Colchicine as a treatment option for inherited epidermolysis bullosa.

Squamous cell carcinoma and junctional epidermolysis bullosa

Digenic Inheritance in Epidermolysis Bullosa Simplex

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.

BackgroundInherited epidermolysis bullosa (EB) is a group of skin diseases characterized by blistering of the skin and mucous membranes.There are four major types of EB (EB simplex, junctional EB, dystrophic EB and Kindler syndrome) caused by different gene mutations. Dystrophic EB is derived from mutations in the type VII collagen gene (COL7A1), encoding a protein which is the predominant component of the anchoring fibrils at the dermal-epidermal junction.For the first time in literature, we have evaluated the presence of anti-skin autoantibodies in a wider cohort of patients suffering from inherited EB and ascertained whether they may be a marker of disease activity.MethodsSera from patients with inherited EB, 17 with recessive dystrophic EB (RDEB), 10 with EB simplex (EBS) were analysed. As much as 20 patients with pemphigus vulgaris, 21 patients with bullous pemphigoid and 20 healthy subjects were used as controls.Anti-skin autoantibodies were tested in all samples with the Indirect Immunofluorescence (IIF) method and the currently available ELISA method in order to detect anti-type VII collagen, anti-BP180 and anti-BP230 autoantibodies.ResultsThe mean concentrations of anti-type VII collagen autoantibodies titres, anti-BP180 and anti-BP230 autoantibodies were statistically higher in RDEB patients than in EBS patients.The sensitivity and specificity of the anti-type VII collagen ELISA test were 88.2% and 96.7%. The Birmingham Epidermolysis Bullosa Severity score, which is used to evaluate the severity of the disease, correlated with anti-skin autoantibodies titres.ConclusionsThe precise pathogenic role of circulating anti-skin autoantibodies in RDEB is unclear. There is a higher prevalence of both anti-type VII collagen and other autoantibodies in patients with RDEB, but their presence can be interpreted as an epiphenomenon.

A Rare Skin Disorder with Bacteremia in a Neonate.

Background: inherited epidermolysis bullosa is a group of genetic skin disorders caused by mutations in genes encoding structural proteins of epidermis and dermo-epidermal junction. Clinical manifestations are characterized by spontaneous or trauma-induced skin and/or mucosal blistering, and extensive wounds. Cell therapy is considered to be a perspective therapeutic approach in improving wound healing process.
 Aims: to assess safety and efficacy of human skin equivalent in the treatment of inherited epidermolysis bullosa patients
 Materials and methods: 7 patients (5 female and 2 male subjects from the age of 20 to 55) with inherited epidermolysis bullosa with different clinical subtypes were enrolled in the study: 3 patients with intermediate recessive dystrophic epidermolysis bullosa, 2 patients with severe recessive dystrophic epidermolysis bullosa, 1 patient with dominant dystrophic epidermolysis bullosa and 1 patient with junctional epidermolysis bullosa. Transplantation of composite allogeneic living skin equivalent comprising allogeneic keratinocytes and fibroblasts in low concentration (5 mg/ml) embedded within a type I collagen gel matrix was performed. The living skin equivalent was developed at N.K. Koltsov Institute of Developmental Biology. 19 erosions and ulcers with a surface area between 0,4 cm2 and 120 cm2 were evaluated. At day 14 clinical assessment was performed. To assess level of expression immunofluorescence antigen mapping was used.
 Results: at day 14 complete erosion closure was achieved in 10 (53%) erosions. 4 (21%) erosions reduced in size 75%. Size reduction between 25% and 75% was shown in a single (5%) case. No clinical efficacy was demonstrated in 4 (21%) cases. Collagen VII expression increased comparing to baseline level and accompanied clinical improvement.
 Conclusions: the obtained data showed clinical efficacy of topical treatment with living skin equivalent, although no statistically significant difference was seen between living skin equivalent and atraumatic non-adhesive dressings.
 Keywords: inherited epidermolysis bullosa, junctional epidermolysis bullosa, recessive dystrophic epidermolysis bullosa, erosions, healing, topical treatment.

