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Stem Cell Research Jun 2024Marfan Syndrome, a connective tissue disorder caused by Fibrillin-1 (FBN1) gene mutations, induces disease in the ocular, musculoskeletal, and cardiovascular systems and...
Marfan Syndrome, a connective tissue disorder caused by Fibrillin-1 (FBN1) gene mutations, induces disease in the ocular, musculoskeletal, and cardiovascular systems and increases aortic vulnerability to rupture associated with high mortality rates. We describe an induced pluripotent stem cell line (HFD1) generated from patient-derived human dermal fibroblasts harboring a heterozygous c.3338-2A>C intronic splice acceptor site variant preceding Exon 28 of FBN1. The clonal line, which produces abnormal FBN1 splice variants, has a normal karyotype, expresses appropriate stemness markers, and maintains trilineage differentiation potential. This line represents a valuable resource for studying how abnormal splicing variants contribute to Marfan Syndrome.
PubMed: 38941881
DOI: 10.1016/j.scr.2024.103475 -
Diagnostics (Basel, Switzerland) Jun 2024To assess the feasibility and diagnostic accuracy of MRI-derived 3D volumetry of lower lumbar vertebrae and dural sac segments using shape-based machine learning for the...
PURPOSE
To assess the feasibility and diagnostic accuracy of MRI-derived 3D volumetry of lower lumbar vertebrae and dural sac segments using shape-based machine learning for the detection of Marfan syndrome (MFS) compared with dural sac diameter ratios (the current clinical standard).
MATERIALS AND METHODS
The final study sample was 144 patients being evaluated for MFS from 01/2012 to 12/2016, of whom 81 were non-MFS patients (46 [67%] female, 36 ± 16 years) and 63 were MFS patients (36 [57%] female, 35 ± 11 years) according to the 2010 Revised Ghent Nosology. All patients underwent 1.5T MRI with isotropic 1 × 1 × 1 mm 3D T2-weighted acquisition of the lumbosacral spine. Segmentation and quantification of vertebral bodies L3-L5 and dural sac segments L3-S1 were performed using a shape-based machine learning algorithm. For comparison with the current clinical standard, anteroposterior diameters of vertebral bodies and dural sac were measured. Ratios between dural sac volume/diameter at the respective level and vertebral body volume/diameter were calculated.
RESULTS
Three-dimensional volumetry revealed larger dural sac volumes ( < 0.001) and volume ratios ( < 0.001) at L3-S1 levels in MFS patients compared with non-MFS patients. For the detection of MFS, 3D volumetry achieved higher AUCs at L3-S1 levels (0.743, 0.752, 0.808, and 0.824) compared with dural sac diameter ratios (0.673, 0.707, 0.791, and 0.848); a significant difference was observed only for L3 ( < 0.001).
CONCLUSION
MRI-derived 3D volumetry of the lumbosacral dural sac and vertebral bodies is a feasible method for quantifying dural ectasia using shape-based machine learning. Non-inferior diagnostic accuracy was observed compared with dural sac diameter ratio (the current clinical standard for MFS detection).
PubMed: 38928716
DOI: 10.3390/diagnostics14121301 -
Journal of Vascular Surgery Jun 2024This study aimed to determine the influences of varying severity of sleep apnea syndrome (SAS) on the outcomes after thoracic endovascular aorta repair (TEVAR) in...
OBJECTIVE
This study aimed to determine the influences of varying severity of sleep apnea syndrome (SAS) on the outcomes after thoracic endovascular aorta repair (TEVAR) in patients with Stanford type B aortic dissection (TBAD).
METHODS
This observational study focused on individuals with TBAD plus SAS who received TEVAR between January 2018 and December 2022. Patients were divided into groups according to the results of the portable sleep-breathing monitoring systems (PSMS): mild SAS (MSAS) and moderate-to-severe SAS (MSSAS). Clinical profiles were collected and analyzed.
RESULTS
A total of 121 cases with TBAD plus SAS who underwent TEVAR were enrolled in this study. Two groups were formed by stratifying these cases: MSAS (74 cases) and MSSAS (47 cases). The MSSAS cases were found to be older relative to MSAS cases (51.7 ± 8.3 vs. 57.1 ± 12.8 years, p = 0.012) and had a higher body mass index (BMI; 25.7 ± 2.3 vs. 27.0 ± 2.3 kg/m, p = 0.038). The investigation did not find any appreciable differences between the MSAS and MSSAS groups in terms of complications (endoleak: p = 0.403, SINE: p = 1.000, stent displacement: p = 1.000). However, the MSSAS group exhibited a significantly higher overall mortality rate compared to MSAS group (log-rank p = 0.027). The tendency continued when examining cases with Marfan syndrome (MFS) combined with MSSAS, where the overall mortality rate was significantly greater compared to MFS cases with MSAS (log-rank p = 0.037). The absence of a significant difference was noteworthy in the freedom from reintervention between the MSAS and MSSAS groups (log-rank p = 0.278). The overall mortality rate was significantly higher in MSSAS group even after adjusting for varying potential confounders in the multivariate cox regression analysis (HR 95%CI: 1.875 [1.238-2.586], p = 0.012). A markedly higher rate of distal stent dilation in the MSSAS group was also observed compared to the MSAS group (2.5 [2, 3] vs. 4 [2, 5.5] mm/year, p = 0.029).
CONCLUSIONS
MSSAS is associated with a significantly higher risk of overall mortality and dilation rate of the distal stent after TEVAR for TBAD patients. Hence, aggressive efforts to reverse the severity of SAS in time in these individuals appear necessary.
PubMed: 38925349
DOI: 10.1016/j.jvs.2024.06.023 -
Annals of Vascular Diseases Jun 2024Hereditary aortic aneurysms and dissections, such as Marfan syndrome, differ in that they occur in younger patients without generally recognized risk factors, have a... (Review)
Review
Hereditary aortic aneurysms and dissections, such as Marfan syndrome, differ in that they occur in younger patients without generally recognized risk factors, have a predilection for the thoracic rather than the abdominal aorta, and are at risk for dissection even at smaller aortic diameters. Early diagnosis, careful follow-up, and early intervention, such as medication to reduce aortic root growth and prophylactic aortic replacement to prevent fatal aortic dissection, are essential for a better prognosis. Molecular genetic testing is extremely useful for early diagnosis. However, in actual clinical practice, the question often arises as to when and to which patient genetic testing should be offered since the outcome of the tests can have important implications for the patient and the relatives. Pre- and post-test genetic counseling is essential for early intervention to be effective. (This article is a secondary translation of Jpn J Vasc Surg 2023; 32: 261-267.).
PubMed: 38919319
DOI: 10.3400/avd.ra.24-00013 -
International Ophthalmology Jun 2024Subluxation of the crystalline lens (Ectopia Lentis, EL) can lead to significant visual impairment and serves as a diagnostic criterion for genetic disorders such as the... (Observational Study)
Observational Study
PURPOSE
Subluxation of the crystalline lens (Ectopia Lentis, EL) can lead to significant visual impairment and serves as a diagnostic criterion for genetic disorders such as the Marfan syndrome. There is no established criterion to diagnose and quantify EL. We prospectively investigated the distance between the zonular fibre insertion and the limbus (ZLD) in healthy subjects as a parameter to assess the position of the lens, quantify EL and provide normative data.
METHODS
This prospective, observational, cross-sectional study includes one-hundred-fifty eyes of 150 healthy participants (mean age 28 years, range 4-68). Pupils were dilated with tropicamide 0.5% and phenylephrine 2.5% eyedrops. ZLD was measured in mydriasis at the slit lamp as the distance between the most central visible insertions of the zonular fibres on the lens surface and the corneoscleral limbus. Vertical pupil diameter (PD) and refractive error were recorded. If zonular fibre insertions were not visible, the distance between limbus and the pupillary margin was recorded as ZLD.
