Plantar involvement correlates with obesity, pain and impaired mobility in epidermolysis bullosa simplex: a retrospective cohort study.

BACKGROUND: Epidermolysis bullosa simplex (EBS) is the most common type of EB, a group of rare genodermatoses. Affected individuals suffer from skin blistering and report a high disease burden. In some EBS subtypes, plantar keratoderma (PK) has been described. OBJECTIVES: This study investigated the presence and correlation of PK with body mass index, pain and mobility in EBS. METHODS: Individuals (n = 157) with genetically characterized EBS were included in this retrospective cohort study, and clinical data were collected over 16 years (referral patients to the largest German EB centre). Descriptive statistics and mixed linear models were used to assess correlations. RESULTS: PK was found in 75.8% of patients beginning at a mean age of 4.3 years. Both focal and diffuse PK were observed, and 60% of adults with localized and severe EBS were preobese or obese, with ˜30% of patients reporting severely reduced mobility. The presence of PK, especially diffuse PK, correlated significantly with local infections, obesity, pain and requirement of a wheelchair. CONCLUSION: Along with treating skin fragility and blistering, PK should be considered a potential marker of increased morbidity and may represent a target of EBS therapy development.

Natural history of growth and anaemia in children with epidermolysis bullosa: a retrospective cohort study.

BACKGROUND: Impaired growth and anaemia are major extracutaneous complications of epidermolysis bullosa (EB), but data on their development are lacking. OBJECTIVES: To determine the clinical course of growth and anaemia in children with EB and clarify the impact of nutritional compromise, inflammation and genetic factors. METHODS: A retrospective study was conducted of 200 children, 157 with recessive dystrophic EB (RDEB) and 43 with junctional EB (JEB)-generalized intermediate, followed at the main referral centre in Germany. Growth charts were calculated using the modified LMS method and were correlated with parameters of anaemia, nutrition, inflammation and the molecular defect in a linear model. RESULTS: In our cohort of patients with RDEB, weight impairment started at 12-18 months old; by the age of 10 years, 50% showed wasting. The predicted median weight at age 20 years was 35·2 kg for men and 40·1 kg for women. In JEB, growth resembled that of healthy children. Anaemia was present from the second year of life onwards in RDEB and JEB. Low levels of haemoglobin, iron, vitamin D, zinc and albumin, high levels of C-reactive protein, and absence of collagen VII correlated significantly with low weight in RDEB. No correlation was observed in JEB. CONCLUSIONS: The results highlight that nutritional compromise occurs early in children with RDEB and therefore may require interventions as of the first year or two of life. What's already known about this topic? Children with epidermolysis bullosa (EB) suffer from failure to thrive and anaemia as major extracutaneous complications. The course of growth and the development of anaemia in EB are poorly characterized. What does this study add? A molecularly well characterized cohort of 200 children with EB was followed with regard to anthropometrics, anaemia and inflammation. We demonstrate early onset of growth failure and anaemia, most pronounced in the subset of recessive dystrophic EB. Awareness of early growth delay and nutritional deficiencies will improve EB care in daily practice.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.

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.

FERMT1 promoter mutations in patients with Kindler syndrome.

Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity.

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies.

Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.

Phased-array of microcoils allows MR microscopy of ex vivo human skin samples at 9.4 T.

PURPOSE: The aim of this study was to demonstrate the feasibility of a custom-made phased-array microcoil within a 400 MHz animal system for the morphological characterization of human skin tissue in correlation with histopathology. MATERIALS AND METHODS: A dedicated 7-channel microcoil-based MR detector arranged in a phased-array geometry was developed to combine the advantages of both a large field of view and a high signal-to-noise ratio. Standard gradient echo sequences were adapted for the characterization of skin morphology ex vivo. RESULTS: In this study, the feasibility of using this type of microdetector, combined with specially manufactured sample holders, to achieve high-resolution MR images of fresh and formalin-fixed, normal and hidradenitis suppurativa diseased skin was successfully demonstrated. The setup presented in this work allows reliable acquisitions of high-resolution images with in-plane resolution up to 25 × 25 µm², and 100 µm in the orthogonal direction, thereby allowing the differentiation of typical layers of the skin, sebaceous glands and hair follicle. CONCLUSION: This study demonstrates that MR microscopy on skin biopsies can be applied at low cost on a standard animal MR imaging system. The successful imaging of different skin structures ex vivo is a prerequisite for non-invasive, in vivo application of skin MR microscopy for accurate complementary disease diagnosis in dermatology.