Dear Editors, Inherited epidermolysis bullosa (EB) is a group of genodermatoses characterized by skin blistering, caused by mutations in different genes encoding proteins of the dermo-epidermal junction zone.1, 2 Disease severity ranges from localized subtypes with blisters restricted to acral regions, to severe subtypes with generalized blistering and subsequent scarring or atrophy of the skin. Patients with dystrophic EB pruriginosa (DEBp) suffer from highly pruritic papules and nodules, either localized on the lower legs, or disseminated, clinically resembling prurigo or lichenoid skin disorders.1 Pruritus appears to be a major issue for patients with EB and not only for those suffering from DEBp.3, 4 Specifically, more than 90% of individuals with dystrophic EB (DEB) and junctional EB (JEB), and around 70% of patients with EB simplex reported distressing pruritus with overall itch scores comparable with those of atopic dermatitis.4 The problems caused by itch are sleep disturbance and newly induced blisters due to scratching.4 An immune dysregulation is suggested by the presence of increased cytokines and IgE levels in these individuals.5 A recent publication highlighted a skewed Th2 immunological phenotype in DEBp.6 Subsequent reports described reduction of itch upon treatment with dupilumab, a monoclonal antibody blocking the interleukin 4 (IL4) receptor, in at least 13 cases of DEBp (Table 1).7-10 Dupilumab has been approved for treatment of atopic dermatitis and prurigo nodularis, and efficient off-label use of dupilumab has been described for several other dermatological indications.11 It appears to be highly efficient in treating pruritus of various etiologies, even without history of atopy.11, 12 Here we report on the outcomes of dupilumab treatment in a cohort of 13 patients (6 female, 7 men; mean age 29 years, min 6, max 78 years) with different EB subtypes, all suffering from severe pruritus. The EB subtypes were as follows: one case had EB simplex with plectin deficiency, two had intermediate JEB with laminin 332 deficiency, four had recessive DEB and six had dominant DEB. All patients had itch scores of above 7 (median 8; visual analogue score from 1–10). Itch, which caused new blisters due to scratching, was their most burdensome symptom. IgE levels were increased only in four of eight patients for whom this information was available (median 59 U/ml). Most patients had received different antipruritic treatments such as topical steroids of class II–IV, calcineurin inhibitors and/or antihistamines, or methotrexate combined with several rounds of UV treatments (patient 12), without any significant improvement (Table 1). We employed dupilumab with a loading dosage of 600 mg s.c., followed by 300 mg every 2 weeks. Eleven patients showed a rapid improvement of itch with subsequent amelioration of the underlying EB (Figure 1 and Table 1). The median itch VAS level after treatment decreased to 3. For example, patient 6 showed a significant reduction, both of itch, from VAS 10 before to 2 after dupilumab, and skin blistering. An increase of the intervals between injections to 4 weeks led to a worsening of his skin condition and the necessity of resuming treatment every 2 weeks. Although patient 1 experienced an initial improvement of the symptoms, the skin blistering worsened after the second dupilumab injection and the treatment was discontinued. Patient 13 had an episode of generalized pustular extremely itchy skin eruptions accompanied by fatigue after the second injection of dupilumab and treatment was discontinued. She refused a diagnostic skin biopsy. These lesions responded to systemic prednisolone, combined with topical treatment with class IV steroids. In our cohort, 11 of 13 patients perceived a benefit from treatment with dupilumab, irrespective of their EB subtype or age, suggesting that a broader spectrum of EB patients may benefit from this drug. Dupilumab was tolerated well by most, but not all, patients, while unspecific skin reactions occurred in two patients, leading to treatment discontinuation. Patients who tolerated dupilumab well experienced a significant improvement in skin condition, and they reported better sleep and improved quality of life. None of the patients showed signs of conjunctivitis. Our report shows that targeting Th2 inflammation with dupilumab is a valuable symptom-relief therapy for patients with all types of EB who suffer from severe, intractable pruritus. We thank the patients and their families. We also thank our fellow colleagues from the Department of Dermatology in Freiburg, who also took care of the patients presented here. Open access funding enabled and organized by Projekt DEAL. Nine.

Epidermolysis bullosa (EB) is a rare genetic mucocutaneous disorder characterized by epithelial fragility leading to blister formation on skin and mucous membranes with even minor mechanical trauma. Most EB oral health publications give fragmented information, focusing on only one oral health aspect or one EB type. The aim of this study was to expand the knowledge of the overall oral health status of individuals with dystrophic, junctional, and simplex EB. A comparative multicenter study, including a control group, and based on questionnaires and clinical examinations, was undertaken in three EB expert centers. Most EB (90.2%) participants brushed their teeth at least once a day despite the pain. The prevalence of enamel defects and caries experience did not differ between the 42 EB participants and the 42 age-/sex-matched healthy controls. Gingival inflammation unrelated to dental plaque accumulation was found in EB participants. Blisters, erythema, and erosion/ulceration mainly involved gingiva, buccal mucosa, lips, and palate, with different topographic patterns according to EB type. EB patients whatever the age showed a similar lesion distribution. Simplex and dystrophic EB patients under 12 years old displayed higher lesion severity than junctional EB ones. Only dystrophic type exhibited microstomia and ankyloglossia. Oral health status seemed to benefit from a close collaboration between dental practitioner and dermatologist, and from regular dental examination, starting at a young age and with a focus on prevention. The new appreciation of oral health involvement highlighted by this study is essential for EB patients care, regarding comorbidities and quality of life.

