Author + information
- Alan C. Braverman, MD∗ ()
- Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
- ↵∗Reprint requests and correspondence:
Dr. Alan C. Braverman, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St. Louis, Missouri 63110.
- extracellular matrix proteins
- Loeys-Dietz syndrome
- Marfan syndrome
- transforming growth factor beta
The 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 well-characterized 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)-β 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-β signaling in diseased tissues (lung, aorta, and mitral valve) was recognized in the mouse model (3). TGF-β neutralizing antibody or angiotensin-1 receptor blocker administration rescued the phenotype, providing further evidence that abnormal TGF-β signaling is important in pathogenesis.
In 2005, mutations in the genes encoding the receptors for TGF-β (TGFBR1 and TGFBR2) were recognized as causing a multisystem aneurysm disease, now known as Loeys-Dietz syndrome (LDS), which is differentiated from MFS by craniofacial features, arterial tortuosity, and early and aggressive aortic and branch vessel disease (4). Newly characterized familial TAA syndromes that are due to mutations in other genes regulating TGF-β signaling were recently discovered, including disorders as a result of mutations in SMAD3, which share features with LDS, but also with osteoarthritis, and mutations in the gene encoding TGFB2 ligand (TGFB2), which has features overlapping those in LDS and MFS (1,2). In this issue of the Journal, Bertoli-Avella et al. (5) report the features of an aortic aneurysm syndrome due to mutations in TGFB3, which shares features of other conditions (such as LDS and MFS) that are due to perturbations in the TGF-β signaling pathway.
Mutations in vascular smooth muscle contractile element and cytoskeletal genes also cause TAA disease. Smooth muscle alpha-actin (ACTA2) mutations cause 14% of familial TAA disease cases, and have features including livedo reticularis, iris flocculi, premature coronary and cerebrovascular disease, patent ductus arteriosus, Moyamoya disease, and bicuspid aortic valve (6). MYLK and PRKG1 gene mutations predominantly lead to TAA disease, whereas MYH11 mutations may also be associated with patent ductus arteriosus (1,2).
When managing the patient with a heritable TAA syndrome, recognition of the specific disease and mutation present are important because aortic and branch vessel prognosis varies depending on the mutated gene. Many families with TAA disease who undergo mutation analysis will not have a pathogenic gene mutation identified. However, discovery of novel gene mutations in TAA disease is continuing at a rapid pace. Familial TAA diseases are notable for having marked interfamilial and intrafamilial phenotypic variability, a wide range of ages of onset, and variable penetrance. For instance, among families with ACTA2 mutations, the penetrance of aortic disease is approximately 50% (6). In families with TAA disease and no identifiable mutation, one must continue to follow and perform imaging surveillance in relatives.
A cursory physical examination is not enough to determine risk.
Evaluating the patient with TAA disease requires an understanding of features associated with these conditions, which may inform the underlying diagnosis. This includes a careful family history inquiring about facial dysmorphology, myopia, ocular lens dislocation, premature cataracts, bifid uvula, spine disease, pectus deformities, cleft palate, clubfoot, pneumothorax, bicuspid aortic valve, cerebral aneurysm, aortic or branch vessel aneurysm, patent ductus arteriosus, premature vascular disease, aortic dissection, or sudden death. Examining the patient with TAA disease requires more than a cardiovascular examination; one must examine the patient like a dysmorphologist. Features signifying a potential genetic aneurysm disorder include hypertelorism, bluish sclera, abnormal uvula, dental crowding, tall palate, malar hypoplasia, retrognathia, elongated digits, pectus deformities, scoliosis, flat feet, club feet, joint contractures, hyperflexible joints, soft velvety skin, hyperlucent skin, atrophic scars, abnormal bruising, and varicose veins. One cannot expect all cardiologists or surgeons to become expert in this evaluation, and partnering with an experienced medical geneticist is recommended when evaluating aneurysm syndromes and in interpreting mutation analysis. Foundation websites provide useful information on characteristics of many conditions (7–9). Careful review of the computed tomography or magnetic resonance imaging scan may demonstrate arterial tortuosity, branch vessel enlargement, or lumbosacral dural ectasia, all features suggesting an underlying aortopathy syndrome.
