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Article |

Incidence of Aortic Root Dilatation in Pectus Excavatum and Its Association With Marfan Syndrome FREE

Diane Rhee, MD; David Solowiejczyk, MD; Karen Altmann, MD; Ashwin Prakash, MD; Welton M. Gersony, MD; Charles Stolar, MD; Charles Kleinman, MD; Kwame Anyane-Yeboa, MD; Wendy K. Chung, MD, PhD; Daphne Hsu, MD
[+] Author Affiliations

Author Affiliations: Divisions of Pediatric Cardiology (Drs Rhee, Solowiejczyk, Altmann, Prakash, Gersony, and Kleinman), Pediatric Surgery (Dr Stolar), Clinical Genetics (Dr Anyane-Yeboa), and Molecular Genetics, and Department of Medicine (Dr Chung), Columbia University Medical Center, Morgan Stanley Children's Hospital of New York–Presbyterian, New York, New York; and Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, New York (Dr Hsu).


Arch Pediatr Adolesc Med. 2008;162(9):882-885. doi:10.1001/archpedi.162.9.882.
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Objective  To investigate the incidence of aortic root dilatation in pectus excavatum.

Design  Retrospective medical record review and echocardiographic reanalysis.

Setting  Morgan Stanley Children's Hospital of New York–Presbyterian.

Participants  Surgical candidates with pectus excavatum (n = 37) and age-matched controls (n = 44) referred for an echocardiogram from 1994 to 2002.

Interventions  Two-dimensional and color Doppler transthoracic echocardiograms.

Outcome Measures  The aortic annulus and root were measured and z scores were calculated and compared. Medical records were reviewed for genetic evaluation.

Results  Patients with pectus excavatum and age-matched controls were reanalyzed. There was no difference in age, weight, height, or body surface area between patients and controls. There were no differences in the mean aortic annulus diameter, mean aortic annulus z score, or mean aortic root measurements. However, the aortic root z score was significantly higher in the pectus excavatum group compared with the controls: 0.9 (SD, 1.06) vs 0.0 (SD, 1.25) (P = .001). There were more patients with an aortic root z score of 2 or greater in the pectus excavatum group (9 of 37 patients) than in the control group (0 of 43 controls), with a calculated odds ratio of 29.7 (95% confidence interval, 1.10-1.59). Genetic evaluation was performed in 5 patients with a pectus excavatum and dilated aortic root; 2 of them received diagnoses of Marfan syndrome.

Conclusions  Aortic root dilatation is more common in patients with pectus excavatum than in a control population. Echocardiographic screening may be useful in the identification of aortic root dilatation in patients with isolated pectus excavatum.

Figures in this Article

Pectus excavatum is one of the most common congenital defects of the thoracic cage, occurring in 1 in 400 to 1 in 1000 births.1,2 Pectus excavatum may exist as an isolated lesion or in association with a genetic syndrome such as Marfan syndrome (MFS). Marfan syndrome is an autosomal dominant condition caused by mutations in FBN1 or TGFBR2, occurs in 1 in 3000 to 1 in 10 000 live births, and affects the cardiovascular, skeletal, ocular, and pulmonary systems.36 The Berlin nosology7 and, most recently, the Ghent nosology8 were set as the clinical guidelines to aid in the diagnosis of MFS (Table 1). In patients with MFS, aortic root dilatation is a common finding and can be a serious source of morbidity and mortality.46,9 Pectus excavatum is seen in two-thirds of patients with MFS or related connective tissue diseases.9,10 Seliem et al11 compared aortic root diameters indexed to body surface areas (BSAs) in patients with an “isolated” pectus excavatum, those with MFS, and a healthy control population. They did not find a significant difference between the isolated pectus excavatum and healthy control groups. The findings of this study are limited, as the indexed relationship between aortic root diameter and BSA has been shown to be nonlinear; the use of aortic root z scores is the current standard for comparison of aortic diameters among patients of differing size.12

Table Graphic Jump LocationTable 1. Ghent Nosology for the Diagnosis of Marfan Syndromea

The utility of screening for cardiac manifestations, such as aortic root dilatation, in patients with isolated pectus excavatum has not been well defined. Given the high prevalence of both features in patients with MFS, we sought to investigate the prevalence of aortic root dilatation (defined by an aortic root z score ≥ 2) in patients with pectus excavatum.

