Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations
ABSTRACT Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date.
The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families.
Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations.
This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.
Article: Familial thoracic aortic aneurysms[Show abstract] [Hide abstract]
ABSTRACT: Purpose of review A lot of new data have been obtained in familial thoracic aortic aneurysms, including description of new entities and better understanding of pathophysiology. The aim of this review is to put them in perspective. Recent findings The new data have been collected, put together, and allowed a new classification scheme to be proposed by the Montalcino Aortic Consortium on the basis of the role of proteins coded by the culprit gene (either protein of the extracellular matrix or protein of the transforming growth factor-beta pathway, or protein of the contractile apparatus of the smooth muscle cell). These groups of diseases include aortic aneurysm, but the extent of extra-aortic vascular risk and the presence of extra-aortic (skeletal, ophthalmologic, neurological, or immunological) features vary according to the gene involved. This understanding also sheds light on the therapeutic benefits that can be foreseen for new molecules, or old molecules used in a newer way. Summary Classification of familial forms of thoracic aortic aneurysm should allow a better understanding of these diseases and therefore standardization of initial evaluation of the patients (vascular evaluation limited or not to the aorta, and extravascular evaluation, including or not skeleton, eyes, neurology, digestive tract, and immunological diseases) and individualization of therapy (adapted to both the genotype and the phenotype).Current Opinion in Cardiology 11/2014; 29(6):492-498. DOI:10.1097/HCO.0000000000000114 · 2.59 Impact Factor
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ABSTRACT: The prevalence of aortic aneurysm is five times higher in men than women among the general population. Similar sexual dimorphism also exists in syndromic aortic aneurysms triggered by TGF-β signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-β receptor, Alk5, specifically in smooth muscle cells (Alk5(iko)) causes spontaneous aortic aneurysm formation. This model recapitulated an extreme scenario of the dimorphism in aortic aneurysm development between genders. In a comparative experiment, all Alk5(iko) males (n=42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5(iko) females (n=14) presented only a subclinical phenotype characteristic of scarcely scattered elastin breaks. Removal of male hormones via orchiectomy (n=7) resulted in only minimal influence on aortic pathology. However, reduction of female hormones via ovariectomy (n=15) increased the phenotypic penetrance from zero to 53%. Finally, an elevation of systolic blood pressure by 30 points unmasked the subclinical phenotype of Alk5(iko) females (n=17) to 59%. This exaggerated phenotypic penetrance was coupled with an early intensification of ERK signaling, a molecular signature that correlated to 100% phenotypic penetrance in normotensive Alk5(iko) males. In conclusion, aortic aneurysm induced by Alk5(iko) exhibits dimorphic incidence between genders with females less susceptible to aortic disease. This sexual dimorphism is partially the result from the protective effects of female hormones. Hypertension, a known risk factor for aortic aneurysm, is able to break the female sex protective effects through mechanisms associated with enhanced ERK activity.AJP Heart and Circulatory Physiology 11/2014; 308(2):ajpheart.00521.2014. DOI:10.1152/ajpheart.00521.2014 · 4.01 Impact Factor
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ABSTRACT: The major diseases affecting the thoracic aorta are aortic aneurysms and acute aortic dissections (TAAD). Medical treatments can slow the enlargement of aneurysms, but the mainstay of treatment to prevent premature deaths due to dissections is surgical repair of the TAA, typically recommended when the aortic diameter reaches 5.0 - 5.5 cm. Studies on patients with acute aortic dissections indicate that up to 60% occur at aortic diameters less than 5.5 cm. Clinical predictors are thus needed to identify those at risk for dissection at aortic diameter less than 5.0 cm, and to determine the aortic diameter that justifies the risk of surgical repair to prevent an acute aortic dissection. Data from genetic studies over the past decade have established that mutations in specific genes can identify patients at risk for the disease and predict the risk of early dissection at diameters less than 5.0 cm. This information has the potential to optimize the timing of aortic surgery to prevent acute dissections.Journal of Thoracic and Cardiovascular Surgery 08/2014; DOI:10.1016/j.jtcvs.2014.07.070 · 3.99 Impact Factor