Marfan Research Articles

Zonular fibre Insertion-to-Limbus Distance (ZLD): normative data to assess lens position and diagnose ectopia lentis

PurposeSubluxation 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.MethodsThis 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.Results145 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).ConclusionAverage 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.

Outcomes of endovascular therapy for Stanford type B aortic dissection in patients with sleep apnea syndrome

ObjectiveThis 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). MethodsThis 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: mild SAS (MSAS) and moderate-to-severe SAS (MSSAS). Clinical profiles were collected and analyzed. ResultsA 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 years vs 57.1 ± 12.8 years; P = .012) and had a higher body mass index (BMI; 25.7 ± 2.3 kg/m2vs 27.0 ± 2.3 kg/m2; P = .038). The investigation did not find any appreciable differences between the MSAS and MSSAS groups in terms of complications (endoleak, P = .403; stent-induced new entry, P >.999; and stent displacement: P >.999). However, the MSSAS group exhibited a significantly higher overall mortality rate compared with the MSAS group (log-rank P = .027). The tendency continued when examining cases with Marfan syndrome combined with MSSAS, where the overall mortality rate was significantly greater compared with Marfan syndrome cases with MSAS (log-rank P = .037). The absence of a significant difference was noteworthy in the freedom from reintervention between the MSAS and MSSAS groups (log-rank P = .278). The overall mortality rate was significantly higher in MSSAS group even after adjusting for varying potential confounders in the multivariate cox regression analysis (hazard ratio [HR], 1.875; 95% confidence interval [CI], 1.238-2.586; P = .012). A markedly higher rate of distal stent dilation in the MSSAS group was also observed compared with the MSAS group (HR, 2.5 mm/year [95% CI, 2-3 mm/year] vs HR, 4 mm/year [95% CI, 2.0-5.5 mm/year]; P = .029). ConclusionsMSSAS 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 seem to be necessary.

Innovation in pathogenesis and management of aortic aneurysm.

Aortic aneurysm (AA) refers to the persistent dilatation of the aorta, exceeding three centimeters. Investigating the pathophysiology of this condition is important for its prevention and management, given its responsibility for more than 25000 deaths in the United States. AAs are classified based on their location or morphology. various pathophysiologic pathways including inflammation, the immune system and atherosclerosis have been implicated in its development. Inflammatory markers such as transforming growth factor β, interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-2 and many more may contribute to this phenomenon. Several genetic disorders such as Marfan syndrome, Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease. Recent years has seen the investigation of novel management of AA, exploring the implication of different immune suppressors, the role of radiation in shrinkage and prevention, as well as minimally invasive and newly hypothesized surgical methods. In this narrative review, we aim to present the new contributing factors involved in pathophysiology of AA. We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.

MRI-Derived Dural Sac and Lumbar Vertebrae 3D Volumetry Has Potential for Detection of Marfan Syndrome

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 mm3 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 (p &lt; 0.001) and volume ratios (p &lt; 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 (p &lt; 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).

Tissue material properties, whole-bone morphology and mechanical behavior in the Fbn1C1041G/+ mouse model of Marfan syndrome

Marfan syndrome (MFS) is a connective tissue disorder caused by pathogenic mutations in FBN1. In bone, the protein fibrillin-1 is found in the extracellular matrix where it provides structural support of elastic fiber formation, stability for basement membrane, and regulates the bioavailability of growth factors. Individuals with MFS exhibit a range of skeletal complications including low bone mineral density and long bone overgrowth. However, it remains unknown if the bone phenotype is caused by alteration of fibrillin-1′s structural function or distortion of its interactions with bone cells. To assess the structural effects of the fibrillin-1 mutation, we characterized bone curvature, microarchitecture, composition, porosity, and mechanical behavior in the Fbn1C1041G/+ mouse model of MFS. Tibiae of 10, 26, and 52-week-old female Fbn1C1041G/+ and littermate control (LC) mice were analyzed. Mechanical behavior was assessed via in vivo strain gauging, finite element analysis, ex vivo three-point bending, and nanoindentation. Tibial bone morphology and curvature were assessed with micro computed tomography (μCT). Bone composition was measured with Fourier transform infrared (FTIR) imaging. Vascular and osteocyte lacunar porosity were assessed by synchrotron computed tomography. Fbn1C1041G/+ mice exhibited long bone overgrowth and osteopenia consistent with the MFS phenotype. Trabecular thickness was lower in Fbn1C1041G/+ mice but cortical bone microarchitecture was similar in Fbn1C1041G/+ and LC mice. Whole bone curvature was straighter below the tibio-fibular junction in the medial–lateral direction and more curved above in LC compared to Fbn1C1041G/+ mice. The bone matrix crystallinity was 4 % lower in Fbn1C1041G/+ mice compared to LC, implying that mineral platelets in LCs have greater crystal size and perfection than Fbn1C1041G/+ mice. Structural and mechanical properties were similar between genotypes. Cortical diaphyseal lacunar porosity was lower in Fbn1C1041G/+ mice compared to LC; this was a result of the average volume of an individual osteocyte lacunae being smaller. These data provide valuable insights into the bone phenotype and its contribution to fracture risk in this commonly used mouse model of MFS.

Challenges in prompt identification and surgical correction of Marfan Syndrome aortic disease in a middle-income country: a case series study

BackgroundMarfan 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.MethodsA 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.ResultsFifty 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).ConclusionIn 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.

Phenotype of Skin Dermal Mast Cells in Marfan Syndrome in Terms of Extracellular Matrix Remodeling

Phenotype of Skin Dermal Mast Cells in Marfan Syndrome in Terms of Extracellular Matrix Remodeling

Neurological abnormalities in individuals with Marfan syndrome: results from a genetically confirmed Italian cohort.

Neurological abnormalities have been frequently reported in individuals with Marfan Syndrome (MFS). However, available data relies solely on retrospective studies predating current diagnostic criteria. Cross-sectional study comprehensively investigating neurological abnormalities within a prospective cohort of adults (≥ 18years) with genetically confirmed MFS referred to an Italian hub center for heritable connective tissue diseases (Jan. 1st - Nov. 15th, 2021). We included a total of 38 individuals (53% female). The commonest neurological symptom was migraine (58%), usually without aura (73%). Neuropsychological testing was generally unremarkable, whilst anxiety and depression were highly prevalent within our cohort (42% and 34%, respectively). The most frequent brain parenchymal abnormality was the presence of cortico-subcortical hypointense spots on brain MRI T2* Gradient-Echo sequences (39%), which were found only in patients with a prior history of aortic surgery. Migraineurs had a higher frequency of brain vessels tortuosity vs. individuals without migraine (73% vs. 31%; p = 0.027) and showed higher average and maximum tortuosity indexes in both anterior and posterior circulation brain vessels (all p < 0.05). At univariate regression analysis, the presence of brain vessels tortuosity was significantly associated with a higher risk of migraine (OR 5.87, CI 95% 1.42-24.11; p = 0.014). Our study confirms that neurological abnormalities are frequent in individuals with MFS. While migraine appears to be associated with brain vessels tortuosity, brain parenchymal abnormalities are typical of individuals with a prior history of aortic surgery. Larger prospective studies are needed to understand the relationship between parenchymal abnormalities and long-term cognitive outcomes.

Incidence and Outcomes of Brucella Endocarditis in a High-Prevalence Area: A Single-Center Study.

To analyze the clinical characteristics of Brucella endocarditis (BE) and observe the factors related to death to provide guidance for clinical treatment. This study examined all patients with BE admitted to The First People's Hospital of Kashi Prefecture between January 2017 and November 2023. Clinical characteristics and follow-up outcomes were collected for analysis. This study revealed 774 cases of brucellosis and 14 cases of BE, with an overall incidence rate of 1.88%. Most of the patients were male (71.43%) and lived in areas where brucellosis is common. Patients ranged in age from 26 to 68years. Common symptoms reported among patients included chest tightness and fatigue, and a significant portion also presented with congestive heart failure. Most patients exhibited normal white blood cell counts (WBC) but had elevated levels of C-reactive protein (CRP). Transthoracic ultrasound (TTE) revealed cardiac valve vegetation in all patients, along with positive blood cultures. Six patients (42.86%) completed heart surgery, and ten (71.43%) completed anti-infection treatment. Six patients died, five of whom did not undergo surgery. The other patient with Marfan syndrome died after surgery. Sex, WBC count, neutrophil (NEUT) and total bilirubin (TBIL) were significant factors associated with regression in BE patients (P < 0.05) according to univariate analysis. Patients with BE in Kashi have a severe clinical presentation at diagnosis, but early detection with improved cardiac ultrasound and aggressive treatment can improve the prognosis.

FUNCTIONAL COMPONENT OF THE CARDIOVASCULAR SYSTEM IN INDIVIDUALS WITH CONNECTIVE TISSUE DYSPLASIA

The article discusses connective tissue dysplasia (CTD) and its genetic basis, classification issuesin the International Classification of Diseases (ICD), research on CTD in Uzbekistan, and the association of CTD with cardiovascular complications, particularly arrhythmias. Various studies and classifications related to CTD are mentioned, emphasizing thegenetic mutations underlying the disease and the prevalence of arrhythmias in syndromic forms such as Marfan syndrome and Ehlers-Danlos syndrome. The text underscores the importance of close monitoring, early detection, and appropriate management of arrhythmias in patients with CTD to optimize outcomes and reduce complications.Based on the foregoing, the purpose of this work is to establish in posttalontogenesis the laws of the formation and involution of bronchial vascular and lymphatic systems in a person, epithelial connective tissue relationships in the air and respiratory parts of the lung (1.4).

Treatment and Outcomes of 844 Cases of Pneumothorax in Heritable Connective Tissue Disorders

BackgroundCharacteristics, 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. MethodsA nationwide Japanese inpatient database that included data of 524 patients with SSP (884 hospitalizations) and 137,821 with primary spontaneous pneumothorax between July 2010 and March 2020 was used in this study. Hospitalization for SSP (n = 884) was categorized into surgical (n = 459) and nonsurgical (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 characteristics of patients with different underlying heritable connective tissue disorders. ResultsCompared with the nonsurgical group, the surgical group had less frequent readmission for pneumothorax (26% vs 44%; hazard ratio, 0.47; 95% CI, 0.38-0.58). Young patients (2.46; 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 to 39 years with Ehlers-Danlos syndrome, and in those aged ≥40 years with Birt-Hogg-Dubé syndrome. ConclusionsDetailed information on the characteristics and clinical course of SSP in heritable connective tissue disorders will aid in the clinical decision-making process.

A new combinatory pharmacological treatment strategy involving antioxidants to ameliorate aortic aneurysm progression in Marfan syndrome

A new combinatory pharmacological treatment strategy involving antioxidants to ameliorate aortic aneurysm progression in Marfan syndrome

Ventricular arrhythmias in a child with Marfan syndrome: case report

We present a severe disease progression observed in a 13-year-old patient diagnosed with Marfan syndrome and associated cardiac rhythm disorders, including polymorphic ventricular premature contractions and persistent ventricular tachycardia resistant to a wide range of antiarrhythmic medications. We conducted an analysis of contemporary perspectives on the etiology of ventricular tachyarrhythmias and their impact on the prognosis of patients with Marfan syndrome. Conclusions were drawn regarding the selection of treatment strategies for this specific patient population.

Risk Factors for Retinal Detachment in Marfan Syndrome After Pediatric Lens Removal

Purpose: To determine Retinal Detachment (RD) risk factors after lens removal surgery in children with Marfan syndrome.Design: Retrospective case control study.Methods:Setting: Institutional case-seriesStudy population: All children (<18 years) with Marfan syndrome that underwent lens removal surgery.Observation procedure: Clinical and surgical characteristics were extracted from children's electronic files: age, Axial Length (AL), gender, number of surgeries received, Intra Ocular Lens (IOL) implantation at the first surgery, complete removal of the capsular bag, final best corrected visual acuity.Main outcome measure: Risk factors associated with RD occurrence.Results: Among 158 eyes included (85 children), 35 eyes (22.2%) developed RD during follow-up. Bilateral detachment occurred in 11 patients (45.8%). Age at the time of the lens removal surgery was not different between groups. Children in the RD group had a higher AL (p<.001), longer follow-up, IOL implantation, and capsular residue. Multivariate analysis identified capsular residue (odds ratio [OR] 16.8; 95% confidence interval [CI], 1.9-148.8; P=0.01), and axial length by (OR 1.3; 95% CI, 1.01-1.7; P=0.03) as predictors for RD.Conclusion: Marfan syndrome children with increased AL were more likely to develop a RD after lens surgery. When considering lens removal surgery in a pediatric population presenting Marfan's syndrome, a complete capsular removal seemed to be the safer option regarding RD risk.

Proteomics analysis on aortic smooth muscle cells reveals new potential targets for the treatment of Marfan syndrome-associated thoracic aortic aneurysm

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Background Thoracic aortic aneurysm (TAA) is characterized by the abnormal enlargement of the initial segment of the aorta. Patients with genetic Marfan syndrome (MFS) develop TAA in young age, since mutations of fibrillin-1 contribute to thoracic aortic wall detrimental weakening. Presently, effective treatment options for this life-threatening condition are lacking, and existing pharmacological approaches are merely palliative, by postponing the need for surgical aortic replacement. To identify new treatments or MFS-related TAA (MFS-TAA), current research is concentrated on pinpointing specific biological targets and mechanisms underlying this aortic disorder. Purpose This study is aimed to unveil potential therapeutic targets that could be exploited for treating MFS-TAA by adopting an advanced proteomics technique. Material and Methods A label-free quantitative mass spectrometry technique was employed, utilizing a hybrid quadrupole-time of flight mass spectrometer coupled with a UPLC Mclass system and a nano-source, to analyze and compare the protein expression levels in vascular smooth muscle cells (VSMC) isolated from the aortas of MFS patients (MFS-VSMC) and healthy subjects (HC-VSMC). The proteomics findings were subsequently validated through qRT-PCR and Western blot assays. Results The proteomics investigation yielded 16 proteins displaying statistically significant differences. Among these, five proteins were notably more abundant in MFS-VSMC compared to HC-VSMC: nestin (NES, p&amp;lt;0.01), filamin B (FLNB, p&amp;lt;0.05), A-kinase anchor protein 12 (AKAP12, p&amp;lt;0.05), catenin delta-1 (CTNND1, p&amp;lt;0.05), and heparan sulfate proteoglycan core protein (HSPG2, p&amp;lt;0.05). The Gene Ontology (GO) analysis performed on cellular components of these 5 items using the clusterProfiler R package highlighted the enrichment of GO terms generally related to transmembrane proteins and anchoring junctions. Specifically, enriched GO terms included cell cortex (p&amp;lt;0.002), focal adhesion (p&amp;lt;0.002), cell-substrate junction (p&amp;lt;0.002), and intermediate filament binding (p&amp;lt;0.03). To verify these findings, two out of the five proteins with increased expression in MFS-VSMC (i.e., nestin and filamin B) were subjected to validation experiments. Results confirmed the elevated gene expression and protein levels of both nestin (p&amp;lt;0.05) and filamin B (p&amp;lt;0.05) in MFS-VSMC samples when compared with HC-VSMC. Conclusions Taken together, these results suggest that proteins with increased expression in MFS-VSMC may represent valuable biological target of MFS-TAA. This may encompass their potential both as diagnostic tools and/or mechanistic mediators of TAA in MFS subjects. In details, the pharmacological targeting of nestin and filamin B may represent a novel and exploitable therapeutic option for limiting/inhibiting TAA onset or progression in MFS pathological scenario.

Inhibition of alphaV integrins with cilengitide downregulates in vitro pro-fibrotic events in aortic smooth muscle cells and limits in vivo thoracic aortic aneurysm progression

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health "Ricerca Finalizzata - Giovani Ricercatori" Background The ‘greatest artery’, i.e., the aorta, can be affected by either acute conditions or chronic disorders, such as the aneurysm, which is the segmental aortic dilation with at least 50% increase in the normal diameter. Aortic dilation can often lead to lethal events, such as aortic dissection and/or vessel rupture. The aneurysms occurring in the thoracic trait of the aorta (TAA) may depend on comorbidities, such as hypertension (i.e., sporadic non-syndromic TAA, sTAA), or on genetically determined conditions, such as Marfan syndrome (MFS). To date, the surgical replacement of aorta represents the most effective therapeutic approach in all TAA patients, since an etiologic pharmacological treatment is still lacking. Thus, the identification of novel disease targets is mandatory. Integrin receptors are key players in cellular mechanotransduction responses. Specifically, integrins containing αV subunit have been described as important mechanotransduction mediators and responsible for pro-fibrotic molecular events. Recently, it has been reported the effectiveness of a broad αV integrin inhibitor in limiting the TAA progression by acting on FAK/AKT/mTORC signaling pathway in a MFS in vivo model. However, the specific αV integrin subgroup directly involved in this detrimental process is yet not known. Purpose We evaluated the effectiveness of a specific αVβ3 and αVβ5 integrin inhibitor (i.e., cilengitide) in downregulating pro-fibrotic in vitro events on vascular smooth muscle cells (VSMC) isolated from TAA patients’ aortic wall, and in limiting in vivo thoracic aortic dilation on a MFS mice model. Results By comparison with healthy control (HC)-VSMC, both sTAA-VSMC and MFS-VSMC showed higher levels of αVβ3 and αVβ5 integrins as well as pro-fibrotic collagen I. The in vitro inhibition of these two αV integrins mediated by cilengitide resulted more effective in collagen I downregulation when compared with GLPG0187 (pan αV inhibitor). Noteworthy, the cilengitide-mediated αV integrin inhibition consistently tempered pro-fibrotic phenotype of sTAA- and MFS-VSMC by directly acting on both canonical (p-SMAD2/3) and non-canonical (p-ERK1/2) TGF-β downstream pathways and by downregulating mechanotransduction mediators (e.g., RhoA GTPase, ROCK1, talin-1). The 2D-echocardiographic results on MFS mice treated with cilengitide confirmed the greater effectiveness of this drug in limiting the TAA progression, in comparison not only with vehicle but also with the broad integrin inhibitor GLPG0187. Conclusion Altogether, our results improve the know-how on αV integrin inhibition, highlighting the role of cilengitide as potential target for future therapeutic approaches to limit TAA progression, both in sporadic and in MFS patients.

