Introduction:Alport syndrome (AS) is a genetically heterogenous kidney disease characterized by microhematuria, proteinuria, and progressive chronic kidney disease (CKD). Although early renin-angiotensin system inhibitors (RASi) are standard of care, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in AS is limited. Thus, this study evaluated SGLT2i effects in adult patients with AS. Methods:We conducted a retrospective, observational study, including patients with genetically confirmed AS with significant proteinuria treated with combined RASi + SGLT2i. Clinico-laboratory data were collected longitudinally and compared with the preceding decade on stable RASi alone. Chronic estimated glomerular filtration rate (eGFR) and proteinuria slopes, changes in time-averaged proteinuria, subgroups responses, and secondary SGLT2i effects were assessed. Results:Eighteen adult patients with AS (mean age: 54.3 ± 15.4 years; baseline eGFR: 61.9 ± 26.5 ml/min per 1.73 m2; median proteinuria: 1010.0 [521.8-1662.5] mg/g) initiated RASi + SGLT2i therapy. Over 24.5 ± 13.5 months, the chronic eGFR slope improved significantly (-3.48 to +0.72 ml/min per 1.73 m2/yr, P < 0.001). Time-averaged proteinuria decreased by 24.1% (P = 0.005), and longitudinal proteinuria slope improved (P = 0.038). Subgroup analyses confirmed consistent responses among patients with heterozygous COL4A3/COL4A4 carriers, normal body mass index (BMI), and preserved renal function. Secondary effects included increases in hemoglobin and bicarbonate, alongside reduction in serum uric acid and weight loss. Three nonserious adverse events occurred, and no patient progressed to kidney failure (KF). Conclusion:This real-world study suggests a potential nephroprotective role of SGLT2i in adult patients with AS, including heterozygous COL4A3/COL4A4 carriers. Benefits appeared independent of baseline BMI and renal function, supporting consideration of earlier initiation. Prospective studies are required to validate these findings and refine treatment timing.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are prevalent conditions characterized by symptomatic joint hypermobility and a substantial public health burden, for which no causal treatment is currently available. In the absence of a defined molecular basis or validated diagnostic biomarkers, diagnosis of hEDS relies solely on the 2017 clinical criteria, with individuals who do not meet these criteria classified as HSD. Although currently categorized as distinct entities, the biological relationship between hEDS and HSD remains a subject of active debate within the scientific community. We performed targeted serum proteomic profiling using the proximity extension assay technology, quantifying 458 proteins in large cohorts of hEDS (n = 88) and HSD (n = 88) patients, alongside healthy controls (n = 176). Compared to controls, 54 proteins were differentially expressed in hEDS patients and 49 in HSD patients. No statistically significant differences were observed between hEDS and HSD groups. When the combined patient cohort was analyzed, 69 proteins showed differential expression relative to controls. The proteins were distributed across the predefined PEA panels, which include proteins involved in inflammatory, cardiometabolic, neurological, organ damage, and developmental processes. This targeted serum proteomic analysis identified overlapping protein expression changes in hEDS and HSD relative to controls, while revealing no detectable differences between the two conditions. These findings suggest the presence of shared molecular features across the hEDS/HSD spectrum and identify a set of candidate circulating proteins that warrant further investigation and independent validation in larger, well-characterized cohorts.

BACKGROUND:Sonic hedgehog-medulloblastoma (SHH-MB) represents a biologically diverse and clinically challenging subgroup, especially in high-risk variants characterized by metastatic dissemination. Despite progress in molecular stratification, current treatments rely on intensive multimodal regimens associated with substantial long-term neurotoxicity. Identifying novel oncogenic mechanisms that can be therapeutically exploited is therefore a critical priority. METHODS:We combined transcriptomic analyses of patient datasets with immunohistochemistry, RNAscope, and protein profiling to evaluate PTX3 expression in MB subgroups. Functional studies were performed in SHH-MB cell lines following PTX3 knockdown or knockout. Effects on proliferation, migration, and angiogenesis were assessed through multiple in vitro assays. In vivo relevance was tested using subcutaneous and orthotopic xenograft models. Mechanistic insights were obtained through phospho-kinase arrays, Western blotting and GSEA. A high-throughput drug screen and combination studies with specific inhibitors and standard chemotherapy (vincristine/cisplatin/cyclophosphamide; VCC) were performed to assess therapeutic potential. RESULTS:Our results reveal that PTX3 was strongly enriched in SHH-MB subgroup, where it supported proliferation, motility, and angiogenesis. Mechanistically, PTX3 activated a TLR4-dependent IRAK1/PI3K-Akt/GSK-3/β-catenin signaling cascade. Genetic downregulation or pharmacologic blockade of PTX3-TLR4 significantly reduced tumor growth and angiogenesis in vivo. Moreover, the TLR4 inhibitor TAK-242 markedly impacted SHH-MB growth in vitro, and combination therapy of TAK-242 and VCC produced additive/synergistic effects in vitro and significantly prolonged survival in orthotopic SHH-MB-bearing mice. CONCLUSIONS:Our findings identify PTX3-TLR4 signaling as key oncogenic driver and a promising therapeutic vulnerability in SHH-MB. Targeting this pathway enhances the efficacy of standard therapy and represents a rationale for mechanism-based combination strategies.

