Heritable thoracic aortic aneurysm disease: recognizing phenotypes, exploring genotypes.

SEE PAGE 1324 T he discovery of a thoracic aortic aneurysm (TAA) or aortic dissection requires evaluation of relatives for similar disease because 20% will have an affected relative. Heritable TAA diseases are due to mutations in a number of genes that affect the aorta and its branches with differing severity. Many disorders are associated with wellcharacterized syndromic features (e.g., Marfan syndrome [MFS]), whereas others predominantly involve the thoracic aorta, occasionally associated with cerebral aneurysm or bicuspid aortic valve (1,2). Heritable TAA syndromes may be classified based on the specific genes mutated, involving extracellular matrix proteins, the transforming growth factor (TGF)-b signaling pathway, vascular smooth muscle cytoskeleton or contractile elements, or other signaling pathways (1,2) (Table 1). MFS, as a result of mutations in FBN1, is perhaps the most well-recognized aneurysm syndrome, and involves the aorta and heart, eyes, skeleton, lung, and dura. Evidence for increased TGF-b signaling in diseased tissues (lung, aorta, and mitral valve) was recognized in the mouse model (3). TGF-b neutralizing antibody or angiotensin-1 receptor blocker administration rescued the phenotype, providing further evidence that abnormal TGF-b signaling is important in pathogenesis. In 2005, mutations in the genes encoding the receptors for TGF-b (TGFBR1 and TGFBR2) were recognized as causing a multisystem aneurysm disease, now known as Loeys-Dietz syndrome (LDS), which is