Prevalence of unsuspected abnormal echocardiograms in adolescents with down syndrome

Abstract

The purpose of this article is to describe the prevalence of cardiac disease previously undiagnosed in healthy asymptomatic children and adolescents with Down syndrome (DS). Subjects with DS ages 10–20 years were recruited from two sites, the Children’s Hospital of Philadelphia (Philadelphia, PA) and Children’s National Health System (Washington, DC) for a cross-sectional study of body composition and cardiometabolic risk. Echocardiographic and clinical data were collected from patients enrolled in the parent study of cardiometabolic risk. Nine (6%) new cardiac diagnoses were identified out of 149 eligible patients. All new findings resulted in outpatient referrals to pediatric cardiology. Current guidelines recommend screening all newborns with DS for congenital heart disease. Older patients with DS may benefit from rescreening.

1 |. INTRODUCTION

Approximately 50% of patients with Down syndrome (DS) have congenital heart disease (CHD; Freeman et al., 1998). The most common defects include ventricular septal defects, complete atrioventricular canal, and tetralogy of Fallot. The American Academy of Pediatrics recommends universal neonatal cardiac evaluation and an echocardiogram for this population (American Academy of Pediatrics. Committee on Genetics, 2001). Assessment in older children ages 5–13 years is recommended for follow-up of known heart defects, and in ages 13 years and older if there is a concern for possible cardiac-related symptoms (such as increased fatigue, dyspnea, chest pain with exertion) or an abnormal finding on physical examination (Bull & the Committee on Genetics, 2011; Selikowitz, 1992). In the current era of routine neonatal cardiac screening, data regarding the need for additional surveillance for the identification of heart disease in patients with DS after the newborn period are limited.

A cohort of patients with DS was enrolled in a multicenter study, “Cardiometabolic Risk and Obesity in Adolescents with Down Syndrome,” that included an echocardiogram as part of the protocol. New cardiac findings were found in this population in the absence of concerns for CHD.

2 |. METHODS

2.1 |. Editorial policies and ethical considerations

Our study was approved by the institutional review boards of both the Children’s Hospital of Philadelphia (CHOP, Philadelphia, PA) and Children’s National Health System (CNHS, Washington, DC). Both sites reviewed all procedures and the study followed the tenants of the Declaration of Helsinki. Parental informed consent and subject assent, where possible, were obtained.

Subjects (n = 154) with DS ages 10–20 years were recruited from both sites for a cross-sectional study of body composition and cardiometabolic risk. Participants underwent fasting blood work, dual X-ray absorptiometry (DXA) for body composition, pulse wave velocity, and echocardiogram; details of this study were previously published (Kelly et al., 2019). Families were asked to self-report cardiac disease and/or symptoms, and available electronic medical records were reviewed. Cardiac exams were not performed.

Prior to enrollment, participants completed a screening questionnaire that included cardiac history. Exclusion criteria for the parent study, which focused on cardiometabolic risk, included major organ system illness not related to DS, current or previous oncologic process, CHD with residual structural abnormalities, pulmonary hypertension, pregnancy, additional genetic disorder known to affect glucose tolerance, familial hypercholesterolemia, or current treatment with medications known to affect insulin sensitivity or lipids (other than diabetes agents in known diabetes mellitus); diabetes mellitus was not exclusionary for this DS cohort.

Echocardiograms were performed on a Philips IE; standard pediatric images as outlined by the American Society of Echocardiography were acquired, recorded digitally and analyzed offline by a single reviewer (MC; Lai et al., 2006). Those youth who underwent an echocardiogram with previously unrecognized cardiac abnormalities were identified.

Because of concerns that BMI may not accurately depict adiposity in DS, whole-body fat and visceral adipose area was measured by whole-body DXA (Hologic Horizon or Discovery bone densitometer [Hologic, Inc., Bedford, MA] at CHOP or a Hologic Discovery [Hologic] at CNMC) and analyzed in software version 13.3, 13.4, and 13.5.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

3 |. RESULTS

Of the 212 adolescents with DS who were screened (n = 180 CHOP, n = 32 CNMC), eight were excluded from overall study participation due to a history of persistently medically significant CHD (n = 4 CHOP, n = 4 CNMC; Figure 1), and 50 others were excluded due to noncardiac reasons (n = 48 CHOP, n = 2 CNMC; Figure 1); 154 individuals with DS participated and completed the parent study. Five participants included in the parent study did not undergo echocardiogram due to noncompliance (n = 3) or CHD diagnosis likely to affect the main echocardiographic outcome of LV mass (n = 2).

