Loeys-Dietz syndrome and pregnancy: The first ten years.

The physiological and haemodynamic changes that occur in pregnancy and the postpartum period increase the risk of aortic dissection. Loeys-Dietz syndrome results from mutations in the genes encoding components of the TGF-ß signalling pathway; aortic pathology is of particular concern in this condition but other vascular abnormalities can also be present. Significant maternal morbidity and mortality has been described in patients with Loeys-Dietz syndrome, but successful and uncomplicated pregnancies are still possible. Nevertheless, all patients with this condition should, at present, be treated as very high risk in pregnancy and the postpartum period, until reliable risk prediction tools become available. This review summarises the recent advances in the understanding of the pathophysiology of this condition, and the management strategies currently advocated.

Neurovascular manifestations of connective-tissue diseases: A review.

Patients with connective tissue diseases are thought to be at a higher risk for a number of cerebrovascular diseases such as intracranial aneurysms, dissections, and acute ischemic strokes. In this report, we aim to understand the prevalence and occurrences of such neurovascular manifestations in four heritable connective tissue disorders: Marfan syndrome, Ehlers-Danlos syndrome, Neurofibromatosis Type 1, and Loeys-Dietz syndrome. We discuss the fact that although there are various case studies reporting neurovascular findings in these connective tissue diseases, there is a general lack of case-control and prospective studies investigating the true prevalence of these findings in these patient populations. Furthermore, the differences observed in the manifestations and histology of such disease pathologies encourages future multi-center registries and studies in better characterizing the pathophysiology, prevalence, and ideal treatment options of neurovascular lesions in patents with connective tissue diseases.

Plan of Action for Inherited Cardiovascular Diseases: Synthesis of Recommendations and Action Algorithms.

The term inherited cardiovascular disease encompasses a group of cardiovascular diseases (cardiomyopathies, channelopathies, certain aortic diseases, and other syndromes) with a number of common characteristics: they have a genetic basis, a familial presentation, a heterogeneous clinical course, and, finally, can all be associated with sudden cardiac death. The present document summarizes some important concepts related to recent advances in sequencing techniques and understanding of the genetic bases of these diseases. We propose diagnostic algorithms and clinical practice recommendations and discuss controversial aspects of current clinical interest. We highlight the role of multidisciplinary referral units in the diagnosis and treatment of these conditions.

Massive hemoptysis in Loeys-Dietz syndrome.

We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.

TGF-ß signalopathies as a paradigm for translational medicine.

This review focusses on impact of a better knowledge of pathogenic mechanisms of Marfan and related disorders on their treatment strategies. It was long believed that a structural impairment formed the basis of Marfan syndrome as deficiency in the structural extracellular matrix component, fibrillin-1 is the cause of Marfan syndrome. However, the study of Marfan mouse models has revealed the strong involvement of the transforming growth factor-ß signalling pathway in the pathogenesis of Marfan. Similarly, this pathway was demonstrated to be key in the pathogenesis of Loeys-Dietz and Shprintzen-Goldberg syndrome. The elucidation of the underlying pathogenic mechanisms has led to new treatment strategies, targeting the overactive TGF-ß pathway. Various clinical trials are currently investigating the potential new treatment options. A meta-analysis will contribute to a better understanding of the various trial results.

Clinical Exome Sequencing as a Novel Tool for Diagnosing Loeys-Dietz Syndrome Type 3.

OBJECTIVE/BACKGROUND: In rare genetic vascular syndromes the diagnosis may not be apparent from the phenotype, but might be important for proper management. METHODS: A previously healthy woman without dysmorphic features presented with pregnancy associated vascular dissections and aneurysms. Next generation clinical exome sequencing was performed. RESULTS: The differential diagnosis of spontaneous arterial dissection is outlined. The patient's diagnosis became evident after clinical exome sequencing detected a novel missense mutation in the evolutionary conserved region of SMAD3, confirming the diagnosis of Loeys-Dietz syndrome (LDS) type 3. A brief overview of the various types of LDS and their management is presented. CONCLUSION: Clinical exome sequencing proved useful in diagnosing LDS type 3 where detailed vascular surveillance and timely intervention with a low threshold is recommended.

CT angiographic evaluation of genetic vascular disease: role in detection, staging, and management of complex vascular pathologic conditions.