Expression of the sweat-derived innate defence antimicrobial peptide dermcidin is not impaired in Staphylococcus aureus colonization or recurrent skin infections.

Antimicrobial peptides are an integral part of innate immunity, and contribute to the protection of human skin from Staphylococcus aureus colonization and infection. We sought to investigate whether the expression of the eccrine sweat-derived staphylocidal antimicrobial peptide dermcidin might influence S. aureus colonization or recurrent skin and soft-tissue infections (SSTIs). Eccrine sweat was collected from 18 patients with recurrent S. aureus SSTIs, 28 patients who were intermittent or permanent S. aureus carriers, and 32 noncarriers. Expression and proteolytic degradation of dermcidin was investigated using ELISA and surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We found no significant differences in the overall amount or the proteolytic degradation pattern of dermcidin-derived peptides between healthy noncarriers, intermittent and permanent carriers, and patients with recurrent S. aureus SSTIs. S. aureus colonization or recurrent SSTIs do not seem to be associated with diminished dermcidin expression in eccrine sweat.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Phenotypic spectrum of epidermolysis bullosa associated with α6ß4 integrin mutations.

BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.

[New developments in hereditary blistering skin diseases]. / Neues über hereditäre, blasenbildende Hauterkrankungen.

Hereditary blistering skin diseases were described more than hundred years ago, but only the rapid scientific developments in molecular genetics in the last years have revealed the full spectrum of these diseases, delineated disease mechanisms and pointed to novel therapeutic strategies. Not only the classic forms of epidermolysis bullosa, but also new syndromic forms with multiorgan involvement, or skin fragility disorders that manifest with erosive, crusty lesions and pigment anomalies, instead of marked skin blistering belong to the group of hereditary blistering diseases. Understanding the biological functions of skin structures that provide intraepidermal and dermo-epidermal adhesion has furthered development of novel cell- and molecule-based therapies that are currently being tested in preclinical and clinical pilot trial settings.

Conradi-Hünermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects).

BACKGROUND: There is confusion in the literature concerning disorders caused by EBP (emopamil-binding protein) mutations in males. OBJECTIVES: To study the clinical and genetic differences in males affected either with Conradi-Hünermann-Happle (CHH) syndrome (X-linked dominant chondrodysplasia punctata, CDPX2) or with a nonmosaic, X-linked recessive disorder for which we propose the acronymic term MEND syndrome (male EBP disorder with neurological defects). METHODS: We report a 7-year-old boy with a history of transient scaly erythematous lesions on his limbs, trunk and scalp soon after birth. DNA was isolated from ethylenediamine tetraacetic acid-blood samples of the patient and the four coding exons of the EBP gene were amplified by polymerase chain reaction. We review all published cases of CHH syndrome in males in the literature and elaborate the clinical and genetic differences between CHH syndrome in males and MEND syndrome. RESULTS: We found at position 33 of the EBP gene the variant c.33C>A leading to the same nonsense mutation p.Y11X that had previously occurred de novo in a female with typical manifestations of CHH syndrome. When the known male cases with EBP mutations were reviewed, a striking nosological difference between the mosaic and nonmosaic phenotypes was evident. Clear-cut clinical criteria are elaborated to distinguish between CHH syndrome in males and MEND syndrome. CONCLUSIONS: Because the clinical outcome and prognosis are different it is important to distinguish between males with CHH syndrome that represents a mosaic phenotype, and those with MEND syndrome that is a nonmosaic trait.

Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene.

Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling-Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin-2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki-67 were increased and levels of E-cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte-mediated inflammation, possibly via p120-catenin-dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.

[Epidermolysis bullosa : Diagnosis and therapy]. / Epidermolysis bullosa : Diagnostik und Therapie.

Hereditary epidermolysis bullosa is characterized by mechanically induced blistering of the skin and mucous membranes. The causative mechanisms are based on mutations in genes for structural proteins of the epidermis and the dermal-epidermal junction zone. EB is genetically and clinically heterogeneous. Based on the clinical phenotype alone, the diagnosis is difficult in newborns and toddlers, and sometimes even in adults. A precise diagnosis is only possible with laboratory tests like immunofluorescence mapping, electron microscopy and mutation analysis in specialized centers. The treatment is symptomatic and based on the principles of good wound management and - for severe cases - on multidisciplinary care. New data on the pathogenetic mechanisms of epidermolysis bullosa deliver perspectives for development of novel molecular therapies.