R. Thomas Collins

Long-Term Outcomes of Patients With Cardiovascular Abnormalities and Williams Syndrome

Williams syndrome (WS) is a congenital disorder affecting the vascular, connective tissue, and central nervous systems of 1 in 8,000 live births. Previous reports have reported high frequencies of cardiovascular abnormalities (CVAs) in small numbers of patients with WS. A retrospective review was undertaken of patients with WS evaluated at our institution from January 1, 1980 through December 31, 2007. WS was diagnosed by an experienced medical geneticist and/or by fluorescence in situ hybridization. CVAs were diagnosed using echocardiography, cardiac catheterization, or computed tomographic angiography. Freedom from intervention was determined using Kaplan-Meier analysis. The study group was 270 patients with WS. The age at presentation was 3.3 +/- 5.9 years with follow-up of 8.9 +/- 9.0 years (range 0 to 56.9). CVAs were present in 82% of the patients. The most common lesions were supravalvar aortic stenosis in 45% and peripheral pulmonary stenosis in 37%; 20% had both. Other common lesions included mitral valve prolapse and regurgitation in 15%, ventricular septal defect in 13%, and supravalvar pulmonary stenosis in 12%. Surgical or catheter-based interventions were performed in 21%. The rate of freedom from intervention was 91%, 81%, 78%, 72%, and 62% at 1, 5, 10, 20, and 40 years. Eight patients died. In conclusion, CVAs are common in patients with WS, but supravalvar aortic stenosis and peripheral pulmonary stenosis occurred less frequently in this large cohort than previously reported. In patients with WS and CVAs, interventions are common and usually occur by 5 years of age. Most patients with WS do not require intervention during long-term follow-up, and the overall mortality has been low.

Cardiovascular Disease in Williams Syndrome

Williams syndrome (WS), also referred to as Williams-Beuren syndrome (Online Mendelian Inheritance in Man 194050), is a congenital, multisystem disorder involving the cardiovascular, connective tissue, and central nervous systems.1 WS occurs in ≈1 in 10 000 live births2 as a result of the de novo deletion of ≈1.55 to 1.83 Mb on chromosome 7q11.23.3 Familial cases can occur but are far less common than de novo cases.4 The deletion involves 26 to 28 genes, including the ELN gene, which codes for the protein elastin.5 Hemizygosity of the ELN gene coding for elastin has been demonstrated to be responsible for the vascular pathology in WS.6 The remaining 25 to 27 deleted genes contribute to the phenotypic findings in patients with WS and have recently been reviewed in detail elsewhere.5 In 1961, Williams et al7 reported their experience with 4 patients with supravalvar aortic stenosis (SVAS), mental retardation, and abnormal facial features. The following year, Beuren and colleagues8 reported similar findings in 5 patients, and they subsequently reported detailed cardiac and angiographic data from 10 such patients.9 Their findings, combined with other characteristic features, led both groups to theorize that a previously unrecognized syndrome was the likely origin, a theory that led to the eponym Williams-Beuren syndrome. After the reports of Williams et al7 and Beuren et al8 were published, the basis for the diagnosis of WS was the presence of a constellation of distinctive phenotypic characteristics. Genetic analysis at that time was limited essentially to karyotyping and microscopic inspection of individual chromosomes, which Beuren et al9 reported in 3 of their patients. With improved molecular genetics diagnostic techniques, Ewart et al10 used fluorescent in situ hybridization to demonstrate hemizygosity of the ELN locus in patients with WS. …

Cardiovascular Abnormalities, Interventions, and Long-term Outcomes in Infantile Williams Syndrome

OBJECTIVE To determine the prevalence of cardiovascular abnormalities (CVA) and outcomes in patients with Williams syndrome presenting before 1 year of age. STUDY DESIGN A retrospective review was undertaken of consecutive patients with WS at our institution from January 1, 1980, through December 31, 2007. WS was diagnosed by an experienced medical geneticist and/or by fluorescence in situ hybridization. CVA were diagnosed with the use of echocardiography, cardiac catheterization, or computerized tomographic angiography. Freedom from intervention was determined using Kaplan-Meier analysis. RESULTS The study group was 129 patients with CVA. Age at presentation was 127 +/- 116 days, with follow-up of 8.0 +/- 7.5 years (0 to 42 years). The most common lesions were peripheral pulmonary artery stenosis (62%) and supravalvar aortic stenosis (57%). Other CVA were common. CV interventions were performed in 29%, with 58% of those before 1 year. Freedom from intervention was 85%, 73%, and 66% at 1, 5, and 25 years, respectively. Four patients died. CONCLUSIONS CVA are the most common manifestations of infantile Williams syndrome and occur with greater frequency than previously reported. In those with CVA, interventions are common and usually occur by 5 years of age. Most of these patients do not require intervention on long-term follow-up, and overall mortality is low.

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin‐1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy‐number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

Pre-hypertension and Hypertension in Pediatrics: Don't Let the Statistics Hide the Pathology

C ardiovascular diseases (CVD) are the leading cause of death in western societies. These diseases are associated with a number of risk factors, such as hypertension (HTN), a leading cause of cardiovascular (CV) morbidity and mortality in adults. Pre-hypertension (PHTN), white coat hypertension (WCH), and sustained HTN in pediatric patients have pathologic effects on the heart and arterial tree. Pediatric HTN frequently goes underdiagnosed. The current approach to the diagnosis and treatment of pediatric HTN is not based on evidence of long-term CV risk. In our opinion, the approach to HTN in pediatrics needs to be changed; the diagnosis of all forms of HTN (PHTN, WCH, HTN) needs to be given more attention. Interventions such as dietary modification and lifestyle changes should be initiated sooner rather than later. Greater research efforts are needed to determine physiologically appropriate cutoffs for the diagnosis of PHTN and HTN on the basis of long-term outcomes and CV risk. Risk factors for CVD present in childhood persist into adulthood. Specifically, elevations in blood pressure (BP) during childhood have been shown to predict the presence of HTN in adulthood. Also, systolic BP (SBP) in childhood is a consistent and independent predictor of arterial stiffness in adulthood; patients who have higher SBP levels in childhood have stiffer arteries as adults. Although the tracking of elevated BP into adulthood is concerning, there are demonstrable changes in the heart and arterial tree already present in children with elevated BP, which is more worrisome. In adolescents and young adults, elevated BP is associated with the presence of early atherosclerotic lesions. In a post-mortem study of 204 subjects aged 3 to 39 years, Berenson et al demonstrated that SBP correlated with the presence of fatty streaks and fibrous plaques in the coronary arteries more strongly than did body mass index, total cholesterol level, low-density lipoprotein cholesterol level, or triglycerides level. Burke et al demonstrated in children that left ventricular mass increased as SBP became higher. Recent evidence has shown that WCH, often considered a benign phenomenon, results in similar changes in the heart and arterial tree as does HTN. Thus, it is our opinion that HTN, whether sustained HTN or WCH, is an important medical condition and deserves careful diagnostic and management considerations in pediatric patients.

Pulmonary Artery Sling in an Asymptomatic 15-Year-Old Boy

A 15-year-old boy was evaluated for a 3-month history of sharp pain in the upper left chest. Notable findings on the physical examination included a low-frequency long systolic ejection murmur in the left infraclavicular region. The results of a 15-lead ECG were normal (Figure 1). A complete transthoracic echocardiogram was performed and the result was reported as normal (Figure 2). Because of the unusual character of the murmur, the referring cardiologist sent the patient for cardiac magnetic resonance imaging. Figure 1. A 15-lead ECG demonstrates normal sinus rhythm with sinus arrhythmia. The intervals and morphologies are normal, with no evidence of atrial or ventricular enlargement. Figure 2. Parasternal short-axis echocardiogram with color demonstrates the LPA arising from the right and coursing leftward. A complete cardiac magnetic resonance study was performed that included gadolinium-contrasted images. On axial and 3D reconstruction gadolinium-enhanced images, the left pulmonary artery (LPA) was seen arising from the superior aspect of the right pulmonary artery (RPA) (Figures 3 and 4⇓). The LPA was mildly compressed and coursed posterior to the trachea at the level of the carina. No significant compression of the main stem, right, or left bronchi were present (Figures 5 and 6⇓). Pulmonary …

Contemporary management of congenital malformations of the heart in infants with Ellis - van Creveld syndrome: a report of nine cases.

