CLINICAL MANAGEMENT FOR EPIDERMOLYSIS BULLOSA DYSTROPHICA

Inherited epidermolysis bullosa: An update and suggested dental care considerations

To summarize the contemporary scientific evidence available regarding restorative dental treatment in patients with Amelogenesis imperfecta (AI). An electronic literature search was conducted using the search term "Amelogenesis imperfecta" and the PubMed/MEDLINE database as well as Google Scholar. Prospective and retrospective clinical studies that investigated the outcome of direct and/or indirect dental restorative treatment in patients with AI, were published in English, and had an observation time of at least 1 year were included in this review. The articles identified were screened and analyzed by two reviewers according to inclusion and exclusion criteria in three review rounds. Six prospective or retrospective clinical studies analyzing longevity and complications associated with dental restorative treatment in patients with AI met the inclusion criteria. Extracted data suggest that in patients with AI, indirect restorations feature superior predictability and longevity than direct restorations. As endodontic complications were infrequently observed and periodontal parameters regularly improve with the insertion of indirect restorations, dental treatment in patients with AI should focus on indirect restorations as soon as possible. While adhesive bonding techniques to enamel surfaces in patients with AI feature merely limited predictability and longevity and as the available data is scarce, further laboratory and clinical studies should be performed to investigate the performance of minimally invasive indirect restorations bonded to enamel in patients with AI. Scientific evidence indicates that indirect restorations should be preferred over direct restorations in patients with AI.

Squamous cell carcinoma and junctional epidermolysis bullosa

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.

BackgroundInherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by fragility and blistering of skin and mucous membranes. Clinical features combined with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy allow to define the EB type and subtype. Molecular diagnosis is nowadays feasible in all EB subtypes and required for prenatal diagnosis. The extent of skin and mucosal lesions varies greatly depending on EB subtype and patient age. In the more severe EB subtypes lifelong generalized blistering, chronic ulcerations and scarring sequelae lead to multiorgan involvement, major morbidity and life-threatening complications. In the absence of a cure, patient management remains based on preventive measures, together with symptomatic treatment of cutaneous and extracutaneous manifestations and complications. The rarity and complexity of EB challenge its appropriate care. Thus, the aim of the present study has been to generate multicentre, multidisciplinary recommendations on global skin care addressed to physicians, nurses and other health professionals dealing with EB, both in centres of expertise and primary care setting.MethodsAlmost no controlled trials for EB treatment have been performed to date. For this reason, recommendations were prepared by a multidisciplinary team of experts from different European EB centres based on available literature and expert opinion. They have been subsequently revised by a panel of external experts, using an online-modified Delphi method to generate consensus.ResultsRecommendations are reported according to the age of the patients. The major topics treated comprise the multidisciplinary approach to EB patients, global skin care including wound care, management of itching and pain, and early diagnosis of squamous cell carcinoma. Aspects of therapeutic patient education, care of disease burden and continuity of care are also developed.ConclusionThe recommendations are expected to be useful for daily global care of EB patients, in particular in the community setting. An optimal management of patients is also a prerequisite to allow them to benefit from the specific molecular and cell-based treatments currently under development.

Epidermolysis Bullosa: The Expanding Mutation Database

Epidermolysis bullosa (EB) is a group of rare congenital genetic conditions that result in painful blistering of the skin and mucous membranes, which occur with minor trauma or friction. There are many types and subtypes of EB that need to be distinguished, as the management and prognosis of each can vary significantly. We aim to perform an up-to-date literature review on congenital EB for healthcare providers in pediatrics. We performed a review of existing literature in the English language on EB via PubMed Clinical Queries, using key words such as "epidermolysis bullosa", "congenital" and "children". We reviewed EB based on the following subheadings: epidemiology, diagnosis, therapy, prognosis, and clinical prediction guidelines. EB is due to mutation in a number of genes, some types are autosomal dominant while others are autosomal recessive. The underlying mechanism is a defect in attachment between or within the epidermis and dermis of the skin. There are four main types: epidermolysis bullosa simplex, dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, and Kindler syndrome. The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing. The severity of EB can range from mild to fatal. Severe complications may arise in some EB types and subtypes within the eye, ear, nose, upper airway, gastrointestinal and genitourinary tracts. There is no cure for the condition to date. Optimal management must be multidisciplinary, and involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications. EB presents in different forms. Treatment is supportive. The prognosis of milder forms is good. Children severely affected with EB and their families live a misery life with impaired quality of life. Health care workers must be aware of the suffering in these families and proactively support them.

