Epidermolysis Bullosa in children: the central role of the pediatrician

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 Gesu 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

Early immunopathological diagnosis of ichthyosis with confetti in two sporadic cases with new mutations in keratin 10.

Ichthyosis with confetti (IC) is a severe non-syndromic ichthyosis due to heterozygous mutations in the KRT10 gene. The disease manifests at birth with erythroderma and scaling and is characterised by the gradual development of numerous confetti-like spots of normal skin. Diagnosis of IC is frequently delayed until adolescence or even adulthood. We report 2 young children who were first diagnosed as having congenital ichthyosiform erythroderma. However, the development of thick, confluent hyperkeratotic plaques together with the histopathological finding of keratinocyte vacuolisation in the suprabasal epidermis evoked IC. Immunofluorescence analysis showed a highly reduced keratin 10 expression within the cytoplasm of suprabasal keratinocytes and its characteristic mislocalisation to the nuclei. The diagnosis was confirmed by the identification of 2 previously unreported mutations in intron 6 and exon 7 of KRT10. Careful clinical examination then showed the presence of the first spots of normal skin in both patients at the age of 2.5 and 5 years, respectively. These cases point to the usefulness of immunofluorescence analysis of keratin 10 expression for an early diagnosis of IC

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement

inborn errors of immunity associated with atopy (IEIs-A) are a group of inherited monogenic disorders that occur with immune dysregulation and frequent skin involvement. several pathways are involved in the pathogenesis of these conditions, including immune system defects, alterations of skin barrier and metabolism perturbations. current technological improvements and the higher accessibility to genetic testing, recently allowed the identification of novel molecular pathways involved in IEIs-A, also informing on potential tailored therapeutic strategies. compared to other systemic therapy for skin diseases, biologics have the less toxic and the best tolerated profile in the setting of immune dysregulation. Here, we review IEIs-A with skin involvement focusing on the tailored therapeutic approach according to their pathogenetic mechanism

Topical corticosteroid phobia in parents of pediatric patients with atopic dermatitis: a multicentre survey

BACKGROUND: Families of children affected with atopic dermatitis (AD) often report fear and anxiety regarding treatment with topical corticosteroids (TCS), which may lead to reduced compliance. The objective of our study was to measure, through a standardized questionnaire, fear of TCS in families of pediatric patients with AD and to identify items associated with fear. METHODS: Families of pediatric patients with AD were enrolled in 9 Italian centers of pediatric dermatology. Enrolled parents were invited to fill in a questionnaire including questions on sociodemographic and clinical characteristics and 3 sets of questions on corticosteroid phobia (general fear, specific fears, behaviours regarding TCS). Determinants of the level of general fear were investigated through multivariable analysis. RESULTS: A total of 300 outpatients with AD were enrolled. Most parents (80%) had a high instruction level. Eighty-one percent reported to have a certain amount of fear of TCS. At the multivariable analysis, fear of TCS was associated with the following items: believing that TCS treatment advantages do not overweight disadvantages (P = 0.011); believing that TCS may be dangerous independently from the specific side effect (P < 0.001). Moreover, TCS fear was associated with fear of applying too much cream (P = 0.001). CONCLUSION: TCS phobia is widespread among Italian families of children with AD. Fear of TCS is associated with fear of applying too much cream, thus increasing the risk of poor compliance and treatment failure. Therapeutic education of families on the use of TCS should be implemented. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13052-017-0330-7) contains supplementary material, which is available to authorized users

Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa

This guideline were initiated by DEBRA International; financial support was provided by DEBRA Austria. The generous assistance of Rebecca Bodan, Lisa Brains, Sharon Cassidy and Kelsey Townsend-Miller is gratefully acknowledged in providing patient or lay input into this guideline. The authors acknowledge the guidance of Kattya Mayre-Chilton (DEDRA International). Johann Bauer (Paracelsus University and EB House, Salzburg, Austria), Christine Bodemer (Hôpital Universitaire Necker, Paris, France), Judith Fischer (Institute of Human Genetics, University of Freiburg, Germany), Jemima Mellerio (St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, U.K.), Francis Palisson (Universidad del Desarrollo and DEBRA, Chile), Eli Sprecher (Department of Dermatology, Tel Aviv Sourasky Medical Center, Israel) and Jouni Uitto, Leila Youssefian and Hassan Vahidnezhad (all from the Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, U.S.A.) are acknowledged as reviewers

