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

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

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

Objective: To investigate the incidence of aortic root ence in age, weight, height, or body surface area be- dilatation in pectus excavatum. tween patients and controls. There were no differences in the mean aortic annulus diameter, mean aortic annu- Design: Retrospective medical record review and echo- lus z score, or mean aortic root measurements. How- cardiographic reanalysis. ever, the aortic root z score was significantly higher in the pectus excavatum group compared with the con- Setting: Morgan Stanley Children’s Hospital of New trols: 0.9 (SD, 1.06) vs 0.0 (SD, 1.25) (P=.001). There York–Presbyterian. were more patients with an aortic root z score of 2 or greater in the pectus excavatum group (9 of 37 patients) Participants: Surgical candidates with pectus excava- than in the control group (0 of 43 controls), with a cal- tum (n=37) and age-matched controls (n=44) referred culated odds ratio of 29.7 (95% confidence interval, 1.10- for an echocardiogram from 1994 to 2002. 1.59). Genetic evaluation was performed in 5 patients with Interventions: Two-dimensional and color Doppler a pectus excavatum and dilated aortic root; 2 of them re- transthoracic echocardiograms. ceived diagnoses of Marfan syndrome. Conclusions: Aortic root dilatation is more common in Outcome Measures: The aortic annulus and root were patients with pectus excavatum than in a control popu- measured and z scores were calculated and compared. lation. Echocardiographic screening may be useful in the Medical records were reviewed for genetic evaluation. identification of aortic root dilatation in patients with isolated pectus excavatum. Results: Patients with pectus excavatum and age- matched controls were reanalyzed. There was no differ- Arch Pediatr Adolesc Med. 2008;162(9):882-885

ECTUS EXCAVATUM IS ONE OF tum, those with MFS, and a healthy control the most common congeni- population. They did not find a significant tal defects of the thoracic cage, difference between the isolated pectus ex- occurring in 1 in 400 to 1 in cavatum and healthy control groups. The 1000 births.1,2 Pectus excava- findings of this study are limited, as the in- tumP may exist as an isolated lesion or in as- dexed relationship between aortic root di- sociation with a genetic syndrome such as ameter and BSA has been shown to be non- Marfan syndrome (MFS). Marfan syn- linear; the use of aortic root z scores is the drome is an autosomal dominant condi- current standard for comparison of aortic Author Affiliations: Divisions tion caused by mutations in FBN1 or diameters among patients of differing size.12 of Pediatric Cardiology The utility of screening for cardiac (Drs Rhee, Solowiejczyk, TGFBR2, occurs in 1 in 3000 to 1 in 10 000 Altmann, Prakash, Gersony, and live births, and affects the cardiovascular, manifestations, such as aortic root dilata- Kleinman), Pediatric Surgery skeletal, ocular, and pulmonary sys- tion, in patients with isolated pectus ex- (Dr Stolar), Clinical Genetics tems.3-6 The Berlin nosology7 and, most re- cavatum has not been well defined. Given (Dr Anyane-Yeboa), and cently, the Ghent nosology8 were set as the the high prevalence of both features in pa- Molecular Genetics, and clinical guidelines to aid in the diagnosis tients with MFS, we sought to investigate Department of Medicine of MFS (Table 1). In patients with MFS, the prevalence of aortic root dilatation (de- (Dr Chung), Columbia aortic root dilatation is a common finding fined by an aortic root z scoreՆ2) in pa- University Medical Center, and can be a serious source of morbidity tients with pectus excavatum. Morgan Stanley Children’s and mortality.4-6,9 Pectus excavatum is seen Hospital of New York– in two-thirds of patients with MFS or re- Presbyterian, New York, 9,10 METHODS New York; and Division of lated connective tissue diseases. Seliem 11 Pediatric Cardiology, Children’s et al compared aortic root diameters in- Hospital at Montefiore, Bronx, dexed to body surface areas (BSAs) in pa- After receiving approval from our institutional New York (Dr Hsu). tients with an “isolated” pectus excava- review board, we conducted a retrospective echo-