OBJECTIVE: Arterial dissection and aneurysm rupture are significant sources of morbidity and mortality in patients with connective tissue diseases. This article provides a detailed analysis of cardiovascular involvement in Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. CONCLUSION: Although these syndromes share some overlapping features, they have discriminating clinical and imaging features, and knowledge of these features enables the radiologist to aid the referring clinician in making the correct diagnosis.

Loeys-Dietz syndrome: a primer for diagnosis and management.

Loeys-Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys-Dietz syndrome.

Cerebral arterial angioplasty in a patient with Loeys-Dietz syndrome.

A 14-year-old boy with Loeys-Dietz syndrome (LDS) had an acute neurologic decline 6 days after a subarachnoid hemorrhage. Cerebral angiography at presentation did not show an aneurysmal source of the hemorrhage. However, on post-bleed day 6 the patient experienced an acutely worsening headache and subsequently lost consciousness. Head CT showed new subarachnoid blood and repeat angiography demonstrated a basilar tip aneurysm. Endovascular coil embolization was performed and his neurologic status improved postoperatively until post-bleed day 9 when he became unresponsive. A CT angiogram demonstrated severe proximal vasospasm. After an unsuccessful attempt to treat the vasospasm medically, the patient was transported to the neurointerventional suite for intra-arterial vasodilator treatment, which also failed to ameliorate the vasospasm. The endovascular surgeons were then faced with the conundrum of attempting a high-risk cerebral angioplasty in a pediatric patient with LDS or returning to maximal medical treatment for severe refractory vasospasm.

Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management.

Aortic root and ascending aortic dilatation are indicators associated with risk of aortic dissection, which varies according to underlying etiologic associations, indexed aortic root size, and rate of progression. Typical aortic involvement is most commonly seen in syndromic cases for which there is increasing evidence that aortic aneurysm represents a spectrum of familial inheritance associated with variable genetic penetrance and phenotypic expression. Aortic root and ascending aortic dimensions should be measured routinely with echocardiography. Pharmacologic therapy may reduce the rate of progression. Timing of surgical intervention is guided by indexed aortic size and rate of change of aortic root and ascending aorta dimensions. Lifelong surveillance is recommended.

Marfan syndrome: from gene to therapy.

PURPOSE OF REVIEW: Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-ß) signaling. RECENT FINDINGS: In this review, we focus on the impact of the revised MFS clinical diagnostic criteria. We discuss lessons that have been learned from molecular findings in relevant Marfan-related conditions, such as sporadic thoracic aortic aneurysm/dissection, stiff skin syndrome, acromelic dysplasias and Loeys-Dietz syndrome. We explore the latest insights into the role of the alternative TGF-ß signaling pathways in MFS pathogenesis. Finally, we give an update on the current and future treatment strategies. SUMMARY: The recent insights into the pathogenesis of MFS and related disorders have offered a prime example of translational medicine with immediate bridge between molecular findings and therapeutic options.

Management of pregnancy in patients with congenital heart disease.

Congenital heart diseases are the most common birth defects in humans, affecting approximately 0.8% of all live births. In the past, many of the more severe defects resulted in profound disability and death during childhood, and adult survival was exceptional. The past 4 decades have seen dramatic improvements in the survival and quality of life of patients with the more severe defects. As a result of these improvements, the challenges of caring for adults with congenital heart disease are only now being realized. Most women with congenital heart disease are now expected to reach childbearing age and maternal cardiac disease is the major cause of maternal morbidity and mortality. As such, appropriate pre-pregnancy counseling and management during pregnancy are fundamental components of the care of these patients. This article describes the circulatory changes that occur during normal pregnancy and delivery, addresses the risks posed during pregnancy by specific congenital lesions, and reviews the current data on pregnancy outcomes in patients with individual congenital defects.

Glue embolus complicating the endovascular treatment of a patient with Loeys-Dietz syndrome.

A 34-year-old [corrected] woman was diagnosed with Loeys-Dietz syndrome. Five months later, the patient presented with a symptomatic 2.6-cm subclavian pseudoaneurysm. Staged endovascular treatment was initiated with left vertebral artery embolization, followed by sac ablation and stent graft exclusion. The pseudoaneurysm cavity was filled with n-butylcyanoacrylate ("glue") via a microcatheter. Despite balloon occlusion of the pseudoaneurysm orifice, a small amount of glue debris embolized to the brachial artery, necessitating a vein bypass. In this case, distal embolization of glue may have been avoided by leaving a microcatheter in the aneurysm sac for glue injection after first deploying the stent graft.