Mutations in the gene encoding TGFB3 ligand, TGFB3, were recently reported in 2 young patients with skeletal features overlapping those seen with Marfan syndrome and LDS (10,11). In this issue of the Journal, an international coalition compiled clinical and genetic information on 43 patients from 11 families with TGFB3 mutations (5). Importantly, aortic aneurysms and dissections are new to the constellation of features described in patients with TGFB3 mutations. Advanced sequencing techniques and mutation analysis were utilized. Prediction modeling to assess the effects of alterations in TGFB3 function was performed. Histopathological examination of aortic wall specimens demonstrated elastic fiber fragmentation of various degrees. Immunohistochemical examination of aortic tissue revealed increased TGF-β signaling in the aortic wall, differing from the hypothesis proposed by Rienhoff et al. (10).
The phenotype of patients with TGFB3 mutations includes many features recognized in LDS (due to mutations in TGFB1 and 2) including hypertelorism, bifid uvula, cleft palate, and clubfoot. Many patients also have features present in MFS, such as high-arched palate, pectus deformity, tall stature, hypermobile joints, and arachnodactyly. No individuals with TGFB3 mutations are reported as having ectopia lentis (a feature discriminating for MFS). The authors (5) highlight a striking interfamilial clinical variability in phenotype, with some individuals having multiple classic LDS features and others having none. This emphasizes the importance of complete evaluation of all first-degree relatives and of mutation analysis, even when outward features are not apparent.
The hallmark of initial reports of LDS as a result of mutations in TGFBR1 and 2 included marked arterial tortuosity and early and aggressive arterial disease, such as aortic dissection at young age and relatively small aortic dimensions (4). On the basis of this initial report in the Journal, the vascular disease related to TGFB3 mutations may have a less aggressive vascular phenotype than LDS. Bertoli-Avella et al. (5) report their cohort of patients as having a median age of 34 years (range 3 to 74 years), a median age of aortic dissection of 47.5 years (range 30 to 80) years, and a median age at death of 56 years (range 40 to 80 years) (5). Unlike LDS, few patients in this cohort had branch vessel disease. Distinct from LDS 1 and 2, TGFB3 mutations are not reported to lead to significant arterial tortuosity, which may be important because the severity of arterial tortuosity has been associated with aortic outcomes in other connective tissues disorders (12). However, information from additional patients will be necessary to more fully understand the TGFB3 mutation spectrum and to predict aortic and vascular risk among affected individuals.
The past several years have witnessed the discovery of multiple gene mutations leading to aortic aneurysm syndromes. Mutations in TGFB3 should be added to the list of genes examined when evaluating an individual with these features. Having evaluated patients with heritable TAA syndromes, I am often struck by how subtle the clinical findings may be. Physical features, age of onset, and severity of vascular disease may vary among affected family members. All mutated genes do not carry the same degree of vascular risk. Not all patients with a gene mutation may develop aortopathy leading to clinical events. These issues present challenges for screening, imaging surveillance, medical therapy, and recommendations for timing of prophylactic aortic and vascular surgery.
Many heritable TAA syndromes are relatively rare. As reported by Dr. Bertoli-Avella et al. (5), the phenotype of TGFB3 mutation disease overlaps with those of other recognized heritable TAA disorders, especially LDS. Collaboration among experts in the field is necessary to compile adequate experience in the ever-increasing types of heritable TAA disease, to detail natural history, and to inform management decisions, especially regarding vascular disease.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Braverman is the Chair of the Professional Advisory Board of the Marfan Foundation.
- American College of Cardiology Foundation
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- ↵The Marfan Foundation. Available at: http://www.marfan.org. Accessed January 23, 2015.
- Loeys-Dietz Syndrome Foundation. Available at: http://www.loeysdietz.org/en. Accessed January 23, 2015.
- TAD Coalition: Thoracic Aortic Disease. Available at: http://www.tadcoalition.org. Accessed January 23, 2015.
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