Summary
Background
Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical ...disease, recent data argue for additional inflammatory mechanisms.
Objectives
To assess the inflammation in the skin of patients with EBS‐gen sev.
Methods
A first immunohistochemical retrospective study was performed on frozen skin samples from 17 patients with EBS‐gen sev. A second multicentre prospective study was conducted on 10 patients with severe EBS‐gen sev. Blister fluid and epidermis were processed for immunochemical analysis and quantitative real‐time polymerase chain reaction. Cytokine expression was analysed in blister fluid and compared with that in controls.
Results
Histological analysis showed a constant dermal perivascular CD4+ lymphocyte infiltrate in skin biopsies of both blister (n = 17) and rubbed skin (n = 5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases, and increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of T helper 17 cytokines were detected in lesional skin. Three adult patients with EBS‐gen sev were treated with apremilast, with a dramatic improvement of skin blistering and good tolerance.
Conclusions
Our study demonstrates the importance of inflammation in patients with EBS‐gen sev and underlines the key role for T helper 17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder.
What's already known about this topic?
Epidermolysis bullosa simplex generalized severe (EBS‐gen sev) is a rare disabling skin disorder related to skin fragility.
What does this study add?
We showed the presence of an immune infiltrate characterized by a T helper (Th)17 phenotype in the skin of patients with EBS‐gen sev.
There was a marked improvement of the skin condition in patients with EBS after treatment with apremilast, an anti‐Th17 molecule.
What is the translational message?
Our results demonstrate the importance of inflammation in EBS‐gen sev and underline the key role of Th17 activation.
Anti‐Th17 molecules such as apremilast provide a promising new therapeutic approach for this disabling disorder.
Linked Comment: Mellerio. Br J Dermatol 2019; 180:258–260.
Plain language summary available online
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Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with ...intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.
Single-cell technologies offer insights into molecular feature distributions, but comparing them poses challenges. We propose a kernel-testing framework for non-linear cell-wise distribution ...comparison, analyzing gene expression and epigenomic modifications. Our method allows feature-wise and global transcriptome/epigenome comparisons, revealing cell population heterogeneities. Using a classifier based on embedding variability, we identify transitions in cell states, overcoming limitations of traditional single-cell analysis. Applied to single-cell ChIP-Seq data, our approach identifies untreated breast cancer cells with an epigenomic profile resembling persister cells. This demonstrates the effectiveness of kernel testing in uncovering subtle population variations that might be missed by other methods.
Summary
Background
Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise.
Objectives
To describe the dermatological ...manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations.
Methods
We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study.
Results
Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations.
Conclusions
The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.
What's already known about this topic?
Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and almost entirely without expert dermatological input.
A broad spectrum of dermatological findings is present in NS and better knowledge might help to define phenotype–genotype correlations and differentiate forms of NS from other RASopathies, specifically cardiofaciocutaneous syndrome.
What does this study add?
NS with PTPN11 mutations is usually associated with a mild and nonspecific cutaneous phenotype.
NS with multiple lentigines is typically associated with specific mutations of PTPN11 but atypical forms can be linked to RAF1 or NRAS mutations.
Absence of PTPN11 mutation in NS is associated with a higher frequency of keratinization disorders and hair abnormalities, the latter being commonly observed in cardiofaciocutaneous syndrome.
What is the translational message?
Abnormalities of the genes of the Ras–MAPK signalling pathway that are involved in NS underlie a spectrum of cutaneous manifestations including hair abnormalities, keratinization, pigmentary and connective tissue disorders and multiple melanocytic naevi.
This study adds new information to improve the definition of the cutaneous phenotype of NS and differentiate it phenotypically from RASopathies, specifically cardiofaciocutaneous syndrome and Costello syndrome.
Linked Comment: Carcavilla. Br J Dermatol 2019; 180:1293.
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Genetics and dermatology Morice-Picard, F
Annales de dermatologie et de vénéréologie
146, Številka:
4
Journal Article
Recenzirano
Many types of genodermatosis exist, with numerous modes of transmission. The development of molecular genetic methods, in particular the most recent sequencing techniques, can be used to identify an ...increasing number of genes involved in these forms of genodermatosis while providing confirmation or more details regarding clinical diagnosis. Thanks to this approach, it is possible to determine risk of recurrence and to formulate an antenatal strategy. These technologies have led to improved molecular definition and to a better understanding of the physiopathological mechanisms involved in different genodermatoses such as bullous epidermolysis, keratinisation disorders, pigmentation disorders, potentially tumoral conditions, and epidermal and pilar dysplasia. The large amount of information provided by high-throughput sequencing makes it possible to study modifying genes as well as genotype-phenotype correlations. However, this genetic information in its turn poses problems of interpretation and of control of the resulting data. The use of genetics in dermatology for the purposes of diagnosis or research requires a consultation to provide patients with information regarding the genetic tests involved and the potential consequences thereof for them and their families. Furthermore, with pangenomic approaches there is a higher probability of fortuitous discovery of abnormalities such as variants associated with risks predisposing to cancer or neurodegenerative disease. Collaboration between dermatologists and geneticists enables optimisation of patient management in terms of diagnosis and genetic counselling in the event of such rare diseases. Therapeutic applications are beginning to be developed. The scope of therapeutic application includes gene therapy, replacement therapy (enzyme therapy) and targeted therapy.
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