RESULTS
145 right and 5 left eyes were examined. 93% of study subjects were Caucasian, 7% were Asian. In eyes with visible zonular fibre insertions (n = 76 eyes), ZLD was 1.30 ± 0.28 mm (mean ± SD, range 0.7-2.1) and PD was 8.79 ± 0.57 mm (7.5-9.8). In the remaining 74 eyes, ZLD was 1.38 ± 0.28 mm (0.7-2.1), and PD was 8.13 ± 0.58 mm (6.7-9.4). For all eyes, ZLD was 1.34 ± 0.29 mm (0.7-2.1), and PD was 8.47 ± 0.66 mm (6.7-9.8). Refractive error and sex did not significantly affect ZLD. Smaller PD and older age were associated with larger ZLD (P < 0.001 and P = 0.036, respectively).
CONCLUSION
Average ZLD was 1.34 mm in eyes of healthy subjects. Older age correlated with larger ZLD. These normative data will aid in diagnosing and quantifying EL.
Topics: Humans; Ectopia Lentis; Male; Female; Prospective Studies; Cross-Sectional Studies; Adult; Child; Adolescent; Middle Aged; Young Adult; Aged; Child, Preschool; Lens, Crystalline; Limbus Corneae; Pupil
PubMed: 38913255
DOI: 10.1007/s10792-024-03163-0 -
Biomolecules & Biomedicine Jun 2024Dear Editor, We have read the article "The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan...
Letter regarding "The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders".
Dear Editor, We have read the article "The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders", recently published in your esteemed journal. We are a team dedicated to diagnosing, approaching, and managing patients with connective tissue disorders, particularly hypermobile spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS). We appreciate the research group's effort to address the complexity of connective tissue disorders using a multi-panel genetic approach and their analysis of genotype-phenotype associations in a cohort of Mexican patients. However, we would like to express our concern regarding two specific points that we consider crucial for the comprehensive understanding and management of these disorders. Read more in the PDF.
PubMed: 38912888
DOI: 10.17305/bb.2024.10799 -
Advances in Experimental Medicine and... 2024Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and...
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
Topics: Humans; Chromosome Aberrations; DNA Copy Number Variations; Genetic Predisposition to Disease; Heart Septal Defects, Ventricular; Mutation; Transcription Factors
PubMed: 38884729
DOI: 10.1007/978-3-031-44087-8_27 -
The Annals of Thoracic Surgery Jun 2024Characteristics, practice patterns, and clinical outcomes of secondary spontaneous pneumothorax (SSP) with heritable connective tissue disorders (Marfan, Ehlers-Danlos,...
BACKGROUND
Characteristics, practice patterns, and clinical outcomes of secondary spontaneous pneumothorax (SSP) with heritable connective tissue disorders (Marfan, Ehlers-Danlos, and Birt-Hogg-Dubé syndromes) are unclear.
METHODS
A nationwide Japanese inpatient database, which included data on 524 patients with SSP (884 hospitalizations) and 137821 with primary spontaneous pneumothorax (PSP) between July 2010 and March 2020, was used in this study. Hospitalization for SSP (n=884) was categorized into surgical (n=459) and non-surgical (n=425) groups, and the patient characteristics, treatment, and outcomes were compared between the groups. Multivariable analyses were performed to evaluate risk factors for pneumothorax recurrence. We also compared the patient characteristics among those with different underlying heritable connective tissue disorders.
RESULTS
Compared to the non-surgical group, the surgical group had less frequent readmission for pneumothorax (26% vs. 44%; hazard ratio, 0.47; 95% confidence interval, 0.38-0.58). Young patients (hazard ratio, 2.46; 95% confidence interval, 1.83-3.32) or those with Birt-Hogg-Dubé syndrome (2.53; 1.77-3.63) had a high risk of recurrence. Pneumothorax occurred frequently in teenagers with Marfan syndrome, in those aged 20-39 years with Ehlers-Danlos syndrome, and in those aged ≥40 years with Birt-Hogg-Dubé syndrome.