FIGURE 1.

Consort diagram

Echocardiograms were completed in 149 participants (mean age 14.7 ± 3.3 years, range 10.0–20.99) of whom 92 (61.7%) had previously known CHD. All echocardiograms were completed prospectively as part of the parent study. Previous echocardiograms were not available for review. Documentation of previous CHD was determined by parental report or if available, by chart review. Of the patients with reported CHD diagnoses, the prevalence of each diagnosis was as follows: complete atrioventricular septal defect (CAVC) 30%, ventricular septal defect (VSD) 29%, atrial septal defect (ASD) 28%, patent ductus arteriosus (PDA) 23%, bicuspid aortic valve 9%, coarctation of the aorta 3%, and mitral valve prolapse 3%. Nine additional patients had valve insufficiency, dilation of the aorta or cardiomyopathy (each <1%). Nearly 19% of patients had multiple diagnoses.

Nine patients had cardiac findings not previously diagnosed (mean age 15.4 ± 3.7 years, range 11.1–20.99 years; Tables 1 and 2). One finding was a new arrhythmia; the others were structural abnormalities. Three findings were in participants with previously known heart disease. Patient 1 was found to have a persistent PDA that the parents had reported as having closed spontaneously. Patient 2, previously followed for an ASD, was diagnosed with new aortic insufficiency. Patient 3, previously followed for a VSD, had a new diagnosis of a cleft mitral valve. The rest of the participants with new findings had no previous history of heart disease. Patient 4 had a small pericardial effusion that required follow-up but no treatment. Patient 5 was diagnosed with left ventricular hypertrophy (LVH) in the absence of hypertension or outflow tract obstruction. This subject reported a heart murmur that was unrelated to new LVH diagnosis. Patient 6 had a newly diagnosed VSD, had never had an echocardiogram and parents were not aware of any heart murmur, nor any cardiac concerns. Patient 7 was diagnosed with transitional atrioventricular canal (TAVC) that required open-heart surgery. This subject reported a heart murmur but had not been referred to cardiology in the past; this child has done well since his surgery. Patient 8 was diagnosed with an arrhythmia on the echocardiogram; cardiology consultation confirmed the presence of premature ventricular contractions (PVCs). Lastly, Patient 9 was diagnosed with mild aortic insufficiency and thickened trileaflet aortic valve. All new diagnoses resulted in nonurgent referrals to cardiology.

TABLE 1.

New findings in DS subjects with known structural heart disease

Patient number	Age, gender	New cardiac finding	Cardiac history
1	14 M	PDA	Resolved PDA, ASD
2	13 M	Mild aortic insufficiency, with a trileaflet aortic valve	Resolved ASD
3	14 M	Cleft mitral valve (not previously reported)	VSD

Abbreviations: ASD, atrial septal defect; DS, Down syndrome; PDA, patent ductus arteriosus; VSD, ventricular septal defect.

TABLE 2.

New findings in DS subjects without known structural heart disease

Patient number	Age, gender	New cardiac finding	Cardiac history
4	20 M	Small, globally distributed pericardial effusion	None
5	20 F	Mild left ventricular hypertrophy	Heart murmur
6	13 F	VSD	None
7	11 M	Transitional atrioventricular canal with moderate ASD, RV dilation, elevated RV pressure	Heart murmur
8	11 F	Frequent PVC (intact atrial septum, normal aortic arch)	None
9	17 F	Mild aortic insufficiency; thickened trileaflet aortic valve	None

Abbreviations: ASD, atrial septal defect; PDA, patent ductus arteriosus;

PVC, premature ventricular contraction; RV, right ventricle;

VSD, ventricular septal defect.

4 |. DISCUSSION

Approximately 6% of the adolescents with DS in our study had newly recognized echocardiographic abnormalities that warranted follow-up. CHD was identified in the absence of concerns for CHD, including in children who had been followed by cardiology. One patient required open-heart surgery for a TAVC defect. Three of nine participants with new findings had previously diagnosed CHD; this is in part due to new findings that can develop over time and previously unrecognized diagnoses. These new cardiac findings were unrelated to past cardiac history. These data suggest that new findings of heart disease can be found in adolescents with DS, with or without previous known heart disease, and without obvious signs or symptoms of heart disease by medical history or physical examination. This could be due in part to diagnoses that are difficult to exclude in the newborn period, difficulty performing echocardiograms on the DS population, and that some findings may develop over time.

