Early Surgical Experience With Loeys-Dietz: A New Syndrome of Aggressive Thoracic Aortic Aneurysm Disease

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1 Early Surgical Experience With Loeys-Dietz: A New Syndrome of Aggressive Thoracic Aortic Aneurysm Disease Jason A. Williams, MD, Bart L. Loeys, MD, Lois U. Nwakanma, MD, Harry C. Dietz, MD, Philip J. Spevak, MD, Nishant D. Patel, BA, Katrien François, MD, Julie DeBacker, MD, Vincent L. Gott, MD, Luca A. Vricella, MD, and Duke E. Cameron, MD Division of Cardiac Surgery, McKusick-Nathans Institute of Genetic Medicine, Division of Pediatric Cardiology, and Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and the Department of Cardiac Surgery and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Background. Loeys-Dietz syndrome (LDS) is a recently described genetic aortic aneurysm syndrome resulting from mutations in receptors for the cytokine transforming growth factor-. Phenotypic features include a bifid uvula, hypertelorism, cleft palate, and generalized arterial tortuosity, but risk of thoracic aortic rupture and dissection is the principle focus of management and exceeds that of most known connective tissue disorders. Our surgical experience with LDS was reviewed to assess outcomes and develop guidelines for management of this aggressive disease. Methods. We retrospectively reviewed medical records of all LDS patients from two institutions and obtained follow-up data from medical records and patient contacts. Results. Clinical criteria and genotyping were used to identify 71 patients. Before surgical intervention, 6 patients (9%) died from aneurysm rupture or dissection, which occurred in several patients with aortic diameters of less than 4.5 cm and as early as 6 months of age. Thoracic aortic aneurysm surgery was performed in 14 children and 7 adults. Operations included valve-sparing root replacement (VSRR) in 13, Bentall procedure in 5, arch replacement in 2, and VSRR with arch replacement in 1. There were no deaths at the primary operation, although 3 patients died 2, 5, and 11 years after surgery from rupture of the descending thoracic (n 2) or abdominal aorta (n 1). Conclusions. LDS is an aggressive aortic aneurysm disease with a propensity toward rupture and dissection at a younger age and smaller aortic diameters than in other connective tissue disorders, particularly in the ascending aorta. Early recognition of the phenotype, prophylactic intervention, and meticulous surveillance of the distal aorta and vascular tree are warranted for optimal management. (Ann Thorac Surg 2007;83:S757 63) 2007 by The Society of Thoracic Surgeons A recently recognized connective tissue disorder, known as Loeys-Dietz syndrome (LDS), is characterized by premature and aggressive aortic aneurysm and dissection. It was originally described in 16 individuals within 10 different families and shows autosomal dominant inheritance with variable clinical expression [1]. The most common phenotypic abnormalities are aortic aneurysm, aortic dissection, widely spaced eyes (hypertelorism), bifid uvula or cleft palate, or both, generalized arterial tortuosity, and aneurysms throughout the arterial tree (Fig 1). Genetic mutations leading to the LDS phenotype have also been identified. Six of the original 10 families demonstrated mutations in the gene encoding for transforming growth factor- type II receptor (T RII). Further Presented at Aortic Surgery Symposium X, New York, NY, April 27 28, Address correspondence to Dr Cameron, Pediatric Cardiac Surgery, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287; dcameron@csurg.jhmi.jhu.edu. evaluation of the remaining four families with a similar phenotype but absent mutations in the gene for T RII demonstrated mutations in the gene encoding TGF- type I receptor (T RI). Mutations in the genes for either receptor are associated with increased downstream signaling of the cytokine TGF- in blood vessels, which causes overproduction of collagen, loss of elastin content, and disarray of elastic fibers [1 3]. These connective tissue alterations are believed to cause the phenotypic abnormalities seen in LDS. Many of the phenotypic features of patients with LDS overlap with those of other connective tissue disorders, such as Marfan syndrome. However, LDS patients exhibit several distinct genotypic and phenotypic characteristics not seen in these other disorders [1, 2, 4, 5]. The early clinical experience with this syndrome reveals that LDS has a unique and more malignant natural history. This report describes our early surgical experience with LDS to better define the