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Background Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. Objectives To investigate the genetic aetiology and molecular mechanisms underlying BDCS. Methods We ascertained multiple individuals from eight unrelated families affected with BDCS (F1–F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head–tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. Results In eight families with BDCS, we identified overlapping 18–135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Conclusions Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex–Dupré–Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1.Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1.The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene.ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management.ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

Der Morbus Darier (MD) und Morbus Hailey-Hailey (MHH) sind seltene Erkrankungen, die durch Mutationen im ATPase, Sarcoplasmic/Endoplasmic Reticulum CaFünf Patienten mit uneindeutiger Diagnose und acht Kontrollen mit eindeutiger Diagnose wurden klinisch, histologisch, genetisch und immunhistochemisch hinsichtlich der Expression von STIM1 und ORAI1 untersucht.MD-Patienten zeigten durchweg eine zytoplasmatische STIM1-Expression, während Patienten mit MHH ein membrangebundenes Expressionsmuster aufwiesen. Im Gegensatz dazu fand sich keine differentielle Expression von ORAI1.Unsere Ergebnisse legen eine subzelluläre Kompartimentierung von STIM1 als neuen Biomarker für die Unterscheidung der beiden Erkrankungen nahe.

Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.Epidemiological data from different countries have been published, but none are available from Germany.In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization.Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries.Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

Die Porphyrien sind klinisch variable und genetisch heterogene, vorwiegend hereditäre metabolische Krankheiten, die durch eine Dysfunktion spezifischer Enzyme der Hämbiosynthese verursacht werden. Wir geben einen Überblick zur Ätiopathogenese, Klinik, Differenzialdiagnose, Labordiagnostik und Therapie dieser komplexen Stoffwechselkrankheiten und stellen die weltweit häufigste Porphyrieform (Porphyria cutanea tarda), die häufigste Porphyrie des Kindesalters (erythropoetische Protoporphyrie) und die häufigste neurokutane Porphyrie (Porphyria variegata) detailliert vor.

Mutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease.Here, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied.After morpholino (MO)-mediated ncstn-knockdown, the possibilities of phenotype rescue through co-injection of ncstn-MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied.MO-mediated ncstn-knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R.Human NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS.

BackgroundBazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11.4 Mb interval on chromosome Xq25-27.1. However, the genetic mechanism of BDCS remains an open question.MethodsTo investigate the genetic etiology of BDCS, we ascertained eight families with individuals affected with BDCS (F1-F8). Whole exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array-comparative genomic hybridization and quantitative PCR were used to explore copy number variations (CNV) in BDCS families, followed by long-range gap-PCR and Sanger sequencing to amplify duplication junction and define the precise head-tail junctions, respectively. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from BDCS patients and sporadic BCCs to detect the expression of corresponding genes. The ACTRT1 variant (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with allele frequency calculator.ResultsIn eight BDCS families, we identified overlapping 18-135kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. We detected ARHGAP36 expression near the control hair follicular stem cells compartment, and found increased ARHGAP36 levels in hair follicles in telogen, BCCs and trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted ACTRT1 variants maximum tolerated minor allele frequency in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss-of-function of ACTRT1 is unlikely to cause BDCS.ConclusionsOur data support the pathogenicity of intergenic duplications at Xq26.1, most likely leading to dysregulation of ARHGAP36, establish BDCS as a genomic disorder, and provide a potential therapeutic target for both inherited and sporadic BCCs.

El presente trabajo de investigación intenta describir la satisfacción del aprendizaje en los estudiantes de derecho de pregrado con relación a la educación virtual durante el presente año 2021. Se usó un enfoque cuantitativo, el mismo que cuenta diseño no experimental-transversal y del tipo descriptivo. Se utilizó dos cuestionario, el primero de 12 preguntas para la variable independiente de educación virtual y 11 preguntas para la variable dependiente de Satisfacción del aprendizaje a una muestra de 320 estudiantes de derecho de la universidad César Vallejo, Lima Norte 2021 por lo que arrojó un resultado positivo y significativo de las dimensiones en su relación Se concluye que la satisfacción del aprendizaje en los estudiantes de derecho es positiva con relación a la educación virtual en sus cuatro dimensiones de los Recursos de aprendizaje virtual, Acompañamiento virtual, Colaboración virtual y competencia de parte de la institución educativa superior. Lima Norte Escuela de Posgrado Evaluación y Aprendizaje Biodiversidad, cambio climático y calidad ambiental Apoyo a la reducción de brechas y carencias en la educación en todos sus niveles Educación de calidad

Darier disease (DD) and Hailey-Hailey disease (HHD) are rare disorders caused by mutations in the ATPase, Sarcoplasmic/Endoplasmic Reticulum CaFive individuals with ambiguous diagnostic findings and eight controls with an unambiguous diagnosis were studied clinically, histologically, genetically, and by immunohistochemistry for STIM1 and ORAI1.DD patients consistently showed a cytoplasmic STIM1 expression while patients with HHD revealed a membrane-associated staining pattern. In contrast, ORAI1 did not show a differential expression pattern.Our data suggest subcellular compartmentalization of STIM1 as novel biomarker for the distinction of the two disorders.

