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The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life‐threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case‐by‐case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 – May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non‐congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft‐versus‐host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho‐epithelial Kazal‐type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6‐step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin‐subthematic group Ichthyosis. [ABSTRACT FROM AUTHOR]

New glycine substitution mutations in type VII collagen underlying epidermolysis bullosa pruriginosa but the phenotype is not explained by a common polymorphism in the matrix metalloproteinase-1 gene promoter. Identical glycine substitution mutations in type VII collagen may underlie both dominant and recessive forms of dystrophic epidermolysis bullosa. [Extracted from the article]

Background: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic disorders characterized by fragility of the skin and mucosae, resulting in blisters and erosions. Several epidemiological studies in other populations have been carried out, reporting varying and sometimes inconclusive figures, highlighting the need for standardized epidemiological analyses in well‐characterized cohorts. Objectives: To evaluate the epidemiological data on EB in the Netherlands, extracted from the molecularly well‐characterized cohort in the Dutch EB Registry. Methods: In this observational study all EB‐patients that were based in the Netherlands and captured in the Dutch EB Registry between 1988 and 2018 were included. The epidemiological outcomes were based on complete diagnostic data (clinical features, immunofluorescence, electron microscopy and mutation analysis), with longitudinal follow‐up. Results: A total of 464 EB‐patients (287 families) were included. The incidence and point‐prevalence of EB in the Netherlands were 41.3 per million live births and 22.4 per million population, respectively. EB Simplex (EBS), Junctional EB (JEB), Dystrophic EB (DEB) and Kindler EB were diagnosed in 45.7%, 18.8%, 34.7% and 0.9% of the EB‐patients, respectively, with an incidence and point‐prevalence of 17.5 and 11.9 (EBS), 9.3 and 2.1 (JEB), 14.1 and 8.3 (DEB), 0.5 and 0.2 (Kindler EB). In 90.5% of the EB‐patients the diagnosis was genetically confirmed. During the investigated time period 73 EB‐patients died, 72.6% of whom as a direct consequence of their EB. Conclusion: The epidemiological outcomes of EB in the Netherlands are high, attributed to a high detection rate in a well‐organized set‐up, indicating that EB might be more common than previously assumed. These epidemiological data help to understand the extensive need for (specialized) medical care of EB‐patients and is invaluable for the design and execution of therapeutic trials. This study emphasizes the importance of thorough reporting systems and registries worldwide. Linked Commentary: L. Bruckner‐Tuderman. J Eur Acad Dermatol Venereol 2021; 35: 783–784. https://doi.org/10.1111/jdv.17165. [ABSTRACT FROM AUTHOR]

Complete remission off therapy was achieved by two patients (29%) with BP and five patients (31%) with MMP (Table 1). Overall, eight patients (35%) relapsed after a median time of 56 weeks [two patients with BP (29%) and six patients with MMP (38%)] (Table 1). In particular, the number of patients receiving prednisone decreased from 18 patients (78%) at M0 to 13 patients (57%) at M6. [Extracted from the article]

Summary: Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering.The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype.Clinical and genetic aspects, genotype–phenotype correlations, disease‐modifying factors and natural history of EB are reviewed.Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment:Pope. Br J Dermatol 2020; 183:603. Linked Comment:Pope. Br J Dermatol 2020; 183:603. Plain language summary available online [ABSTRACT FROM AUTHOR]

Linked Comment: Uitto. Br J Dermatol 2020; 182:526–527. Plain language summary available online [ABSTRACT FROM AUTHOR]

The article focuses on cardiomyopathyin patients with epidermolysis bullosa simplex with mutations in KLHL24 and expand the phenotypic spectrum by incorporating additional findings. It mentions electron microscopy revealed a striking paucity of intermediate filaments in the basal keratinocytes along with numerous and prominent mitochondria. It also mentions immunofluorescence antigen mapping (IFM) staining on human embryonic stem cell 9-derived cardiomyocytes for the presence of KLHL24.

Epidermolysis bullosa simplex (EBS) is a mechanobullous genodermatosis that may be caused by mutations in the genes KRT5 and KRT14 encoding the basal epidermal keratins 5 (K5) and 14 (K14). Three main clinical subtypes of EBS exist, differing in onset, distribution and severity of skin blistering. Previous reports of KRT5 and KRT14 mutations suggest a correlation between the location of the mutation and the severity of the associated EBS phenotype. The prevalence of KRT5/ KRT14 mutations and the genotype-phenotype correlation in the largest tissue-confirmed EBS population is investigated. KRT5 and KRT14 genomic DNA and cDNA sequences of 76 clinically well-defined unrelated EBS probands were amplified and then subjected to direct sequencing and product length analysis. Immunofluorescence microscopy on patients' skin biopsies with antibodies against K5 and K14 was performed to study protein expression. In 57 of 76 (75%) probands 41 different KRT5 and KRT14 mutations were identified, of which 12 were novel. Mutations affecting the highly conserved helix boundary motifs of the rod domains of K5 and K14, and the K14 helix initiation motif in particular, were associated with the severest, EBS Dowling-Meara, phenotype. In 21 EBS probands (37%) the mutation was de novo. In 19 probands (25%) KRT5 or KRT14 mutations were excluded. The phenotype-genotype correlation observed in this large EBS population underscores the importance of helix boundary motifs for keratin assembly. Only three-quarters of biopsy-confirmed EBS probands have KRT5 or KRT14 mutations, indicating genetic heterogeneity in EBS. Alternative gene candidates are discussed. [ABSTRACT FROM AUTHOR]

Background Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families. Objectives To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance. Methods Wild-type and mutant pEGFP- KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo-osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly. Results Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced. Conclusions Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder. [ABSTRACT FROM AUTHOR]

Summary: Epidermolysis bullosa (EB) is a group of rare inherited disorders in which the skin is more fragile than usual, and outside forces like minor injury or rubbing cause blisters or ulcers that may be slow to heal and often leave scars. EB comprises four main types, with more than 30 subtypes. The diagnosis is based on clinical manifestations, meaning how it looks, mode of inheritance, level of skin splitting and the genetic defect. A group of experts from countries all over the world developed these guidelines on behalf of the charity DEBRA International, to provide information on the laboratory diagnosis of EB. Publications (i.e. scientific studies about EB that had been published in journals) were identified in public databases. Sixty‐four papers were appraised, and their quality rated. Based on this, the authors recommend the following: If EB is suspected, laboratory diagnosis is always required, after informed consent. If available and affordable, both genetic (DNA) testing and analysis of a skin sample (by a process called immunofluorescence) should be performed to allow complete diagnosis. However, this is not always possible. Prioritisation can shorten the time to diagnosis and save resources but requires expertise. For example, in a new‐born, analysis of a skin sample should be the first diagnostic step since it delivers the results within a few days. In parallel, genetic testing should always be performed. If the EB type can be clinically recognized or the disease is mild, genetic testing by a process called next‐generation sequencing is recommended, because no valuable information is expected by analysis of the skin.If the genetic defect is detected in one affected person, parents and other family members can be tested for confirmation and genetic counselling.If no genetic defect is detected, research methods must be employed, or the diagnosis reconsidered. Precise diagnosis of EB enables early prediction of the disease severity and its management, genetic counselling and prenatal diagnosis, and inclusion in therapy trials. This is a summary of the study: Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa Linked Article: Has et al. Br J Dermatol 2020; 182:574–592 [ABSTRACT FROM AUTHOR]

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