Revisiting inconsistency in large pharmacogenomic studies

In 2013, we published a comparative analysis of mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized in the 471 cancer cell lines screened in the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE). While we found good concordance in gene expression profiles, there was substantial inconsistency in the drug responses reported by the GDSC and CCLE projects. We received extensive feedback on the comparisons that we performed. This feedback, along with the release of new data, prompted us to revisit our initial analysis. We present a new analysis using these expanded data, where we address the most significant suggestions for improvements on our published analysis - that targeted therapies and broad cytotoxic drugs should have been treated differently in assessing consistency, that consistency of both molecular profiles and drug sensitivity measurements should be compared across cell lines, and that the software analysis tools provided should have been easier to run, particularly as the GDSC and CCLE released additional data. Our re-analysis supports our previous finding that gene expression data are significantly more consistent than drug sensitivity measurements. Using new statistics to assess data consistency allowed identification of two broad effect drugs and three targeted drugs with moderate to good consistency in drug sensitivity data between GDSC and CCLE. For three other targeted drugs, there were not enough sensitive cell lines to assess the consistency of the pharmacological profiles. We found evidence of inconsistencies in pharmacological phenotypes for the remaining eight drugs. Overall, our findings suggest that the drug sensitivity data in GDSC and CCLE continue to present challenges for robust biomarker discovery. This re-analysis provides additional support for the argument that experimental standardization and validation of pharmacogenomic response will be necessary to advance the broad use of large pharmacogenomic screens

Surgical treatment of septate uterus in cases of primary infertility and before assisted reproductive technologies

Septate uterus is the most common congenital uterine malformation in women with infertility. Several criteria are available for the definition of septate uteri, such as the one proposed by the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynecological Endoscopy (ESGE) (ESHRE/ESGE), or by the American Society for Reproductive Medicine (ASRM), with notable differences between the two. Recently, a simplified classification was proposed by the Congenital Uterine Malformations Experts (CUME), where a septum is defined as an internal indentation depth≥10mm. To date, there is no consensus on the management of women with a septate uterus and infertility. We have performed an extensive literature appraisal and reviewed all the available international guidelines in order to propose a management strategy for infertile patients with a uterine septum. Hysteroscopic septum incision seems to improve natural conception rates in the year following surgery. Moreover, it improves in vitro fertilization (IVF) outcomes when performed before the embryo transfer, by improving embryo implantation rates. On the other hand, for patients with an arcuate uterus (indentation&lt;1.5cm according to the ASRM guidelines) and infertility, it seems that assisted reproductive technologies are the most appropriate first line treatment. However, in cases of recurrent implantation failure or recurrent pregnancy loss following IVF, hysteroscopic section could be proposed. Overall, we recommend hysteroscopic septum incision for patients with primary infertility, and for patients undergoing assisted reproductive technologies

A phase i study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates

<p>Abstract</p> <p>Background</p> <p>Defects in skin barrier function are associated with an increase risk of eczema and atopic sensitisation. Ceramide-dominant triple lipid mixture may improve and maintain the infant skin barrier function, and if shown to be safe and feasible, may therefore offer an effective approach to reduce the incidence of eczema and subsequent atopic sensitisation. We sort to assess the safety and compliance with daily application of a ceramide-dominant triple lipid formula (EpiCeram™) commencing in the neonatal period for the prevention of eczema.</p> <p>Methods</p> <p>Ten infants (0-4 weeks of age) with a family history of allergic disease were recruited into an open-label, phase one trial of daily application of EpiCeram™ for six weeks. The primary outcomes were rate of compliance and adverse events. Data on development of eczema, and physiological properties of the skin (transepidermal water loss, hydration, and surface pH) were also measured.</p> <p>Results</p> <p>Eighty percent (8/10) of mothers applied the study cream on 80% or more of days during the six week intervention period. Though a number of adverse events unrelated to study product were reported, there were no adverse skin reactions to the study cream.</p> <p>Conclusions</p> <p>These preliminary results support the safety and parental compliance with daily applications of a ceramide-dominant formula for the prevention of eczema, providing the necessary ground work for a randomised clinical trial to evaluate EpiCeram™ for the prevention of eczema.</p> <p>Trial registration</p> <p>The study was listed at the Australian/New Zealand Clinical Trial Registry (ANZCTR): reg. no. <a href="http://www.anzctr.org.au/ACTRN12609000727246.aspx">ACTRN12609000727246</a>.</p

A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects

Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations