マルファン症候群／ロイス・ディーツ症候群

Marfan syndrome (MFS) aortopathy involves extracellular matrix disruption, altered mechanical cues, and maladaptive vascular smooth muscle cell (VSMC) remodeling. However, the mechanosensitive regulators associated with MFS-related VSMC dysfunction remain unclear. This study aimed to identify and validate mechanosensitive candidate genes in MFS aortopathy. Public VSMC transcriptomic data from GSE128101 were re-analyzed to identify differentially expressed genes (DEGs). Protein-protein interaction analysis, functional enrichment, and minimum redundancy maximum relevance analysis were used to prioritize mechanosensitive candidates. Candidate genes were examined in independent MFS-related datasets and validated by qRT-PCR in primary aortic medial VSMCs from MFS patients and donor controls. TRPV4 localization was assessed by immunofluorescence. TRPV4 function was evaluated in primary human aortic smooth muscle cells using overexpression and siRNA-mediated knockdown, followed by proliferation, wound-closure, inflammatory cytokine, and NF-κB pathway assays. A total of 436 DEGs were identified in MFS-derived aortic VSMCs. Functional analyses highlighted extracellular matrix remodeling, mechanotransduction-related, inflammatory, and cytoskeleton-associated pathways. TRPV4 was the top-ranked mechanosensitive candidate, with TRPM5 also identified as an overlapping candidate. qRT-PCR confirmed increased TRPV4 and TRPM5 expression in MFS-derived VSMCs. MFS-derived VSMCs also showed elevated inflammatory gene expression and enhanced membrane-associated TRPV4 localization. In vitro, TRPV4 overexpression promoted proliferation, wound closure, inflammatory cytokine secretion, and NF-κB pathway phosphorylation, whereas TRPV4 knockdown showed opposite effects. These exploratory findings identify TRPV4 as a leading mechanosensitive candidate associated with MFS-related VSMC remodeling and inflammatory activation. Larger cohorts, MFS-specific models, and direct mechanistic assays are required to determine its biomarker or therapeutic relevance.

PURPOSE: Phenotypic heterogeneity is a hallmark of Marfan syndrome (MFS) with ectopia lentis (EL), yet genotype-phenotype correlations for ocular traits remain incompletely understood. This study aimed to identify genomic determinants of extreme ocular phenotypes using a combined phenotype-first and genotype-first analytical strategy. METHODS: A two-stage discovery-validation genotype-phenotype association study included 490 patients with MFS with FBN1 variants (246 retrospective and 244 prospective validation). Age-adjusted Z-scores were calculated for axial length (AL) and corneal curvature radius (CCR), whereas central corneal thickness (CCT) and white-to-white distance (WTW) were analyzed using raw measurements. Extreme phenotype sampling identified candidate associations, validated prospectively. A genotype score integrating mutational effect and genomic position was developed. RESULTS: FBN1 genotype was significantly associated with Z-AL, with suggestive exploratory associations for WTW and CCT. Haploinsufficient (HI) variants correlated with higher Z-AL, whereas dominant-negative (DN) variants affecting non-critical residues (Others) were enriched among lower Z-AL individuals. Variants in the TGF-β regulatory region (exons 43-65) further distinguished higher Z-AL individuals from those carrying DN variants affecting critical residues (-Cys + CaB). The genotype score demonstrated a significant positive association with Z-AL (β = 0.724, 95% confidence interval [CI] = 0.371-1.077, P < 0.001), independent of age, sex, and EL severity. Higher scores were also associated with thinner CCT and larger WTW, likely secondary to progressive axial elongation. EL severity showed no significant correlation with genotype. CONCLUSIONS: Extreme phenotype sampling with independent validation reveals reproducible genotype-phenotype correlations in the MFS ocular system. The genotype score provides preliminary genotype-guided risk stratification for ocular biometric variability.

Secondary spontaneous pneumothorax (SSP) carries a clinically important risk of recurrence, but the available evidence is dispersed across heterogeneous disease-specific and treatment cohorts. This systematic review aimed to identify clinical, radiological, physiological, disease-related, clinical-course, and treatment-related determinants of recurrence after SSP. PubMed/MEDLINE was searched on 19 July 2026 without a date restriction. Adult and adult-inclusive SSP cohorts were eligible, as were mixed spontaneous-pneumothorax cohorts containing patients with SSP when a recurrence determinant was evaluated. Evidence without SSP-specific estimates was classified as indirect. Of 77 records screened, 50 reports were sought, 31 were retrieved and assessed, two were excluded at full text, and 29 studies were included. Nineteen reports could not be retrieved and were classified as unavailable rather than scientifically excluded. Because of substantial heterogeneity in populations, interventions, recurrence definitions, follow-up periods, and effect measures, a narrative synthesis was undertaken without meta-analysis. Recurrence was associated with severe emphysematous or fibrotic lung damage, non-chronic obstructive pulmonary disease (non-COPD) aetiology, prolonged air leak, impaired forced expiratory volume in one second (FEV1), Birt-Hogg-Dubé syndrome, chest deformity in Marfan syndrome, and selected malignancy-related radiographic features. Definitive recurrence prophylaxis, video-assisted thoracoscopic surgery (VATS)-based procedures, pleural interventions, and medical pleurodesis were generally associated with lower recurrence than drainage alone. Technical comparisons suggested that the effectiveness of lesion control and pleural intervention may be more important than the number of thoracoscopic ports. Evidence favouring thoracotomy over VATS arose from mixed cohorts and should be interpreted cautiously. SSP recurrence risk should therefore be assessed using the underlying disease, structural lung damage, physiological reserve, behaviour of the index episode, and suitability for definitive pleural intervention.

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.

Although aortic complications are common in patients with Marfan syndrome (MFS), spontaneous peripheral arterial rupture is rare. Herein, we report a 40-year-old woman with MFS who presented with left-sided chest pain and hoarseness due to a massive intrathoracic hematoma. She had undergone multiple thoracic surgeries for aortic dissection. Rupture of fragile neovessels associated with surgery-related inflammation was suspected. Hemostasis was achieved by transcatheter embolization of the left lateral thoracic and supreme intercostal arteries. Intrathoracic bleeding should be considered in patients with MFS presenting with chest pain or hoarseness, particularly those receiving anticoagulation therapy or those who have undergone prior thoracic surgery.