Loeys-Dietz syndrome: a primer for diagnosis and management.
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ABSTRACT:
SUBMITTER: MacCarrick G
PROVIDER: S-EPMC4131122 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
Loeys-Dietz syndrome: a primer for diagnosis and management.
MacCarrick Gretchen G Black James H JH Bowdin Sarah S El-Hamamsy Ismail I Frischmeyer-Guerrerio Pamela A PA Guerrerio Anthony L AL Guerrerio Anthony L AL Sponseller Paul D PD Loeys Bart B Dietz Harry C HC
Genetics in medicine : official journal of the American College of Medical Genetics 20140227 8
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. ...[more]
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Project description:BackgroundThis study aimed to investigate the influence of early diagnosis (ED) on surgical outcomes in patients definitively diagnosed with Loeys-Dietz syndrome (LDS).MethodsA retrospective review was conducted on 38 patients with LDS who underwent aortic surgery at our institution between January 1995 and June 2022. The primary endpoint was freedom from aortic reoperation.ResultsAmong the patients, the median age at the initial surgery was 33 (range: 39-44) years, and 23 (60.5%) patients were male. Twenty-one (55.3%; aortic dissection or rupture (n = 2) and aneurysm (n = 19)) patients were diagnosed with LDS before the initial surgery (ED group). Meanwhile, the remaining 17 (44.7%; aortic dissection or rupture (n = 13) and aneurysm (n = 4)) patients were after surgery [delayed diagnosis (DD) group]. The ED group had significantly lower rates of emergency surgery and concomitant arch procedure (P < .001, respectively) but a higher rate of valve-sparing root surgery (P = .018) compared to the DD group. No in-hospital mortality was observed in either group. Nevertheless, the ED group had a shorter postoperative hospital stay (median difference: 3 days, P = .032) and a lower rate of aortic reoperation (P = .013).ConclusionEarly detection of LDS may help in preventing acute aortic syndrome, reducing the risk of aortic reoperation, and potentially shortening hospital stay. Careful medical management before surgery could contribute to better clinical outcomes and an improved quality of life for patients with LDS.
| S-EPMC11363540 | biostudies-literature
Project description:Background and purposeLoeys-Dietz syndrome (LDS) is a recently described entity that has the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its neuroradiologic manifestations have not been well delineated. We sought to describe the neuroradiologic features of LDS and to assess the manifestations that would warrant follow-up imaging.Materials and methodsTwo neuroradiologists retrospectively reviewed CT angiography (CTA), MR imaging, and plain film studies related to the head and neck in 25 patients ranging from 1 to 55 years of age, all of whom had positive genetic testing and clinical characteristics of LDS. Arterial tortuosity was evaluated by subjective assessment of 2D and 3D volumetric CTA and MR angiography data. Craniosynostosis and spinal manifestations were assessed by using plain films and CT images. MR images mostly of the head were reviewed for associated findings such as hydrocephalus, Chiari malformation, etc. Clinical manifestations were collated from the electronic patient record.ResultsAll patients had extreme arterial tortuosity, which is characteristic of this syndrome. Thirteen patients had scoliosis, 12 had craniosynostosis, 8 had intracranial aneurysms, 6 had spinal instability, 3 had dissections of the carotid and vertebrobasilar arteries, 3 had hydrocephalus, 4 had dural ectasia, 2 had a Chiari malformation, and 1 had intracranial hemorrhage as a complication of vascular dissection.ConclusionsSignificant neuroradiologic manifestations are associated with LDS, predominantly arterial tortuosity. Most of the patients in this series were young and, therefore, may require serial CTA monitoring for development of intra- and extracranial dissections and aneurysms, on the basis of the fact that most of the patients with pseudoaneurysms and dissection were older at the time of imaging. Other findings of LDS such as craniosynostosis, Chiari malformation, and spinal instability may also need to be addressed.
| S-EPMC7051610 | biostudies-literature
Project description:Marfan syndrome (MFS) and Loeys-Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable.
| S-EPMC8536070 | biostudies-literature
Project description:BackgroundLoeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly presents with vascular abnormalities. Owing to the rarity and severity of the condition, consensus guidelines for aortic surgery thresholds vary. In addition, evaluation of coronary arteries in patients with LDS (either routinely or before aortic root surgery) remain undefined. In this case report, we discuss a patient with LDS who found to have an ectatic aortic root and a coronary artery aneurysm and discuss guidelines for evaluation and management in this patient population.Case summaryA 48-year-old woman was incidentally found to have a 45 mm ectatic aortic root during evaluation for a neck mass. As part of pre-operative evaluation for aortic root replacement, left heart catheterization revealed a left main coronary artery aneurysm. Family history revealed aortic aneurysms, sudden cardiac death, and tall height. Physical examination was notable for pectus excavatum and elongated limbs. Workup for inflammatory aetiologies of aortic root dilation was negative. Genetic testing revealed a heterozygous pathogenic TGBF3 variant, consistent with LDS Type 5. She subsequently underwent two-vessel coronary artery bypass, excision of her left main coronary artery aneurysm, and ascending aortic replacement.DiscussionIn this case, we describe a patient with LDS who was noted to have a coronary artery aneurysm, a rare finding in the initial presentation of disease. In addition, we examine guidelines regarding evaluation of management of aortic root disease and coronary aneurysms.
