Search

Background and Aims: Neurological abnormalities have been frequently reported in individuals with Marfan Syndrome (MFS). However, available data relies solely on retrospective studies predating current diagnostic criteria., Methods: Cross-sectional study comprehensively investigating neurological abnormalities within a prospective cohort of adults (≥ 18 years) with genetically confirmed MFS referred to an Italian hub center for heritable connective tissue diseases (Jan. 1st - Nov. 15th, 2021)., Results: 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)., Conclusions: 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., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Despite knowledge of the pathophysiology and clinical complications of connective tissue diseases (CTD), little is known regarding their impact on men's sexual health disorders., Aim: To investigate the prevalence of penile fracture (PF) in patients with Ehlers-Danlos Syndrome (EDS) and Marfan syndrome (MFS) in comparison with disease-free controls between 18 and 45 years of age., Methods: A multicenter, international, electronic health record network (TriNetX) was queried to identify adult male patients (between 18 and 45 years) with or without EDS and MFS between 1993 and 2023 using ICD-10 codes. The prevalence of PF was compared between patients with and without the diseases of interest. Prevalence ratios (PR) were generated with 95% confidence intervals., Outcome: Prevalence of PF in patients with EDS and MFS when compared to disease-free controls., Results: The number of patients with EDS, MFS, and control groups was 8060, 8642, and 20 184 547, respectively, with a mean age of 27.8 ± 7.58, 28.6 ± 7.4, and 31.6 ± 8.04 years. Men with EDS had a higher prevalence of PF (PR 30.18, 95% CI [17.08-53.19]; P < 0.0001). Similarly, men with MFS had a higher prevalence of PF (PR 23.4, 95% CI [12.6-43.7]; P < 0.0001)., Clinical Implications: This study demonstrates an association between CTD and men's sexual health disorders. It may be important to counsel such men about the risks of PF., Strengths and Limitations: This is the largest study to date to demonstrate an association between CTD and men's sexual health disorders. While the large sample sizes in this study contribute to the robustness of the findings, the study is limited by the use of a claims-based dataset, which does not provide further details about disease course and complications, and the use of a univariate analysis only., Conclusions: Patients with EDS and MFS are possibly at an elevated risk for PF. Due to the limitations of the TriNetX database, the analysis was limited to a univariate one, thus limiting the ability to control for confounders and limiting the generalizability of these findings. Further prospective research is needed to corroborate these findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Connective tissue disorders are proposed in the literature to be predisposing risk factors for pelvic floor disorders. Prior data characterizing the prevalence of and symptom burden related to pelvic floor disorders are limited for individuals with Marfan syndrome and are nonexistent for those with Loeys-Dietz syndrome., Objective: The objective of this study was to determine the prevalence and severity of symptoms related to pelvic floor disorders among individuals with Marfan syndrome and Loeys-Dietz syndrome using the Pelvic Floor Distress Inventory-20 (PFDI-20)., Study Design: In this cross-sectional study, a survey including the PFDI-20 was administered to biologically female individuals older than 18 years with a confirmed diagnosis of Marfan syndrome or Loeys-Dietz Syndrome. Respondents were solicited through the websites, email lists, and social media forums of The Marfan Foundation and The Loeys-Dietz syndrome Foundation., Results: A total of 286 respondents were included in the final analysis, 213 with Marfan syndrome and 73 with Loeys-Dietz syndrome. The median PFDI-20 score of the cohort was 43.8. Individuals with Loeys-Dietz syndrome had higher PFDI-20 scores and were more likely to have established risk factors for pelvic floor disorders that correlated with their PFDI-20 scores compared with those with Marfan syndrome., Conclusions: Respondents with Marfan syndrome and Loeys-Dietz syndrome experience a high burden of symptoms related to pelvic floor disorders. Despite the similar pathophysiology and clinical manifestations of these disorders, there were differences in PFDI-20 responses that may suggest that these diseases differ in the ways they affect the pelvic floor., Competing Interests: C.A.F. received authorship royalties from UpToDate and Elsevier. All other authors have declared they have no conflicts of interest., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

Marfan syndrome is a connective tissue disease with autosomal dominant inheritance and variable clinical presentation. The main clinical manifestations recognition could contribute to early diagnosis and cardiovascular complication prevention. We aimed to evaluate the clinical profile of a Marfan syndrome outpatient cohort., Methods: Retrospective cross-sectional study was carried out with outpatients over 12 years of age whose electronic medical records contained the clinical information and complementary exams necessary for study inclusion. Data were analyzed using descriptive statistics and comparisons were performed using student's t-test and chi-square or Fisher's exact test. P-values<0.05 were considered statistically significant., Results: 75 patients (29.5 ± 13.4 years) were included and 43(57 %) were female. Positive family history for the syndrome was observed in 55(73 %) patients and ectopia lentis in 37(49 %). Positive systemic score (≥7) was identified in 60(80 %) individuals and the most frequent score components were: skin striae in 64(85 %), scoliosis in 59(79 %), wrist and thumb sign in 45(60 %), moderate or severe myopia in 43(57 %) and plain flat foot in 40(53 %). Cardiovascular symptoms occurred in 17(23 %) patients: dyspnea in 10(13 %) and palpitations in 6(8 %). Mitral valve prolapse was observed in 32(43 %) participants and aortic root dilation (z-score ≥ 2) in 53(71 %), without significant difference between the groups with or without these alterations concerning sex, age, or symptom presence., Conclusion: Clinical profile of a Marfan syndrome outpatient cohort includes adolescents and young adults, most without cardiovascular symptoms and with a high incidence of skeletal, ophthalmological, and cardiovascular involvement. Recognizing these clinical signs could contribute to early disease diagnosis in the general population., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Literature data suggest high inter-study variability in mitral valve prolapse (MVP) prevalence among individuals with thoracic skeletal abnormalities (TSA). This systematic review aimed at estimating the overall prevalence of MVP in individuals with the most common TSA, including not only the oldest studies (before the year 2000) but also the most recent ones (after the year 2000)., Methods: PubMed and EMBASE databases were systematically reviewed in November 2023. Studies assessing the relationship between MVP and TSA and estimating the MVP prevalence in pectus excavatum (PE), pectus carinatum (PC), scoliosis, straight back syndrome (SBS) and Marfan syndrome (MS) were included. There was no limitation on time periods., Results: Twenty-five studies with a total of 2800 patients (27.9 ± 13.9 years, 48.2% females) were analyzed. The highest prevalence of MVP was observed among MS patients (47.3%), while the lowest was detected in PC individuals (23%). Prevalence of MVP was similar among PE (30.8%), scoliosis (26.3%) and SBS (25.5%) patients. When dividing the studies on the basis of temporal period, the average MVP prevalence was approximately two-fold higher in all studies conducted before the year 2000 in comparison with the most recent ones, regardless of TSA type. This discrepancy might be primarily ascribed to relevant differences in the echocardiographic criteria employed for MVP diagnosis before (less specific) and after (more specific) the year 2000, respectively., Conclusions: The estimated MVP prevalence in TSA individuals is significantly higher than that observed in the general population. Individuals with TSA should be screened for MVP presence on transthoracic echocardiography., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Abstract: This article provides a comprehensive review of Marfan Syndrome (MFS), covering its epidemiology, etiology, clinical presentations, diagnostics, complications, and treatment modalities. The Ghent II Nosology of MFS criteria are crucial in MFS diagnosis, guiding clinicians in identifying high-risk patients. Nursing implications underscore the importance of screenings, assessments, and close follow-ups to optimize the continuum of care for individuals with MFS., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study aimed to investigate the incidence and prevalence of, and treatment patterns for ocular complications in Korean patients with Marfan syndrome., Methods: Incidence and prevalence of Marfan syndrome was calculated from 2010 to 2018, based on data from the Korean National Health Insurance Service (KNHIS). Diagnosis codes (for cataract, ectopia lentis, retinal detachment, etc.) and surgery reimbursement codes (lensectomy, phacoemulsification, buckling, vitrectomy, etc.) in the patients with Marfan syndrome were retrieved by complete enumeration of the data., Results: The annual prevalence of Marfan syndrome adjusted by age and sex was gradually increased from 2.44 per 100,000 in 2010 to 4.36 per 100,000 in 2018. The age group of 10-19 years showed the highest prevalence. The prevalence of ectopia lentis was 21.7%, of whom 43.0% underwent surgeries. Surgery for RD was performed in 253 (14.1%) of 2044 patients during the study period., Conclusion: Although the most prevalent ophthalmologic manifestation was ectopia lentis, total prevalence rate of RD was more than 10% in the study period; thus, regular fundus examination is recommended for the patients with Marfan syndrome.

Background: Pregnancy is a high-risk time for patients with Marfan syndrome or Loeys-Dietz syndrome because of the risk for cardiovascular complications, including the risk for aortic dissection. Little is known about the differences in obstetrical and cardiac outcomes based on delivery hospital setting (academic or academic-affiliated vs community medical centers)., Objective: This study aimed to evaluate the obstetrical and cardiac outcomes of patients with Marfan syndrome or Loeys-Dietz syndrome based on delivery hospital setting., Study Design: This was a secondary analysis of a retrospective, observational cohort study of singleton pregnancies among patients with a diagnosis of Marfan syndrome or Loeys-Dietz syndrome from 1990 to 2016. Patients were identified through the Marfan Foundation, the Loeys-Dietz Syndrome Foundation, or the Cardiovascular Connective Tissue Clinic at Johns Hopkins Hospital. Data were obtained via self-reported obstetrical history and verified by review of medical records. Nonparametric analyses were performed using Fisher's exact tests and Wilcoxon rank-sum tests., Results: A total of 273 deliveries among patients with Marfan syndrome or Loeys-Dietz syndrome were included in this analysis (Table 1). More patients who had a known diagnosis before delivery of either Marfan syndrome or Loeys-Dietz syndrome delivered at an academic hospital as opposed to a community hospital (78.6% vs 59.9%; P=.001). Patients with Marfan syndrome or Loeys-Dietz syndrome who delivered at academic centers were more likely to have an operative vaginal delivery than those who delivered at community centers (23.7% vs 8.6%; P=.002). When the indications for cesarean delivery were assessed, connective tissue disease was the primary indication for the mode of delivery at community centers when compared with academic centers (55.6% vs 43.5%; P=.02). There were higher rates of cesarean delivery for arrest of labor and/or malpresentation at community hospitals than at academic centers (23.6% vs 5.3%; P=.01). There were no differences between groups in terms of the method of anesthesia used for delivery. Among those with a known diagnosis of Marfan syndrome or Loeys-Dietz syndrome before delivery, there were increased operative vaginal delivery rates at academic hospitals than at community hospitals (27.2% vs 15.1%; P=.03) (Table 2). More patients with an aortic root measuring ≥4 cm before or after pregnancy delivered at academic centers as opposed to community centers (33.0% vs 10.2%; P=.01), but there were no significant differences in the median size of the aortic root during pregnancy or during the postpartum assessment between delivery locations. Cardiovascular complications were rare; 8 patients who delivered at academic centers and 7 patients who delivered at community centers had an aortic dissection either in pregnancy or the postpartum period (P=.79)., Conclusion: Patients with Marfan syndrome or Loeys-Dietz syndrome and more severe aortic phenotypes were more likely to deliver at academic hospitals. Those who delivered at academic hospitals had higher rates of operative vaginal delivery. Despite lower frequencies of aortic root diameter >4.0 cm, those who delivered at community hospitals had higher rates of cesarean delivery for the indication of Marfan syndrome or Loeys-Dietz syndrome. Optimal delivery management of these patients requires further prospective research., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thoracic aortic disease (TAD) poses substantial risks during pregnancy, particularly for women with genetic conditions such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. This review examines the epidemiology, risk assessment, and management of TAD in pregnancy. Preconception counseling is vital considering the hereditary nature of TAD and potential pregnancy-related complications. Genetic testing and imaging surveillance aid in risk assessment. Medical management, including beta-blockade and strict blood pressure control, is essential throughout pregnancy. Surgical interventions may be necessary in certain cases. A multidisciplinary approach involving cardiologists, obstetricians, cardiac surgeons, anesthesiologists, and other specialists with expertise in cardio-obstetrics is essential for optimal outcomes. Patient education and shared decision-making play vital roles in navigating the complexities of TAD in pregnancy and improving maternal and neonatal outcomes., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM&#95;000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder., (© 2023. The Author(s).)