INTRODUCTION Ellis - van Creveld syndrome is an autosomal recessive disorder manifest by short-limb dwarfism, thoracic dystrophy, postaxial polydactyly, dysplastic nails and teeth, and an approximately 60% incidence of congenital malformations of the heart. Despite patients with Ellis - van Creveld syndrome being regarded as having a high surgical risk, few data are available regarding their outcomes following surgery for congenital malformations of the heart in the current era. MATERIALS AND METHODS In this retrospective report, we summarise the clinical observations and outcomes of nine infants with Ellis - van Creveld syndrome who underwent surgery for congenital malformations of the heart between 2004 and 2009. RESULTS We identified 15 patients with Ellis - van Creveld syndrome during the study period; 11 (73%) had haemodynamically significant congenital malformations of the heart warranting surgery. In two of these patients, surgery was not performed. Of the nine patients who underwent surgery, all of whom were infants, eight (89%) had various forms of an atrioventricular septal defect and one patient (11%) had hypoplastic left heart syndrome (mitral and aortic atresia). Among the nine patients who underwent surgery, four (44%) died at a median of 102 days with a range of 25-149 days post-operatively, mostly from respiratory failure. Respiratory morbidity was seen in all surviving patients, of whom three underwent tracheostomy. CONCLUSIONS Surgery for congenital malformations of the heart can be successful in infants with Ellis - van Creveld syndrome, but mortality is high and post-operative respiratory morbidity should be expected.

Congenital Heart Surgery on In-Hospital Mortality in Trisomy 13 and 18

In this large, multicentered, database-derived study, CHS is associated with a significant decrease in in-hospital mortality in infants with T13 and T18. BACKGROUND AND OBJECTIVES: Congenital heart disease (CHD) is common in trisomy 13 (T13) and trisomy 18 (T18), but surgical repair has not been offered in most centers. Data on outcomes of congenital heart surgery (CHS) for T13 and T18 are lacking. We sought to determine the impact of CHS on in-hospital mortality in T13 and T18. METHODS: Data from the 2004 to 2015 Pediatric Health Information System database were used to identify inpatients with T13 or T18 and CHD. Data were restricted to newborns with T13 or T18 admitted at ≤14 days of age. Hospital readmissions were examined to analyze longer-term in-hospital mortality. In-hospital mortality and length of stay were compared between infants with and without CHD and with and without CHS. RESULTS: The study cohort included 1020 infants with T18 and 648 infants with T13. CHD was present in 91% of infants with T18 and 86% of infants with T13. CHS was performed in 7% of each group. In-hospital mortality was decreased in those who underwent CHS (64% lower in T18 [P <.001]; 45% lower in T13 [P = .003]) and remained decreased throughout the 24 months of follow-up. In-hospital mortality was decreased in infants with higher weight, female sex, and older age at admission. CONCLUSIONS: CHS is associated with decreased in-hospital mortality in T18 and T13. These results suggest CHS may be beneficial in select cases.

Population‐based study of hospital costs for hospitalizations of infants, children, and adults with a congenital heart defect, Arkansas 2006 to 2011

BACKGROUND Congenital heart defects (CHDs) are common birth defects and are associated with high hospital costs. The objectives of this study were to assess hospitalization costs, across the lifespan, of patients with CHDs in Arkansas. METHODS Data from the 2006 to 2011 Healthcare Cost and Utilization Project Arkansas State Inpatient Databases were used. We included hospitalizations of patients whose admission occurred between January 1, 2006, and December 31, 2011, and included a principal or secondary CHD ICD-9-CM diagnosis code (745.0-747.49, except 747.0 and 745.5 for preterm infants). Hospitalizations were excluded if they involved out-of-state residents, normal newborn births, or if missing data included age at admission, state of residence, or hospital charges. Children were defined as those < 18 years-old at time of admission. RESULTS Between 2006 and 2011, there were 2,242,484 inpatient hospitalizations in Arkansas. There were 9071 (0.4%) hospitalizations with a CHD, including 5,158 hospitalizations of children (2.2% of hospitalizations among children) and 3,913 hospitalizations of adults (0.2% of hospitalizations of adults). Hospital costs for these CHD hospitalizations totaled

Hospital Utilization in Adults with Single Ventricle Congenital Heart Disease and Cardiac Arrhythmias

355,543,696. The average annual cost of CHD hospitalizations in Arkansas was