To accurately determine the frequency with which complications arise in the ears, noses, and throats of patients with inherited epidermolysis bullosa (EB) as well as the cumulative risk of tracheolaryngeal stenosis or stricture. Cross-sectional study (3,280 patients) with a nested, randomly sampled longitudinal subcohort (n=450), representing data collection, stratified by major EB subtype, of the National EB Registry, an epidemiologic project focused on enrolling all EB patients within the continental United States from 1986 to 2002, to permit generalization of findings to the entire American EB population. Systematic epidemiologic case finding and data collection were performed throughout the continental United States, followed by subclassification of patients by EB subtype. ENT complications were quantified via contingency tables (as frequencies) and lifetable analyses. Frequencies of surgical procedures were also determined. The most important clinical ENT complication in inherited EB was tracheolaryngeal stenosis or stricture, arising during early childhood and primarily within infants and children with junctional EB (JEB) (cumulative risk of 39.8% and 12.8% in Herlitz and non-Herlitz JEB, respectively, by ages 6 and 9). Other uncommon complications included chronic otitis media, chronic otitis externa, and hearing loss. Given the potential risk for sudden airway occlusion and death, meticulous surveillance by a pediatric otolaryngologist is a critical part of the overall management of infants and children with EB, especially those with JEB and two rare subtypes of generalized EB simplex. Elective tracheostomy should be considered in EB infants and children with evidence of airway embarrassment.

Inherited epidermolysis bullosa (EB) is a group of genodermatoses with considerable clinical and genetic heterogeneity. Clinical diagnosis of the EB subtypes is frequently imprecise and requires confirmation with genetic testing. There is still limited study using genetic testing to identify EB subtypes in Indonesia. This study aims to identify the pathogenic variants of inherited EB patients at the Department of Dermatology and Venereology, Universitas Padjadjaran-Dr Hasan Sadikin General Hospital in Bandung, West Java, Indonesia and to describe the correlation between the phenotype and genotype of our patients. Twelve patients clinically diagnosed with EB were included in this study. Genetic testing was performed in collaboration with KK Women's and Children's Hospital, Singapore. Pathogenic variants were identified in the COL7A1 gene in seven patients, namely Dominant Dystrophic EB (DDEB) with mutation types c.5945G>T, c.6218G>A, Recessive Dystrophic EB (RDEB) c.2005C>T, c.6081dup, c.1268C>T, c.1784C>T which are all known mutations. Novel mutations were found in the COL7A1 gene in two patients namely DDEB c.6253G>T and RDEB c.6740C>T. Two EB Simplex (EBS) patients showed mutation KRT14 gene as c.356T>C, c.373C>T which are known mutation. In addition, a novel mutation in LAMA3 gene c.2649del was found in one Junctional EB (JEB) patient. The molecular diagnoses of 12 Indonesian EB patients were identified, of which three were novel pathogenic variants. Concordance between the initial clinical diagnosis and genetic testing was only 33%. This demonstrated the importance of early genetic testing for accurate diagnosis, prognostication, management and genetic counselling.

BackgroundInherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by exacerbated skin and/or mucosal fragility and blister formation after minor mechanical trauma. Level of cleavage in the skin, clinical features with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy and/or gene involved, type(s) of mutation present and sometimes specific mutation(s), allow to define the EB type and subtype. This family of genodermatoses exposes patients to several complications, cutaneous squamous cell carcinoma (cSCC) being the most severe of them.ObjectiveThe aim of this systematic review was to document patients with EB who developed cSCC.MethodsA systematic literature search was performed, from inception to March 2014, using Medline, Embase, Cochrane and ClinicalTrials.gov databases. Only articles published in English and French were selected. The diagnosis of EB had to be confirmed by EM and/or IFM and/or mutation analysis, while cSCC had to be confirmed by histological analysis.ResultsOf 167 references in the original search, 69 relevant articles were identified, representing 117 cases. cSCCs were identified in all types of EB, though predominantly in recessive dystrophic EB (RDEB) forms (81 cases (69.2 %)). The median age at diagnosis was 36 years old (interquartile range (IQR), 27-48 years and range, 6-71 years) for all forms. Of those with measurements in the literature (88 cases (75.2 %)), tumor size was greater than 2 centimeters in 52 cases (59.1 %). The histopathological characteristics were specified in 88 cases (75.2 %) and well-differentiated forms predominated (73.9 %). No conclusion could be drawn on the choice of surgical treatment or the management in advanced forms.LimitationsThis study was retrospective and statistical analysis was not included due to various biases. This study design did not allow to infer prevalence, nor EB subtype risk for cSCC occurrence.ConclusionsOur study correlated with historical data shows that most of the cSCCs occurred in subjects with the RDEB subtype, however reports also show that cSCCs can present in any patients with EB. The first signs of cSCC developed at a younger age in EB patients than in non-EB patients. Interestingly, the cSCC duration, before its diagnosis, was shorter in individuals with RDEB than with junctional EB (JEB) and dominant dystrophic EB (DDEB).This study further emphasizes the importance of regular monitoring of EB patients, particularly with the RDEB subtype as they developed cSCC at a younger age.

BACKGROUND: Epidermolysis bullosa (EB) is a rare disease characterized by blistering and erosion of the skin and mucus membranes in response to minor external forces. Research focusing on daily skin care in EB patients is sparse. Two international clinical practice guidelines (CPGs) have been published in English, but they have not yet been translated into other languages such as Japanese. Therefore, their recommendations have not been adapted to multiple geographic regions in the world. This multiple case series describes our approach to the skin care of 3 Japanese patients with EB. RESULTS: All 3 patients were diagnosed with genetic EB. A 13-year-old male patient had dominant dystrophic EB and suffered skin breakdown covering nearly 1% to 6% of his total body surface area (TBSA) during a 21-week data collection period. A 3-year-old male patient had EB simplex; he suffered skin breakdown covering 2% to 40% of his TBSA during a 36-week data collection period. The third case was a 5-year-old male patient with recessive dystrophic EB who experienced skin breakdown covering 2% to 40% of his TBSA during a 35-week data collection period. Blisters were punctured daily and treated with a soft silicone dressing. Daily application of moisturizers was undertaken to prevent the skin from drying out and itching. CONCLUSION: Our experience suggests that application of published CPGs promoted wound healing. Nevertheless, given the nature of the disease, a complete resolution to an individual's vulnerability to skin lesions even with relatively minor trauma remains elusive. Additional research is needed to explore interventions for skin and ulcer care, along with symptom management, including pain and pruritus.

Epidermolysis bullosa (EB) represents a group of rare, genetically heterogeneous disorders characterized by the formation of blisters and erosions of the skin and mucous membranes in response to minor mechanical trauma. EB is classified into four major types-EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, each associated with mutations in specific genes that encode structural proteins essential for skin integrity. The clinical spectrum of EB ranges from mild forms, presenting with localized skin involvement, to severe variants that lead to widespread blistering, mutilating scarring, and significant morbidity. The pathophysiology of EB is complex, involving disruptions in the adhesion between the dermis and epidermis, leading to compromised structural stability of the skin. Current therapeutic strategies focus on symptom management, including wound care, infection prevention, and pain control, as no definitive cure exists. Advances in gene therapy, stem cell therapy, and protein replacement therapy hold promise for future treatment paradigms. This review aims to elucidate the molecular underpinnings, clinical manifestations, and emerging therapeutic approaches for EB, providing a comprehensive overview for clinicians and researchers engaged in the management and study of this challenging condition.

Both epidermolysis bullosa (EB) and nonischemic cardiomyopathy (CM) are rare clinical entities. An association between EB and dilated CM (DCM) has been appreciated for at least 25 years, but a common mechanism of disease has not emerged.1 In this report, we present a patient with EB and left ventricular noncompaction (LVNC), a newly recognized type of CM.2 EB is a broad group of diseases characterized by skin fragility and blistering. Dystrophic EB occurs as either a dominantly or recessively inherited (RDEB) type, with scarring and blistering in the sublamina densa layer of the skin. DCM has been described in several patients with RDEB,1 but the relationship between these conditions has not been understood. For this reason, RDEB patients at our EB Center are screened yearly with echocardiograms. Outcomes for patients with RDEB are generally determined by comorbidities, and treatment currently focuses on symptomatic management; however, active areas of research include gene, protein, and stem cell therapies. There …

Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course. Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB. A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard. The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations. Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases.