Marfan Research Articles

Association of Ocular Manifestations of Marfan Syndrome With Cardiovascular Complications

To evaluate associations between ocular manifestations of Marfan syndrome and cardiovascular complications. Retrospective cohort study. The TriNetX Analytics platform, a federated health research network of aggregated deidentified electronic health record data of more than 119 million patients, was used to identify patients diagnosed with Marfan syndrome. Univariate logistic regression models were used to evaluate the association of ocular manifestations of Marfan syndrome (such as retinal tears/detachment, lens dislocation, and myopia), with cardiovascular comorbidities. Additional sensitivity analyses were performed using propensity matching. Odds ratios and 95% CIs were calculated for incidence of cardiovascular comorbidities (including aortic dissection, valvular disease, and arrhythmias) following diagnosis of Marfan syndrome. A total of 19,105 patients were identified who were diagnosed with Marfan disease without ocular manifestations, and an additional 3887 Marfan patients with ocular comorbidities. Patients who were diagnosed with ocular disease included 883 with ectopic lens, 417 with retinal tear or detachment, 683 with aphakia, 534 with pseudophakia, and 2465 with myopia. Patients with any ocular manifestations of Marfan were significantly more likely to be diagnosed with all cardiovascular comorbidities modeled including aortic aneurysm and dissection (OR 2.035; P < .0001), mitral valve prolapse (OR 2.725; P < .0001), tricuspid valve disorders (OR 2.142; P < .0001), cardiac arrhythmias (OR 1.836; P < .0001), and all cardiovascular outcomes combined (OR 2.194; P < .0001). In a large and diverse cohort of patients with Marfan syndrome, ocular manifestations of the disorder appear strongly associated with cardiovascular comorbidities.

A case of death in a patient with Marfan syndrome after re-infection with SARS-CoV-2

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has shown a wide range of manifestations, including cardiovascular. A clinical description of left ventricular aneurysm rupture in a 33-year-old patient after infection with SARS-CoV-2 is presented.

Rehabilitation for Marfan Syndrome

Abstract: Marfan syndrome is a spectrum of disorders caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission. The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin. Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate. The skeleton of patients with Marfan syndrome typically displays multiple deformities. Mitral valve prolapses that requires valve replacement can occur as well. Given the variable expressivity of Marfan Syndrome, no single sign is pathognomonic; the diagnosis is made on clinical grounds on the basis of typical abnormalities. We reported a boy, 12 years old, referred from surgeon with diagnosis pectus carinatum pro brace. Chest protusion appeared since age 6, getting bigger without any complaint but cosmetic. Other complaints on feet which looked flat, sometimes ankle sore after long distance running or futsal. He was the first child and no family history had a condition like him. His hobby was playing futsal, and daily activities were independent without assistive devices. General appearance and vital signs were normal, cardiorespiratory assessment was normal, BMI on percentile 10-25, arm span to height ratio 1.09, lens subluxation of left eye, lens dislocation of right eye, poor standing balance, inadequate toe off, thoracic hyperkyphotic, positive wrist sign, true leg length discrepancy of 1 cm (left&gt;right), bilateral ankle ROM limitation, rigid flat feet suspected bilateral vertical talus, left hallux valgus, Marfan syndrome score 9, and normal echocardiography. In this patient, we gave semi rigid thoraco-lumbo-sacral orthosis (TLSO) with 3 points pressure system and rigid bar on protution area (custom molded). resistance exercise (F: 3x/week, I: moderate fatigue, Borg scale 13-15/20, T: 8-15 reps/ set, 2-3 set/ session, T: major muscle group upper and lower extremities aerobic exercise (F: 3x/week, I: moderate to vigorous, borg scale 13-15/20, T: ≥60 min/session, @5-10 min warming up and cooling down (stretching), T: sport (swimming, running, cycling). The patient was referred to a surgeon for a brace. In conclusion, this case report highlights the multidisciplinary management of patients with Marfan syndrome. Keywords: Marfan syndrome; typical abnormalities; multiple deformities

Aortic challenges in Marfan syndrome, is the management of the aortic root enough?

Aortic challenges in Marfan syndrome, is the management of the aortic root enough?

Longitudinal changes of refractive error in preschool children with congenital ectopia lentis.

Congenital ectopia lentis (CEL) is a hereditary eye disease which severely impacts preschool children's visual function and development. This study aimed to evaluate the longitudinal changes in spherical equivalent (SE) refractive error in preschool children with CEL. A retrospective cohort study was conducted at Zhongshan Ophthalmic Center, Guangzhou, China. Medical records of CEL patients under 6-year-old who were diagnosed with Marfan syndrome at the initial visit from January 2014 to March 2022 were collected and were divided into surgery and non-surgery groups. Mean change rate of SE in the two groups was evaluated, and the potential associated factors of SE change rate were investigated by mixed-effect regression model. A total of 94 preschool patients from 14 provinces of China were included. Among the 42 children of the surgery group, the mean age with standard deviation (SD) was 5.02 ± 0.81years and patients experienced a myopic shift of -0.05 ± 0.09D/month in average. The mean age with SD of the 52 children of the non-surgery group was 4.34 ± 1.02years, and the mean myopic shift was -0.09 ± 0.14D/month. The mixed-effect regression model identified that higher degree of myopia at baseline was associated with slower myopic shift both in surgery (β = 0.901, 95% CI: 0.822 ~ 0.980, P < 0.001) and in non-surgery group (β = 1.006, 95% CI: 0.977 ~ 1.034, P < 0.001) in CEL patients. Surgical treatment (β = 2.635, 95% CI: 1.376 ~ 3.894, P < 0.001) was associated with slower myopic shift in all participants CEL patients. Myopic progression was slower in the surgery group than in the non-surgery group of CEL. Preschool CEL patients who met the surgical indication are suggested being performed with timely surgery to slow down the myopic progression.

Frequency of Cardiac Valvulopathies in Patients With Marfan Syndrome: A Systematic Review and Meta-Analysis.

Marfan syndrome (MFS) is a progressive connective tissue disease with a broad range of clinical manifestations. We sought to establish the spectrum of structural valvular abnormalities as cardiovascular involvement has been identified as the most life-threatening aspect of the syndrome. This was a systematic review with a meta-analysis of studies indexed in Medline from the inception of the database to November 7, 2022. Using the random-effects model, separate Forest and Galbraith plots were generated for each valvular abnormality assessed. Heterogeneity was assessed using the I2 statistics whilst funnel plots and Egger's test were used to assess for publication bias. From a total of 35studies, a random-effects meta-analysis approximated the pooled summary estimates for the prevalence of cardiac valve abnormalities as mitral valve prolapse 65% (95% CI: 57%-73%); mitral valve regurgitation 40% (95% CI: 29%-51%); aortic valve regurgitation 40% (95% CI: 28%-53%); tricuspid valve prolapse 35% (95% CI: 15%-55%); and tricuspid valve regurgitation 43% (95% CI: 8%-78%). Only one study reported on the involvement of the pulmonary valve (pulmonary valve prolapse was estimated at 5.3% (95% CI: 1.9%-11.1%) in a cohort of 114 patients with MFS). We believe this study provides a description of the structural valvular disease spectrum and may help inform providers and patients in understanding the clinical history of MFS in the current treatment era with its increased life expectancy.

What To Expect In An Unexpected Spontaneous Bilateral Ectopia Lentis

Introduction : Ectopia lentis is present in 50% to 80% of Marfan syndrome sufferers. In many people the position of lens is fixed, some individuals’ lens experience subluxation which took amount of time. This case presents a young patient with rare manifestation of spontaneous bilateral ectopia lentis, both lens luxated within two days after admission due to secondary glaucoma.&#x0D; Case Illustration : A 14 years old patient came to the emergency department with acute glaucoma like symptoms: pain and redness in both eyes, along with headache and nausea. The patient appeared highly suspectedof Marfan syndrome appearance with tall stature, and arachnodactyly; both eyes shown visual acuityof 1/300, low digital palpation, ectopia lentis and anteriorly subluxated lens in both eyes, positive fundus reflex. Posterior segment USG B-scan is normal. Patient then prescribed with oral Acetazolamide, Timolol Maleate eye drop, and Prednisolone eye drop, then scheduled for lensectomy. Just within 2 days after admission, right eye shown lens anteriorly luxated with 20/100 visual acuity, while left eye appears aphakic with ectopia lentis at vitreous with 1/60 visual acuity. The physician immediately sent the patient to higher referral hospital then received secondary implant on right eye and secondary implant with vitrectomy procedure on left eye.&#x0D; Discussion : Drastic measure took place given the presence of both lenses' dislocation, one into anterior chamber, another into vitreous cavity. Collaboration with cardiologist is necessary to perceived other potential comorbid.&#x0D; Conclusion : Physician do need always to be prepared for even the uncommon complications to occur, hence have to be prepared for the unexpected.

Bilateral Anterior and Posterior Lens Dislocation in Marfan Syndrome in Teenager : A Case Report

Introduction : The zonular defect leads to ectopia lentis, which is a hallmark of Marfan ocular abnormalities. Bilateral dislocation of lens in marfan’s syndrome occurs frequently in same location. In this case the lens of RE dislocated in the anterior chamber and the lens of LE was found in vitreous cavity. Iris fixation IOL and Yamane’s scleral fixation technique are prompt treatment for crystalline lens displacement.&#x0D; Case Illustration : A 14 year-old male patient came with chief complaint a painless blurred vision on LE since 2 weeks before visit Ophthalmologist. The BCVA in both eyes was 6/30 RE and 1/60 LE. There was no history of ocular injury nor development disorder. Lens dislocation in anterior chamber was found in RE and aphakic lens was found in LE during slit lamp examination. The IOP ODS were 9.7 mmHg and 3.0 mmHg. Further examination from funduscopy showed the lens of LE was seen in vitreous cavity.&#x0D; Discussion : Bilateral dislocation of lens in opposite position are quite rare. To avoid many of the potential complications, Iris Fixation IOL placement is preferred choice to improve visual impairment on the right eye. Yamane’s Scleral Fixation technique has been performed on left eye however challenging and time consuming it is, to achieve excellent improvement with minimal or no intra- and postoperative complications.&#x0D; Conclusion : This case shows that manifest of crystalline lens in marfan syndrome could happen differently to each eye. Different surgical approach especially IOL placement technique is crucial and must be considered carefully depends on the condition during surgery.

Navigating toward gene therapy in Marfan syndrome: A hope for halting aortic aneurysm

Navigating toward gene therapy in Marfan syndrome: A hope for halting aortic aneurysm

Novel variant of FBN2 in a patient with congenital contractual arachnodactyly

Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.

(197) The Impact of Connective Tissue Disorders on Rates of Penile Fracture and Peyronie’s Disease

Abstract Introduction Ehlers Danlos Syndrome (EDS) and collagen-related hypermobility disorders are well known to cause frequent joint dislocations, easy bruising, and poor wound healing. Marfan syndrome is caused by a mutation in the protein fibrillin, a key component of collagen and elastin connective tissue, whose dysfunction causes the marfanoid phenotype. Currently, little is known regarding the impact of connective tissue disorders on men’s sexual health. As a first step in exploring this association, we investigated two physical phenomena that may be impacted by collagen disorders, penile fractures and Peyronie’s disease. Objective This study aims to investigate rates of penile fracture and Peyronie’s disease in EDS and Marfan syndrome patients. Methods A multi-center, international, electronic health record network (TriNetX) was queried to identify adult male patients with or without EDS between 1993 and 2023 using ICD-10 codes Q79.6, Q79.60, and Q79.62 specific for EDS and EDS related hypermobility syndrome. TriNetX was separately queried for Marfan syndrome using ICD-10 code Q87.4. Incidence and prevalence of penile fractures and Peyronie’s disease were compared between patients with and without the diseases of interest. Penile fractures were identified using ICD-10 codes S39.840, S39.84A, S39.84S, S39.84D. Peyronie’s disease was defined using ICD-10 code N48.6. Odds ratios were generated with 95% confidence intervals. All statistical analyses were conducted within the TriNetX platform. Results Data was queried from 82 healthcare organizations to yield 11,937 EDS patients, and from 101 healthcare organizations to yield 13,705 Marfan syndrome patients. 109 healthcare organizations contributed data to yield a control group of 63,790,628 men. Men with EDS had a 25 times higher rate of penile fractures (0.09%) compared to men without EDS (OR 25; 95% CI [13.8-47.8]). Men with Marfan’s syndrome had a 23 times higher rate of penile fractures (0.08%) compared to men without Marfan’s syndrome (OR 23; 95% CI [12.4-43.1]). Men with Marfan’s syndrome also had a significantly higher incidence of Peyronie’s disease compared to men without Marfan’s syndrome (OR 1.9; 95% CI [1.2-3]). The difference in rates of Peyronie’s disease was not significantly higher for men with EDS (OR 1.4; 95% CI [0.8 – 2.5]). Conclusions Patients with EDS and Marfan syndrome are at an over 20 times higher risk for penile fracture. These increased risks may be due to EDS’s and Marfan syndrome’s effects on collagen and fibrillin/elastic fibers, respectively, which are significant structural components of the corpora cavernosa. Patients with these syndromes should be aware of this increased risk and further research is needed to establish how to council these patients about taking appropriate precautions. Disclosure No.

