Evaluating Variation in the Cardiac Management of Children with Hereditary Thoracic Aortic Disease in the United States.

Hereditary thoracic aortic diseases (HTAD) such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and vascular Ehlers-Danlos syndrome (VEDS) frequently result in complex cardiovascular pathology that can lead to premature death. However, given limited research and lack of detailed pediatric management guidelines, practice in the U.S. is largely guided by personal experience and/or advice from other professionals. A REDCap survey was composed that covered topics including genetic testing, imaging, and medication choice (all in children), among others. After piloting, the survey was distributed via email and advertised on PediHeartNet. Email addresses of providers were obtained through an established aortic research collaborative and a clinic directory offered through The Marfan Foundation. There were 64 survey responses (pediatric cardiologists 66%; geneticists 13%, genetic counselors 6%; the remaining 15% was comprised of a combination of cardiothoracic surgeons, adult cardiologists, adult congenital specialists, combined cardiology and genetics specialist, nurse practitioners, physician assistants, and nurse coordinators). The most supported indication for genetic evaluation in a child with mild aortic root dilation was family history of thoracic aortic dissection (100%), in contrast to mild root dilation with no other HTAD features (39% supported, 45% did not, 15% saying it would depend on other factors). The majority would start medical therapy in MFS at an aortic root z-score of 2, however differences existed regarding medication preferences for initiation (47% angiotensin receptor blockers, 36% beta blockers, 17% would not or cannot prescribe medication/defer medication choice to another provider). Variation existed for cross-sectional imaging indications and modality and for exercise restrictions, although on average respondents were more lenient than the Bethesda guidelines. While there are areas of general agreement in the cardiac management of children with HTAD, there are also several areas of considerable variation. This highlights the need for additional study in these areas with the ultimate goal of creating consensus guidelines.

[Latest advances in the diagnosis and treatment of Marfan syndrome]. / 马方综合征的最新诊疗进展.

Marfan syndrome (MFS) is a multisystem connective tissue disease with autosomal dominant inheritance. It is mainly caused by FBN1 gene mutation and often has different clinical manifestations. Neonatal MFS is especially rare with severe conditions and a poor prognosis. At present, there is still no radical treatment method for MFS, but early identification, early diagnosis, and early treatment can effectively prolong the life span of patients. This article reviews the latest advances in the diagnosis and treatment of MFS.

The Musculoskeletal Manifestations of Marfan Syndrome: Diagnosis, Impact, and Management.

PURPOSE OF REVIEW: Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5-10,000 (Chiu et al. Mayo Clin Proc. 89(1):34-42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476-85, 4). RECENT FINDINGS: The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30-50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149-58, 147, Murdoch et al. N Engl J Med. 286(15):804-8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308-1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the "systemic features score" (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.

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.

Pathophysiology and Pathogenesis of Marfan Syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease manifests in many different ways, the most life-threatening manifestations are related to cardiovascular complications including mitral valve prolapse, aortic insufficiency, dilatation of the aortic root, and aortic dissection. In the past 30 years, research efforts have not only identified the genetic locus responsible but have begun to elucidate the molecular pathogenesis underlying this disorder, allowing for the development of seemingly rational therapeutic strategies for treating affected individuals. In spite of these advancements, the cardiovascular complications still remain as the most life-threatening clinical manifestations. The present chapter will focus on the pathophysiology and clinical treatment of Marfan syndrome, providing an updated overview of the recent advancements in molecular genetics research and clinical trials, with an emphasis on how this information can focus future efforts toward finding betters ways to detect, diagnose, and treat this devastating condition.

Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models.

Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-ß) signaling. Paradoxically, TGF-ß hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-ß overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos.

There are urgent demands for efficient treatment of heritable genetic diseases. The base editing technology has displayed its efficiency and precision in base substitution in human embryos, providing a potential early-stage treatment for genetic diseases. Taking advantage of this technology, we corrected a Marfan syndrome pathogenic mutation, FBN1T7498C. We first tested the feasibility in mutant cells, then successfully achieved genetic correction in heterozygous human embryos. The results showed that the BE3 mediated perfect correction at the efficiency of about 89%. Importantly, no off-target and indels were detected in any tested sites in samples by high-throughput deep sequencing combined with whole-genome sequencing analysis. Our study therefore suggests the efficiency and genetic safety of correcting a Marfan syndrome (MFS) pathogenic mutation in embryos by base editing.

