Loeys–Dietz syndrome: a primer for diagnosis and management

MacCarrick, Gretchen; Black, James H.; Bowdin, Sarah; El-Hamamsy, Ismaı̈l; Frischmeyer‐Guerrerio, Pamela A.; Guerrerio, Anthony L.; Sponseller, Paul D.; Loeys, Bart; Dietz, Harry C.

doi:10.1038/gim.2014.11

Cited by 453 publications

(468 citation statements)

References 69 publications

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“…When compared with MFS, LDS also shows many unique features (Table 1) in the craniofacial, skeletal, cutaneous, and cardiovascular systems (MacCarrick et al 2014). Patients with LDS can also show evidence of immunologic dysregulation including asthma, eczema, and gastrointestinal inflammation that associates with increased numbers of Tregulatory cells that inappropriately secrete proinflammatory T-helper 2 cytokines (Frischmeyer-Guerrerio et al 2013).…”

Section: Loeys -Dietz Syndromementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Loeys -Dietz Syndromementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…Abdominal aortic aneurysms have been reported in both MFS and LDS. Involvement of vasculature throughout the body, including cerebral vessels, occurs in LDS [6,25].…”

Section: Clinical Diagnosismentioning

confidence: 99%

“…LDS, ATS. The interval has been suggested to be one year in the first instance and then at least two-yearly for LDS [25], though earlier recommendations had been for yearly MRA [23]. Abnormal results should translate into an increased screening frequency and referral as appropriate.…”

Section: Surveillance For Aortic Dilatation a Usual Practice Is Clinmentioning

confidence: 99%

Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome

Zentner

West

Adès

2017

Heart, Lung and Circulation

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Key Points1. A number of inherited conditions can predispose the aorta, and less commonly other blood vessels, to dilatation and/ or rupture.2. Broadly speaking, these conditions are recognised as syndromic when accompanied by a number of systemic features or non-syndromic when the aortic dilatation appears to exist in isolation.3. The commonest syndromic aortopathy is Marfan syndrome and the commonest nonsyndromic aortopathy is that which accompanies congenital bicuspid aortic valve.4. Mutations in a number of genes have been identified, particularly in syndromic aortopathy.5. Although genotype-phenotype relationships exist, the phenotypes of the syndromic aortopathies may have significant overlap .6. When a syndromic aortopathy is suspected, review by a clinical geneticist is instrumental in characterising the clinical signs and the family history.7. Confirmation of a diagnosis (either clinically or by gene testing) allows identification of individuals at increased risk of aortic sequelae who will benefit from active medical management.8. Medical management is usually undertaken by a cardiologist with referral to other specialists (eg cardiothoracic surgeons) as appropriate.9. At risk family members should be offered predictive testing if a mutation is identified, and should otherwise be screened in keeping with the presumptive clinical diagnosis and assessment of risk.10. Pregnancy and the post-partum period confer a higher risk for aortic complications: a. Women with a personal or family history of aortopathy need appropriate preconception screening and counseling.b. Intervention may be required pre-conception and they should be managed closely throughout pregnancy, ideally in a high-risk obstetric clinic. A c c e p t e d M a n u s c r i p t 3 pregnancy, beta blockers can be used in pregnancy) and should include involvement of a cardiologist in the management and decision making for delivery.11. A clinical diagnosis of an inherited aortopathy can be made in the absence of a positive genetic test if the systemic features are consistent with a specific syndromic aortopathy. A familial history of aortic dissection in the absence of both a positive gene test and systemic examination findings may be more difficult to manage without a working clinical diagnosis. However, an inherited risk of dissection should nonetheless be considered in this setting, particularly if the process has affected young individuals and/or in the absence of traditional risk factors.

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“…10) Moreover, mutations in TGFB3 were recently associated with syndromic aortic aneurysms and dissections, 14) and mutations in these TGF-β signal-related genes were found in families with non-syndromic familial thoracic aortic aneurysm and dissection (FTAAD). Thus, further classification based on the molecular mechanisms of FTAADs might be required.…”

Section: Loeys-dietz Syndrome (Lds)mentioning

confidence: 99%

“…Although LDS patients present several characteristics of MFS, LDS is characterized by rapidly progressive aortic/arterial tortuosity and aneurysmal disease that is known to result in ruptures at an early age and at smaller dimensions, and by widely spaced eyes (hypertelorism) and bifid uvula or cleft palate. [9][10][11] Until recently, mutations in TGFB2, 12,13) TGFB3, 14) and SMAD3, 15,16) which encode main members of the TGF-β/SMAD signal transduction pathway, were also reportedly associated with diseases that resemble MFS. Fibrillin-1 also regulates TGF-β bioavailability, and thus traditional definitions for the pathogenesis of MFS and related diseases have been dramatically revised.…”

mentioning

confidence: 99%

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

et al. 2016

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SummaryMarfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management. (Int Heart J 2016; 57: 271-277)

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Loeys–Dietz syndrome: a primer for diagnosis and management

Cited by 453 publications

References 69 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

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