Identification of two novel large deletions in FBN1 gene by next-generation sequencing and multiplex ligation-dependent probe amplification.

Mutations in fibrillin-1 (FBN1) are known to be associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Most FBN1 mutations are missense or nonsense mutations. Traditional molecular genetic testing for the FBN1 gene, like Sanger sequencing, may miss disease-causing mutations in the gene's regulatory regions or non-coding sequences, as well as partial or complete gene deletions and duplications. Next-generation sequencing, multiplex ligation-dependent probe amplification and gap PCR were conducted on two MFS patients to screen for disease-causing mutations. We identified two large deletions in FBN1 from two MFS patients. One patient had a 0.23 Mb deletion (NC_000015.9:g.48550506_48779360del) including 5'UTR-exon6 of FBN1. The other patient harbored a 1416 bp deletion (NC_000015.9:g.48410869_48412284del) affecting the last exon, exon 66, of the FBN1 gene. Our results expanded the number of large FBN1 deletions and highlighted the importance of screening for large deletions in FBN1 in clinical genetic testing, especially for those with the classic MFS phenotype.

TGFβ level in healthy and children with Marfan syndrome-effective reduction under sartan therapy.

Transforming growth factor β (TGFβ) metabolism plays an important role in the pathogenesis of Marfan syndrome (MFS). Accordingly, drug therapy uses TGFβ receptor blockade to slow down the cardiovascular manifestations, above all aortic root dilatation. Angiotensin II type 1 receptor blockers (ARBs) have been shown to reduce TGFβ levels in adults. Data on childhood are lacking and are now being investigated in the TiGer For Kids study presented here. We examined 125 children without chronic disease and 31 pediatric Marfan patients with a proven FBN1 variant with regard to TGFβ levels. In addition, we measured TGFβ levels during the initiation of ARB therapy in pediatric Marfan patients. In children without chronic disease, TGFβ levels were found to decrease from childhood to adolescence (p < 0.0125). We could not measure a relevantly increased TGFβ level in pediatric Marfan patients. However, we showed a significant suppression of the TGFβ level after treatment with ARBs (p < 0.0125) and a renewed increase shortly before the next dose. The TGFβ level in childhood changes in an age-dependent manner and decreases with age. The TGFβ level drops significantly after taking ARBs. Based on our experience and data, a TGFβ receptor blockade in childhood seems reasonable. So far, TGFβ level cannot be used as an MFS screening biomarker.

Postoperative longitudinal refractive changes in children younger than 8 years with ectopia lentis and Marfan syndrome.

To evaluate the postoperative longitudinal refractive changes in children younger than 8 years with ectopia lentis and Marfan syndrome (MFS). Zhongshan ophthalmic center, Guangzhou, China. Retrospective cohort study. Medical data of patients diagnosed with ectopia lentis and MFS that underwent surgery younger than 8 years were collected. Refractive errors and ocular biometric parameters were collected preoperatively and at each follow-up visit. Patients were stratified into groups according to age at surgery, and only the eye operated on first was selected. Multivariate analysis was performed to determine the association between refractive shift and potential risk factors. In total, 54 eyes of 54 patients were enrolled. The median age at surgery was 6.21 years (interquartile range [IQR], 5.25 to 6.85), and the median follow-up was 2.0 years (IQR, 1.2 to 2.8 years). At age 8 years, patients demonstrated a median myopic shift ranged from -1.75 diopters (D) (IQR, -2.75 to -1.00 D) for the 4-year-old group to -0.13 D (IQR, -0.50 to -0.06 D) for the 7-year-old group. Multivariate analysis showed that greater myopic shift was associated with younger age at surgery ( P = .004), male sex ( P = .026), and shorter preoperative axis length ( P = .005). A tendency toward increasing postoperative myopic was demonstrated in children with ectopia lentis and MFS, with the greatest myopic shift in the younger age groups. If the goal is to reach emmetropia by age 8 years, the immediate postoperative hypermetropic targets should be 1.75 D for age 4 years, 1 D for age 5 years, 0.5 D for age 6 years, and 0 to 0.25 D for age 7 years.

Abstract TP280: Monogenetic Stroke Syndrome Testing in Adults: A Single Center Experience

As access and coverage of genetic testing has increased, it is being used more commonly in adults with strokes. However, no clear guidelines exist for who should undergo genetic testing. Our retrospective review aims to provide guidance in this regard and show our experience. Genetic testing was ordered at our comprehensive stroke center between June 2022 and September 2023. Tests were ordered from GeneDx and genetic material was collected by buccal swab after consent was obtained. Most of the testing was done routinely in the outpatient setting, but was rarely performed inpatient when diagnosis would change acute management. Genetic testing was ordered for 41 patients. Tests ordered included whole exome sequencing, mitochondrial genome sequencing, Marfan syndrome and thoracic aortic aneurysm and dissection panel, Disorders of connective tissues panel and expedited whole genome sequencing. Indications for testing included evaluation of carotid and vertebral dissections, recurrent stroke, cryptogenic stroke, and leukoencephalopathy. The average age of tested patients was 47. Of these patients, 6 had not had a stroke and the testing was ordered to evaluate etiology of vertebral or carotid dissections. Of the 35 patients being evaluated for stroke etiology, 60% had at least one stroke or TIA prior to presentation. Of patients tested, 14 had evidence of dissection in the carotid arteries or vertebral arteries. At the time of analysis, 27 patients had results available, of which 15 had negative results. Positive results with pathogenic variant were seen in 4 patients. Pathologic variants detected included mutations in ABCC6, NOTCH3, MT-TL1, HBB, and MCCACHC genes. Variants of unknown significance were seen in 8 patients. These variants included mutations in MYLK, COL5A1, COL5A2, KRIT1, CCM2, XPR1, MT-CYB, MT-ND4, and MT-ATP6 genes. This study highlights that in the right clinical population, like young patients with recurrent stroke, genetic testing can be helpful to elucidate the etiology of cerebrovascular disease when standard stroke work up is inconclusive. With retrospective review, we aim to provide guidance on indications for genetic testing in adults with stroke and dissection.

Sequence of Events Which Led to Significant Hypoxemia in a Patient with Marfanoid Features Undergoing Elective Cesarean Section Under General Anaesthesia: A Case Report

The airway and respiratory system abnormalities seen in Marfan syndrome pose a significant challenge to the anaesthetist. Here, we discuss the chain of events that occurred during the induction of a primi mother, with Marfanoid features complicated with low platelet count and anaemia due to bone marrow hypoplasia. We then discuss the concerns of Marfan Syndrome and its features concerning anaesthetic management.

Valvulopathies and Genetics: Where are We?