Historic data have demonstrated increased prevalence of valvular regurgitation, specifically mitral and aortic, and mitral valve prolapse in adults with DS. In a 1993 report from Geggel et al., new onset valve regurgitation was not present before age 18, and these authors recommended screening adult patients (Geggel, O’Brien, & Feingold, 1993). More recently, in 2010, Vis et al. conducted a study in 138 institutionalized adults with DS but without known heart disease (mean age of 44.4 years; Vis et al., 2010). Twenty-four patients (17%) were diagnosed with a cardiac abnormality not previously noted, six of whom required semi-urgent care. Furthermore, 77% of the 138 patients had mild to moderate regurgitation of one or more valves. Our study identified a much lower prevalence of valvular abnormalities, which likely reflects the younger age of our population and suggests acquired valvular regurgitation evolves in adulthood.

Data from a recent study in Sweden suggest a shift in the prevalence of specific complex congenital heart defects in the DS population (Bergström et al., 2016). Overall, the risk of CHD was unchanged, with the most common defects being CAVC, VSD, and ASD. However, in livebirths the risk of CAVC in DS decreased from 46 to 30% between the years 1992 and 2012. During that same time period there was an increase in the VSD rate, from 14 to 31%. The authors suggest that this change is due to improved early detection and increased termination rates. In our study, the overall incidence of previously known CHD was 61.7% and in our population the rate of CAVC is 30% and of VSD is 29%. Historic surveillance data suggest an incidence of overall CHD of 40–60% (Hoffman & Kaplan, 2002; Khoury & Erickson, 1992). Our data are not from a random sample and therefore we cannot conclude a phenotypic shift in CHD trends in the United States.

To date, this is the largest echocardiogram screening study of adolescents with DS. These results represent a general screening study as all subjects received an echocardiogram as part of a study protocol without other preselection, besides study exclusion criteria.

4.1 |. Limitations

These results may not be generalizable to the general population of DS given several limitations. First, potential selection bias exists since many of our cohorts were already being followed in a tertiary care center. However, many were also recruited from local pediatric practices, DS support groups, fund-raising events, and internet advertisement. Furthermore, some of the inclusion/exclusion criteria for the parent study may have limited our cohort and thus may not truly represent a population-representative sample. The extent to which the cohort reflects the general DS population is not clear, and patients who are living in a more rural or remote location may have an even higher incidence of undiagnosed heart disease given the limitation of access to cardiac subspecialists. Additionally, as this was a cross-sectional study and discovery of new CHD was not a primary outcome of the parent study, prior medical records were not consistently available and follow-up information was not available on most patients with new diagnoses. To that end we cannot comment on adherence to the practice of newborn screening echocardiograms as this information was not collected.

4.2 |. Summary

We have identified previously unrecognized cardiac disease in an asymptomatic population of adolescents with DS. Our findings coupled with previous studies suggest that a recommendation for repeat cardiac evaluation of adolescents with DS and without regular cardiac follow-up should be considered. Factors to consider in making this recommendation would be future morbidity of new cardiac findings, and costs relative to benefit for detection of new cardiac findings. Two of the subjects in our study should have been referred to cardiology based on pathologic murmur alone (TAVC and VSD). Cardiac pathology may be missed by practitioners due to technical difficulty of auscultation in patients with obesity or lack of cooperation with a quiet exam, inaccurate family reporting of previous echocardiographic findings, and low sensitivity of ECG findings. Most adolescents with DS can tolerate an echocardiogram without sedation. Fortunately, none of the cardiac disease in our study needed urgent medical or surgical intervention, though all required cardiology follow-up and one patient required cardiac surgery.

Abbreviations:

CAVC

complete atrioventricular canal

CHD

congenital heart disease

DS

Down syndrome

ECG

electrocardiogram

LVH

left ventricular hypertrophy

PDA

patent ductus arteriosus

PVC

premature ventricular contraction

TAVC

transitional atrioventricular canal

VSD

ventricular septal defect