natural history and to establish guidelines for surgical management by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 S758 AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL Ann Thorac Surg SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME 2007;83:S Fig 1. This photograph of a young boy with Loeys-Dietz syndrome demonstrates the characteristic feature of hypertelorism that occurs in 90% of patients with this disorder. Patients and Methods Patient Selection After obtaining Institutional Review Board approval, we retrospectively reviewed the medical records of all patients with the diagnosis of LDS. Informed consent was waived because of the retrospective nature of this study. In some instances, patients were evaluated and treated before the initial description of LDS, and some initially had been referred to our institutions as patients with Marfan syndrome. Patients from The Johns Hopkins Medical Institutions, Baltimore, Maryland, and the Ghent University Hospital, Ghent, Belgium, were included in this study. For the purposes of this report, patients were classified as children if they were younger than 18 years old at the time of the index operation. Patients 18 years or older at the index operation were considered adults. The cohort was divided into three groups according to clinical history and treatment strategy. The first group consists of patients who died before surgical intervention at our institutions. The second group consists of patients who underwent surgery for LDS at our institutions. Although many of these patients have undergone multiple surgical interventions at our institutions or elsewhere, the first operation performed at one of our institutions is considered the index operation for the purposes of this report. The third group of patients consists of those who have not undergone surgical intervention and are currently medically managed or are awaiting surgery. Medical management consists of blood pressure control using -blockers or angiotensinconverting enzyme inhibitors, or both, in addition to routine surveillance of the arterial tree using echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI). Data Collection and Patient Variables Data were collected from hospital admission records, operative reports, discharge summaries, and outpatient records; echocardiography, CT, and MRI reports; and telephone interviews. Collected variables included demographics, medical and surgical history; preoperative medications and cardiovascular imaging; associated LDS abnormalities; operative details; postoperative cardiovascular imaging, medications, and complications; need for late surgical reintervention; and mortality data. Whenever possible, we recommended that patients have echocardiograms every 3 months, both before and after surgery, to assess the aortic root. We also recommended that patients undergo annual CT or MR angiography for surveillance of the entire arterial tree. Collected variables for clinical and research purposes included ejection fraction, aortic root dimensions, presence of valvular pathology (aortic and mitral regurgitation), presence and extent of dissection at any location within the arterial tree, and presence and size of aneurysms at any location within the arterial tree. Follow-Up Data Mortality data were retrieved from autopsy records, death certificates, and reports from the patient s primary physician. Follow-up data were obtained from hospital and clinic records, telephone interviews with patients or their family members, and from echocardiograms, CT, and MRI. Results Clinical criteria and genotyping identified 71 patients with LDS, of whom 32 (45%) were children, and 39 (55%) were adults. Six (9%) died before surgery at our institutions from aneurysm rupture or intracerebral hemorrhage. Aortic surgery was performed in 30% of patients (21/71), and 62% (44/71) are medically managed or are awaiting surgery. Of the surgically treated patients, 62% (13/21) had a preoperative diagnosis of LDS; whereas, 38% (8/21) were diagnosed postoperatively when the Table 1. Age, Aortic Dimension, and Cause of Death of 6 Loeys-Dietz Syndrome Patients Who Died Before Surgery at Our Institutions Patient Age at Death (yrs) Aortic Root Diameter (cm) Cause of Death Aortic root dissection Intracerebral hemorrhage 3 9 Unknown Abdominal aortic rupture Descending thoracic aortic dissection a 5 35 Unknown Descending thoracic aortic dissection b Aortic root dissection a This patient underwent aortic root replacement at an outside hospital prior to referral to our institution. b Dissection was associated with pregnancy.

3 Ann Thorac Surg AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL 2007;83:S SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME S759 Table 2. Preoperative Clinical Characteristics of the 21 Patients Undergoing Aortic Surgery for Loeys-Dietz Syndrome a Variable Children n 14 Adults n 7 Mean age Male gender 7 4 Country of Origin United States 13 4 Belgium 0 3 Greece 1 0 Race White 11 7 Black 1 0 Other 2 0 Aortic insufficiency ( 2 ) 1 0 Preoperative NYHA class I 13 6 II 1 1 III 0 0 IV 0 0 a One child and 4 adults underwent surgery at outside institutions before undergoing surgery at our institutions. The details of these procedures are summarized in Tables 3A and 3B. NYHA New York Heart Association. genetic mutation and phenotype were described. In this series, 31% (22/71) of all the patients and 33% (7/21) of surgical patients have a relative with the diagnosis of LDS. Preoperative Mortality Six patients now known to carry the diagnosis of LDS died before undergoing surgical intervention at our institutions. Genotyping of tissue taken before death or postmortem confirmed the diagnosis of LDS in all 6. Four children (age 18 years) and two adults died after dissection or rupture of the thoracic aorta, abdominal aorta, or cerebral vasculature. Table 1 lists the ages, aortic dimensions, and causes of death for each of these patients. Of note, thoracic aortic dissection occurred in 2 patients whose aortic root was less than 4.5 cm before rupture, one of whom was only 6 months old at the time of death. Catastrophic vascular events also occurred in 3 patients younger than age 10, with the youngest being 6 months old. Preoperative Patient Characteristics Aortic aneurysm surgery was performed on 21 LDS patients (30%) from the United States, Belgium, and Greece. Mean age at operation for the entire cohort was years (range, 0.8 to 40); there were 14 children and 7 adults. Table 2 lists their relevant preoperative clinical characteristics. Before undergoing surgery at our institutions, 5 patients (24%) had previous cardiovascular surgical intervention. All patients undergoing surgery at our institutions were in New York Heart Association (NYHA) functional class I or II. Only one patient had clinically significant aortic valve incompetence, and no patient had clinically significant mitral valve disease. Surgical Procedures One patient underwent emergent surgical intervention for acute type A dissection. The remaining 20 patients underwent elective operative (Fig 2A). Two patients who had aortic arch replacement had a previous aortic root replacement at another institution. Mean cross-clamp and cardiopulmonary bypass (CPB) times were, respectively, minutes and minutes for pediatric patients and minutes and minutes for the adults. When possible, valve -sparing root replacement (VSRR) was performed for aortic root aneurysm, especially in children (Fig 2B). Three children had the Bentall procedure with mechanical prostheses. One underwent surgery in 1992, before VSRR was an established therapy for aortic root aneurysm. Another child required aortic valve replacement for bicuspid aortic valve disease. The third child underwent urgent surgical for a type A dissection. Two adults also had the Bentall procedure. One had surgery in 1989 and the other had a degenerated aortic homograft. Operative Results No operative or in-hospital deaths occurred in our series. One significant postoperative complication occurred in an adult patient, who required a permanent pacemaker after the Bentall procedure. Mean length of stay in the intensive care unit was days for the children and days for adults. The mean total length of stay was days for the children and days for the adults. Fig 2. (A) Indications for surgery in 21 patients with Loeys-Dietz syndrome undergoing surgical. (B) Aortic operations in 21 patients with Loeys-Dietz syndrome.*both patients had undergone prior aortic root replacement at outside institutions. (VSRR valvesparing root replacement.)

4 S760 AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL Ann Thorac Surg SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME 2007;83:S Table 3A. Operative Characteristics of 14 Pediatric Patients Undergoing Aortic Surgery for Pathology Related to Loeys-Dietz Syndrome Patient Age (yrs) Aortic Root Diameter (cm) Index Operation a (IO) Before IO Other Vascular Operations After IO Current Status VSRR Alive VSRR Alive VSRR Alive VSRR Alive VSRR Alive VSRR Alive VSRR 1. PDA aneurysm Alive resection VSRR Alive VSRR Alive VSRR Alive VSRR/Arch 1. TAAA Decreased b 2. Bentall Unknown Bentall 1. Arch replacement Alive Bentall 1. MVR Alive 2. RCA aneurysm Bentall Alive a The first operation performed at one of our institutions is considered the index operation. b Died secondary to DTAA rupture 11 years after VSRR/Arch. DTAA descending thoracic aortic aneurysm; MVR mitral valve replacement; PDA patent