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.
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ABSTRACT: We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor beta receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFbeta signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling. These data definitively implicate perturbation of TGFbeta signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.Nature Genetics 04/2005; 37(3):275-81. · 35.21 Impact Factor
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ABSTRACT: To describe the clinical findings and natural history in 22 carriers of an R460H mutation in the transforming growth factor beta receptor 2 gene (TGFbetaR2) from a five-generation kindred ascertained by familial aortic dissection. 13 of the confirmed carriers were interviewed and examined, and information about the remaining carrier was obtained from medical records. Clinical information about deceased individuals was obtained, when possible, from postmortem reports, death certificates and medical records. There have been eight sudden deaths; the cause of death was aortic dissection in all six cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in one case in the absence of aortic root dilatation. Subarachnoid haemorrhage, due to a ruptured berry aneurysm, had occurred in two individuals. Four gene carriers and one deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, two had tortuous carotid arteries and one a tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. Despite the predisposition to aortic dilatation and dissection, individuals did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. No one individual had ocular lens dislocation. Striae and herniae were common. There was some overlap with Ehlers-Danlos syndrome type 4, OMIM 130050, with soft translucent skin, which is easily bruised. Other features were arthralgia, migraine and a tendency to fatigue easily, varicose veins and prominent skin striae. This family provides further evidence that mutations in TGFbetaR2 cause a distinct syndrome that needs to be distinguished from Marfan syndrome to direct investigation and management of patients and shows the natural history, spectrum of clinical features and variable penetrance of this newly recognised condition.Journal of Medical Genetics 01/2007; 43(12):908-16. · 5.70 Impact Factor
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ABSTRACT: Two-dimensional echocardiography is increasingly used to measure aortic root dimensions, which provide prognostic information in aortic regurgitation and the Marfan syndrome. Aortic root dilatation is currently detected by nomograms based on M-mode echocardiographic data. Aortic root diameters measured by 2-dimensional echocardiography at the anulus, sinuses of Valsalva, supra-aortic ridge and proximal ascending aorta in 135 normal adults and 52 normal children were compared with age, gender, body habitus, blood pressure and stroke volume, and with M-mode findings and normal limits. Two-dimensional measurements at the sinuses of Valsalva were larger than M-mode aortic root values (p less than 0.001), and use of 2-dimensional values with M-mode nomograms falsely diagnosed aortic dilatation in 40% of normal children and 19% of normal adults. Two-dimensional measurements at the sinuses closely correlated with body surface area in children (r = 0.93, p less than 0.0005), moderately in adults younger than 40 years of age (r = 0.71, p less than 0.0005) and weakly in older adults (r = 0.40, p less than 0.0005). In adults, gender influenced aortic root size at all levels (p less than 0.001), but dimensions were similar when indexed for body surface area. Age strongly influenced supraaortic ridge and ascending aortic diameters; blood pressure and stroke volume had no independent effect on aortic size. In conclusion, (1) 2-dimensional echocardiographic aortic root dimensions are influenced by age and body size but not by blood pressure; (2) aortic root dilatation is overdiagnosed when aortic diameter at the sinuses of Valsalva is compared with M-mode nomograms; (3) nomograms comparing aortic diameter with body surface area should be used in children; and (4) although use of nomograms based on body size in adults should maximize sensitivity for aortic dilatation, 98% specificity is attained by use of an upper normal limit of 2.1 cm/m2 for aortic diameter at the sinuses of Valsalva in both men and women.The American Journal of Cardiology 10/1989; 64(8):507-12. · 3.21 Impact Factor