The porphyrias are clinically variable and genetically heterogeneous, predominantly hereditary metabolic diseases, which are caused by a dysfunction of specific enzymes in heme biosynthesis. Here, we provide an overview of the etiopathogenesis, clinic, differential diagnosis, laboratory diagnostics and therapy of these complex metabolic disorders and cover in detail the most common form of porphyria worldwide (porphyria cutanea tarda), the most frequent childhood porphyria (erythropoietic protoporphyria), and the most common neurocutaneous porphyria (variegate porphyria).

Genetisch bedingte Erkrankungen mit Hyper- oder Hypotrichose sind klinisch und genetisch ausgesprochen heterogen. Dies trifft in besonderem Mase auf ektodermale Dysplasien, aber auch auf hereditare Syndrome zu, bei denen auser den Haaren weitere Strukturen und Organe betroffen sind. In dieser Ubersichtsarbeit besprechen wir verschiedene Krankheitsbilder mit vermehrtem und vermindertem Haarwachstum, wobei der Fokus auf den klinischen Merkmalen und den zugrunde liegenden genetischen Defekten liegt.

Skin tumors can manifest solitarily and sporadically but can also be multiple and familial. Beside the skin, hereditary cutaneous tumor syndromes also affect extracutaneous organs and are clinically and genetically heterogeneous. Taking the medical history, a clinical examination and dermatopathological characterization of the respective neoplasia will help the dermatologist to reach a diagnosis at an early stage. Subsequently, this diagnosis can be unambiguously confirmed by molecular genetic analysis. Here, we provide an overview and update on selected hereditary cutaneous tumor syndromes.

Basal cell carcinoma (BCC) is the most common malignant tumor among fair-skinned individuals, and its incidence had been steadily rising in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 2 addresses issues such as proper risk stratification, the various therapeutic approaches, and prevention as well as follow-up of patients with basal cell carcinoma.

Basal cell carcinoma is the most common malignant tumor among fair-skinned individuals, and its incidence has been rising steadily in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 1 highlights new developments in genetics in particular as well as aspects regarding epidemiology, diagnosis, and histology.

Kontinuierliche medizinische Fortbildung (Continuing Medical Education, CME) ist die wesentliche Grundlage der studentischen Lehre sowie der Aus- und Weiterbildung von Arzten. Eine moderne und adaquate Patientenversorgung ist ohne sie nicht denkbar. Vor kurzem zwang die durch das schwere akute respiratorische Syndrom-Coronavirus 2 (SARS-CoV-2) verursachte Pandemie die gesamte medizinische Gemeinschaft, ihre Gewohnheiten bezuglich der medizinischen Fortbildung und Lehre sowie des Lernens in der Medizin zu andern. Infolgedessen ruckten uber soziale Medien (Social Media) verbreitete digitale Aus-, Fortbildungs- und Lehrformate, medizinische Online-Enzyklopadien, webbasierte medizinische Lernportale und medizinische Podcasts in den Vordergrund. In diesem Beitrag geben wir einen Uberblick zu aktuelle Konzepten in der medizinischen Online-Fortbildung, unter besonderer Berucksichtigung der Dermatologie.

Continuing medical education (CME) is the essential basis for student teaching and for training and further development of physicians. Without it, modern and adequate patient care is unthinkable. Recently, the coronavirus pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV2), forced the entire medical community to change its usual habits of advanced medical training, teaching and learning. As a result, digital training and teaching via social media, online medical encyclopedias, web-based learning platforms and educational podcasts moved to the fore. Here, we give an overview on current concepts for online medical education, with special consideration of dermatology.

Mutations in the tumor suppressor gene CYLD underlie phenotypically heterogeneous hereditary tumor disorders of the skin appendages. These diseases are inherited autosomal dominantly and include Brooke-Spiegler syndrome (BSS; OMIM 605041), familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma (MFT; OMIM 601606). Clinically, cylindromas, trichoepitheliomas and spiradenomas can be found in affected individuals. We sought to elucidate the molecular genetic basis in individuals with newly diagnosed cylindromas, trichoepitheliomas and/or spiradenomas. Mutation analysis using polymerase chain reaction (PCR)-based techniques was performed in seven German patients and one Turkish patient. We detected two missense, two nonsense, two deletions and two duplication mutations in the CYLD gene, of which seven have not yet been reported. No genotype-phenotype correlation was detected amongst the patients. Our data provide additional information on the clinical and molecular genetic heterogeneity of disorders associated with CYLD mutations.