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Criteria

Organ System Major Minor Skeletal Must meet Ն4ofthe Must meet Ն2ofthe system following criteria: PC, following: facial PE requiring surgery, appearance, joint arm span to height hypermobility, moderate ratio Ͼ1.05, U:L to severe PE, or high extremity ratio Ͻ0.86, arched palate with teeth wrist and thumb signs, crowding scoliosis Ͼ20° or spondylolisthesis, reduced extension of elbows (Ͻ170°), B flatfoot, or protrusio acetabuli Ocular system Ectopia lentis Must meet Ն2ofthe following: flat cornea, myopia, iris or ciliary muscle hypoplasia, or increased axial length of globe Cardiovascular Must meet Ն1ofthe Must meet Ն1ofthe system following: dilatation of following: MVP with or ascending aorta without MR, mitral valve involving the aortic annulus calcification root or ascending onset at Ͻ40 y, aortic dissection descending or abdominal aorta dissection at Ͻ50 y, Figure. Parasternal long-axis view of the left ventricular outflow tract. or idiopathic PA dilatation A, Healthy aortic root. B, Abnormally dilated aortic root and mitral valve ϩ at Ͻ40 y prolapse (arrow). Indicates aortic annulus (measurements are made at the hinge points of the aortic valve); , aortic root (measurements are made inner Pulmonary None Pneumothorax and/or apical * edge to inner edge at the widest point at the level of the sinus of Valsalva). system bleb Integument None Striae atrophicae without significant weight gain or cardiograms offline. A second blinded senior echocardiogra- loss and/or recurrent pher (K.A.) remeasured the studies to assess interobserver incisional hernia variability. The aortic root and aortic annulus diameters were Dura mater Lumbrosacral dural None measured in the 2-dimensional parasternal long-axis view. Mea- ectasia (CT or MRI) surements were made at the end of systole, with the aortic valves open, using the inner-edge technique (Figure). The mean of Abbreviations: CT, computed tomography; MR, mitral regurgitation; the 2 measurements was used. Body surface area was calcu- MRI, magnetic resonance imaging; MVP, mitral valve prolapse; PA, pulmonary 12 artery; PC, pectus carinatum, PE, pectus excavatum; U:L, upper to lower. lated using the Haycock formula based on height and weight aFor diagnosis, the index case must fulfill the major criteria in 2 organ measured at the time of the echocardiogram, as recorded in the systems and at least involvement of 1 minor criterion in a third organ system. patients’ medical records. The BSA was then used to derive the If there is an affected family member, then major criteria in 1 organ system and z score. A z score is a measure of the mean of a distribution minor criteria involvement of another organ system must be met for diagnosis. normalized by the standard deviation of the distribution. Aor- tic root dilatation was defined as having a z score of 2.0 or greater.12 The z score conversion was obtained using a pub- cardiographic and limited medical record review. The case popu- lished database by Sluysmans et al.12 Medical records were re- lation consisted of patients with pectus excavatum. These pa- viewed for results of a clinical genetic evaluation for MFS. tients were referred by their primary physician, without being suspected of having a connective tissue disorder, to the general STATISTICAL ANALYSIS pediatric surgeon for the consideration of reconstructive repair of the pectus excavatum. Patients who underwent a routine screen- An unpaired t test was used to compare continuous variables ing echocardiogram as part of the evaluation from June 1994 to between the control and pectus excavatum groups. ␹2 Analy- February 2002 were included in the study. If the patient had more sis was used to compare categorical variables. Statistical sig- than 1 echocardiogram, the initial one was reanalyzed. Clinical nificance was set at PՅ.05. An odds ratio (reported with a 95% genetic screening was not routinely performed on all patients. Age- confidence interval) was calculated to quantify an association matched controls were children referred to the echocardiogra- between the variables. Interobserver variability was analyzed phy laboratory for an echocardiogram to assess their intracar- by calculating the ␬ coefficient. diac anatomy. Their echocardiographic results were determined to be normal. RESULTS ECHOCARDIOGRAPHY There were a total of 37 patients with pectus excavatum One senior echocardiographer (D.S.) who was blinded to pa- and 44 age-matched controls. The demographic data for tient group reanalyzed 2-dimensional and color Doppler echo- each group are summarized in Table 2. There were no