CONCLUSIONS
Detailed information on the characteristics and clinical course of SSP in heritable connective tissue disorders will aid the clinical decision-making process.
PubMed: 38878950
DOI: 10.1016/j.athoracsur.2024.05.037 -
Multimedia Manual of Cardiothoracic... Jun 2024Single-stage total aortic replacement represents a comprehensive approach for patients at high risk of aorta-related complications between procedures. It not only avoids...
Single-stage total aortic replacement represents a comprehensive approach for patients at high risk of aorta-related complications between procedures. It not only avoids staged surgical treatment but also facilitates quicker rehabilitation. Opting for a radical surgery in such cases can yield superior outcomes compared with a staged approach, making it particularly suitable for young patients with aorta-related risk factors. Moreover, a single-stage aorta repair reduces the likelihood of subsequent aortic interventions.
Topics: Humans; Aortic Dissection; Marfan Syndrome; Blood Vessel Prosthesis Implantation; Aortic Aneurysm, Thoracic; Male; Adult
PubMed: 38869837
DOI: 10.1510/mmcts.2024.017 -
Journal of Cardiothoracic Surgery Jun 2024Marfan Syndrome is an autosomal dominant disease caused by pathogenetic variants in the FBN1 gene. The progressive dilatation of the aorta and the potential risk of...
BACKGROUND
Marfan Syndrome is an autosomal dominant disease caused by pathogenetic variants in the FBN1 gene. The progressive dilatation of the aorta and the potential risk of acute aortic syndromes influence the prognosis of these patients. We aim to describe population characteristics, long-term survival, and re-intervention patterns in patients who underwent aortic surgery with a previously confirmed clinical diagnosis of Marfan Syndrome in a middle-income country.
METHODS
A retrospective single-center case series study was conducted. All Marfan Syndrome patients who underwent aortic procedures from 2004 until 2021 were included. Qualitative variables were frequency-presented, while quantitative ones adopted mean ± standard deviation. A subgroup analysis between elective and emergent procedures was conducted. Kaplan-Meier plots depicted cumulative survival and re-intervention-free. Control appointments and government data tracked out-of-hospital mortality.
RESULTS
Fifty patients were identified. The mean age was 38.79 ± 14.41 years, with a male-to-female ratio of 2:1. Common comorbidities included aortic valve regurgitation (66%) and hypertension (50%). Aortic aneurysms were observed in 64% without dissection and 36% with dissection. Surgical procedures comprised elective (52%) and emergent cases (48%). The most common surgery performed was the David procedure (64%), and the Bentall procedure (14%). The in-hospital mortality rate was 4%. Complications included stroke (10%), and acute kidney injury (6%). The average follow-up was 8.88 ± 5.78 years. Survival rates at 5, 10, and 15 years were 89%, 73%, and 68%, respectively. Reintervention rates at 1, 2.5, and 5 years were 10%, 14%, and 17%, respectively. The emergent subgroup was younger (37.58 ± 14.49 years), had the largest number of Stanford A aortic dissections, presented hemodynamic instability (41.67%), and had a higher requirement of reinterventions in the first 5 years of follow-up (p = 0.030).
CONCLUSION
In our study, surveillance programs played a pivotal role in sustaining high survival rates and identifying re-intervention requirements. However, challenges persist, as 48% of the patients required emergent surgery. Despite not affecting survival rates, a greater requirement for reinterventions was observed, emphasizing the necessity of timely diagnosis. Enhanced educational initiatives for healthcare providers and increased patient involvement in follow-up programs are imperative to address these concerns.
Topics: Humans; Marfan Syndrome; Male; Female; Retrospective Studies; Adult; Middle Aged; Aortic Dissection; Young Adult; Aortic Aneurysm
PubMed: 38849906
DOI: 10.1186/s13019-024-02793-w