Visual Outcomes in Ectopia Lentis in Marfan Syndrome: A Study of Four Surgical Techniques in Children and Adults.

Background/Objectives: To evaluate how the surgical technique and type of implanted intraocular lens influence the postoperative visual acuity and complications in ectopia lentis associated to Marfan syndrome patients. Materials and Methods: The medical records and videos of ectopia lentis surgeries in patients (children and adults) with Marfan syndrome, were retrospectively reviewed and compared. The study included 33 eyes that underwent four different intraocular lens implantation (IOL) techniques: IOL in conjunction with a simple capsular tension ring, IOL in conjunction with a Cionni modified capsular tension ring (m-CTR), two-point scleral IOL fixation and IOL with one haptic in the bag and one haptic sutured to the sclera. Results: Vision significantly improved from a mean preoperative visual acuity of 0.1122 to a mean postoperative visual acuity of 0.4539 in both age groups (p < 0.0001), with no difference in the primary outcome between children and adults. The most common surgical technique used in both age groups was IOL in conjunction with an m-CTR. There was only one major postoperative complication requiring additional surgery. Conclusions: Zonular weakness mainly influenced by age was the most important selection criterion for the surgical approach. Regardless of the technique employed, the postoperative visual acuity was improved in both adults and children.

Evidence of cardiomyopathy associated with Marfan syndrome in children.

OBJECTIVE: Marfan syndrome (MFS)-associated cardiomyopathy, defined as ventricular dilation and dysfunction unexplained by volume loading, is not well defined in children. This study evaluated ventricular size and function in paediatric MFS using cardiac MRI (cMRI). METHODS: This retrospective cohort study examined patients with MFS <19 years old at first cMRI. Left ventricular (LV) ejection fraction (EF) <55% was considered abnormal, as were z-scores >2. Combined mitral and aortic regurgitation indexed to LV stroke volume <20% defined absent/mild volume load. Biventricular volumes and EF on serial cMRI studies were compared with normative paediatric cMRI values, with measures converted to z-scores as appropriate. Longitudinal changes in volumes and EF were evaluated by mixed linear regression. Associations between ventricular, aortic and mitral characteristics were evaluated. RESULTS: 58 patients (60% male) were evaluated. Median age at initial cMRI was 13.6 years (IQR 10.0-15.8 years). Among patients with absent/mild LV volume load at initial cMRI (n=44, 76%), indexed LV end-diastolic volume (EDV) was significantly increased above normative values (median z-score 1.8, IQR 0.6-3.5, p<0.0001) and LVEF was abnormal in 48% (21/44). In the absence of volume loading, mitral valve prolapse (MVP) was associated with larger ventricular volumes and lower LVEF. Among those with serial cMRIs, LVEF and EDV z-scores did not significantly change over a mean follow-up time between cMRI studies of 1.5 years. CONCLUSION: Ventricular dilation and reduced EF are common in children with MFS and occur with no/mild LV volume load, suggesting intrinsic cardiomyopathy. MVP may be associated with cardiomyopathy.

Health-related quality of life in children and adolescents with Marfan syndrome or related disorders: a controlled cross-sectional study.

BACKGROUND: This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson's or Spearman's coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. RESULTS: Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. CONCLUSIONS: This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

Temporomandibular disorders in individuals with Marfan syndrome: an exploratory analysis.