Purpose: To investigate the population-based incidence and de novo mutation rate of Marfan syndrome and risk of ectopia lentis., Methods: Patients newly diagnosed with Marfan syndrome in Olmsted County, Minnesota, from January 1, 1976, through December 31, 2005, were identified through medical records review. Outcome measures were Marfan incidence, de novo mutation rate, risk of ectopia lentis., Results: Marfan syndrome was identified in 17 patients during the 30-year period, yielding an incidence of 0.52 per 100,000 people/year (95% CI, 0.27-0.77). Mean age at diagnosis was 24.4 years (range, 1.7 year to 51.3 years). Nine patients (53%) were female. Of the 17, 5 (29%) were new mutations, with a calculated mutation rate of 3.8 ± 1.7 × 10 -5 . Four (24%) were diagnosed with ectopia lentis, including 3 at the time of their Marfan diagnosis. Of the 14 patients at risk for developing ectopia lentis after being diagnosed with Marfan syndrome, 1 (7%) developed it during a mean follow-up of 9 years (range, 0-6.4). Twelve (71%) were diagnosed with dilated ascending aorta during a mean follow-up of 13.2 years (range, 6.7 months to 28.9 years)., Conclusions: Incidence and de novo mutation rate of Marfan syndrome in this population-based cohort was higher than prior reports. Ectopia lentis, whose prevalence in North America has not been reported previously, occurred in approximately one-fourth of study patients and more commonly around the time of initial Marfan diagnosis., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Objective: Aneurysmal pathology of the aorta is well-defined in the Marfan syndrome (MFS) population. Owing in part to the rarity of pathologies, the prevalence of intracranial aneurysms (IA) in MFS is poorly defined. There is debate as to whether or not there is an association between the two. The aim of this study was to evaluate the prevalence of IA in a population of patients with MFS who underwent intracranial imaging., Methods: This was a single-center retrospective review of patients with MFS. Between 1995 and 2021, 983 patients were reviewed. We identified 198 patients with MFS who had intracranial imaging. Imaging consisted of CTA and/or MRA, and was read by an attending radiologist. Details of the aneurysm, patient demographics, and aortic characteristics were collected., Results: The prevalence of IA was 7.1% (14/198). Age of patients with IA (55.0 ± 15.1 years) was not significantly different than those without IA (52.6 ± 16.0 years) (P = .58). The most common location of IA was the internal carotid artery. The mean diameter of the IA was 7 ± 5.8 mm. No ruptures of the internal carotid artery were identified. One patient (0.5%) underwent intervention for the IA. There were no significant differences found in aortic characteristic including dimensions, history of dissection, or aneurysm., Conclusions: In a large, single-center experience over 20 years, we identified patients with confirmed MFS who underwent intracranial imaging. The prevalence of IA in our experience was 7.1%. There were no patient or aortic characteristics found to be significantly associated with IA; however, this finding may be due to the small number of aneurysms. Although this number is higher than the historically reported prevalence in the general population, a collection of experiences from multiple institutions will likely be required to truly define the risk of IA in MFS and to determine whether screening is warranted., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Ophthalmic complications are profound in Marfan syndrome (MFS). However, the overall burden is not well described. Our purpose was to evaluate the ocular morbidity in a nationwide perspective., Methods: We identified the ocular morbidity in patients with MFS (n=407) by use of Danish national healthcare registers, using number and timing of hospital contacts related to ophthalmic diagnoses, to ophthalmic surgery and to prescriptions for ophthalmic medication. An age-matched and gender-matched background population (n=40 700) was used as comparator., Results: Among MFS, 56% (226/407) of the patients had at least one registration of an ophthalmic diagnosis as inpatient or outpatient during the study period (HR of 8.0 (95% CI 7.0 to 9.2)). Seven out of 11 main groups of diagnoses were affected, including 'Lens', 'Choroid and retina', 'Ocular muscles, binocular movement, accommodation and refraction', 'Glaucoma', Visual disturbances and blindness', 'Vitreous body and globe', and 'Sclera, cornea, iris and ciliary body'. The number of surgical procedures as well as the use of ophthalmic medication in patients with MFS was significantly increased., Conclusion: This nationwide epidemiological study of ocular morbidity in MFS demonstrates a profound burden and emphasises the need for thorough and experienced ophthalmological surveillance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate bone fragility in patients with hereditary connective tissue disorders (HCTD), including Ehlers-Danlos syndrome (EDS), Marfan's syndrome (MFS) and Loeys-Dietz syndrome (LDS)., Methods: From inception to June 2022, potentially eligible studies were identified in the Medline and EMBASE databases using search strategy that included terms for "HCTD", "Fracture" and "Osteoporosis". Eligible studies must consist of a group of patients with HCTD and report prevalence/incidence of fracture/osteoporosis in their participants, with or without comparison with healthy individuals. Point estimates with standard errors were obtained from each study and combined using the generic inverse variance method., Results: Among the 4206 articles identified, 19 studies were included. The pooled prevalence of fracture in EDS, MFS, and LDS were 44% (95% confidence interval [CI], 25% to 65%, I 2 88%), 17% (95% CI, 11% to 26%, I 2 68%), 69% (95% CI, 47% to 85%, I 2 83%), respectively. The pooled prevalence of osteoporosis in EDS was 17% (95% CI, 8% to 34%, I 2 96%). EDS was associated with fracture [pooled odds ratio {OR} 4.90 (95% CI, 1.49 - 16.08, I 2 86%)], but not osteoporosis [pooled OR 1.34 (95% CI, 0.28 - 6.36, I 2 87%). One study reported a 5% (95% CI, 3% to 8%) prevalence of osteoporosis in MFS, which was associated with fracture [incidence rate ratio 1.35 (95% CI, 1.18 - 1.55)] and osteoporosis [subhazard ratio 3.97 (95% CI, 2.53 - 6.25)]., Conclusion: EDS was associated with fracture, which could be independent of osteoporosis status. MFS had a milder degree of increased risk of fracture and osteoporosis. Despite no data from cohort studies, there was a significantly higher rate of fracture in LDS., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction: Marfan syndrome (MFS) is the most common inherited connective tissue disorder and its association with intracranial aneurysms (ICAs) has been debated for more than two decades. Here, we report the prevalence of ICAs at screening neuroimaging in a population of genetically confirmed MFS patients and present the results of a meta-analysis including our cohort of patients and those of previous studies., Patients and Methods: We enrolled 100 consecutive MFS patients, who underwent screening with brain magnetic resonance angiography at our tertiary center between August 2018 and May 2022. We did a PubMed and Web of Science search to retrieve all studies on the prevalence of ICAs in patients with MFS published before November, 2022., Results: Of the 100 patients included in this study (94% Caucasians, 40% females, mean age 38.6 ± 14.6 years), three had an ICA. We pooled the current study with five previously published studies, including a total of 465 patients, 43 of which harbored at least one unruptured ICA, leading to an overall ICA prevalence of 8.9% (95% CI 5.8%-13.3%)., Discussion and Conclusion: In our cohort of genetically confirmed MFS patients, the prevalence of ICAs was 3%, which is substantially lower compared to previous studies based on neuroimaging. The high frequency of ICA found in previous studies could be explained by selection bias and lack of genetic testing, which may have led to the inclusion of patients with different connective tissue disorders. Further studies, including several centers and a large number of patients with genetically confirmed MFS, are needed to confirm our results.

Background Aortic dissection (AD) during pregnancy and puerperium is a rare catastrophe with devastating consequences for both parent and fetus. Population-level incidence trends and outcomes remain relatively undetermined. Methods and Results We queried a US population-based health care database, the National Inpatient Sample, and identified all patients with a pregnancy-related AD hospitalization from 2002 to 2017. In total, 472 pregnancy-related AD hospitalizations (mean age, 30.9±0.6 years) were identified from 68 514 000 pregnancy-related hospitalizations (0.69 per 100 000 pregnancy-related hospitalizations), with 107 (22.7%) being type A and 365 (77.3%) being type B. The incidence of AD appeared to increase over the 16-year study period but was not statistically significant ( P for trend >0.05). Marfan syndrome, primary hypertension, and preeclampsia/eclampsia were found in 21.9%, 14.4%, and 11.5%, respectively. On multivariable logistic regression analysis, Marfan syndrome was associated with the highest risk of developing AD during pregnancy and puerperium (adjusted odds ratio, 3469.36 [95% CI, 1767.84-6831.75]; P <0.001). The in-hospital mortalities of AD, type A AD, and type B AD were 7.3%, 4.3%, and 8.1%, respectively. Length of hospital stay for the AD, type A AD, and type B AD groups were 7.7±0.8, 10.4±1.9, and 6.9±0.9 days, respectively. Conclusions We quantified population-level incidence and in-hospital mortality in the United States and observed an increase in the incidence of pregnancy-related AD. In contrast, its in-hospital mortality appears lower than that of non-pregnancy-related AD.

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0-21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype-phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objective: The evaluation of post-traumatic stress disorder (PTSD), depression, anxiety and insomnia in patients with Marfan syndrome (MFS) during the third wave of the COVID-19 pandemic in a region of northern Italy (Lombardy) and the investigation of which mental health, sociodemographic and clinical factors were associated with PTSD., Design: Descriptive observational design with cross-sectional data collection procedure., Setting: A single Italian MFS-specific specialised and reference centre in Lombardy (Italy) between February and April 2021., Participants: 112 adults with MFS. The majority of participants were female (n=64; 57.1%), with a high school diploma (n=52; 46.4%) and active workers (n=66; 58.9%). The mean age was 41.89 years (SD=14.00), and the mean time from diagnosis was 15.18 years (SD=11.91)., Primary and Secondary Outcomes: Descriptive statistics described PTSD, which was the primary outcome, as well as depression, anxiety and insomnia, which were the secondary outcomes. Four linear regression models described the predictors of PTSD total score and its three domains: avoidance, intrusion and hyperarousal., Results: One out of 10 patients with MFS had mild psychological symptoms regarding depression, anxiety and insomnia, and scores of PTSD that indicated clinical worries about the mental health status. The presence of PTSD was mainly predicted by anxiety (β=0.647; p<0.001), being older, taking psychoactive medication and being unemployed., Conclusion: Depression, anxiety and insomnia should be monitored in patients with MFS in order to minimise PTSD insurgence. Specific psychosocial interventions should be developed and tested for this population and adopted in clinical practice, given the relevance of mental health outcomes during the pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Thoracic aortic aneurysms and thoracoabdominal aneurysms are often found incidentally. Complications include dissection or rupture. Most of the thoracic aortic aneurysms and thoracoabdominal aneurysms develop in patients with risk factors for atherosclerosis. Younger patients without significant cardiovascular risk factors may have a genetic basis and include syndromes such as Marfan, Ehlers-Danlos, and Loeys-Dietz and bicuspid aortic valve. Most thoracic aneurysms grow slowly over time and factors that accelerate growth rate include dissection, aneurysm size, bicuspid valve disease, and Marfan syndrome. Size cutoffs where complications occur determine when surgery or intervention should be considered., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p < 0.0001). There were no differences in HADS anxiety or depression scores. In older MFS patients, with a more severe cardiovascular phenotype, chronic pain, and a higher unemployment rate, significantly more symptoms of depression were observed, when compared with the general population (p = 0.027) or compared with younger MFS patients (p = 0.026). Multivariate analysis, showed that anxiety was associated with chronic pain (p = 0.022) and symptoms of depression with unemployment (p = 0.024). MFS patients report significantly more severe fatigue as compared with the general population. Since the cause of fatigue is unclear, more research may be needed. Psychological intervention, for example, cognitive behavioral therapy, may contribute to a reduction in psychological symptoms., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Marfan syndrome (MS) most often shows as thoracic aortic aneurysm (TAA) or aortic dissection, but it may also involve other vascular territories. This study aimed to identify those extrathoracic vascular manifestations most frequently associated with MS., Methods: A systematic review of the literature with Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was carried out. The following databases were included: MEDLINE, Embase, Web of Science, Cumulative Index of Nursing and Health Sciences Literature (CINHAL); Spanish database MEDESY Cochrane Central Register of Controlled Trials (CENTRAL)., Results: A total of 10,008 articles were identified, leaving 155 for the first stage of data analysis (total incidence of aneurysms) and 83 for the second (descriptive data analysis). Overall, 518 aneurysms were identified: 149 in the head and neck, 94 in the extremities, and 275 in the aortic, iliac, and visceral sectors. Mostly, they were simultaneously discovered during studies of the TAA. In the abdominal aorta, the presentation with rupture in 11 of 32 patients stands out. Resection and bypass were the most frequently used methods for repair in the treated cases., Conclusions: Although its frequency in the general population is unknown, this systematic review suggests that extrathoracic aneurysmal arterial involvement in the MS may be more frequent than expected. We believe screening for aneurysms in other vascular sectors may be advisable, especially in patients with MS and TAA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to explore sex and gender differences regarding aortic events in Marfan patients., Methods: We analysed all data from our connective tissue disorder database. Only patients with Marfan syndrome were included. For analysis, patients were divided by sex. Female patients were further divided into 2 subgroups: with versus without children. Aortic events were defined as Stanford type A aortic dissection (TAAD) or type B aortic dissection (TBAD) or any aortic intervention., Results: A population of 183 Marfan patients was analysed for the purpose of this study. One hundred four (57%) were male and 79 (43%) were female patients. Thirty-seven (47%) of the 79 female patients had at least 1 child. Male patients had a significantly higher probability of experiencing an aortic event (P = 0.015) compared to female patients. However, there was no increased probability for recurrent events in male patients compared to female patients (P = 0.063). Follow-up revealed no sex and gender differences in the occurrence of Stanford TAAD or TBAD between male and female patients (P = 0.324/P = 0.534). While 11% of women with children suffered from peripartum aortic events, 24% experienced Stanford TAAD unrelated to pregnancy., Conclusions: Male patients have a higher risk of aortic events than female patients. The majority of women were not aware of their Marfan syndrome diagnosis before conceiving. One out of 10 women suffered from peripartum Stanford TAAD or TBAD. Twice as many female patients with children suffered from aortic dissection unrelated to childbirth. There were no sex and gender differences affecting mortality in Marfan patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting multiple systems, particularly the cardiovascular system. The leading causes of death in MFS are aortopathies and valvular disease. We wanted to identify the frequency of arrhythmia and postural orthostatic tachycardia syndrome, length of hospital stay, health care-associated costs (HAC), and in-hospital mortality in patients with MFS. Methods and Results The National Inpatient Sample database from 2005 to 2014 was queried using International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) codes for MFS and arrhythmias. Patients were classified into subgroups: supraventricular tachycardia, ventricular tachycardia (VT), atrial fibrillation, atrial flutter, and without any type of arrhythmia. Data about length of stay, HAC, and in-hospital mortality were also abstracted from National Inpatient Sample database. Adjusted HAC was calculated as multiplying HAC and cost-to-charge ratio; 12 079 MFS hospitalizations were identified; 1893 patients (15.7%) had an arrhythmia; and 4.9% of the patients had postural orthostatic tachycardia syndrome. Median values of length of stay and adjusted HAC in VT group were the highest among the groups (VT: 6 days, $18 975.8; supraventricular tachycardia: 4 days, $11 906.6; atrial flutter: 4 days, $11 274.5; atrial fibrillation: 5 days, $10431.4; without any type of arrhythmia: 4 days, $8336.6; both P =0.0001). VT group had highest in-patient mortality (VT: 5.3%, atrial fibrillation: 4.1%, without any type of arrhythmia: 2.1%, atrial flutter: 1.7%, supraventricular tachycardia: 0%; P <0.0001) even after adjustment for potential confounders (without any type of arrhythmia versus VT; odds ratio [95% CI]: 3.18 [1.62-6.24], P =0.001). Conclusions Arrhythmias and postural orthostatic tachycardia syndrome in MFS were high and associated with increased length of stay, HAC, and in-hospital mortality especially in patients with VT.

Objective: Surveillance metrics in pediatric and young adult Marfan syndrome (pMFS) are challenging. We evaluated the utility of aortic root cross-sectional area/height index (CSA/Ht) on echocardiogram among pMFS patients as a risk stratification and surgical triage metric., Methods: Genotype or phenotype positive pMFS patients aged 25 years or younger seen at our center from 2001 to 2020 were identified. Time-related transition to surgery was modeled using parametric methods. Predictive utility of CSA/Ht compared with aortic root diameter (ARd) and root Z score (ARz) were modeled using nonlinear multivariable parametric and nonparametric longitudinal regression models., Results: Seventy-nine patients (43% female) presented at median age of 5.8 years (15th-85th percentile, 0.75-17 years) with median follow-up of 4.4 years (range, 0-18.5 years). Baseline echocardiography data were: CSA/Ht, 3.9 ± 1.4 cm 2 /m; ARd, 2.4 ± 0.89 cm; and ARz, 2.4 ± 1.7. CSA/Ht tracked ARd better compared with ARz (r = 0.91 vs 0.24). Eighteen patients underwent surgery. Surgical procedures included at least 2 components in 17 (aortic, mitral, tricuspid, aortic root, and arch procedures) and isolated mitral valve procedures in 1 patient. Time-related transition to surgery showed a prominent early phase to 1 year post presentation, followed by a slowly increasing late phase. CSA/Ht had a more linear correlation versus ARz during periods of rapid somatic growth in surgical patients. Surgical repair occurred at CSA/Ht between 5 and 7 cm 2 /m., Conclusions: CSA/Ht tracked ARd well over time. CSA/Ht between 5 and 7 cm 2 /m might be a promising metric for surgical triage in pMFS patients. CSA/Ht surgical threshold values in pMFS patients occurred at lower than current accepted "surgical" threshold values for CSA/Ht in adult Marfan syndrome patients., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Even in the absence of significant valvular disease, patients with Marfan syndrome (MFS) have evidence of impaired left ventricular (LV) performance, suggestive of a primary cardiomyopathy. However, the true prevalence and long-term outcomes of this disease process remain largely unknown. We performed a retrospective analysis of all adult patients with confirmed MFS followed at Stanford Health Care. Those with significant valvular regurgitation, coronary artery disease, or previous cardiac surgery were excluded. LV systolic dysfunction was defined as a LV ejection fraction (LVEF) <55% on transthoracic echocardiography. A total of 753 patients with confirmed MFS were followed up over a median duration of 8 years (interquartile range 4 to 13). Of those, 241 patients (53% women, 71% White) met inclusion criteria and comprised the study cohort. LV systolic dysfunction was present in 30 patients (12%), with a median age of onset of 25 years (interquartile range 19 to 37), median EF of 52% (interquartile range 48 to 54), and evidence of clinical heart failure (New York Heart Association functional class ≥II) in 10% of patients. LV systolic dysfunction was more common in patients with larger aortic root diameters (≥4.0 cm: Odds ratio = 4.5, 95% confidence interval = 1.2 to 17.1) but was not associated with other cardiovascular manifestations of MFS or traditional atherosclerotic risk factors. In conclusion, apart from significant valvular pathology, LV systolic dysfunction was prevalent in MFS from a young age, suggestive of a primary cardiomyopathy. LV dysfunction was typically mild and subclinical and occurred more commonly in patients with more pronounced aortopathies., Competing Interests: Disclosures The authors have no conflict of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction and Objectives: Pregnancy in women with Marfan syndrome (MS) is associated with an increased risk of aortic events. The clinical evidence on pregnant patients with MS is limited and there is no specific consensus on their optimal management. We report our multicenter experience., Methods: From January 2004 to January 2020, 632 patients with MS underwent periodic monitoring in Marfan units. During this period, we identified all pregnant women with MS and analyzed the incidence of aortic events during pregnancy and puerperium., Results: There were 133 pregnancies in 89 women with MS (8 women with prior aortic surgery). There were no maternal deaths, but 5 women had aortic events during the third trimester and puerperium (type A dissections in 2, type B dissection in 1, and significant [≥ 3mm] aortic growth in 2). The aortic event rate was 3.7%. Pregestational aortic diameter≥ 40mm showed a nonsignificant association with aortic events (P=.058). Fetal mortality was 3% and 37.6% of births were cesarean deliveries., Conclusions: Women with MS have an increased risk of aortic events during pregnancy, especially in the third trimester and postpartum period. Patients with MS and aortic diameters ≥40mm should be assessed in experienced centers for prophylactic aortic surgery before pregnancy. It is important to provide early diagnosis, prepregnancy study of the aorta, beta-blocker administration, and close monitoring during pregnancy, especially during the last trimester and postpartum., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Periodontitis is an inflammatory condition caused by a bacterial plaque and characterized by progressive destruction of the tooth-supporting apparatus. Patients with Marfan syndrome (MFS) exhibit a connective tissue disorder, which can also affect oral soft and hard tissue. Thus, the aims of this cross-sectional study were to assess the association between periodontitis and MFS and secondly, to compare periodontal parameters and prevalence of disease with a control group (CG) without MFS. 152 patients (MFS = 76, CG = 76) were recruited to evaluate the following periodontal parameters: probing depth, gingival margin, clinical attachment level, plaque index, and bleeding on probing. The 2017 World Workshop guideline was followed for the diagnosis of the periodontal status. A multivariate analysis was performed using a multinomial logistic regression adjusted for age, gender, and smoking. The level of significance required was p < 0.05. Patients with MFS did not show a higher prevalence of periodontitis compared to the CG. However, patients with MFS did have higher values in probing depth, gingival recession, clinical attachment level, and plaque index compared to the CG patients ( p < 0.05). In conclusion, although similar prevalence of periodontitis was found among the studied groups, MFS patients showed worse periodontal parameters., Competing Interests: Cosimo Galletti, Jorge Toledano-Serrabona, Gisela Teixido-Tura, Inmaculada Llobet-Poal, and Carles Subirà Pifarré declare no conflict of interest. Octavi Camps-Font has participated as a coinvestigator in clinical trials sponsored by Mundipharma (Cambridge, UK) and Menarini Richerche (Florence, Italy). Octavi Camps-Font also reports grants and nonfinancial support from Avinent (Santpedor, Spain). Cosme Gay-Escoda reports grants, personal fees, and nonfinancial support from Mundipharma (Cambridge, UK) and Menarini Richerche (Florence, Italy)., (Copyright © 2022 Cosimo Galletti et al.)

Objectives: The goal of this study was to evaluate the surgical outcomes of a valve-sparing root replacement using the reimplantation technique for annuloaortic ectasia in patients with Marfan syndrome (MFS) and in those with Loeys-Dietz syndrome (LDS)., Methods: We reviewed 103 patients with MSF with mutations in the fibrillin-1 gene and 28 patients with LDS with mutations in the transforming growth factor-beta receptor and 2, SMAD3 and transforming growth factor beta-2 from 1988 to 2020., Results: Forty-four (42.7%) patients with MFS [26 men, 31 (7.6) years] and 10 (35.7%) patients with Loeys-Dietz syndrome (LDS) [7 men, 22 (standard deviation: 8.6) years] who had no aortic dissection and underwent valve-sparing root replacement were included. The preoperative sinus diameter [46 (45-50.5) mm in those with MFS vs 48 (47-50) mm in those with LDS, p = 0.420] and the percentage of aortic insufficiency > grade 2+ [31.8% (10/44) in patients with MFS vs 10.0% (1/10) in those with LDS, p = 0.667] revealed no significant differences between the 2 groups. The cumulative incidences of aortic insufficiency greater than grade 1 (p = 0.588) and aortic valve reoperation (p = 0.310) were comparable between the 2 groups. Patients with LDS had a higher tendency towards aortic dissection after the initial operation (p = 0.061) and a significantly higher cumulative incidence of aortic reoperation (p = 0.003) versus those with MFS., Conclusions: Patients with MFS and those with LDS showed similar cumulative incidences of recurrent aortic valve insufficiency and aortic valve reoperation. Those with LDS revealed a higher cumulative incidence of aortic reoperation and a greater tendency towards aortic dissection after the initial operation compared with those with MFS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present study was to assess the overall burden of musculoskeletal disease in patients with Marfan syndrome., Materials and Methods: A registry-based, nationwide epidemiological study of patients with a Ghent II verified Marfan syndrome diagnosis from 1977 to 2014. Each patient was matched on age, and sex with up to 100 controls from the background population., Results: We identified 407 patients with Marfan syndrome and 40,700 controls and compared their musculoskeletal diagnoses and surgical treatments using Cox proportional hazards ratio (HR). The risk of a registration of a musculoskeletal diagnosis in patients with Marfan syndrome was significantly increased compared to controls (HR: 1.94 (1.69-2.24). One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9). Scoliosis was more common in women with Marfan syndrome compared to men (HR: 4.30 (1.73-1.08)). One out of 11 were registered with a pectus deformity HR: 40.8 (28.1-59.3), and one out of six with a deformity of the foot. Primarily pes planus (HR: 26.0 (15.2-44.3). The proportion of patients with Marfan syndrome (94/407) that underwent musculoskeletal surgery was also significantly higher (HR: 1.76 (1.43-2.16)). The major areas of surgery were the spine, pectups correction, and surgery of the foot/ankle. Ten patients with Marfan syndrome had elective orthopedic surgery without being recognized and diagnosed with Marfan syndrome until later in life. None of these had scoliosis, pectus deformity or a foot deformity. Among patients with an aortic dissection, the age at dissection was 34.3 years in those with at least one major musculoskeletal abnormality. In patients without a major abnormality the age at dissection was 45.1 years (p < 0.01)., Conclusions: The extent of musculoskeletal disease is quite significant in Marfan syndrome, and many will need corrective surgery during their life span. Surgeons should be aware of undiagnosed patients with Marfan syndrome when treating patients with a Marfan syndrome like-phenotype., (© 2022. The Author(s).)

Marfan syndrome is characterized by several (severe) medical disorders, the most important of which is aortic dilatation. Treatment of these disorders has consequences for oral care, in particular with regard to endocarditis prophylaxis and the use of anticoagulation. Furthermore, several orofacial anomalies of Marfan syndrome relevant to dental care are described in the literature. These anomalies may affect different areas within the spectrum of dental care, ranging from orthodontics to periodontology. Within these areas, Marfan syndrome is associated with a characteristic countenance and the prevalence of temporomandibular dysfunction, caries, endodontic anomalies and periodontitis. Medical-dental interaction with patients with Marfan syndrome should also be taken into consideration.

Background: Marfan syndrome (MFS) is a connective tissue disorder characterised by complex aortic pathology and a high prevalence of obstructive sleep apnoea (OSA). OSA produces intrathoracic transmural stresses that may accelerate aortic injury. The current study was designed to examine the associations between OSA risk and markers of aortic enlargement in MFS., Method: Consecutive patients with MFS were recruited at Johns Hopkins if they completed a STOP-BANG survey. Composite survey scores were categorised into those with low OSA risk (STOP-BANG <3) and high OSA risk (STOP-BANG ≥3). Participants' aortic data were collated to ascertain aortic root diameter, dilatation and prior aortic root replacement. Regression analyses were used to examine associations between OSA risk strata and these aortic parameters., Results: Of the 89 participants studied, 28% had a high OSA risk and 32% had aortic grafts. Persons with high OSA risk had greater aortic root diameter (mm) (ß=4.13, SE=1.81, p=0.027) and aortic root dilatation (ß=2.80, SE=1.34, p=0.046) compared with those with low OSA risk . In addition, the odds of prior aortic root replacement was three times greater in those with high OSA risk compared with those with low OSA risk., Conclusion: In MFS, high OSA risk is associated with aortic enlargement and a threefold increased risk of having had prior aortic root replacement. These findings invite further exploration of the relationship between OSA and aortic disease in MFS, and studies to clarify whether targeted interventions for OSA might mitigate aortic disease progression in MFS., Registration Number: IRB00157483., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We sought to identify risk factors for intracranial aneurysms (IAs) in Marfan syndrome (MFS) patients and to describe their characteristics., Methods: Patients with confirmed MFS and vessel-dedicated brain imaging from January 1, 1980-December 1, 2020 were categorized according to the presence (IA) or absence (NIA) of IAs. Unmatched logistic regression analysis and propensity score matching were used for comparison., Results: We included 159 patients, of whom 18 (11.3%) patients had radiographic diagnosis of IAs. Three patients (16.7%) had multiple lesions for a total of 24 IAs. One patient (5.5%) had de novo IA formation. Four patients (22.2%) underwent treatment: Two (11.1%) had open surgical clipping for ruptured aneurysms, and two (11.1%) patients had endovascular embolization for growth. In the unmatched analysis, current tobacco smoker status (odds ratio [OR]: 4.20; confidence interval [CI]: 1.11-15.6; P = 0.027) and history of coronary artery disease (CAD) (OR: 5.79; CI 1.76-20.2; P = 0.004) increased the odds for IA. Propensity score matching yielded 18 IA and 18 NIA patients matched for age, gender, race, prior stroke, and family history of aneurysms. History of CAD (IA = 11 [61.1%] vs. NIA = 4 (22.2%), P = 0.043) and current smoker status (IA = 6 [33.3%] vs. NIA = 0 (0%), P < 0.01) were significantly higher in the IA cohort. Body mass index (P = 0.622), diabetes (P = 0.180), hypertension (P = 0.732), prior stroke (P = 1.00), family history (P = 0.732), alcohol (P = 0.314), recreational drugs (P = 1.00), and other aneurysms (P = 0.585) were not statistically significant., Conclusions: Prevalence of IAs in our series of MFS patients was 11.3%, and de novo formation was 5.5%. MFS patients with a history of CAD and current smoker status had an increased risk of IA. Neurovascular radiographic screening should be considered in all patients with MFS, particularly in patients who smoke or have a history of heart disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: We aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)., Methods and Results: We included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys-Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7-10) mm vs. 7 (6-8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001)., Conclusion: MAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Late morbidity and mortality related to aortic branches in patients with aortic dissection (AD) have not been well described. We investigated the fate of aortic branches in a population cohort of patients with newly diagnosed AD., Methods: We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, Minnesota, residents with a diagnosis of AD from 1995 to 2015. Only patients with >30 days of available follow-up imaging studies were included in the present analysis. The primary outcome was freedom from any branch-related event (any intervention, aneurysm, malperfusion, rupture, or death occurring after the acute phase >14 days). The secondary outcome was the diameter change in the aortic branches. Univariate and multivariable Cox proportional hazards models were used to identify the predictors of branch-related events. Univariate and multivariate linear regression models were used to assess the aortic branch growth rate., Results: Of 77 total incident AD cases, 58 patients who had survived and had imaging follow-up studies available were included, 28 (48%) with type A and 30 (52%) with type B AD. The presentation was acute in 39 patients (67%), 6 (10%) of whom had had branch malperfusion. Of 177 aortic branches involved by the AD, 81 (46%) had arisen from the true lumen, 33 (19%) from the false lumen, and 63 (36%) from both. After the acute phase, freedom from any branch-related event at 15 years was 48% (95% confidence interval [CI], 32%-70%). A total of 31 branch-related events had occurred in 19 patients within 15 years, including 12 interventions (76% freedom; 95% CI, 63%-92%), 10 aneurysms (67% freedom; 95% CI, 50%-90%), 8 cases of malperfusion (76% freedom; 95% CI, 61%-94%), and 1 rupture (94% freedom; 95% CI, 84%-100%). No branch-related deaths had occurred. Type B AD (hazard ratio [HR], 3.5; 95% CI, 1.1-10.8; P = .033), patency of the aortic false lumen (HR, 6.8; 95% CI, 1.1-42.2; P = .038), and malperfusion syndrome at presentation (HR, 6.0; 95% CI, 1.3-28.6; P = .023) were predictors of late aortic branch-related events. The overall growth rate of aortic branches was 1.3 ± 3.0 mm annually. Patency of the aortic false lumen, initial branch diameter, and Marfan syndrome were significantly associated with diameter increase., Conclusions: In patients with AD, aortic branch involvement was responsible for significant long-term morbidity, without any related mortality. Type B AD, patency of the aortic false lumen, and malperfusion syndrome at presentation resulted in a greater risk of branch events during the long-term follow-up. Dilatation of the aortic branches was observed in one third of cases during follow-up, especially in the case of a patent aortic false lumen or the presence of Marfan syndrome., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Marfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype-phenotype correlation of patients with MFS, and no clear genotype-phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype-phenotype relationship in MFS, especially in this large and populous ethnic group.

Objectives: Studies indicate that other cardiovascular problems than aortic disease are a burden for patients with Marfan syndrome (MFS). The aim of the study was to assess the extent of this issue., Methods: A registry-based population study of patients with a Ghent II verified MFS diagnosis. Each patient was matched with up to 100 controls on age and sex. From the Danish healthcare system, we identified 407 MFS patients (from 1977 to 2014) and their cardiovascular events and compared them with those in 40,700 controls. Total follow-up time was 16,439 person years., Results: Mitral valve disease was significantly more common in MFS [HR: 58.9 (CI 38.1-91.1)] and happened earlier and more often in women than men with MFS [age at first registration: 22 vs. 38 years, HR: 2.1 (CI 1.0-4.4)]. Heart failure/cardiomyopathy was also more common in MFS [HR: 8.7 (CI 5.7-13.4)] and men were more affected than women, and at younger age [39 vs. 64 years, HR: 0.18 (CI 0.06-0.55)]. In all cases, atrioventricular block [HR: 4.9 (1.5-15.6)] was related to heart surgery. Supraventricular [HR: 9.7 (CI 7.5-12.7)] and ventricular tachycardia [HR: 7.7 (CI 4.2-14.3)] also occurred more often than in the control group. The risk of sudden cardiac death was increased [HR: 8.3 (CI 3.8-18.0)] but the etiology was unclear due to lack of autopsies., Conclusion: Non-aortic cardiovascular disease in patients with MFS is exceptionally prevalent and the range of diseases varies between women and men. Physicians caring for MFS patients must be aware of this large spectrum of cardiovascular diseases.

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.

Background: Aortic branch aneurysms are not included in the diagnostic criteria for Marfan syndrome (MFS); however, their prevalence and eventual prognostic significance are unknown., Objectives: The goal of this study was to assess the prevalence of aortic branch aneurysms in MFS and their relationship with aortic prognosis., Methods: MFS patients with a pathogenic FBN1 genetic variant and at least one magnetic resonance or computed tomography angiography study assessing aortic branches were included. Aortic events and those related to aneurysm complications were recorded during follow-up., Results: A total of 104 aneurysms were detected in 50 (26.7%) of the 187 patients with MFS (mean age 37.9 ± 14.4 years; 54% male) included in this study, with the iliac artery being the most common location (45 aneurysms). Thirty-one patients (62%) had >1 peripheral aneurysm, and surgery was performed in 5 (4.8%). Patients with aneurysms were older (41.9 ± 12.7 years vs. 36.7 ± 14.8 years; p = 0.040) and had more dilated aortic root (42.2 ± 6.4 mm vs. 38.8 ± 8.0 mm; p = 0.044) and dyslipidemia (31.0% vs. 9.7%; p = 0.001). In a subgroup of 95 patients with no previous aortic surgery or dissection followed up for 3.3 ± 2.6 years, the presence of arterial aneurysms was associated with a greater need for aortic surgery (hazard ratio: 3.4; 95% confidence interval: 1.1 to 10.3; p = 0.028) in a multivariable Cox analysis adjusted for age and aortic diameter., Conclusions: Aortic branch aneurysms are present in one-quarter of patients with MFS and are related to age and aortic dilation, and they independently predict the need for aortic surgery. The systematic use of whole-body vascular assessment is recommended to identify other sites of vascular involvement at risk for complications and to define the subgroup of patients with more aggressive aortic disease., Competing Interests: Funding Support and Author Disclosures This study was funded by Instituto de Salud Carlos III through the project PI17/00381, La Marató de TV3 (project no. 20151330). Dr. Guala has received funding from the European Union Seventh Framework Programme FP7/People (grant agreement no. 267128) and from the Spanish Ministry of Science, Innovation and Universities (IJC2018-037349-I). Dr. La Mura was supported by a research grant provided by the Cardiopath PhD programme. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM&#95;032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.

Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires., Methods: This observational, multicenter study included 107 children, aged 4-18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent-Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ)., Results: Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores ( M = 53 ( SD = 12), p = 0.004, d = 0.3), pain VAS scores ( M = 2.8 ( SD = 3.1), p < 0.001, d = 1.27), general health VAS scores ( M = 2.5 ( SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores ( M = 0.9 ( SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue ( p < 0.001, r s = 0.68), pain ( p < 0.001, r s = 0.64) and general health ( p < 0.001, r s = 0.59)., Conclusions: Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care.

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., (© 2021 Wiley Periodicals LLC.)

Background: This study investigated the association between subjective well-being and perception for collaboration among clinical departments of adult Marfan syndrome (MFS) patients., Methods: We performed a self-administered questionnaire survey to ask about current medical treatment and support systems and subjective well-being for 114 patients with MFS aged 18-64 years. It was hypothesized that patients' perception of collaboration between clinical departments would raise their subjective well-being. Mean value differences were predicted by a multiple regression analysis model, with supportive medical staff, age, sex, aorta dissection, family history, marriage status, and educational background adjusted., Results: Patients' perception of collaboration between clinical departments and being married raised SWLS scores (mean difference for patients' perception of collaboration versus not = 3.41, 95% CI = 0.28, 6.53, p = .03; for married versus single = 5.22, 95% CI = 1.75, 8.69, p = .003)., Conclusion: Our results have suggested that it is necessary to maintain and enhance the medical treatment system with the patients for improving the subjective well-being of MFS patients. In addition, the result indicated the need for intervention to the patients themselves and also their family so that it allows patients to receive physical and emotional support from people close to them., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Marfan syndrome (MFS), a rare genetic disease, has a prevalence of 6.5 in 100,000. Studies show that patients with MFS have reduced areal bone mineral density (BMD) compared with non-MFS individuals. We have previously shown that patients with MFS have reduced volumetric BMD and compromised trabecular and cortical bone microarchitecture. The present study was a registry-based, nationwide, population-based, cohort study using register data, aimed to evaluate fracture risk and fracture rates in MFS. We included 406 (196 women) patients with MFS through the Danish National Patient Register and 40,724 (19,327 women) persons, randomly selected and matched from the Civil Registry System. A total of 21.9% of the MFS and 18.9% of the reference population had experienced at least one fracture from 1995 to 2018. The fracture incidence rate was 27.5 per 1000 person-years in the MFS cohort (highest in young men and old women with MFS), and 20.3 per 1000 person-years in the reference population. The overall incidence rate ratio between the MFS and the reference population was 1.35 (95% confidence interval [CI ] 1.18-1.55) for all fractures. When evaluating the risk of being registered with an osteoporosis diagnosis in the Danish National Patient Register, starting relevant treatment for osteoporosis or experiencing a hip or spine fracture, 10.3% of the MFS cohort and 3.3% of the reference population could be classified as being osteoporotic. The between-group subhazard ratio was 3.97 (95% CI 2.56-6.25). Patients with MFS started treatment with an antiosteoporotic drug at a younger age than the reference population (57 [interquartile range 55-67] versus 71 [63-73]) years. The life expectancy in MFS is increasing, resulting in more patients facing diseases that are related to old age, such as age-related bone loss and increased risk of fractures. Our data suggest that bone health and fracture prevention needs to be part of the standard care for patients with MFS. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

The prevalence of obstructive sleep apnea (OSA) is increased in children and adults with Marfan syndrome (MFS) compared to the general population and has been shown to be associated with rapid aortic root dilation and dissection in adults. Early diagnosis and treatment of OSA may decrease long-term cardiac morbidity. We therefore studied the utility of noninvasive OSA screening tools in children with MFS. We hypothesized that youth with MFS would have higher OSA screening scores than the general pediatric population. Subjects with confirmed MFS were recruited from a single pediatric center. Data collected included cardiac history, retrospective polysomnogram (PSG) data, and prospectively collected Pediatric Sleep Questionnaire (SRBD-PSQ) and Epworth Sleepiness Scale (ESS-CHAD) scores. Fifty-one individuals aged 2-21 years old were identified. Nineteen subjects completed the surveys, 53% female, median age 16 years. Of those that completed the survey, mean SRBD-PSQ score was 0.24 ± 0.21 and mean ESS-CHAD was 6.4 ± 3.7. Comparatively, published normative data for pediatric control subjects were 0.24 ± 0.21 for SRBD-PSQ and 5.4 ± 3.7 for ESS-CHAD. In conclusions, youth with MFS had similar OSA screening scores compared to published pediatric controls. Given these findings and high prevalence of OSA in MFS youth, standard questionnaires may not be an appropriate tool for identifying children at risk for OSA in this population. In the absence of evidence-based guidelines, physicians caring for children with MFS should consider referral for PSG, even in the absence of classic symptoms.