Non-pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review.

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non-pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non-pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non-pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid-2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence-based non-pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer-based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non-pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo-controlled, clinical trials methodology.

Urinary Disorders and Marfan Syndrome: A Series of 4 Cases.

Marfan syndrome is a genetic disease responsible for causing cardiovascular, eye and musculoskeletal damages. Urinary disorders are not common. We present 4 cases of chronic urinary tract symptoms, with 2 different pathophysiological processes. Three patients presented with spinal cord infarct following aortic dissection surgery. They were affected by an overactive bladder with detrusor overactivity and detrusor-sphincter dyssynergia. One patient complained of voiding dysfunction, possibly related to dural ectasia. Although a rare outcome, urinary disorders may appear in Marfan syndrome, by the occurrence of surgical complications in aortic surgery or possibility of sacral nerve root compression. If so, medical care is necessary to prevent uro-nephrological complications.

Prolonged use of eptifibatide as a bridge to maintain drug-eluting stent patency in a patient receiving extracorporeal membrane oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been used as a bridge to cardiac recovery in patients following a major cardiac event. There is a lack of literature surrounding prolonged use of eptifibatide and optimal dosing during ECMO. This case report describes our experience with extended durations and standard dosing of eptifibatide in the setting of ECMO. CASE: A 40-year-old male with a history of Marfan's syndrome, aortic root and ascending aortic aneurysm status post a modified Bentall with a St. Jude mechanical aortic valve conduit and hemi-Cabrol with a Dacron graft to the left main coronary artery presented with exertional chest pain and was found to have an anastomotic narrowing to the left main which occluded while awaiting surgical revision. A rescue percutaneous coronary intervention at the anastomotic site was performed. Due to hemodynamic instability, he was placed on femoral VA-ECMO. The patient was started on anticoagulation for the ECMO circuit and eptifibatide to maintain stent patency. The patient experienced several bleeding episodes for which he received supportive care, endoscopic intervention and left gastric artery embolization. Eptifibatide was maintained at standard dosing and the heparin infusion was withheld. A coronary angiogram revealed no thrombus within the Cabrol graft a patent stent previously placed at the site of the distal graft-coronary anastomosis. The patient was decannulated from ECMO and underwent coronary artery bypass grafting and division of the hemi-Cabrol graft. CONCLUSION: While eptifibatide was effective in maintaining stent patency, our patient experienced several bleeding episodes during ECMO. Thus, the risks and benefits of concurrent antiplatelet and anticoagulant therapy must be appropriately weighed in this patient population. Additionally, as the need for dual antiplatelet therapy due to coronary stent implantation is increasing, further studies are needed to validate optimal dosing of eptifibatide in patients at a high risk of bleeding during ECMO.

What Is Marfan Syndrome?

This JAMA Patient Page describes the autosomal dominant genetic disorder of Marfan syndrome and its diagnosis and treatment.

A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc.

Genetic diagnostics of inherited aortic diseases : Medical strategy analysis.

Genetic aortic syndromes (GAS) include Marfan, Loeys-Dietz, vascular Ehlers-Danlos, and Turner syndrome as well as congenital bicuspid aortic valve. The clinical management of these diseases has certain similarities and differences. We employed medical strategy analysis to test the utility of genetic diagnostics in the management of GAS. We chose the standpoint of the cardiologist for our analysis. In the first step, the medical goals in the management of GAS are specified. In the second step, the accuracy of genetic diagnostics for GAS is examined. Finally, conclusions can be drawn about the utility of genetic diagnostics in managing GAS. We found that genetic diagnostics is necessary to exclude GAS, to diagnose GAS, and to specify disease types. Second, combining phenotype with genotype information maximizes the predictability of the course of disease. Third, with genetic diagnostics it is possible to predict the birth of children with causative mutations for GAS and to initiate drug therapy to prevent the onset of aortic dilatation or to slow down its progression to aortic aneurysm. Finally, genetic diagnostics improves prognostic predictions and thereby contributes to a better timing of elective surgery and to a better choice of procedures. The findings of our medical strategy analysis indicate the high utility of genetic diagnostics for managing GAS.