BACKGROUND: This study aims to analyze to what extent patients with Marfan syndrome (MFS) are affected by temporomandibular disorders (TMD) and its impact on oral health-related quality of life (OHRQoL). To collect data, an online questionnaire was created to recruit participants from Germany, Austria, and Switzerland through social media and support groups. The questionnaire consists of free-text questions, the German versions of the Oral Health Impact Profile (OHIP-G14), the Depression Anxiety Stress Scale (DASS), and the Graded Chronic Pain Status (GCPS). RESULTS: A total of 76 participants with diagnosed MFS were included. Of these, 65.8% showed TMD symptoms, the most common being pain or stiffness of the masticatory muscles in the jaw angle (50.0%). Only 14.5% of the participants were already diagnosed with TMD. Of the participants with an increased likelihood of a depression disorder, 76.9% showed TMD symptoms. Of those with a critical score for an anxiety disorder, 90.9% showed TMD symptoms. 73.3% of participants with TMD symptoms reached the critical score for a stress disorder. TMD symptoms were associated with a higher risk for chronic pain. In the median, participants with TMD showed statistically notably higher OHIP-G14 scores than participants without TMD (11.5 [IQR 17] vs. 1 [IQR 3] points, p ≤ 0.001). CONCLUSION: TMD symptoms had a noticeable impact on OHRQoL in patients with MFS, i.e., chronic pain and psychological impairment. TMD seems underdiagnosed, and more research is needed to prevent the associated chronification of pain and psychological burden to improve the OHRQoL.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively).    Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: • Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. • Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: • Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. • Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Combined free-running four-dimensional anatomical and flow magnetic resonance imaging with native contrast using Synchronization of Neighboring Acquisitions by Physiological Signals.

BACKGROUND: Four-dimensional (4D) flow magnetic resonance imaging (MRI) often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel delineation. In this work, a novel technique is developed to acquire and reconstruct 4D flow data with excellent dynamic visualization of blood vessels but without the need for contrast injection. Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS) uses pilot tone (PT) navigation to retrospectively synchronize the reconstruction of two free-running three-dimensional radial acquisitions, to create co-registered anatomy and flow images. METHODS: Thirteen volunteers and two Marfan syndrome patients were scanned without contrast agent using one free-running fast interrupted steady-state (FISS) sequence and one free-running phase-contrast MRI (PC-MRI) sequence. PT signals spanning the two sequences were recorded for retrospective respiratory motion correction and cardiac binning. The magnitude and phase images reconstructed, respectively, from FISS and PC-MRI, were synchronized to create SyNAPS 4D flow datasets. Conventional two-dimensional (2D) flow data were acquired for reference in ascending (AAo) and descending aorta (DAo). The blood-to-myocardium contrast ratio, dynamic vessel area, net volume, and peak flow were used to compare SyNAPS 4D flow with Native 4D flow (without FISS information) and 2D flow. A score of 0-4 was given to each dataset by two blinded experts regarding the feasibility of performing vessel delineation. RESULTS: Blood-to-myocardium contrast ratio for SyNAPS 4D flow magnitude images (1.5 ± 0.3) was significantly higher than for Native 4D flow (0.7 ± 0.1, p < 0.01) and was comparable to 2D flow (2.3 ± 0.9, p = 0.02). Image quality scores of SyNAPS 4D flow from the experts (M.P.: 1.9 ± 0.3, E.T.: 2.5 ± 0.5) were overall significantly higher than the scores from Native 4D flow (M.P.: 1.6 ± 0.6, p = 0.03, E.T.: 0.8 ± 0.4, p < 0.01) but still significantly lower than the scores from the reference 2D flow datasets (M.P.: 2.8 ± 0.4, p < 0.01, E.T.: 3.5 ± 0.7, p < 0.01). The Pearson correlation coefficient between the dynamic vessel area measured on SyNAPS 4D flow and that from 2D flow was 0.69 ± 0.24 for the AAo and 0.83 ± 0.10 for the DAo, whereas the Pearson correlation between Native 4D flow and 2D flow measurements was 0.12 ± 0.48 for the AAo and 0.08 ± 0.39 for the DAo. Linear correlations between SyNAPS 4D flow and 2D flow measurements of net volume (r2 = 0.83) and peak flow (r2 = 0.87) were larger than the correlations between Native 4D flow and 2D flow measurements of net volume (r2 = 0.79) and peak flow (r2 = 0.76). CONCLUSION: The feasibility and utility of SyNAPS were demonstrated for joint whole-heart anatomical and flow MRI without requiring electrocardiography gating, respiratory navigators, or contrast agents. Using SyNAPS, a high-contrast anatomical imaging sequence can be used to improve 4D flow measurements that often suffer from poor delineation of vessel boundaries in the absence of contrast agents.