Epidermolysis Bullosa (EB) is a rare genetic disorder characterized by fragile skin that blisters and tears easily, leading to significant morbidity and mortality. Depending on the specific genetic mutations and the proteins involved, EB can be classified into several subtypes whose molecular complexity is compounded by the variability in mutation types (missense, nonsense, insertions, deletions), their locations within the genes, and the resultant effects on protein function. This systematic review aimed to identify and synthesize available evidence on wound healing interventions and the nutritional profile of children diagnosed with EB. A comprehensive search yielded 28 articles, including 21 clinical trials and seven observational studies, encompassing 994 patients with various EB subtypes. The majority of studies described subtypes such as Simplex EB (EBS), Junctional EB (JEB), Dystrophic EB (DEB), and EB Kindler. The primary interventions for wound healing included dressings with collagen, biocellulose, and various topical creams. Nutritional assessment was limited, with only six studies examining nutritional status, predominantly through anthropometry and dietary intake analysis. Subgroup analyses indicated higher malnutrition rates among patients with DEB compared to JEB. The review underscores the importance of addressing wound healing and nutritional challenges in EB management. Further research is needed to explore effective interventions and optimize care for this vulnerable population.<strong>Keyword</strong><strong>s</strong>Nutrition; pediatrics; wound healing; epidermolysis bullosa

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.

Eye involvement in inherited epidermolysis bullosa: Experience of the National Epidermolysis Bullosa Registry

Epidermolysis bullosa (EB) is a severe hereditary disease characterized by defective epithelial adhesion causing mucocutaneous fragility. The major types are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and more than 35 EB subtypes. Another very rare type of EB is Kindler EB (KEB). Clinically, it is a very heterogeneous disease which ranges from localized to extensive skin lesions with frequent multisystem extra cutaneous involvement. The role of a pediatrician-dermatologist cooperation within a multidisciplinary team is fundamental for both the diagnosis and management contributing to these patients’ better life expectancy. Aim of this study is to describe clinical and laboratory characteristics of the main EB subtypes focusing on nutritional and gastrointestinal aspects, providing information to aid the paediatric management of children with EB. This retrospective study reviewed the cases of 160 pediatric EB patients (76 male and 84 female): 31 patients affected by EBS (mean age ± SD: 4.37 ± 7.14), 21 patients affected by JEB (mean age ± SD: 9.26± 17.30) and 108 with DEB (mean age ± SD: 11.61 ± 13.48). All patients were admitted at the Bambino Gesù Children’s Hospital in Rome, between June 2005 to June 2020. The reduced gastrointestinal absorption, chronic losses, esophageal stenosis and chronic inflammatory state, represent the basis of nutritional problems of EB patients. In particular, anemia represents one of the most important complications of DEB patients which could require transfusion-dependent patterns. Malnutrition, vitamin deficiencies and anemia have been related to growth delay in EB patients. A specific diet with a balance of all macronutrients is required and improving caloric intake with sugar limitations is fundamental to prevent dental caries and tooth decay typical of EB patients. While sepsis proved to be the major cause of morbidity and mortality in younger patients, squamous cell carcinoma was mostly observed in older patients, especially those affected by DEB. Patients with EB require regular monitoring for complications and sequelae with a frequency of evaluations which varies based on age and EB subtypes. Cooperation among medical teams involving paediatricians, dermatologists, specialist clinicians including nutritionists such as families and patient’s association is fundamental to approach the disease and improve the quality of life of these patients.

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB

Oral soft tissues in hereditary epidermolysis bullosa

A Rare Skin Disorder with Bacteremia in a Neonate.

Background: Inherited epidermolysis bullosa (EB) includes a group of rare genetic disorders affecting the skin and mucous membranes. These disorders are characterized by extreme fragility and blister formation after minimal or no trauma. Oral and systemic manifestations vary by subtype; the more severe forms often present with extensive intra-oral blistering, scarring, microstomia, vestibular obliteration, ankyloglossia, and—in some cases—oral cancer. This study aims to collect data on oral-health practices and challenges in people with EB to inform preventive strategies and dental care. Methods: An international, structured online questionnaire with 31 items was distributed to individuals with a confirmed diagnosis of EB. The survey explored clinical and oral manifestations, home-care routines (oral hygiene and diet), experiences with dental professionals, and the impact of oral health on quality of life. Results: Eighty-two questionnaires were completed. Dystrophic EB was the most often reported subtype (69.5%). Most respondents (67.1%) experienced recurrent oral blisters and/or erosions. Many reported relying exclusively on soft foods and struggling with mechanical plaque removal because of microstomia and pseudo-syndactyly. Severe oral pain hindered effective brushing in 17% of participants. Hand contractures and microstomia interfered with oral hygiene in 74% and 31% of participants, respectively. Nearly 30% sought dental care only when in pain. Among those who did not attend regular check-ups or hygiene sessions (44.6%), the most cited reason was that dental clinics were inadequately equipped or trained to manage EB. Conclusions: Because dental procedures carry significant risks for patients with EB, preventive care should begin in early childhood. Yet many patients are still insufficiently informed about essential preventive measures and lack access to dental professionals trained in EB management.