. The other four cases had sparse epidermal deposits of collagen type VII and included an affected foetus with autosomal recessive DEB. These findings suggest that the frequency of intraepidermal LH7.2 in DEB may be much higher than previously thought. The presence of abundant intraepidermal collagen type VII is of prognostic significance and can disappear over months. We recommend that biopsies of infants suspected of having EB are taken during the neonatal period.

Squamous cell carcinoma in epidermolysis bullosa. Treatment with systemic chemotherapy

Dystrophic epidermolysis bullosa is associated with a high incidence of cutaneous squamous cell carcinoma. Despite aggressive surgical treatment, metastases occur frequently, and survival is generally poor. Chemotherapy for advanced disease has usually been avoided because of the potential for severe cutaneous toxicity. Two patients with autosomal recessive dystrophic epidermolysis bullosa and advanced squamous cell carcinoma are described. Both received cisplatin-based systemic chemotherapy without significant toxicity.