Exploring the potential relationship between collagen cross-linking and impaired myocardial relaxation in Marfan syndrome: An observational study using serum biomarkers.

BACKGROUND: Increased collagen cross-linking (CCL) has been described in hypertensive cardiomyopathy by means of reduced serum ratio of serum carboxyterminal telopeptide of collagen type I (CITP) to matrix metalloproteinase-1 (MMP1). Previous studies have demonstrated the existence of primary impaired diastole in patients with Marfan syndrome (MFS), but little is known about the pathophysiology of this condition. METHODS: 60 MFS patients (without previous cardiovascular surgery or significant valvular regurgitation) and 24 healthy controls (age and sex-matched) were enrolled. All participants underwent a comprehensive transthoracic echocardiographic study, including left atrial and left ventricular speckle-tracking strain analysis. CITP and MMP1 were measured in peripheral blood. RESULTS: All participants had normal diastolic function according to guidelines. Peak left atrial strain in the reservoir phase (LASr) was significantly reduced in the MFS cohort compared to controls (32.2 ± 9.4 vs 43.9 ± 7.0%; p < 0.001). Serum CITP and CITP:MMP1 ratio were lower among MFS patients, showing significant correlations with LASr (R = 0.311; p = 0.020 and R = 0.437; p = 0.001, respectively). The MFS cohort was divided into quartiles of LASr. MFS patients in the lowest quartile of LASr (<26%) had significantly lower values of CITP:MMP1 ratio compared to the other quartiles. CONCLUSIONS: The analysis of serum biomarkers revealed the presence of increased CCL in association with reduced LASr in the MFS cohort. Our results suggest that excessive CCL may play a role in the development of primary myocardial impairment in these patients. Future studies are needed to confirm our findings and evaluate the prognostic role of CCL markers in the MFS population.

Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome.

The mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

Anesthesia in Parturients Presenting with Marfan Syndrome.

BACKGROUND: Pregnant women with Marfan syndrome (MS) have a high risk of aortic dissection around delivery and their optimal management requires a multi-disciplinary approach, including proper cardio-obstetric care and adequate pain management during labor, which may be difficult due to the high prevalence of dural ectasia (DE) in these patients. OBJECTIVES: To evaluate the multidisciplinary management of MS patients during labor. METHODS: Nineteen pregnant women (31 pregnancies) with MS were followed by a multi-disciplinary team (cardiologist, obstetrician, anesthesiologist) prior to delivery. RESULTS: Two patients had kyphoscoliosis; none had previous spine surgery nor complaints compatible with DE. In eight pregnancies (7 patients), aortic root diameter (ARd) before pregnancy was 40 to 46 mm. In this high-risk group, one patient underwent elective termination, two underwent an urgent cesarean section (CS) under general anesthesia, and five had elective CS; two under general anesthesia (GA), and three under spinal anesthesia. In 23 pregnancies (12 patients), ARd was < 40 mm. In this non-high-risk group three pregnancies (1 patient) were electively terminated. Of the remaining 20 deliveries (11 patients), 14 were vaginal deliveries, 9 with epidural analgesia and 5 without. Six patients had a CS; four under GA and two2 under spinal anesthesia. There were no epidural placement failures and no failed responses. There were 2 cases of aortic dissection, unrelated to the anesthetic management. CONCLUSIONS: The optimal anesthetic strategy during labor in MS patients should be decided by a multi-disciplinary team. Anesthetic complications due to DE were not encountered during neuraxial block.

Predictive Physical Manifestations for Progression of Scoliosis in Marfan Syndrome.

STUDY DESIGN: A retrospective study of the prospective cohort. OBJECTIVE: To demonstrate the accurate distribution of the severity of scoliosis in patients with Marfan syndrome, and to identify the predictive physical features for progression of scoliosis in Marfan syndrome. SUMMARY OF BACKGROUND DATA: To date, no study has unveiled the risk factors for the progression of scoliosis in Marfan syndrome. METHODS: We retrospectively obtained data from a prospective cohort of the Marfan syndrome clinic at our institute. We enrolled patients whose whole spine radiographs in the standing position were evaluated at the age of 15 or above, from January 2014 to March 2020. The collected variables were physical manifestations defined as in the systemic score of the revised Ghent nosology. We classified the degree of scoliosis into four categories: "not apparent," "mild" (10° ≤ Cobb < 25°), "moderate" (25° ≤ Cobb < 40°), and "severe" (40° ≤ Cobb or surgery conducted). To identify the risk factors for progression of scoliosis in Marfan syndrome, we conducted univariate and multivariate association analyses between severe scoliosis and each physical manifestation. RESULTS: We identified 131 eligible patients (61 men and 70 women) with a mean age of 31.2 years. Scoliosis with a Cobb angle of ≥10° was identified in 116 patients (88.5%). Moderate scoliosis was identified in 33 patients (25.2%) and severe scoliosis in 53 patients (40.5%). The prevalence of each physical manifestation was equivalent to that reported in previous studies. Multivariate logistic regression analysis revealed that female sex (odds ratio, 3.27) and positive wrist sign (4.45) were predictive factors for progression of scoliosis into severe state in patients with Marfan syndrome. CONCLUSIONS: The present study demonstrated the accurate distribution of the severity of scoliosis and identified the predictive factors for progression of scoliosis in patients with Marfan syndrome.Level of Evidence: 3.

Mitral Valve Prolapse and Its Motley Crew-Syndromic Prevalence, Pathophysiology, and Progression of a Common Heart Condition.

Mitral valve prolapse (MVP) is a commonly occurring heart condition defined by enlargement and superior displacement of the mitral valve leaflet(s) during systole. Although commonly seen as a standalone disorder, MVP has also been described in case reports and small studies of patients with various genetic syndromes. In this review, we analyzed the prevalence of MVP within syndromes where an association to MVP has previously been reported. We further discussed the shared biological pathways that cause MVP in these syndromes, as well as how MVP in turn causes a diverse array of cardiac and noncardiac complications. We found 105 studies that identified patients with mitral valve anomalies within 18 different genetic, developmental, and connective tissue diseases. We show that some disorders previously believed to have an increased prevalence of MVP, including osteogenesis imperfecta, fragile X syndrome, Down syndrome, and Pseudoxanthoma elasticum, have few to no studies that use up-to-date diagnostic criteria for the disease and therefore may be overestimating the prevalence of MVP within the syndrome. Additionally, we highlight that in contrast to early studies describing MVP as a benign entity, the clinical course experienced by patients can be heterogeneous and may cause significant cardiovascular morbidity and mortality. Currently only surgical correction of MVP is curative, but it is reserved for severe cases in which irreversible complications of MVP may already be established; therefore, a review of clinical guidelines to allow for earlier surgical intervention may be warranted to lower cardiovascular risk in patients with MVP.

Is SF-12 a valid and reliable measurement of health-related quality of life among adults with Marfan syndrome? A confirmatory study.

INTRODUCTION: The structural validity and reliability of the Short-Form Health Survey 12 (SF-12) has not yet been tested in adults with the Marfan syndrome (MFS). This gap could undermine an evidence-grounded practice and research, especially considering that the need to assess health-related quality of life in patients with MFS has increased due to the improved life expectancy of these patients and the need to identify their determinants of quality of life. For this reason, this study aimed to confirm the dimensionality (structural validity) of the SF-12, its concurrent validity, and its reliability (internal consistency). METHODS: We performed a cross-sectional study in a convenience sample of 111 Italian adults with MFS, collecting anamnestic and socio-demographic information, the SF-12, and short-form Health Survey 36 (SF-36). A confirmatory factor analysis was performed to verify whether the items of SF-12 related to physical restrictions, physical functioning, and bodily pain were retained by the physical summary component of the SF-12. The items referred to the role limitations due to emotional issues, social functioning, and mental health were retained by the mental summary component (MCS12). SF-36 was used to assess the concurrent validity of SF-12, hypothesizing positive correlations among the equivalent summary scores. RESULTS: The two-factor structural solution resulted in fitting the sample statistics adequately. The internal consistency was adequate for the two factors. Furthermore, the physical and mental summary scores of the SF-36 were positively correlated with their equivalent summary scores derived from the SF-12. CONCLUSIONS: This study confirmed the factor structure of the SF-12. Therefore, the use of SF-12 in clinical practice and research for assessing the health-related quality of life among adults with MFS is evidence-grounded. Future research is recommended to determine whether the SF-12 shows measurement invariance in different national contexts and determine eventual demographic variation in the SF-12 scores among patients with MFS.

Blood pressure-independent inhibition of Marfan aortic root widening by the angiotensin II receptor blocker valsartan.

Marfan syndrome (MFS) is a genetic disorder that results in accelerated aortic root widening and aneurysm. However, management of MFS patients with blood pressure (BP)-lowering medications, such as angiotensin II (AngII) receptor blocker (ARB) losartan, continues to pose challenges due to their questionable efficacy at attenuating the rate of aortic root widening in patients. Herein we investigate the anti-aortic root widening effects of a sub-BP-lowering dose valsartan, an ARB previously linked to non-BP lowering anti-remodeling effects. Despite absence of BP-lowering effects, valsartan attenuated MFS aortic root widening by 75.9%, which was similar to a hypotensive dose of losartan (79.4%) when assessed by ultrasound echocardiography. Medial thickening, elastic fiber fragmentation, and phospho-ERK signaling were also inhibited to a similar degree with both treatments. Valsartan and losartan decreased vascular contractility ex vivo between 60% and 80%, in a nitric oxide (NO)-sensitive fashion. Valsartan increased acetylcholine (Ach)-induced vessel relaxation and phospho-eNOS levels in the aortic vessel supporting BP-independent activation of protective endothelial function, which is critical to ARB-mediated aortic root stability. This study supports the concept of achieving aortic root stability with valsartan in absence of BP-lowering effects, which may help address efficacy and compliance issues with losartan-based MFS patient management.

Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy.

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. METHODS: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. RESULTS: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. CONCLUSIONS: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

Maternal health and pregnancy outcome in diagnosed and undiagnosed Marfan syndrome: A registry-based study.

In Marfan syndrome (MFS), pregnancy is considered as high risk due to the deficiency of fibrillin in the connective tissue and increased risk of aortic dissection. The objective was to demonstrate the consequences on maternal health, in women with diagnosed and undiagnosed MFS at the time of pregnancy and childbirth. By using national health care registries, we identified all pregnancy related outcomes, from women with MFS (n = 183) and an age-matched background population (n = 18,300). We found 91 pregnancies during follow-up. Significantly fewer women with MFS gave birth, compared to the background population. No women with known MFS had a pregnancy related aortic dissection but complications related to the cervix were increased (HR:19.8 [95% CI:2.2-177.5]). Fifty women with MFS were undiagnosed at the time of their first pregnancy and/or childbirth. Among these, there were more birth canal related complications HR:27.2 (95% CI: 2.3-315.0), preeclampsia (HR:2.25 [95% CI: 1.11-4.60]), fetal deaths (HR:12.3 [95% CI: 1.51-99.8]), and all delivery-related dissections came from this subgroup. In conclusion, undiagnosed women with MFS experienced more pregnancy and childbirth related complications including fetal death, birth canal issues, preeclampsia, and aortic disease, which emphasizes the need for an early MFS diagnosis and special care during pregnancy and childbirth.

Visual outcomes of lens subluxation surgery with Cionni modified capsular tension rings in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary disease with an incidence of 0.3% in the general population. Approximately 60% of MFS patients with FBN1 gene mutation will suffer ectopia lentis (EL) from the age of 3. With the development of EL, severe loss of vision will accrue because of lens tilt and glaucoma. Cionni modified capsular tension rings (MCTR) has been applied in the surgery for EL in MFS patients. To evaluate visual acuity and safety of using MCTR during lens subluxation surgery in MFS patients, 66 MFS patients (110 eyes) were included in our study, with the mean duration of follow-up of 4.7 months (SD 1.76 months). The capsular bags were preserved in 101 eyes (91.81%) with MCTR implantation. There was an overall significant improvement in BCVA at 1-month follow-up which was maintained at 3 months. Multivariable linear regression revealed that older age at first visit was associated with greater postoperative BCVA at the 1-month follow-up (P = 0.007). A significant difference was found between different degrees of lens subluxation and the length of surgical time and complications. At follow-up, only two eyes (1.98%) were identified to have developed retinal detachments. In conclusion, better visual outcomes can be achieved when patients received an early operation with MCTR implantation.

Subclavian artery aneurysmal rupture and left internal mammary artery extravasation secondary to advanced Marfan syndrome.

This case highlights the unusual life-threatening findings found in a patient with Marfan syndrome (MFS) in the emergency department setting. MFS is a rare autosomal dominant disease that affects 1 in 3000-5000 individuals and has a highly variable range of clinical severity. This case is a 63-year-old male with COPD, scoliosis, aortic and mitral valve replacements on warfarin, and MFS who presented with acute onset hemoptysis, tachypnea, and oxygen saturation of 77% on 4 l nasal cannula. Emergent chest computed tomography angiography (CTA) revealed both a contained rupture of a left subclavian artery aneurysm and active extravasation from his left internal mammary artery (LIMA) into his left chest. The patient was on warfarin and reversed with IV vitamin K and prothrombin complex concentrate. Vascular surgery emergently took the patient to the operating room for embolization of his LIMA and stenting of the contained ruptured left subclavian artery aneurysm. The patient was discharged home one month after admission. This case report illustrates the potential severe sequelae of MFS and the importance of rapid recognition by emergency physicians. An expanded understanding of the pathophysiology of MFS has resulted in great advancement in medical therapies and lifestyle modification and thus has significantly prolonged life expectancy in these patients. Increased awareness and familiarity will facilitate continued high-quality management and treatment by emergency physicians.

A new family with epiphyseal chondrodysplasia type Miura.

Epiphyseal chondrodysplasia, Miura type (ECDM) is a skeletal dysplasia with tall stature and distinctive skeletal features caused by heterozygous NPR2 pathogenic variants. Only four families have been reported. We present a family with five affected individuals (mother, three sons, and daughter). The mother's phenotype was relatively mild: borderline tall stature and elongated halluces operated during childhood. The children were remarkably more severely affected with tall stature, scoliosis, and elongated toes and fingers leading to suspicion of Marfan syndrome. Progressive valgus deformities (at the hips, knees, and ankles) were the main complaints and necessitated orthopedic investigations and surgery. Radiographs showed coxa valga, scoliosis, multiple pseudoepiphyses of the fingers and toes with uneven elongation of the digits and ankle valgus. The two older brothers underwent osteotomies and guided growth for axial deformities and arthrodesis for elongated halluces. Genetic testing confirmed the clinical diagnosis of ECDM: all affected individuals had a heterozygous c.2647G>A (p.Val883Met) NPR2 variant in a highly conserved region in the carboxyl-terminal guanylyl cyclase domain. This two-generation family elucidates the clinical and radiological variability of the disease. These rare cases are important to gain further understanding of the fundamental processes of growth regulation.