オスラー病

Hereditary Hemorrhagic Telangiectasia (HHT) is a currently incurable genetic disorder caused by loss-of-function mutations in the ALK1-BMP9 pathway, leading to dysregulated angiogenesis and consequential vascular malformations. Recent experiments also implicate the mechanotransducers YAP/TAZ in HHT pathology. However, how YAP/TAZ stiffness sensitivity and signaling activity contribute to aberrant HHT angiogenesis remains poorly understood. Here, we extended our previous computational framework of stiffness-mediated YAP/TAZ-VEGF-NOTCH crosstalk to account for ALK1 signalling and predict the resulting angiogenic temporal dynamics. Our simulations predicted that ALK1 knockout impairs NOTCH activation, slowing endothelial phenotypic selection and shuffling while enhancing filopodia activity, features corresponding with hypersprouting. These effects were most pronounced in low stiffness environments, consistent with the previously observed prevalence of HHT vascular malformations in low stiffness organs. Importantly, the temporal dynamics of endothelial phenotypic selection and shuffling, as well as key protein activity levels, were partially restored by direct or cytoskeleton-mediated inhibition of YAP/TAZ resulting from increased NOTCH activation. These computational findings offer more mechanistic insight into the signalling pathways and temporal dynamics of endothelial phenotypic selection underlying HHT vascular anomalies, and suggest that targeting YAP/TAZ and endothelial stiffness sensitivity may offer a promising therapeutic strategy to restore physiological angiogenesis.

BACKGROUND: Hereditary hemorrhagic telangiectasia is a genetic disorder caused by loss-of-function mutations in components of the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. Most prior work has treated BMP (bone morphogenetic protein)-component depletion as mechanistically interchangeable, yet whether distinct genes converge on a shared mechanism remains unclear. We aimed to understand the molecular relationship between BMP signaling and endothelial flow response that leads to arteriovenous malformation formation. METHODS: We expose human endothelial monolayers treated with small interfering RNA against SMAD4 or ALK1 to laminar flow and analyze flow-responsive transcriptomics, flow-responsive BMP signaling activation dynamics, cell polarity, and morphology. We analyze the cell-autonomous and noncell-autonomous migration dynamics of endothelial cells treated with siSMAD4 or siALK1. Using the postnatal mouse retina model, we study endothelial cell distribution changes over time in mosaic settings, and assess the remodeling capabilities of SMAD4iECKO or ALK1iECKO, relative to littermate controls. RESULTS: This study shows that depletion of SMAD4 or ALK1 leads to fundamentally distinct mechanisms of vascular malformation. SMAD4 deficiency enhances endothelial responses to blood flow, including transcriptional activation and migration against flow, causing excessive capillary pruning and the development of single large shunts. In contrast, ALK1 deficiency disrupts flow sensing, impairs cell polarization and migration, and promotes a persistent angiogenic state, resulting in dense, hypervascularized networks. RNA sequencing across static and flow conditions identifies both flow-dependent and flow-independent transcriptional changes, suggesting early defects in endothelial fate specification. Mosaic in vitro models show that mutant cells co-opt neighboring wild-type cells, while in vivo tracking confirms mutation-specific migration behavior. CONCLUSIONS: These findings reveal divergent cellular programs driving arteriovenous malformations and underscore the need for gene-specific diagnostic and therapeutic strategies.

PURPOSE: Pediatric hereditary polyposis syndromes require lifelong surveillance and multidisciplinary management, yet pediatric care remains variable despite multiple evolving guideline frameworks. This review synthesizes current society recommendations and contextualizes their implementation within pediatric clinical practice. METHODS: A narrative review was performed using current literature and major hereditary polyposis guideline frameworks selected for their pediatric relevance and clinical applicability, with emphasis on pediatric considerations in familial adenomatous polyposis (FAP), attenuated FAP, juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), and rare or emerging polyposis syndromes. RESULTS: The reviewed guidelines are broadly concordant in supporting syndrome-directed surveillance, but differ in pediatric specificity, age of initiation, surveillance intervals, and emphasis on extracolonic manifestations. The accompanying tables synthesize recommendations across major societies and highlight areas of concordance and variability for FAP, JPS, PJS, and less common syndromes. Key pediatric distinctions include hepatoblastoma screening in APC-associated disease, hereditary hemorrhagic telangiectasia evaluation in SMAD4-associated JPS, and early small-bowel surveillance in PJS to prevent intussusception. Persistent implementation gaps include management of genotype-negative disease, timing of surgical referral, use of advanced therapeutic endoscopy, and transition to adult care. CONCLUSION: Pediatric hereditary polyposis syndrome management may benefit from an integrated synthesis of society recommendations, individualized by phenotype, genotype, polyp burden, available expertise, and local resources. Consolidated guideline-based tables may serve as practical reference tools that facilitate more consistent pediatric care, although their impact on clinical implementation, consistency of care, and patient outcomes remains to be established.

OBJECTIVE: This study aimed to assess the quality of life in patients with Hereditary Haemorrhagic Telangiectasia (HHT) and to validate the Danish version of the Epistaxis Severity Score (ESS). METHODS: The Danish version of the ESS was created through forward backward translation. The study was conducted through The Danish HHT Database, which includes patients from the national HHT center. Participants completed the Danish ESS, Short Form 36 (SF-36), and Visual Analog Scale (VAS) questionnaires, and filled out a two-week nosebleed diary documenting bleeding time. Haemoglobin and ferritin were obtained from routine clinical follow-up. ESS was validated by correlating ESS with VAS, SF-36, and bleeding time. Quality of life was assessed using VAS, SF-36, and bleeding time. RESULTS: A total of 124 patients were included. Mean participant age was 53 years, and 65% were female. Average ESS was 3.37 distributed in a mild (62.9%), moderate (35.5%), and severe (1.6%) group. The scatter plot indicated a positive correlation between ESS and bleeding time among participants with heavier bleeding. There was a negative correlation between ESS and the SF-36 scale "General Health" subscale (-4.14 (-6.01; -2.27), p < 0.001). All SF-36 subscales except "bodily pain" were found to correlate to ESS. Age was found to be the only predictor of ESS, although the effect size was small (0.025). No associations were found between ESS and gender, HHT type, or anticoagulation therapy. CONCLUSION: The Danish ESS demonstrated good construct validity and inverse correlations with multiple SF-36 domains, confirming its utility for assessing epistaxis severity and quality of life among Danish HHT patients. Although a valuable score, ESS may not represent the full clinical picture of epistaxis severity and should be interpreted alongside other assessment tools.