After receiving approval from our institutional review board, we conducted a retrospective echocardiographic and limited medical record review. The case population consisted of patients with pectus excavatum. These patients were referred by their primary physician, without being suspected of having a connective tissue disorder, to the general pediatric surgeon for the consideration of reconstructive repair of the pectus excavatum. Patients who underwent a routine screening echocardiogram as part of the evaluation from June 1994 to February 2002 were included in the study. If the patient had more than 1 echocardiogram, the initial one was reanalyzed. Clinical genetic screening was not routinely performed on all patients. Age-matched controls were children referred to the echocardiography laboratory for an echocardiogram to assess their intracardiac anatomy. Their echocardiographic results were determined to be normal.

ECHOCARDIOGRAPHY

One senior echocardiographer (D.S.) who was blinded to patient group reanalyzed 2-dimensional and color Doppler echocardiograms offline. A second blinded senior echocardiographer (K.A.) remeasured the studies to assess interobserver variability. The aortic root and aortic annulus diameters were measured in the 2-dimensional parasternal long-axis view. Measurements were made at the end of systole, with the aortic valves open, using the inner-edge technique (Figure). The mean of the 2 measurements was used. Body surface area was calculated using the Haycock formula12 based on height and weight measured at the time of the echocardiogram, as recorded in the patients' medical records. The BSA was then used to derive the z score. A z score is a measure of the mean of a distribution normalized by the standard deviation of the distribution. Aortic root dilatation was defined as having a z score of 2.0 or greater.12 The z score conversion was obtained using a published database by Sluysmans et al.12 Medical records were reviewed for results of a clinical genetic evaluation for MFS.

Place holder to copy figure label and caption
Figure.

Parasternal long-axis view of the left ventricular outflow tract. A, Healthy aortic root. B, Abnormally dilated aortic root and mitral valve prolapse (arrow). + Indicates aortic annulus (measurements are made at the hinge points of the aortic valve); *, aortic root (measurements are made inner edge to inner edge at the widest point at the level of the sinus of Valsalva).

Graphic Jump Location
STATISTICAL ANALYSIS

An unpaired t test was used to compare continuous variables between the control and pectus excavatum groups. χ2 Analysis was used to compare categorical variables. Statistical significance was set at P ≤ .05. An odds ratio (reported with a 95% confidence interval) was calculated to quantify an association between the variables. Interobserver variability was analyzed by calculating the κ coefficient.

There were a total of 37 patients with pectus excavatum and 44 age-matched controls. The demographic data for each group are summarized in Table 2. There were no significant differences between the pectus excavatum and control groups in age, weight, height, or BSA. In the pectus excavatum group, there was no significant difference in height z scores between those with a normal aortic root and those with a dilated one.

Table Graphic Jump LocationTable 2. Characteristics of Individuals With and Without Pectus Excavatum

The mean aortic annulus and root diameters and their corresponding z scores for both groups are summarized in Table 3. Analysis of the interobserver variability of the aortic annulus and root diameters demonstrated a κ coefficient of 0.89.

Table Graphic Jump LocationTable 3. Aortic Dimensions in Patients With Pectus Excavatum and Controls

The aortic annulus and root diameters were not significantly different between the pectus excavatum and the control groups. There was also no significant difference in aortic annulus z scores between the 2 groups. In contrast, there was a significant association between the aortic root z scores and the presence of pectus excavatum (9 of 37 patients) compared with the controls (0 of 44 controls), with a calculated odds ratio of 29.7 (95% confidence interval, 1.10-1.59).

