BACKGROUND: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders.
OBJECTIVE: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.
METHODS: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.
RESULTS: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.
CONCLUSIONS: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.

Objective: To investigate the characteristics of posterior segment lesions in Marfan syndrome (MFS) patients and their relationship with anterior segment biometric parameters and FBN1 genotype. Methods: A cross-sectional study was conducted. A total of 121 MFS patients, 76 males and 45 females, with an average age of (11.72±11.66) years, who visited the Department of Ophthalmology, Eye & ENT Hospital of Fudan University from January 2013 to March 2023 were included. The presence of posterior scleral staphyloma was observed using B-mode ultrasound, and macular lesions were identified and classified using the atrophy-traction-neovascularization system based on ultra-widefield fundus images, color fundus images, and optical coherence tomography scans. Anterior segment biometric parameters, including axial length of the eye, average corneal curvature, corneal astigmatism, horizontal corneal diameter, anterior chamber depth, and lens thickness, were collected, and the direction and extent of lens dislocation were observed. Molecular genetic analysis of FBN1 gene mutations in patients was performed using next-generation sequencing based on a panel of ocular genetic diseases, and the impact of the genotype and anterior segment biometric parameters on the posterior segment manifestations was analyzed. Results: Sixty patients exhibited posterior segment lesions, including retinal detachment (4 cases, 3.31%), macular lesions (47 cases, 38.84%), and posterior scleral staphyloma (54 cases, 44.63%). There was statistically significant difference in axial length of the eye between patients with and without posterior scleral staphyloma [23.09 (22.24, 24.43) and 27.04 (25.44, 28.88) mm], between patients with and without macular lesions [23.16 (22.24, 24.61) and 27.04 (25.74, 28.78) mm], and between patients with and without atrophic macular lesions [23.16 (22.24, 24.61) and 27.04 (25.74, 28.79) mm] (all P<0.001). There was statistically significant difference in anterior chamber depth between patients with and without macular lesions [3.11 (2.75, 3.30) and 3.34 (3.09, 3.60) mm] (P<0.05). There was also statistically significant difference in corneal astigmatism between patients with and without posterior scleral staphyloma [2.15 (1.20, 2.93) and 1.40 (1.00, 2.20) diopters] (P<0.05). The location and region of the FBN1 gene mutation not only showed statistically significant difference from the positive rates of posterior scleral staphyloma and macular lesions (all P<0.05), but also influenced the occurrence of atrophic macular lesions (both P<0.05). Patients with FBN1 mutations located in the transforming growth factor β regulatory sequence had the highest proportion of posterior scleral staphyloma and macular lesions (both 10/11). Conclusions: Posterior scleral staphyloma and macular lesions have a relatively high incidence in MFS patients and tend to progress to more severe grades. The age, axial length of the eye, anterior chamber depth, corneal astigmatism, and location and region of the FBN1 gene mutation are factors affecting the posterior segment lesions in MFS patients.
目的： 探讨马方综合征（MFS）患者眼后节病变的特征及其与眼前节生物学参数及FBN1基因型的关系。 方法： 横断面研究。收集2013年1月至2023年3月于复旦大学附属眼耳鼻喉科医院眼科就诊的MFS患者121例，其中男性76例，女性45例；年龄为（11.72±11.66）岁。采用B超观察是否存在后巩膜葡萄肿，根据超广角眼底像、彩色眼底像和相干光层析扫描结果观察是否存在黄斑病变并判断其类型。黄斑病变按照萎缩-牵引-新生血管分级系统进行分类。收集患眼眼前节生物学参数，包括眼轴长度、角膜平均曲率、角膜散光度数、角膜水平径、前房深度及晶状体厚度，并观察晶状体脱位的方向和范围。采用基于面板的全眼科遗传病基因组进行下一代测序对患者的FBN1基因突变进行了分子遗传学分析，并分析基因型和眼前节生物学参数对眼后节表现的影响。 结果： 共有60例患者出现眼后节病变，包括视网膜脱离（4例，3.31%），黄斑病变（47例，38.84%）和后巩膜葡萄肿（54例，44.63%）。是否合并后巩膜葡萄肿［23.09（22.24，24.43）和27.04（25.44，28.88）mm］，以及是否合并黄斑病变［23.16（22.24，24.61）和27.04（25.74，28.78）mm］的患者间，眼轴长度的差异均有统计学意义（均P<0.001）；是否合并萎缩性黄斑病变的患者，眼轴长度差异亦有统计学意义［23.16（22.24，24.61）和27.04（25.74，28.79）mm，P<0.001］。是否合并黄斑病变的患者中，前房深度［3.11（2.75，3.30）和3.34（3.09，3.60）mm］的差异有统计学意义（P<0.05）；是否合并后巩膜葡萄肿的患者中，角膜散光度数［2.15（1.20，2.93）和1.40（1.00，2.20）D］的差异有统计学意义（P<0.05）。FBN1基因突变的位置和区域与后巩膜葡萄肿及黄斑病变的阳性率之间的差异有统计学意义（均P<0.05）。FBN1突变的位置和区域会影响萎缩性黄斑病变的发生（均P<0.05）。FBN1突变位于转化生长因子β调节序列的患者后巩膜葡萄肿和黄斑病变的占比最高，均为10/11。 结论： MFS患者后巩膜葡萄肿和黄斑病变的发生率较高，并且倾向于向严重程度更高的分级发展。年龄、眼轴长度、前房深度、角膜散光度数，以及FBN1基因突变位点所在位置及区域均是MFS患者眼后节病变的影响因素。.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disease with wide clinical heterogeneity, and mainly caused by pathogenic variants in fibrillin-1 (FBN1).
METHODS: A Chinese 4-generation MFS pedigree with 16 family members was recruited and exome sequencing (ES) was performed in the proband. Transcript analysis (patient RNA and minigene assays) and in silico structural analysis were used to determine the pathogenicity of the variant. In addition, germline mosaicism in family member (Ι:1) was assessed using quantitative fluorescent polymerase chain reaction (QF-PCR) and short tandem repeat PCR (STR) analyses.
RESULTS: Two cis-compound benign intronic variants of FBN1 (c.3464-4 A > G and c.3464-5G > A) were identified in the proband by ES. As a compound variant, c.3464-5_3464-4delGAinsAG was found to be pathogenic and co-segregated with MFS. RNA studies indicated that aberrant transcripts were found only in patients and mutant-type clones. The variant c.3464-5_3464-4delGAinsAG caused erroneous integration of a 3 bp sequence into intron 28 and resulted in the insertion of one amino acid in the protein sequence (p.Ile1154_Asp1155insAla). Structural analyses suggested that p.Ile1154_Asp1155insAla affected the protein\'s secondary structure by interfering with one disulfide bond between Cys1140 and Cys1153 and causing the extension of an anti-parallel β sheet in the calcium-binding epidermal growth factor-like (cbEGF)13 domain. In addition, the asymptomatic family member Ι:1 was deduced to be a gonadal mosaic as assessed by inconsistent results of sequencing and STR analysis.
CONCLUSIONS: To our knowledge, FBN1 c.3464-5_3464-4delGAinsAG is the first identified pathogenic intronic indel variant affecting non-canonical splice sites in this gene. Our study reinforces the importance of assessing the pathogenic role of intronic variants at the mRNA level, with structural analysis, and the occurrence of mosaicism.

BACKGROUND: Marfan syndrome (MFS), which is a dominantly inherited connective tissue disease resulting from a mutation in the FBN1 gene, exhibits variable manifestations affecting the cardiovascular, musculoskeletal, ophthalmologic, and pulmonary systems. Notably, neurologic deficiency, which involves ischemic or hemorrhagic stroke, is a rare but severe manifestation. The safety of rt-PA treatment for ischemic stroke caused by MFS is still under discussion.
METHODS: In the current report, we discuss 3 atypical MFS cases presented as acute ischemic stroke, compared to those exhibiting cardiovascular and musculoskeletal abnormalities.
METHODS: Three patients were diagnosed with acute ischemic stroke accompanied by MFS based on clinical manifestations, imaging examinations, and genetic testings.
METHODS: The first case underwent intravenous thrombolytic therapy with rt-PA, the second case received antiplatelet therapy, and the third case received anticoagulant therapy and perfusion therapy.
RESULTS: The neurologic deficiency of all three patients showed improvement upon discharge, and there were no symptoms of recurrence observed during the follow-up period.
UNASSIGNED: MFS is a rare etiology in young people with embolic stroke of undetermined source. Physicians should take MFS into consideration when they observe the characteristic symptoms during a consultation. The potential pathogenesis of ischemic stroke secondary to MFS may include cardio-embolism, arterial dissection, and hypoperfusion. Although intravenous thrombolysis is a promising therapy to treat acute ischemic stroke, further examinations should be conducted to rule out contraindications in patients with a suspicion of MFS.

BACKGROUND: Isolated abdominal aortic dissection (IAAD) is a rare entity with poorly defined risk factors and wide variation in management. We set forth to compare patient characteristics, management, and outcomes of uncomplicated isolated abdominal aortic dissection (uIAAD) versus high risk and complicated isolated abdominal aortic dissection (hrcIAAD) to investigate whether these categories can be utilized to guide IAAD management and provide risk stratification for intervention.
METHODS: Retrospective chart review was performed to identify all patients with spontaneous IAAD at a tertiary health care system between 1996 and 2022. Demographics, comorbidities, factors relating to initial presentation including imaging findings, and dissection outcomes including long-term all-cause mortality and aortic-related mortality from time of dissection to final available record were abstracted. IAAD demonstrating rupture or malperfusion were designated as complicated, those with aortic diameter greater than 4 cm on presentation or refractory pain were designated as high risk, and the remainder was designated as uIAAD. All variables were compared between hrcIAAD and uIAAD using Fisher\'s exact test, unpaired t-test, and Mann-Whitney U-test as appropriate.
RESULTS: Over the study period, 74 patients presented with spontaneous IAAD (mean age 60 ± 16 years, 61% male) with postdissection follow-up records to an average of 6.8 ± 5.8 years. Of these, 76% presented with uIAAD versus 24% with hrcIAAD. hrcIAAD was diagnosed at a significantly younger age on average than uIAAD (52 ± 14 vs. 62 ± 16 years, P = 0.02), was less likely to present with concomitant hyperlipidemia (0% vs. 41%, P < 0.01), coronary artery disease (6% vs. 47%, P < 0.01), and prior smoking history (39% vs. 72%). hrcIAAD was more likely to present in patients with a genetic aortopathy (27% vs. 7%, P = 0.03). Hypertension was not significantly different between groups. Patients with hrcIAAD were significantly more likely to present with extension into iliac arteries compared to uIAAD (61% vs. 18%, P < 0.01). A much higher proportion of hrcIAAD required hospitalization compared to uIAAD (83% vs. 30%, P < 0.01) and operative intervention (67% vs. 7%, P < 0.01). While there was no significant difference in all-cause mortality between groups, there was a significant difference between aortic-related mortality which only occurred in those with hrcIAAD (28% vs. 0%, P < 0.01).
CONCLUSIONS: Comparison of long-term outcomes suggests that hrcIAAD is associated with increased hospitalization and need for operative intervention compared to uIAAD. Significant differences in atherosclerotic risk factors and proportions of connective tissue disease history between patients who present with hrcIAAD and uIAAD suggest that differences in underlying etiology are largely responsible for whether IAAD progresses towards rupture or has a more benign course and should be considered in risk stratification to guide more specific and targeted management of IAAD.

BACKGROUND: Acute Type A aortic dissection (ATAAD) is a life-threatening cardiovascular disease associated with high mortality rates, where surgical intervention remains the primary life-saving treatment. However, the mortality rate for ATAAD operations continues to be alarmingly high. To address this critical issue, our study aimed to assess the correlation between preoperative laboratory examination, clinical imaging data, and postoperative mortality in ATAAD patients. Additionally, we sought to establish a reliable prediction model for evaluating the risk of postoperative death.
METHODS: In this study, a total of 384 patients with acute type A aortic dissection (ATAAD) who were admitted to the emergency department for surgical treatment were included. Based on preoperative laboratory examination and clinical imaging data of ATAAD patients, logistic analysis was used to obtain independent risk factors for postoperative in-hospital death. The survival prediction model was based on cox regression analysis and displayed as a nomogram.
RESULTS: Logistic analysis identified several independent risk factors for postoperative in-hospital death, including Marfan syndrome, previous cardiac surgery history, previous renal dialysis history, direct bilirubin, serum phosphorus, D-dimer, white blood cell, multiple aortic ruptures and age. A survival prediction model based on cox regression analysis was established and presented as a nomogram. The model exhibited good discrimination and significantly improved the prediction of death risk in ATAAD patients.
CONCLUSIONS: In this study, we developed a novel survival prediction model for acute type A aortic dissection based on preoperative clinical features. The model demonstrated good discriminatory power and improved accuracy in predicting the risk of death in ATAAD patients undergoing open surgery.

Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.

Objective: To evaluate the clinical outcomes of thoracic endovascular aortic repair (TEVAR) in the treatment of Stanford type B aortic dissection (TBAD) in Marfan syndrome patients who had no history of aortic arch replacement. Methods: This is a retrospective case-series study. From January 2009 to December 2019,the clinical data of Marfan syndrome patients who underwent TEVAR for TBAD at the Department of Vascular Surgery were collected. A total of 23 patients were enrolled,including 15 males and 8 females. The age was (38.0±11.0) years (range:24 to 56 years). Among them,12 patients had history of ascending aortic surgery. Details of TEVAR,perioperative complications and reintervention were recorded and survival rate was analyzed by Kaplan-Meier curve. Results: Technical success was 91.3% (21/23). Two patients with technical failure were as follows:one patient had type Ⅰa endoleak at the completion angiography,which healed spontaneously during the follow-up,and the other patient suffered aortic intimal intussusception after the deployment of the first stent-graft, and the second stent-graft was deployed. However, type Ⅲ endoleak was detected,which disappeared during the follow-up. One patient died during hospitalization. The median follow-up time (M(IQR)) was 60 (48) months (range:12 to 132 months). Reintervention was performed on 7 patients,including 3 distal stent-graft-induced new entry,2 distal aortic dilation,1 Ⅰa endoleak and 1 retrograde type A aortic dissection,respectively. Five-year cumulative survival rate was 86.7% (95%CI:86.6% to 86.8%) and the 5-year freedom from reintervention rate was 81.8% (95%CI:61.8% to 92.8%). Conclusions: TEVAR is feasible in the treatment of TBAD in Marfan syndrome patients who has no history of aortic arch replacement. It has high technical success rate and low perioperative complication.
目的： 探讨未接受过主动脉弓部置换的马方综合征患者行胸主动脉腔内修复（TEVAR）治疗Stanford B型主动脉夹层（TBAD）的临床效果。 方法： 本研究为回顾性病例系列研究。回顾性分析2009年1月至2019年12月在复旦大学附属中山医院血管外科行TEVAR治疗TBAD的未接受过主动脉弓部置换的23例马方综合征患者的临床资料。男性15例，女性8例；年龄（38.0±11.0）岁（范围：24~56岁），其中12例患者有升主动脉手术史。分析患者的手术情况、围手术期并发症和再干预情况，采用Kaplan-Meier曲线分析术后生存情况。 结果： 患者技术成功率为91.3%（21/23）。2例手术失败患者，1例出现少量Ⅰa型内漏，随访期间消失；1例出现支架远端内膜脱套，再次植入第2枚支架，两枚支架重叠处出现少量Ⅲ型内漏，随访期间消失。围手术期死亡1例（4.3%）。随访时间［M（IQR）］60（48）个月（范围：12~132个月）。7例患者需要再干预，原因包括远端支架源性新破口3例，远端瘤样扩张2例，Ⅰa型内漏1例及近端逆行撕裂性A型夹层1例。患者5年累积生存率为86.7%（95%CI：86.6%~86.8%），免于主动脉再干预率为81.8%（95%CI：61.8%~92.8%）。 结论： 在未接受过主动脉弓部置换的马方综合征患者中，TEVAR治疗TBAD具有较高的技术成功率和较低的围手术期并发症发生率。.

A 30-year-old woman with ankylosing spondylitis was referred to our clinic with abnormal fetal echocardiography findings, including ascending aortic dilatation, giant main pulmonary artery aneurysm, and aortic and pulmonary valve stenosis at 22 weeks of gestation. The full-term male neonate was born by cesarean section and was transferred to the cardiac intensive care unit soon after delivery for respiratory distress with low percutaneous oxygen saturation. Based on cardiovascular and genetic analysis findings, the patient was diagnosed with Marfan syndrome. Surgery was performed; however, the patient died due to cardiac arrest. In conclusion, main pulmonary artery dilatation and aneurysms are uncommon in Marfan syndrome; therefore, presentation with these findings during the fetal life, as in the present case, is likely a sign of severe Marfan syndrome-related cardiac involvement.

OBJECTIVE: To investigate corneal biomechanical properties and its associations with the severity of lens dislocation in patients with Marfan syndrome.
METHODS: A total of 30 patients with Marfan syndrome and 30 age-, sex- and axial length (AL)-matched controls were recruited. Corneal biomechanical parameters of both groups were measured by CorVis ST and were compared between groups. Potential associations between corneal biomechanical parameters and severity of lens dislocation were also investigated.
RESULTS: Lower applanation 1 velocity (A1V) (0.13 ± 0.004 vs. 0.15 ± 0.003, P = 0.016), shorter applanation 2 time (A2T)(22.64 ± 0.11 vs. 22.94 ± 0.11, P = 0.013), longer peak distance (PD) (5.03 ± 0.07 vs. 4.81 ± 0.05, P = 0.008), longer radius (R) of highest concavity (7.44 ± 0.16 vs. 6.93 ± 0.14, P = 0.012), greater Ambrosio relational thickness horizontal (ARTh) (603 ± 20 vs. 498 ± 12, P < 0.001), and integrated radius (IR) (8.32 ± 0.25 vs. 8.95 ± 0.21, P = 0.033) were detected among Marfan eyes compared with controls (all P < 0.05). Marfan individuals with more severe lens dislocation tended to have increased stiffness parameter as longer A1T, slower A1V, shorter A2T, slower application 2 velocity (A2V), smaller PD and smaller Distance Amplitude (DA) (P < 0.05).
CONCLUSIONS: Marfan patients were detected to have increased corneal stiffness compared with normal subjects. Corneal biomechanical parameters were significantly associated with the severity of lens dislocation in Marfan patients.