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 significant differences between the pectus excavatum and Clinical genetic evaluation was performed in 5 pa- control groups in age, weight, height, or BSA. In the pec- tients, all of whom had pectus excavatum and a dilated aor- tus excavatum group, there was no significant differ- tic root. Following strict Ghent criteria, we diagnosed MFS ence in height z scores between those with a normal aor- in 2 of the 5 patients (patients A and B) (Table 4). Pa- tic root and those with a dilated one. tients C, D, and E each met 2 major criteria in 2 organ sys- The mean aortic annulus and root diameters and their tems and therefore are highly suspected of having MFS. corresponding z scores for both groups are summarized in Table 3. Analysis of the interobserver variability of COMMENT the aortic annulus and root diameters demonstrated a ␬ coefficient of 0.89. The aortic annulus and root diameters were not sig- Marfan syndrome is a genetic syndrome with varying de- grees of phenotypic expression. At times, the diagnosis can nificantly different between the pectus excavatum and 4,5,8 the control groups. There was also no significant differ- be subtle and difficult, especially in children. Specific ence in aortic annulus z scores between the 2 groups. In criteria have been established to standardize the clinical diagnosis, but the syndrome can still pose diagnostic chal- contrast, there was a significant association between the 8 aortic root z scores and the presence of pectus excava- lenges. In our study, patients with isolated pectus exca- tum (9 of 37 patients) compared with the controls (0 of vatum without a suspected connective tissue disorder were 44 controls), with a calculated odds ratio of 29.7 (95% referred for routine echocardiographic evaluation by the confidence interval, 1.10-1.59). general surgical department as part of a screening proto- col. In this population of patients with isolated pectus excavatum, we found a significantly higher prevalence of Table 2. Characteristics of Individuals With and Without aortic root dilatation, based on z scores, than in an age- Pectus Excavatum matched control population. The patients’ heights were simi- lar to the control population, indicating that the patients Mean (SD) with an isolated pectus excavatum did not have the usual tall stature associated with MFS. At most, patients with iso- Patients With Pectus Excavatum Controls lated pectus excavatum may represent a forme fruste. Characteristic (n=37) (n=44) There was no significant dilatation or association in Age, y 11.8 (5.6) 11.5 (5.8) the aortic annulus diameter or z score between patients Body surface area, m2 1.3 (0.44) 1.3 (0.50) with pectus excavatum and controls. Aortic annulus di- Height, cm 147.39 (29.7) 142.05 (33.01) latation is found in many patients with MFS. However, this is not a consistent finding nor is it part of the Ghent

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

Mean (SD)

Patients With Pectus Excavatum Controls Mean Difference Odds 95% Confidence Measure (n=37) (n=44) (SD) Ratio Interval P Value Aortic Annulus Diameter, cm 1.8 (0.28) 1.8 (0.41) −0.03 (0.08) −0.20 to 0.14 .8 z Score 0.8 (1.04) 0.3 (1.47) −0.61 (0.33) −1.27 to 0.05 .1 No. of patients with z scores Ն2 3 1 2.91 0.29 to 29.43 Aortic Root Diameter, cm 2.4 (0.46) 2.2 (0.57) −0.19 (0.12) −0.42 to 0.04 .11 z Score 0.9 (1.06) 0.0 (1.25) −0.88 (0.26) −1.4 to −0.36 .001 No. of patients with z scores Ն2 9 0 29.7a 1.10 to 1.59a

a Estimated, as there were no controls with a dilated aortic root.