| S-EPMC9161713 | biostudies-literature
Project description:BackgroundLarsen syndrome is a hereditary disorder characterized by osteochondrodysplasia, congenital large-joint dislocations, and craniofacial abnormalities. The autosomal dominant type is caused by mutations in the gene that encodes the connective tissue protein, filamin B (FLNB). Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by arterial aneurysms, dissections and tortuosity, and skeletal, including craniofacial, manifestations. Mutations in five genes involved in the transforming growth factor beta (TGF-β) signaling pathway cause five types of LDS. Stickler syndrome is a genetically heterogeneous arthro-ophthalmopathy caused by defects in collagen, exhibiting a wide specter of manifestations in connective tissue. A rare case is reported that was diagnosed with all these three hereditary connective tissue disorders.Case presentationA 19 year-old, Norwegian male with a clinical diagnosis of Larsen syndrome and with healthy, non-consanguineous parents attended a reference center for rare connective tissue disorders. Findings at birth were hypotonia, joint hypermobility, hyperextended knees, adductovarus of the feet, cervical kyphosis, craniofacial abnormalities, and an umbilical hernia. From toddlerhood, he required a hearing aid due to combined conductive and sensorineural hearing loss. Eye examination revealed hyperopia, astigmatism, and exotropia. At 10 years of age, he underwent emergency surgery for rupture of an ascending aortic aneurysm. At 19 years of age, a diagnostic re-evaluation was prompted by the findings of more distal aortic dilation, tortuosity of precerebral arteries, and skeletal findings. High throughput sequencing of 34 genes for hereditary connective tissue disorders did not identify any mutation in FLNB, but did identify a de novo missense mutation in TGFBR2 and a nonsense mutation in COL2A1 that was also present in his unaffected father. The diagnosis was revised to LDS Type 2. The patient also fulfills the proposed criteria for Stickler syndrome with bifid uvula, hearing loss, and a known mutation in COL2A1.ConclusionLDS should be considered in patients with a clinical diagnosis of Larsen syndrome, in particular in the presence of arterial aneurysms or tortuosity. Due to genetic heterogeneity and extensive overlap of clinical manifestations, genetic high throughput sequencing analysis is particularly useful for the differential diagnosis of hereditary connective tissue disorders.
| S-EPMC6119281 | biostudies-literature
Project description:Abstract Background Loeys-Dietz syndrome (LDS) is a heritable disorder that presents with thoracic aortic aneurysm and/or dissection caused by a mutation in one of the transforming growth factor-B receptor or ligand genes. It is associated with widespread familial arterial aneurysm and rupture. Case summary We present a case of a 70-year-old male with a family history of heritable thoracic aortic aneurysm disease who presented to the emergency department with chest pain. His presenting electrocardiogram was significant for ST elevation in the inferior leads with complete heart block. Computed tomography-angiography was done to rule out aortic dissection, which was negative for aortic dissection but did reveal 3.9 cm infrarenal abdominal aortic aneurysm and 2.7 cm bilateral iliac artery aneurysms. He was then taken for invasive angiography and was found to have aneurysmal dilation of the entire right coronary artery measuring up to 6 mm with 100% occlusion secondary to thrombus in the distal segment. He was found to have obstructive disease in the left anterior descending artery and first and second obtuse marginals (OMs). Genetic testing performed confirmed a pathogenic mutation in the TGFBRI gene (TGFBRI c.934G > A p.Gly312Ser) consistent with the diagnosis of LDS. Discussion Although LDS is known to cause arterial aneurysms throughout the arterial tree, there have been no other cases of primary coronary aneurysms reported in this patient population. This case represents the first description of a patient with genetically confirmed LDS presenting with coronary artery aneurysm.
| S-EPMC9552997 | biostudies-literature
Project description:Background: Pathogenic variants in TGFBR1, TGFBR2 and SMAD3 genes cause Loeys-Dietz syndrome, and pathogenic variants in FBN1 cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Methods: Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 ± 18 years. Twenty-six individuals had pathogenic variants in TGFBR1, 40 in TGFBR2, and 17 in SMAD3. For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. Results: In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus (p = 0.014) was more prevalent, the craniofacial score was higher (p < 0.001), the systemic score lower (p < 0.001), and mitral valve prolapse less frequent (p = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 ± 3 versus 73 ± 2 years; p = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 ± 4 versus 48 ± 3 years; p = 0.589), distal aortic repair (72 ± 3 versus 67 ± 2 years; p = 0.777), mitral valve surgery (75 ± 4 versus 65 ± 3 years; p = 0.108), and reintervention (20 ± 3 versus 14 ± 2 years; p = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; p < 0.001), where receiver operating characteristic analysis identified ?33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; p = 0.001), and higher systemic score points at least marginally (HR = 1.175; p = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Conclusions: Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.
| S-EPMC6947024 | biostudies-literature
Project description: Not available
| S-EPMC9735389 | biostudies-literature
Project description:The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field-derived (SHF-derived), but not neighboring cardiac neural crest-derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.
| S-EPMC6355234 | biostudies-literature
Project description:BACKGROUND:Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. METHODS:Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. RESULTS:The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. CONCLUSION:Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.
| S-EPMC6785444 | biostudies-literature