ductus arteriosis; RCA right coronary artery; TAAA thoracic/abdominal aortic aneurysm; VSRR valve-sparing root replacement. Late Results Median follow-up after surgery was 7 months (range, 1 to 154 months). Table 3A summarizes operative characteristics and postoperative outcomes of each pediatric patient undergoing surgery for LDS. All pediatric patients remain NYHA class I or II, but 2 children report mild physical limitations or exercise intolerance related to their cardiac surgery. One child who underwent a remodeling VSRR with arch replacement required a Bentall procedure for aortic insufficiency 5 months after VSRR. The other 8 children who underwent VSRR have no late aortic insufficiency. At late follow-up, 1 pediatric LDS surgical patient died from descending thoracic aortic rupture 11 years after the initial VSRR procedure. This patient originally underwent VSRR with arch replacement and then required a Bentall procedure for aortic insufficiency 5 months after the initial VSRR. Table 3B describes operative characteristics and postoperative outcomes of each adult undergoing surgery for LDS. Like the pediatric patients, all adults remain in NYHA class I or II postoperatively; only 1 adult has reported physical limitations or exercise intolerance related to her cardiac surgery. At late follow-up, 2 adult surgical patients died from vascular complications related to LDS. One had undergone three previous cardiovascular operations at another institution before undergoing a Bentall procedure. The patient died 4.5 years after the Bentall procedure during an attempted of a thoracoabdominal aortic aneurysm. The other patient underwent of an aortic arch pseudoaneurysm after ascending and descending aortic aneurysm s and died 2 years after aortic arch surgery from a ruptured abdominal aortic aneurysm. Preoperative and postoperative vascular imaging has shown that nearly two thirds of the LDS cohort has aneurysm disease extending beyond the ascending aorta. The locations of these aneurysms include the descending thoracic aorta, abdominal aorta, and pulmonary artery, as well as coronary, vertebral, carotid, subclavian, splenic, celiac, superior mesenteric, and inferior mesenteric arteries. Seven (33%) of the 21 surgical patients have required multiple cardiovascular surgical interventions (Tables 3A and 3B). The 21 surgical patients in this series have had 41 cardiovascular operations. Table 4 summarizes our preoperative workup, operative indications, and postoperative follow-up of these patients. Comment The TGF- family of cytokines consists of more than two dozen signaling molecules secreted into the extracellular matrix [6]. These molecules act through a complex signaling pathway on multiple cell types to effect growth and development of normal cells [7, 8]. Actions of TGF- molecules lead to cellular differentiation, proliferation, motility, organization, and death [6]. These cytokines have been specifically implicated in cardiovascular development and function [9]. TGF- molecules guide the formation of endocardial cushions, the coronary vasculature, and the ventricular myocardium during embryogenesis, and they are involved in the processes of myo-

5 Ann Thorac Surg AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL 2007;83:S SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME S761 Table 3B. Operative Characteristics of 7 Adult Patients Undergoing Aortic Surgery for Pathology Related to Loeys-Dietz Syndrome Patient Age (yrs) Aortic Root Diameter (cm) Index Operation a (IO) Before IO Other Vascular Operations After IO Current Status VSRR Alive VSRR Alive VSRR Alive Unknown (homograft) Bentall 1. Root replacement 2. AVR Bentall 1. Repair type B dissection 2. Re-do type B dissection 3. Repair R subclavian aneurysm Arch replacement 1. TAAA 2. Redo DTAA 3. Redo DTAA Unknown Arch replacement 1. Root replacement 2. DTAA 4. Ascending aortic pseudoaneurysm 5. Attempted DTAA 4. Hepatorenal bypass 5. Celiac/SMA aneurysm Alive Deceased b Alive Deceased c a The first operation performed at one of our institutions is considered the index operation. b Died intraoperatively during attempted DTAA 4 years after Bentall. c Died secondary to AAA rupture 2 years after arch replacement. AAA abdominal aortic aneurysm; AVR aortic valve replacement; DTAA descending thoracic aortic aneurysm; SMA superior mesenteric artery; TAAA thoracic/abdominal aortic aneurysm; VSRR valve-sparing root replacement. cardial hypertrophy and vascular remodeling in adults [9]. Knockout models of TGF- 2 yield abnormalities in cardiac, lung, craniofacial, limb, spinal column, eye, inner ear, and urogenital development [10]. Two major genetic perturbations in the TGF- signaling pathway have been described that lead to the LDS phenotype [1, 2]. Approximately two thirds of the patients with this disorder have heterozygous mutations in T RII, and the remaining patients have mutations in T RI. Both are associated with increased TGF- signaling in the aortic media. The defective TGF- receptors in patients with LDS have specific effects on collagen deposition and elastin organization in the extracellular matrix. Patients with mutations in T RI and T RII demonstrate disarrayed elastic fibers and loss of elastin content in the aortic media [1]. Excess collagen deposition is also found within the aortic wall, similar to patients with Marfan syndrome, although excess collagen deposition is greater in LDS patients. These ultrastructural changes result in a weakened vascular media that ultimately leads to dilatation and dissection of the vessel wall. LDS shares certain similarities with other connective tissue disorders, most notably Marfan syndrome, but important genotypic and phenotypic distinctions exist. Marfan syndrome is caused by mutations in the gene encoding fibrillin-1 and is inherited in an autosomal dominant pattern with high penetrance [11 13]. Although abnormalities of fibrillin-1 lead to elastin disarray in the arterial media, the mechanism by which this occurs is distinct from LDS. In unaffected individuals, normal fibrillin-1 inhibits the TGF- pathway, probably by sequestering the latent form of the cytokine and inhibiting its activation. Patients with Marfan syndrome lack sufficient fibrillin-1 to support this function. In this view, the Marfan phenotype is also caused, at least in part, by excessive TGF- signaling [14]. LDS patients have normal fibrillin-1, so the extracellular matrix abnormalities seen in these patients result from alterations in TGF- signaling at a different point in the pathway. Of importance is that the TGF- signaling abnormalities in LDS patients alter the extracellular matrix throughout the arterial tree; in patients with Marfan syndrome, this pathology is generally confined to the ascending aorta and specifically the aortic root [15]. More important for clinical recognition of this syndrome are the unique phenotypic features that differentiate LDS from Marfan syndrome. Major manifestations in Marfan syndrome include skeletal manifestations, eye lens dislocation, aortic root dilatation, and dural ectasia [1, 4, 12 14]. LDS patients are reported to exhibit hypertelorism (90%), cleft palate/bifid uvula (90%), generalized arterial tortuosity (84%), craniosynostosis (48%), patent ductus arteriosus (35%), atrial septal defect (23%), Chiari type I malformation (20%), developmental delay (15%), and hydrocephalus (15%) [1, 2]. None of these phenotypic features are found in patients with Marfan syndrome. In addition, patients with the Marfan craniosynostosis

6 S762 AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL Ann Thorac Surg SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME 2007;83:S Table 4. Clinical Management Strategies for Children and Adult Patients With Loeys-Dietz Syndrome Children Initial work up 1. Genetic testing. 2. CTA with 3-dimensional reconstruction at baseline cerebral, thoracic, abdominal, and pelvic vessels. Repeated yearly or as dictated by baseline findings. 3. Echocardiography at baseline. Repeated every 6 months or as dictated by baseline findings. 4. Genetic counseling and testing of family members. Threshold for surgery a Severe craniofacial features: 1. Aortic root z-score 3.0 or rapidly expanding ( 0.5 cm over 1 year). 2. Effort made to delay surgery until the annulus reaches 1.8 cm, allowing placement of a valvesparing graft of sufficient size to accommodate growth. Mild craniofacial features: 1. Aortic root z-score 4.0 or rapidly expanding ( 0.5 cm over 1 year). 2. Large size or rapid expansion of the descending aorta or other vessels; vessel under consideration will determine absolute size or rate of growth. Follow-up 1. Echocardiography every 3 months for 1 year after root replacement, then every 6 months. 2. CTA from the head through the pelvis every year to evaluate residual aorta and peripheral vessels. 3. Follow-up can be more frequent as the clinical. Same as children Adults 1. Aortic root 4.0 cm or rapidly expanding ( 0.5 cm over 1 year). 2. Descending throacic aorta 5.0 cm or rapidly expanding ( 0.5 cm over 1 year). 3. Abdominal aorta 4.0 cm or rapidly expanding ( 0.5 cm over 1 year). 4. Rapid expansion of peripheral aneurysms; vessel under consideration will determine absolute size or rate of growth. Same as children a These recommendations will not eliminate the risk of dissection and death. Earlier intervention should be considered based upon family history or a patient s or family s individualized assessment of risk versus benefit. CTA computed tomography angiography. (Shprintzen-Goldberg) syndrome generally do not exhibit cleft palate/bifid uvula, arterial tortuosity, vascular aneurysms, patent ductus arteriosus, or atrial septal defect. Taken together, these phenotypic differences allow the clinician to differentiate LDS from other syndromes. It is important to note, however, that LDS patients, like other patients with connective tissue disorders, exhibit significant variability in the clinical expression of this disorder. Whereas one member of a family can be severely affected, another first-degree relative may have only mild phenotypic signs of the syndrome [1, 2]. Among those with TGF- receptor mutations, patients with severe craniofacial features (LDS-I) tend to show a more severe cardiovascular course than those without these features (LDS-II). Nevertheless, both groups show more aggressive and widespread vascular disease than that seen in Marfan syndrome, mandating individualized counseling and management. Perhaps our most important finding is the evidence for the aggressive nature of the aortic pathology in LDS. Fatal aortic and intracerebral catastrophes occurred in 3 patients aged younger than 10 years, a clinical scenario that is extremely rare in Marfan syndrome. Furthermore, fatal aortic rupture and dissection occurred in patients with aortic root diameters smaller than 4.5 cm, also a rare event in Marfan syndrome. Finally, 3 patients undergoing surgery at our institutions (14% of the surgical series) and 1 patient referred for evaluation who had undergone surgery elsewhere all died from aortic catastrophe at sites separate from the site of definitive surgical. In addition to the mortality associated with LDS, high rates of repeat surgical intervention were seen commonly in these patients. Seven (33%) of the 21 surgical patients in this series have required multiple cardiovascular surgical interventions, totaling 41 surgical procedures in all. These findings indicate that not only should surgical intervention be considered earlier and in smaller aortic roots than routinely considered for patients with Marfan syndrome, but these patients also require strict, aggressive, lifelong surveillance of the entire arterial tree to identify problems that are generally amenable to surgical intervention. Of importance is that LDS patients appear to tolerate surgical intervention well. Unlike patients with Ehlers- Danlos syndrome type IV (vascular EDS) who have a high incidence of intraoperative and early postoperative vascular catastrophe, LDS patients do not have friable

7 Ann Thorac Surg AORTIC SURGERY SYMPOSIUM X WILLIAMS ET AL 2007;83:S SURGERY FOR A NEW AORTIC ANEURYSM SYNDROME S763 vascular tissue [16, 17]. They can withstand surgical intervention and have good tolerance for intraoperative manipulation of the aorta. Although each patient should be evaluated individually, the observations reported here have led us to recommend early, prophylactic surgical intervention to avoid vascular catastrophe. Many investigators recommend that patients with Marfan syndrome undergo aortic root replacement at root diameters greater than 5.0 cm [18 20]; however, we favor a threshold of 4 cm in adult LDS patients. We also consider root replacement below this threshold in children who show progressive aortic dilatation and who have an annulus of sufficient size to accept a graft that will accommodate growth. We also recommend more frequent echocardiographic evaluation of the aortic root along with annual CT or MR angiography for surveillance of the entire arterial tree. We have reported here the surgical care of patients with this new syndrome, and to our knowledge, all patients at our institutions who are known to carry a diagnosis of LDS have been included in this series. As with any small surgical series, however, conclusions are limited by the small number of patients and relatively short follow-up. Certainly, as we identify more patients with LDS who undergo corrective surgical for aortic disease, we will develop a better understanding of the natural history of LDS and long-term results of surgical intervention. For now, physicians with special interest in connective tissue disorders and aortic surgeons should be aware of this new syndrome and its aggressive behavior. This study was supported by the Dana and Albert Cubby Broccoli Center for Aortic Diseases, the Mildred and Carmont Blitz Cardiac Research Fund, the Joyce Koons Family Cardiac Fund, National Institutes of Health grants AR41135 and AR049698, the Howard Hughes Medical Institute, the Smilow Family Foundation, and the National Marfan Foundation. Dr Williams is an Irene Piccinini Investigator in Cardiac Surgery. Dr Nwakanma is a Hugh R. Sharp Cardiac Surgery Research Fellow. Dr Cameron is the James T. Dresher, Senior Professor of Cardiac Surgery. Dr Dietz is the Victor A. McKusick Professor of Medicine and Genetics. References 1. Loeys B, Chen J, Neptune E, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 and TGFBR2. Nat Genet 2005;37: Loeys B, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355: Verrecchia F, Chu M, Mauviel A. 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