Spontaneous Intracranial Hypotension Associated with Marfan Syndrome: A Case Report.

Spontaneous intracranial hypotension (SIH) is an uncommon and frequently misdiagnosed condition characterized by a lower-than-normal volume of cerebrospinal fluid (CSF) caused by leakage of CSF through the dural membrane. The primary manifestation of SIH is an orthostatic headache, which is frequently accompanied by nausea and vomiting. Patients with connective tissue disorders are at increased risk for spontaneous CSF leaks due to the structural weakness of their dural membranes. An 18-year-old woman with no reported past medical history presented to the emergency department with 10 days of a bifrontal headache that was orthostatic in nature with associated nausea and vomiting. She was noted to have several marfanoid features on physical examination. Spontaneous intracranial hypotension was ultimately diagnosed and treated successfully with an epidural blood patch. Subsequent genetic testing revealed a diagnosis of Marfan syndrome. Spontaneous intracranial hypotension is an uncommon cause of headache. Individuals with connective tissue disorders such as Marfan syndrome are at increased risk for SIH. Knowledge of the relationship between these two conditions allows for a more rapid diagnosis of SIH.

Anterior scleral thickness in Marfan syndrome: A quantitative analysis.

To investigate the anterior scleral thickness (AST) in patients with Marfan syndrome (MFS). A prospective, cross-sectional study was conducted at the Department of Ophthalmology, Ghent University Hospital, Ghent, including patients with a genetically confirmed clinical diagnosis of MFS and age-, gender- and axial length-matched controls. Subjects with known corneal, conjunctival or scleral pathology and a history of ocular surgery, including pars plana vitrectomy, recent contact lens use or high-grade astigmatism were excluded. Subjects underwent non-cycloplegic autorefraction, Scheimpflug-based corneal tomography, axial length measurement and spectral-domain optical coherence tomography (OCT). AST was manually measured at 1 mm (AST1), 2 mm (AST2) and 3 mm (AST3) from the scleral spur, temporally and nasally. A total of 56 subjects (28 subjects in the MFS group and 28 matched subjects in the control group) were included in this study. In patients with MFS, AST was significantly reduced compared to matched controls, both overall and at every analysed measuring point in the nasal and temporal areas (p < 0.001). Central corneal thickness (CCT) and mean keratometry (Kmean) values were significantly lower in patients with MFS (p < 0.05). A positive correlation was found between nasal AST and CCT in patients with MFS. No correlation was found between AST and Kmean or between AST and axial length. In patients with MFS with ectopia lentis, compared to those without, temporal AST3 was significantly lower (p < 0.05). AST was significantly lower in patients with MFS harbouring a variant predicted to cause haploinsufficiency compared to those with a variant expected to lead to a dominant negative effect for both nasal and temporal measurements. Based on anterior segment OCT measurements, AST of patients with MFS is significantly lower compared to matched controls.

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome

BackgroundMarfan syndrome (MFS) is an autosomal dominant connective tissue disease with wide clinical heterogeneity, and mainly caused by pathogenic variants in fibrillin-1 (FBN1).MethodsA 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.ResultsTwo 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.ConclusionsTo 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.

Are Biomechanical Characteristics of Ascending Aortic Aneurysm Different in Patients With Marfan Syndrome?

Are Biomechanical Characteristics of Ascending Aortic Aneurysm Different in Patients With Marfan Syndrome?