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Ann Thorac Surg 2007;83:S757-S763
© 2007 The Society of Thoracic Surgeons

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Supplement

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

^a Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^b McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^c Division of Pediatric Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^d Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^e Department of Cardiac Surgery, Ghent University Hospital, Ghent, Belgium
^f Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

^_* Address correspondence to Dr Cameron, Pediatric Cardiac Surgery, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287. (Email: dcameron{at}csurg.jhmi.jhu.edu).

Presented at Aortic Surgery Symposium X, New York, NY, April 27–28, 2006.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: Loeys-Dietz syndrome (LDS) is a recently described genetic aortic aneurysm syndrome resulting from mutations in receptors for the cytokine transforming growth factor-ß. 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.

	Introduction

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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).

View larger version (114K): [in this window] [in a new window]   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.

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.

	Patients and Methods

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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 ß-blockers or angiotensin-converting 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

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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 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.

View larger version (62K): [in this window] [in a new window]   Fig 2. (A) Indications for surgery in 21 patients with Loeys-Dietz syndrome undergoing surgical repair. (B) Aortic operations in 21 patients with Loeys-Dietz syndrome.*Both patients had undergone prior aortic root replacement at outside institutions. (VSRR = valve-sparing root replacement.)

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 repair 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 2.5 ± 1.3 days for the children and 1.8 ± 0.5 days for adults. The mean total length of stay was 6.6 ± 2.5 days for the children and 7.4 ± 3.9 days for the adults.

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.

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.

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

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Two major genetic perturbations in the TGF-ß 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 TßRII, and the remaining patients have mutations in TßRI. Both are associated with increased TGF-ß signaling in the aortic media.

The defective TGF-ß receptors in patients with LDS have specific effects on collagen deposition and elastin organization in the extracellular matrix. Patients with mutations in TßRI and TßRII 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-ß 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-ß signaling [14]. LDS patients have normal fibrillin-1, so the extracellular matrix abnormalities seen in these patients result from alterations in TGF-ß signaling at a different point in the pathway. Of importance is that the TGF-ß 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 (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-ß 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 repair.

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 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 repair 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.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
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

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jason A. Williams Lois U. Nwakanma Nishant D. Patel Katrien François Vincent L. Gott Luca A. Vricella Duke E. Cameron Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Williams, J. A. Articles by Cameron, D. E. Search for Related Content PubMed PubMed Citation Articles by Williams, J. A. Articles by Cameron, D. E. Related Collections Great vessels