Systematic review of chronic pain in persons with Marfan syndrome.

The purpose of this study was to explore the literature on chronic pain in adults with Marfan syndrome (MFS), critically appraising and synthesizing relevant literature. A systematic review was conducted by searching the published literature databases using available medical, physical, psychological, social databases and other sources. All studies that addressed pain in MFS, published in peer-reviewed journals were assessed. Of 351 search results, 18 articles satisfied the eligibility criteria. All studies were cross-sectional and quantitative; no randomized controlled trials or intervention studies were found. Most studies had small sample sizes, low response rates and mainly dealt with other aspects of the diagnosis than pain. Only one article dealt mainly with pain. The research on chronic pain in MFS is limited in size and quality. Despite these limitations, studies describe that the prevalence of pain in patients with MFS is high, varying from 47 to 92% and affecting several anatomic sites. In addition, chronic pain limits daily function and few studies describe treatment options for pain in patients with MFS. Research is needed to obtain more evidence-based knowledge for developing more appropriate rehabilitation programs for people with MFS.

[Spontaneous intracranial hypotension and Marfan syndrome]. / Spontanes Liquorunterdrucksyndrom und Marfan-Syndrom.

Spontaneous intracranial hypotension is the most common complication in patients undergoing a lumbar puncture. A much rarer entity is headaches attributed to spontaneous (or idiopathic) low cerebrospinal fluid (CSF) pressure but the combination with a connective tissue disorder is even rarer. The first case of a patient with spontaneous intracranial hypotension and genetically established Marfan syndrome was published in 1995. This article describes the cases of two female patients who presented with postural headache. Magnetic resonance imaging revealed multiple leakages of CSF and both patients had a genetically confirmed diagnosis of Marfan syndrome. The initial symptomatic treatment did not result in a significant relief of the headaches. Epidural blood patching was performed and the intervention was successful in both patients. Finally, the most important epidemiological, diagnostic and pathophysiological aspects are demonstrated and the therapeutic procedures are presented.

[Marfan syndrome in childhood and adolescence]. / Le syndrome de Marfan chez l'enfant et l'adolescent : cas clinique.

The Marfan syndrome is a systemic connective tissue disorder with autosomal dominant inheritance. A mutation of the fibrillin-1 gene, a glycoprotein which is the main constituent of the extracellular matrix, is the cause of the disease. The cardinal features involve the skeletal, ocular and cardiovascular systems. The expression of the Marfan syndrome varies from the severe neonatal presentation to the classical manifestations of the child and young adult, but also comprises isolated features. In children, phenotypical manifestations are age dependent. For these reasons, the diagnosis of Marfan syndrome might be lately revealed by its cardiovascular complications. We report the case of 2 siblings: it illustrates the phenotypic variability that might be observed in a same family, the phenotype evolution with age and the diagnosis challenge in childhood.

Le syndrome de Marfan est une maladie systémique du tissu conjonctif qui se transmet de façon autosomale dominante. Elle est due à une mutation du gène codant pour la fibrilline-1, une glycoprotéine, constituant principal des microfibrilles de la matrice extra-cellullaire. La maladie touche principalement le squelette, les yeux et le système cardiovasculaire. Son expression phénotypique est variable avec des formes néonatales sévères, un tableau classique chez l'enfant ou le jeune adulte ou des lésions isolées d'un seul organe. Chez l'enfant, le phénotype évolue avec l'âge. Ainsi, le syndrome de Marfan peut n'être reconnu que tardivement, par exemple à l'occasion de manifestations de ses complications cardiovasculaires. Le cas d'un adolescent et de sa jeune sœur que nous rapportons ici illustre la variabilité phénotypique au sein d'une même famille, l'évolution des manifestations cliniques et la difficulté diagnostique chez l'enfant.

Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor ß (TGFß) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFß pathway. While TGFß antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFß signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

Inherited neurovascular diseases affecting cerebral blood vessels and smooth muscle.

Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.