Gene panels represent a widely used strategy for genetic testing in a vast range of Mendelian disorders. While this approach aids reliable bioinformatic detection of short coding variants, it often fails to detect many larger variants. Recent studies have recommended the adoption of pangenome references (as opposed to linear reference genomes like GRCh38) to augment detection of large variants from targeted sequencing, potentially providing diagnostic laboratories with the possibility to streamline diagnostic work-ups and reduce costs. Here, we analyze 1969 cardiomyopathy cases and 1805 controls sequenced with the Illumina Trusight Cardio panel using a pangenome-based workflow (GRAF) and five conventional orthogonal methodologies (GATK HaplotypeCaller, GATK-gCNV, ExomeDepth, Manta and Lumpy-SV) to detect variants ≥ 20 bp in size. Following lab-based variant validation by means of PCR and Sanger sequencing, we show that GRAF conjugates higher precision and recall (F1 score 0.86) compared with other methods (F1 0-0.57) in detecting potentially pathogenic variants ≥ 20 bp from short-read panel data. Results were complemented by a comparison of the tools’ performance in detecting ground truth variants on reference sample HG002 from Genome In A Bottle, which confirmed GRAF to outperform other tools also on exome sequencing (F1 0.97 vs. 0-0.94). Notably, in the HG002 benchmark dataset, GRAF also showed slightly improved performance compared to GATK HaplotypeCaller in the identification of small variants (1–19 bp; F1 0.975 vs. 0.968). Our results indicate that pangenome-based workflows aid improved detection of large variants from targeted sequencing data in the clinical context and suggest that they may contribute to more unified variant detection frameworks for all-size genetic variants in the future.

Interstitial deletions of 2q32 are typically identified after investigation for developmental delay. Two genes associated with Ehlers Danlos Syndrome (EDS); COL3A1 and COL5A2 associated with vascular EDS and classical EDS respectively, may be incorporated in the region. Although many reports of 2q32 microdeletion patients exist, there is little mention of these genes with only a few reports highlighting features potentially linked with EDS. This paper reviews the literature and presents eleven new patients with 2q32 deletions that encompass COL3A1 and COL5A2. We describe their clinical manifestations with a particular focus on the EDS phenotype. Most patients showed some minor features of vascular EDS and one patient had vessel rupture at a young age. Analysis of skin biopsy findings from two patients showed features consistent with vascular EDS but no features of classical EDS. The findings from this cohort provide additional evidence that haploinsufficiency is an important disease mechanism in COL3A1 but not COL5A2. We highlight the importance of pre-test counselling for incidental findings from broad genetic testing and appropriate post-test counselling to ensure follow up is provided to manage the implications of a vascular EDS diagnosis.

Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a β1-adrenoceptor antagonist with partial β2 agonist activity capable of reducing rates of vascular events in this setting, though the underlying mechanisms have yet to be elucidated. In particular, no conclusive evidence exists on its impact on blood pressure (BP) parameters in patients with vEDS. Accordingly, the aim of our study was to perform a comprehensive assessment of BP profile in a cohort of patients with vEDS receiving celiprolol titrated to the maximum tolerated dose. Consecutive outpatients with molecularly confirmed vEDS undergoing office BP measurement and 24-h ambulatory BP monitoring (ABPM) were retrospectively evaluated. Using 24-h systolic BP, diastolic BP, mean BP, and pulse pressure (PP) (mmHg) values, indices of short-term BP variability were calculated. A generalized linear regression model was applied to analyze the correlation between initial values of BP parameters and their variation with celiprolol therapy. Overall, 20 subjects were included (12 females). Eight patients (40%) had 24-h ABPM values consistent with hypertension. Five subjects (25%) defined hypertensives at 24-h ABPM had optimal BP control at office BP measurement, suggesting a "masked" hypertension. A significant correlation was found between initial values of indices of short-term PP variability and their change with celiprolol therapy, with a particularly high Pearson's index for PP coefficient of variation (r = -0.926; p < 0.001). In patients with vEDS, 24-h ABPM is confirmed a reliable tool in identifying hypertension phenotypes. Treatment with celiprolol may reduce PP variability proportionally to its initial magnitude. Dedicated studies on larger cohorts should evaluate whether short-term PP variability is a reliable prognostic marker and therapeutic target in this clinical setting. In our study, treatment with celiprolol seemed to reduce short-term PP variability proportionally to its initial magnitude in patients with vEDS. Furthermore, two out of four patients experiencing vascular events during the study period displayed the highest short-term PP variability values recorded in the entire cohort. Further research should evaluate whether such parameters are reliable prognostic markers and therapeutic targets in this clinical setting. ABPM ambulatory blood pressure monitoring, ARV average real variability, BP blood pressure, CV coefficient of variation, DBP diastolic blood pressure, PP pulse pressure, SBP systolic blood pressure, SD standard deviation, TRI time-rate index, vEDS vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a β1-adrenoceptor antagonist with partial β2 agonist activity that has been shown to reduce rates of vascular events in this setting, though the underlying mechanisms are not yet fully understood. Moreover, very few echocardiographic data are available in patients with vEDS. To perform a comprehensive echocardiographic assessment of a cohort of patients with vEDS with or without celiprolol therapy compared with healthy subjects. Twenty patients with genetically confirmed diagnosis of vEDS followed at our Institution (University Hospital of Brescia, Italy) were divided into two groups according to whether or not they were on celiprolol therapy at the maximum recommended dose (400 mg daily) for at least 12 months. Both groups were compared to 10 healthy individuals matched for sex, age, body mass index (BMI), and office blood pressure (BP) values. Each participant underwent transthoracic echocardiography with tissue Doppler analysis (TDI) for a comprehensive evaluation of cardiac structure and function. Mean age was 35 years and mean BMI was 21.6 kg/m2. Female sex was prevalent (60

Background: Dominant mutations in COL3A1 are known to cause vascular Ehlers-Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. Methods: In this study, we conducted a comprehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. Results: Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably, the inhibition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. Conclusions: Overall, our findings advance our understanding of the complex biological mechanisms driving vEDS and lay a solid foundation for future research focused on developing targeted and effective treatment strategies for this life-threatening disorder.

Vascular Ehlers–Danlos syndrome (vEDS) is a rare autosomal dominant connective tissue disease resulting from pathogenic variants in the collagen type III alpha 1 chain (COL3A1) gene, encoding type III procollagen. Patients with vEDS present with severe tissue fragility that can result in arterial aneurysm, dissection, or rupture, especially of medium-caliber vessels. Although early reports have indicated a very high mortality rate in affected patients, with an estimated median survival of around 50 years, recent times have seen a remarkable improvement in outcomes in this population. This shift could be related to greater awareness of the disease among patients and physicians, with improved management both in terms of follow-up and treatment of complications. Increasing use of drugs acting on the cardiovascular system may also have contributed to this improvement. In particular, celiprolol, a β1 cardio-selective blocker with a β2-agonist vasodilator effect, has been shown to reduce rates of vascular events in patients with vEDS. However, the evidence on the true benefits and possible mechanisms responsible for the protective effect of celiprolol in this specific setting remains limited. Drugs targeting the extracellular matrix organization and autophagy–lysosome pathways are currently under investigation and could play a role in the future. This narrative review aims to summarize current evidence and future perspectives on vEDS medical treatment, with a specific focus on vascular prevention.

