Background: Mutations in the transforming growth factor β receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterized by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuousity and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, but only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date.
Methods: We 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.
Results: Statistical analysis 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. Men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. These data suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters less than 5.0 cm than individuals with TGFBR1 mutations.
Conclusion: Our 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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