Clinical genetic evaluation was performed in 5 patients, all of whom had pectus excavatum and a dilated aortic root. Following strict Ghent criteria, we diagnosed MFS in 2 of the 5 patients (patients A and B) (Table 4). Patients C, D, and E each met 2 major criteria in 2 organ systems and therefore are highly suspected of having MFS.

Table Graphic Jump LocationTable 4. Major and Minor Criteria Met in Patients Who Underwent Genetic Evaluation for Ghent Nosology of Marfan Syndromea

Marfan syndrome is a genetic syndrome with varying degrees of phenotypic expression. At times, the diagnosis can be subtle and difficult, especially in children.4,5,8 Specific criteria have been established to standardize the clinical diagnosis, but the syndrome can still pose diagnostic challenges.8 In our study, patients with isolated pectus excavatum without a suspected connective tissue disorder were referred for routine echocardiographic evaluation by the general surgical department as part of a screening protocol. In this population of patients with isolated pectus excavatum, we found a significantly higher prevalence of aortic root dilatation, based on z scores, than in an age-matched control population. The patients' heights were similar to the control population, indicating that the patients with an isolated pectus excavatum did not have the usual tall stature associated with MFS. At most, patients with isolated pectus excavatum may represent a forme fruste.

There was no significant dilatation or association in the aortic annulus diameter or z score between patients with pectus excavatum and controls. Aortic annulus dilatation is found in many patients with MFS. However, this is not a consistent finding nor is it part of the Ghent nosology. Dilatation of the aortic root is reported to start at the sinus of Valsalva, progress to the sinotubular junction, and then progress to the aortic annulus.13,14 The phenotypic finding of MFS is variable and progressive,6 and findings are noted to be age dependent.15 As per the protocol, echocardiograms were reviewed at only 1 point. This study may have reviewed echocardiographic studies too early for the annulus dilatation to manifest. Alternatively, annular dilatation may not be seen in all individuals with pectus excavatum or MFS.

Our data conflict with the findings from Seliem et al,11 who also examined the aortic roots of patients with isolated pectus excavatum, controls, and patients with MFS. Similar to our findings, the study by Seliem et al found no significant difference in the absolute diameter of the aortic root between the pectus excavatum and control groups; the measurements in both groups were statistically smaller than in their group of patients with MFS. When Seliem et al indexed the aortic root size to BSA, they found no difference between the pectus excavatum and the control groups; in fact, predictably, the indexed aortic root diameter was significantly lower in the MFS group than in the other 2 groups.11 The method of indexing the aortic root diameter by dividing it by BSA is valid only if the relationship of that indexed value is linear and passes through the origin. However, this method has been found to be inversely and nonlinearly dependent on BSA. Adjusting for body size by comparing indexed values fails to account for the dependence of the aortic root measurement on the BSA.12 In our study, we used z scores to compare the differences in aortic root diameter between the 2 study groups. Since this conversion normalizes the aortic root dimension to the mean and standard deviation of the dimension expected for a reference (healthy) population, it does not suffer the type of difficulty encountered by using a simple division by BSA.

Genetic screening was not uniformly performed, making it difficult to ascertain whether the reported echocardiographic and skeletal findings were a marker for MFS. However, the higher prevalence of aortic root dilatation found in this group of patients with isolated pectus excavatum indicates the possibility of a subtle form of connective tissue disorder. In the small subgroup of children (5 of 9 patients) with pectus excavatum and evidence of aortic root dilatation who underwent genetic evaluation, 2 of 5 received diagnoses of MFS; in the remaining 3, MFS was highly suspected and these patients are being serially monitored, as MFS can be a progressive disorder.6

Given the retrospective nature of the study, strict guidelines and protocols in the acquisition of images and clinical information were not adhered to. The medical record analysis demonstrated that a standardization of documentation was not in place, limiting its usefulness. Not all patients with a pectus excavatum had a genetic evaluation. The true number of MFS or other connective tissue disorder diagnoses are unknown.

Screening echocardiography can help identify patients who have isolated pectus excavatum with cardiovascular manifestations. The association of pectus excavatum with aortic root dilatation is not sufficient to fulfill the Ghent criteria nor diagnose MFS. However, further genetic evaluation should be performed when these 2 features are present. This study has important implications for pediatricians. The potential benefits of an early diagnosis of MFS include closer follow-up for progressive aortic root dilation and screening family members who may be at risk. In addition to a thorough history and physical examination, we recommend routine echocardiographic screening in patients with pectus excavatum in the evaluation for MFS.

Correspondence: Diane Rhee, MD, Division of Pediatric Cardiology, 3959 Broadway BH 2N, New York, NY 10032 (dr2026@columbia.edu).

Accepted for Publication: February 11, 2008.

Author Contributions:Study concept and design: Rhee, Solowiejczyk, Gersony, Stolar, Kleinman, and Hsu. Acquisition of data: Solowiejczyk, Altmann, Prakash, Stolar, Anyane-Yeboa, and Chung. Analysis and interpretation of data: Rhee, Chung, and Hsu. Drafting of the manuscript: Rhee, Solowiejczyk, Gersony, Kleinman, and Hsu. Critical revision of the manuscript for important intellectual content: Rhee, Solowiejczyk, Altmann, Prakash, Gersony, Stolar, Anyane-Yeboa, Chung, and Hsu. Statistical analysis: Hsu. Administrative, technical, and material support: Rhee and Solowiejczyk. Study supervision: Solowiejczyk, Stolar, and Hsu.

Financial Disclosure: None reported.

Additional Contributions: Robert Sciacca, EngScD, and Marc Richmond, MD, assisted with the statistical analysis.

Mansour  KAThourani  VHOdessey  EADurham  MMMiller  JI  JrMiller  DL Thirty-year experience with repair of pectus deformities in adults. Ann Thorac Surg 2003;76 (2) 391- 395
PubMed Link to Article
Fonkalsrud  EW Current management of pectus excavatum. World J Surg 2003;27 (5) 502- 508
PubMed Link to Article
Rose  PSLevy  HPAhn  NU  et al.  A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genet Med 2000;2 (5) 278- 282
PubMed Link to Article
Groenink  MRozendaal  LNaeff  MS  et al.  Marfan syndrome in children and adolescents. Heart 1998;80 (2) 163- 169
PubMed
Loeys  BNuytinck  LDelvaux  IDe Bie  SDe Paepe  A Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 2001;161 (20) 2447- 2454
PubMed Link to Article
Morse  RPRockenmacher  SPyeritz  RE  et al.  Diagnosis and management of infantile Marfan syndrome. Pediatrics 1990;86 (6) 888- 895
PubMed
Beighton  Pde Paepe  ADanks  D  et al.  International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988;29 (3) 581- 594
PubMed Link to Article
De Paepe  ADevereux  RBDietz  HCHennekam  RCPyeritz  RE Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62 (4) 417- 426
PubMed Link to Article
Geva  THegesh  JFrand  M The clinical course and echocardiographic features of Marfan's syndrome in childhood. Am J Dis Child 1987;141 (11) 1179- 1182
PubMed
Arn  PHScherer  LRHaller  JA  JrPyeritz  RE Outcome of pectus excavatum in patients with Marfan syndrome and in the general population. J Pediatr 1989;115 (6) 954- 958
PubMed Link to Article
Seliem  MADuffy  CEGidding  SSBerdusis  KBenson  DW  Jr Echocardiographic evaluation of the aortic root and mitral valve in children and adolescents with isolated pectus excavatum. Pediatr Cardiol 1992;13 (1) 20- 23
PubMed
Sluysmans  TColan  SD Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005;99 (2) 445- 457
PubMed Link to Article
Mart  CRKhan  SASmith  FC  et al.  A new on-line method for predicting aortic root dilatation during two-dimensional echocardiography in pediatric patients with Marfan syndrome using the sinus of Valsalva to annulus ratio. Pediatr Cardiol 2003;24 (2) 118- 121
PubMed Link to Article
Ha  HISeo  JBSang  HL  et al.  Imaging of Marfan syndrome: multisystemic manifestations. Radiographics 2007;27 (4) 989- 1004
PubMed Link to Article
Dean  J Marfan syndrome: clinical diagnosis and management [published online ahead of print May 9, 2007]. Eur J Hum Genet 2007;15 (7) 724- 733
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Parasternal long-axis view of the left ventricular outflow tract. A, Healthy aortic root. B, Abnormally dilated aortic root and mitral valve prolapse (arrow). + Indicates aortic annulus (measurements are made at the hinge points of the aortic valve); *, aortic root (measurements are made inner edge to inner edge at the widest point at the level of the sinus of Valsalva).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Ghent Nosology for the Diagnosis of Marfan Syndromea
Table Graphic Jump LocationTable 2. Characteristics of Individuals With and Without Pectus Excavatum
Table Graphic Jump LocationTable 3. Aortic Dimensions in Patients With Pectus Excavatum and Controls
Table Graphic Jump LocationTable 4. Major and Minor Criteria Met in Patients Who Underwent Genetic Evaluation for Ghent Nosology of Marfan Syndromea

References

Mansour  KAThourani  VHOdessey  EADurham  MMMiller  JI  JrMiller  DL Thirty-year experience with repair of pectus deformities in adults. Ann Thorac Surg 2003;76 (2) 391- 395
PubMed Link to Article
Fonkalsrud  EW Current management of pectus excavatum. World J Surg 2003;27 (5) 502- 508
PubMed Link to Article
Rose  PSLevy  HPAhn  NU  et al.  A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genet Med 2000;2 (5) 278- 282
PubMed Link to Article
Groenink  MRozendaal  LNaeff  MS  et al.  Marfan syndrome in children and adolescents. Heart 1998;80 (2) 163- 169
PubMed
Loeys  BNuytinck  LDelvaux  IDe Bie  SDe Paepe  A Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 2001;161 (20) 2447- 2454
PubMed Link to Article
Morse  RPRockenmacher  SPyeritz  RE  et al.  Diagnosis and management of infantile Marfan syndrome. Pediatrics 1990;86 (6) 888- 895
PubMed
Beighton  Pde Paepe  ADanks  D  et al.  International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988;29 (3) 581- 594
PubMed Link to Article
De Paepe  ADevereux  RBDietz  HCHennekam  RCPyeritz  RE Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62 (4) 417- 426
PubMed Link to Article
Geva  THegesh  JFrand  M The clinical course and echocardiographic features of Marfan's syndrome in childhood. Am J Dis Child 1987;141 (11) 1179- 1182
PubMed
Arn  PHScherer  LRHaller  JA  JrPyeritz  RE Outcome of pectus excavatum in patients with Marfan syndrome and in the general population. J Pediatr 1989;115 (6) 954- 958
PubMed Link to Article
Seliem  MADuffy  CEGidding  SSBerdusis  KBenson  DW  Jr Echocardiographic evaluation of the aortic root and mitral valve in children and adolescents with isolated pectus excavatum. Pediatr Cardiol 1992;13 (1) 20- 23
PubMed
Sluysmans  TColan  SD Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005;99 (2) 445- 457
PubMed Link to Article
Mart  CRKhan  SASmith  FC  et al.  A new on-line method for predicting aortic root dilatation during two-dimensional echocardiography in pediatric patients with Marfan syndrome using the sinus of Valsalva to annulus ratio. Pediatr Cardiol 2003;24 (2) 118- 121
PubMed Link to Article
Ha  HISeo  JBSang  HL  et al.  Imaging of Marfan syndrome: multisystemic manifestations. Radiographics 2007;27 (4) 989- 1004
PubMed Link to Article
Dean  J Marfan syndrome: clinical diagnosis and management [published online ahead of print May 9, 2007]. Eur J Hum Genet 2007;15 (7) 724- 733
PubMed Link to Article

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