Gene panels represent a widely used strategy for genetic testing in a vast range of Mendelian disorders. While this approach aids reliable bioinformatic detection of short coding variants, it fails to detect most larger variants. Recent studies have recommended the adoption of pangenomes to augment detection of large variants from targeted sequencing, potentially providing diagnostic laboratories with the possibility to streamline diagnostic work-ups and reduce costs.  Here, we analyze a large-scale cohort comprising 1,952 cardiomyopathy cases and 1,805 technically matched controls and show that a pangenome-based workflow, GRAF, conjugates higher precision and recall (F1 score 0.86) compared with conventional orthogonal methods (F1 0-0.57) in detecting potentially pathogenic ≥20bp variants from short-read panel data. Our results indicate that pangenome-based workflows aid precise and cost-effective detection of large variants from targeted sequencing data in the clinical context. This will be particularly relevant for conditions in which these variants explain a high proportion of the disease burden. ### Competing Interest Statement As reflected by the affiliations, several authors of the paper (OK, EA, DT, GB, ST and AJ) are (or were, at the time this study was in development) employees of Seven Bridges Genomics or Velsera Inc, the commercial companies developing GRAF. ### Funding Statement JSW was supported by Sir Jules Thorn Charitable Trust [21JTA], The Medical Research Council (UK), The British Heart Foundation [RE/18/4/34215, SP/17/11/32885, BBC/F/21/220106] and the NIHR Imperial College Biomedical Research Centre. PP, JB and MM were supported by the Ministry of Health of the Czech Republic (grant 15‐34904A) and Conceptual Development of Research Organization, Motol University Hospital, Prague (grant 00064203). VC, VB, MC and MR extend sincere thanks to the Fazzo Cusan family for its generous support. We are also grateful to Dr. Beatrice Boschi and Dr. Irene Giotti from the Careggi University Hospital (Florence, Italy) for having provided the Sanger chromatogram displayed in Supplementary Figure 2. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All patients gave written informed consent, and for each of the four centers contributing sequencing data, approval for the study was given or waived by the relevant regional research ethics committees. Specifically, for London samples, ethical approval was given by the Hampshire B Research Ethics Committee (09/H0504/104+5 and 19/SC/0257) and by the London - West London & GTAC Research Ethics Committee (09/H0707/69). For Prague samples, approval was given by the IRB of Motol University Hospital (Reference No. EK-323/23). For Aswan samples, approval was given by the Local Research Ethics Committee (registered with the Egypt Ministry of Health, the US Department of Health and Human Services (HHS) Institutional Review Board (IRB) and the Federal wide Assurance for the Protection of Human Subject (FWA)), with approval number 20130405MYFAHC\_CMR\_20130330. For Florence samples, approval was waived by the Comitato Etico Area Vasta Centro (CEAVC) based on the informed consent for anonymized research use of the DNA sample given by each patient when referred for genetic testing at the Careggi University Hospital. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a beta1-adrenoceptor antagonist with partial beta2 agonist activity that has been shown to reduce rates of vascular events in this setting, though the underlying mechanisms are not yet fully understood. Moreover, few data on echocardiographic assessment are available in patients with vEDS. Design and method: Twenty patients with genetically confirmed diagnosis of vEDS followed at our Institution were divided into two groups (10 patients each) according to whether or not they were on celiprolol therapy at the maximum recommended dose (400 mg daily) for at least 12 months. Both groups were compared to 10 healthy individuals matched for sex, age, body mass index (BMI), and office blood pressure values. Each participant underwent transthoracic echocardiography with tissue Doppler analysis for a comprehensive evaluation of cardiac structure and function. Results: Mean age was 35 years and mean BMI was 21.6 kg/m2. Female sex was prevalent (60%). Left ventricular (LV) internal diameter values tended to be lower in patients with untreated vEDS than in healthy controls, though this difference was not statistically significant (4.33 vs 4.74 cm, respectively; p=0.053). Similar data were observed for LV mass index (56.9 vs 68.6 g/m2; p=0.093), stroke volume (56.6 vs 71.6 mL; p=0.068), and E/A ratio (1.26 vs 1.66; p=0.082), whereas an opposite trend was observed for e’ lateral (13.2 vs 12.2; p=0.096). No statistically significant difference was found between groups in terms of other parameters of LV mass, systolic and diastolic function. A normal LV geometry was found in all the cases. Indices of mechano-energetic efficiency and ventricular-arterial coupling were also similar between groups. No patient presented with aortic root dilation, mitral valve prolapse, valve insufficiency of more than mild degree, or valve stenosis of any degree. Conclusions: Our study suggests that patients with vEDS have normal cardiac mass and geometry, as well as normal systolic and diastolic function. Celiprolol therapy does not seem to significantly influence such aspects. Future studies on larger cohort of patients should confirm these aspects.

Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD), common overlapping multisystemic conditions featuring symptomatic joint hypermobility, is challenging due to lack of established causes and diagnostic tools. Currently, the 2017 diagnostic criteria for hEDS are used, with non-qualifying cases classified as HSD, although the distinction remains debated. We previously showed extracellular matrix (ECM) disorganization in both hEDS and HSD dermal fibroblasts involving fibronectin (FN), type I collagen (COLLI), and tenascin (TN), with matrix metalloproteinase-generated fragments in conditioned media. Here, we investigated these fragments in patient plasma using Western blotting across diverse cohorts, including patients with hEDS, HSD, classical EDS (cEDS), vascular EDS (vEDS), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and healthy donors, uncovering distinctive patterns. Notably, hEDS/HSD displayed a shared FN and COLLI fragment signature, supporting their classification as a single disorder and prompting reconsideration of the hEDS criteria. Our results hold the promise for the first blood test for diagnosing hEDS/HSD, present insights into the pathomechanisms, and open the door for therapeutic trials focused on restoring ECM homeostasis using an objective marker. Additionally, our findings offer potential biomarkers also for OA, RA, and PsA, advancing diagnostic and therapeutic strategies in these prevalent joint diseases.

Background: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. Methods: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. Results: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. Conclusion: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene encoding type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency leads to soft connective tissues fragility, resulting in life-threatening arterial and organ ruptures. There are no current targeted therapies available. Although the disease usually results from COLLIII misfolding due to triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we performed a comprehensive transcriptome analysis using RNA- and miRNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum stress response, and compromised autophagy, which may significantly impact the molecular pathology. We also present the first detailed miRNAs expression profile in patient cells, demonstrating that several aberrantly expressed miRNAs can disrupt critical cellular functions involved in vEDS pathophysiology, such as autophagy, proteostasis, and mTOR signaling. Target prediction and regulatory networks analyses suggested potential interactions among miRNAs, lncRNAs, and candidate target genes linked to extracellular matrix organization and autophagy-lysosome pathway. Our results highlight the importance of understanding the functional role of ncRNAs in vEDS pathogenesis, shedding light on possible miRNAs and lncRNAs signatures and their functional implications for dysregulated pathways related to disease. Deciphering this complex molecular network of RNA interactions may yield additional evidence for potential disease biomolecules and targets, assisting in the design of effective patient treatment strategies.

Pathogenic variants in TGFBR1 are a common cause of Loeys-Dietz syndrome (LDS) characterized by life-threatening aortic and arterial disease. Generally, these are missense changes in highly conserved amino acids in the serine–threonine kinase domain. Conversely, nonsense, frameshift, or specific missense changes in the ligand-binding extracellular domain cause multiple self-healing squamous epithelioma (MSSE) lacking the cardiovascular phenotype. Here, we report on two novel variants in the penultimate exon 8 of TGFBR1 were identified in 3 patients from two unrelated LDS families: both were predicted to cause frameshift and premature stop codons (Gln448Profs*15 and Cys446Asnfs*4) resulting in truncated TGFBR1 proteins lacking the last 43 and 56 amino acid residues, respectively. These were classified as variants of uncertain significance based on current criteria. Transcript expression analyses revealed both mutant alleles escaped nonsense-mediated mRNA decay. Functional characterization in patient’s dermal fibroblasts showed paradoxically enhanced TGFβ signaling, as observed for pathogenic missense TGFBR1 changes causative of LDS. In summary, we expanded the allelic repertoire of LDS-associated TGFBR1 variants to include truncating variants escaping nonsense-mediated mRNA decay. Our data highlight the importance of functional studies in variants interpretation for correct clinical diagnosis.

The most common conditions with symptomatic joint hypermobility are hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Diagnosing these overlapping connective tissue disorders remains challenging due to the lack of established causes and reliable diagnostic tests. hEDS is diagnosed applying the 2017 diagnostic criteria, and patients with symptomatic joint hypermobility but not fulfilling these criteria are labeled as HSD, which is not officially recognized by all healthcare systems. The 2017 criteria were introduced to improve diagnostic specificity but have faced criticism for being too stringent and failing to adequately capture the multisystemic involvement of hEDS. Herein, we retrospectively evaluated 327 patients from 213 families with a prior diagnosis of hypermobility type EDS or joint hypermobility syndrome based on Villefranche and Brighton criteria, to assess the effectiveness of the 2017 criteria in distinguishing between hEDS and HSD and document the frequencies of extra-articular manifestations. Based on our findings, we propose that the 2017 criteria should be made less stringent to include a greater number of patients who are currently encompassed within the HSD category. This will lead to improved diagnostic accuracy and enhanced patient care by properly capturing the diverse range of symptoms and manifestations present within the hEDS/HSD spectrum.