Valvulopathies are among the most common cardiovascular diseases, significantly increasing morbidity and mortality. While many valvular heart diseases are acquired later in life, an important genetic component has been described, particularly in mitral valve prolapse and bicuspid aortic valve. These conditions can arise secondary to genetic syndromes such as Marfan disease (associated with mitral valve prolapse) or Turner syndrome (linked to the bicuspid aortic valve) or may manifest in a non-syndromic form. When cardiac valve disease is the primary cause, it can appear in a familial clustering or sporadically, with a clear genetic component. The identification of new genes, regulatory elements, post-transcriptional modifications, and molecular pathways is crucial to identify at-risk familial carriers and for developing novel therapeutic strategies. In the present review we will discuss the numerous genetic contributors of heart valve diseases.

Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis.

Marfan syndrome (MFS) is a rare genetic disorder caused by mutations in the Fibrillin-1 gene (FBN1) with significant clinical features in the skeletal, cardiopulmonary, and ocular systems. To gain deeper insights into the contribution of epigenetics in the variability of phenotypes observed in MFS, we undertook the first analysis of integrating DNA methylation and gene expression profiles in whole blood from MFS and healthy controls (HCs). The Illumina 850K (EPIC) DNA methylation array was used to detect DNA methylation changes on peripheral blood samples of seven patients with MFS and five HCs. Associations between methylation levels and clinical features of MFS were analyzed. Subsequently, we conducted an integrated analysis of the outcomes of the transcriptome data to analyze the correlation between differentially methylated positions (DMPs) and differentially expressed genes (DEGs) and explore the potential role of methylation-regulated DEGs (MeDEGs) in MFS scoliosis. The weighted gene co-expression network analysis was used to find gene modules with the highest correlation coefficient with target MeDEGs to annotate their functions in MFS. Our study identified 1253 DMPs annotated to 236 genes that were primarily associated with scoliosis, cardiomyopathy, and vital capacity. These conditions are typically associated with reduced lifespan in untreated MFS. We calculated correlations between DMPs and clinical features, such as cobb angle to evaluate scoliosis and FEV1% to assess pulmonary function. Notably, cg20223687 (PTPRN2) exhibited a positive correlation with cobb angle of scoliosis, potentially playing a role in ERKs inactivation. Taken together, our systems-level approach sheds light on the contribution of epigenetics to MFS and offers a plausible explanation for the complex phenotypes that are linked to reduced lifespan in untreated MFS patients.

Perioperative Management of Marfan Syndrome in Pregnancy and Congestive Heart Failure

Introduction: A mutation in fibrillin-1 (FBN1) leads to the autosomal dominant condition known as Marfan Syndrome (MFS). The condition of pregnancy with MFS may increase morbidity and mortality during pregnancy and delivery. Due to a greater frequency of maternal problems and fetal involvement, pregnancy with Marfan syndrome (MFS) provides challenges to healthcare professionals and patients and requires special treatment. Objective: This study aimed to analyze the perioperative management of Marfan syndrome in pregnancy and congestive heart failure (CHF). Case report: A 27-year-old primigravida with 38-39 weeks gestation presented with a referral letter with a diagnosis of G1P0A0 with scoliosis and peripartum cardiomyopathy. The patient complained of shortness of breath accompanied by cold sweat since the second trimester of gestation. Physical examination revealed the presence of arachnodactyly and spine deformity. The patient underwent an emergency cesarean section with general anesthesia. Breathing problem appeared the next day after cesarean section, the patient was intubated in the ICU. Chest X-ray depicted bilateral pulmonary edema. A mechanical ventilator was set up and fluid restriction had been done. The patient was extubated after showing breathing improvement in the second week in the ICU. Discussion: The diagnosis of MFS in this patient was defined based on the revised Ghent Nosology. MFS with spine deformity causes breathing problems because of the altered geometry of the thoracic cavity. MFS in pregnancy may worsen the breathing problem due to autotransfusion that leads to pulmonary edema. A mechanical ventilator with a specific setting accompanied by fluid restriction is recommended to reduce the fluid overload in the lungs. Conclusion: Mechanical ventilators with specific settings and fluid restriction are effective perioperative management to reduce pulmonary edema on MFS in pregnancy and congestive heart failure.

Severe dural ectasia in a pregnant patient with Marfan syndrome.

Severe dural ectasia in a pregnant patient with Marfan syndrome.