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

Criteria Met by System

Patient Cardiovascular Skeletal Dural Pulmonary Ocular Integument Family A Major Minor Major B Major Major Minor C Major Major D Major Major E Major Major

a Clinical diagnosis of Marfan syndrome requires fulfillment of the major criteria in at least 2 organ systems and involvement of 1 minor criterion in a third organ system. Patients A and B received diagnoses of Marfan syndrome.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 nosology. Dilatation of the aortic root is reported to start tic root dilatation is not sufficient to fulfill the Ghent cri- at the sinus of Valsalva, progress to the sinotubular junc- teria nor diagnose MFS. However, further genetic evaluation tion, and then progress to the aortic annulus.13,14 The phe- should be performed when these 2 features are present. notypic finding of MFS is variable and progressive,6 and This study has important implications for pediatricians. findings are noted to be age dependent.15 As per the pro- The potential benefits of an early diagnosis of MFS in- tocol, echocardiograms were reviewed at only 1 point. clude closer follow-up for progressive aortic root dilation This study may have reviewed echocardiographic stud- and screening family members who may be at risk. In ad- ies too early for the annulus dilatation to manifest. Al- dition to a thorough history and physical examination, we ternatively, annular dilatation may not be seen in all in- recommend routine echocardiographic screening in pa- dividuals with pectus excavatum or MFS. tients with pectus excavatum in the evaluation for 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. Simi- Accepted for Publication: February 11, 2008. lar to our findings, the study by Seliem et al found no sig- Correspondence: Diane Rhee, MD, Division of Pediat- nificant difference in the absolute diameter of the aortic root ric Cardiology, 3959 Broadway BH 2N, New York, NY between the pectus excavatum and control groups; the mea- 10032 ([email protected]). surements in both groups were statistically smaller than in Author Contributions: Study concept and design: Rhee, their group of patients with MFS. When Seliem et al indexed Solowiejczyk, Gersony, Stolar, Kleinman, and Hsu. Acqui- the aortic root size to BSA, they found no difference between sition of data: Solowiejczyk, Altmann, Prakash, Stolar, the pectus excavatum and the control groups; in fact, pre- Anyane-Yeboa,andChung.Analysisandinterpretationofdata: dictably, the indexed aortic root diameter was significantly Rhee, Chung, and Hsu. Drafting of the manuscript: Rhee, 11 lower in the MFS group than in the other 2 groups. The Solowiejczyk, Gersony, Kleinman, and Hsu. Critical revi- method of indexing the aortic root diameter by dividing it sion of the manuscript for important intellectual content: Rhee, by BSA is valid only if the relationship of that indexed value Solowiejczyk, Altmann, Prakash, Gersony, Stolar, Anyane- islinearandpassesthroughtheorigin.However,thismethod Yeboa, Chung, and Hsu. Statistical analysis: Hsu. Adminis- has been found to be inversely and nonlinearly dependent trative,technical,andmaterialsupport:RheeandSolowiejczyk. on BSA. Adjusting for body size by comparing indexed val- Study supervision: Solowiejczyk, Stolar, and Hsu. ues fails to account for the dependence of the aortic root mea- Financial Disclosure: None reported. 12 surementontheBSA. Inourstudy,weusedzscorestocom- Additional Contributions: Robert Sciacca, EngScD, and parethedifferencesinaorticrootdiameterbetweenthe2study Marc Richmond, MD, assisted with the statistical analysis. groups. Since this conversion normalizes the aortic root di- mension to the mean and standard deviation of the dimen- REFERENCES sion expected for a reference (healthy) population, it does not suffer the type of difficulty encountered by using a simple 1. Mansour KA, Thourani VH, Odessey EA, Durham MM, Miller JI Jr, Miller DL. division by BSA. Thirty-year experience with repair of pectus deformities in adults. 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