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a beta1-adrenoceptor antagonist with partial beta2 agonist activity that has been shown to reduce rates of vascular events in this setting, though the underlying mechanisms are not yet fully understood. Aim of the present study was to assess the impact of Celiprolol on blood pressure (BP) and heart rate (HR) in patients with vEDS. Design and method: Patients with genetically confirmed disease referred to our Institution between 2011 and 2022 were divided into two groups according to whether or not they were on Celiprolol therapy. The former were included if on Celiprolol at the dose of 400 mg daily for at least 12 months. Each participant underwent office blood pressure (BP) measurement, 24-h ambulatory BP monitoring (ABPM), and pulse wave analysis (PWA) of the radial artery with calculation of central pulse pressure (PP) and augmentation index (AIx). Results: Overall, 18 patients (11 females) were included. Mean age was 36 years and mean body mass index (BMI) was 22.1 kg/m 2 . Eleven patients were on Celiprolol therapy. No significant differences were found between groups in terms of age, sex, BMI, and presence of hypertension (p>0.05). Patients on Celiprolol therapy displayed higher values of systolic BP (SBP) (124 vs 113 mmHg; p = 0.128), diastolic BP (DBP) (76 vs 67 mmHg; p = 0.236), mean BP (92 vs 83 mmHg; p = 0.173), and HR at office BP measurement, as well as lower AIx (126 vs 140%; p = 0.176) at PWA, although the difference was not statistically significant. Similarly, no significant difference was found for all ABPM parameters (24-h, day-time, and night-time SBP, DBP, mean BP, and HR), as well as central SBP, central DBP, central mean BP, and PP at PWA between groups (p>0.05). Conclusions: Our study suggests little impact of Celiprolol therapy on both BP and HR in patients with vEDS, which hints additional mechanisms behind its protective effect in this clinical setting. Further studies on larger cohorts are needed to clarify these aspects.

JDDG: Journal der Deutschen Dermatologischen GesellschaftEarly View Clinical Letter Phacomatosis pigmentovascularis spilorosea and mutation in the PTPN11 gene: new case with significant neurologic impairment Vincenzo Maione, Vincenzo Maione Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, ItalySearch for more papers by this authorSimone Soglia, Corresponding Author Simone Soglia s.soglia@unibs.it Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, Italy Correspondence to Simone Soglia, MD Department of Dermatology University of Brescia Piazzale Spedali Civili 1 Brescia, Italy E-mail: s.soglia@unibs.itSearch for more papers by this authorLaura Miccio, Laura Miccio Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, ItalySearch for more papers by this authorPiergiacomo Calzavara-Pinton, Piergiacomo Calzavara-Pinton Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, Italy Division of Dermatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorAngela Napolitano, Angela Napolitano Division of Radiology, ASST Papa Giovanni XIII, Bergamo, ItalySearch for more papers by this authorValeria Cinquina, Valeria Cinquina Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this authorMarco Ritelli, Marco Ritelli Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this authorMarina Colombi, Marina Colombi Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this author Vincenzo Maione, Vincenzo Maione Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, ItalySearch for more papers by this authorSimone Soglia, Corresponding Author Simone Soglia s.soglia@unibs.it Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, Italy Correspondence to Simone Soglia, MD Department of Dermatology University of Brescia Piazzale Spedali Civili 1 Brescia, Italy E-mail: s.soglia@unibs.itSearch for more papers by this authorLaura Miccio, Laura Miccio Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, ItalySearch for more papers by this authorPiergiacomo Calzavara-Pinton, Piergiacomo Calzavara-Pinton Division of Dermatology, ASST Spedali Civili di Brescia, Brescia, Italy Division of Dermatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorAngela Napolitano, Angela Napolitano Division of Radiology, ASST Papa Giovanni XIII, Bergamo, ItalySearch for more papers by this authorValeria Cinquina, Valeria Cinquina Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this authorMarco Ritelli, Marco Ritelli Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this authorMarina Colombi, Marina Colombi Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalySearch for more papers by this author First published: 14 June 2022 https://doi.org/10.1111/ddg.14786AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.