Effect of Trisomy 21 on Postoperative Length of Stay and Non-cardiac Surgery After Complete Repair of Tetralogy of Fallot.

Trisomy 21 (T21) is the most common chromosomal abnormality, and is frequently associated with congenital heart disease. Results of previous studies evaluating the effect of T21 on postoperative outcomes and complications following heart surgery have been mixed. Our goal was to determine if T21 is associated with higher frequency of adverse postoperative outcomes following repair of tetralogy of Fallot (TOF). A query of the Pediatric Health Information System was performed for patients who underwent complete repair of TOF from 2004 to 2015. Patients with a genetic syndrome other than T21 and tracheostomy and/or gastrostomy prior to heart surgery were excluded. Two groups were created on the basis of whether patients received a diagnostic code for T21. The adverse outcomes of interest were postoperative mortality, postoperative length of stay (LOS), postoperative gastrostomy, and postoperative tracheostomy. Univariate and Kaplan-Meier analysis were performed to evaluate outcomes. There were a total of 4790 patients; 430 (9%) patients had T21, and 4360 (91%) patients without a genetic diagnosis. There was no significant difference in mortality before discharge between those with and without T21 (2.3% vs 1.4%; p = 0.155). Patients with T21 had longer postoperative LOS (mean of 19.8 days vs 12.4 days; p < 0.001), and higher rates of postoperative gastrostomy (13.3% vs 5.3%; p < 0.02). There was no significant difference between groups for rates of postoperative tracheostomy (1.9% vs 1.2%; p = 0.276). Kaplan-Meier analysis confirmed that patients with T21 had longer postoperative LOS and greater incidence of gastrostomy.

Surgical Outcomes in Syndromic Tetralogy of Fallot: A Systematic Review and Evidence Quality Assessment.

Tetralogy of Fallot (ToF) is one of the most common cyanotic congenital heart defects. We sought to summarize all available data regarding the epidemiology and perioperative outcomes of syndromic ToF patients. A PRISMA-compliant systematic literature review of PubMed and Cochrane Library was performed. Twelve original studies were included. The incidence of syndromic ToF was 15.3% (n = 549/3597). The most prevalent genetic syndromes were 22q11.2 deletion (47.8%; 95% CI 43.4-52.2) and trisomy 21 (41.9%; 95% CI 37.7-46.3). Complete surgical repair was performed in 75.2% of the patients (n = 161/214; 95% CI 69.0-80.1) and staged repair in 24.8% (n = 53/214; 95 CI 19.4-30.9). Relief of RVOT obstruction was performed with transannular patch in 64.7% (n = 79/122; 95% CI 55.9-72.7) of the patients, pulmonary valve-sparing technique in 17.2% (n = 21/122; 95% CI 11.5-24.9), and RV-PA conduit in 18.0% (n = 22/122; 95% CI 12.1-25.9). Pleural effusions were the most common postoperative complications (n = 28/549; 5.1%; 95% CI 3.5-7.3). Reoperations were performed in 4.4% (n = 24/549; 95% CI 2.9-6.4) of the patients. All-cause mortality rate was 9.8% (n = 51/521; 95% CI 7.5-12.7). Genetic syndromes are seen in approximately 15% of ToF patients. Long-term survival exceeds 90%, suggesting that surgical management should be dictated by anatomy regardless of genetics.

Cardiopatías congénitas asociadas a la microdeleción 22q11. 2, en un hospital pediátrico / Congenital heart defects associated with a 22q11. 2 microdeletion at a pediatric hospital

Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)

Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)

Cardiovascular disease in Down syndrome.

PURPOSE OF REVIEW: In the last 40 years, with a better understanding of cardiac defects, and with the improved results of cardiac surgery, the life expectancy of persons with Down syndrome has significantly increased. This review article reports on advances in knowledge of cardiac defects and cardiovascular system of persons with trisomy 21. RECENT FINDINGS: New insights into the genetics of this syndrome have improved our understanding of the pathogenetic mechanisms of cardiac defects. Recent changes in neonatal prevalence of Down syndrome suggest a growing number of children with cardiac malformations, in particular with simple types of defects. Ethnic and sex differences of the prevalence of specific types of congenital heart disease (CHD) have also been underlined. A recent study confirmed that subclinical morphologic anomalies are present in children with trisomy 21, also in the absence of cardiac defects, representing an internal stigma of Down syndrome. The results of cardiac surgery are significantly improved in terms of immediate and long-term outcomes, but specific treatments are indicated in relation to pulmonary hypertension. Particular aspects of the cardiovascular system have been described, clarifying a reduced sympathetic response to stress but also a 'protection' from atherosclerosis and arterial hypertension in these patients. SUMMARY: Continuing dedication to clinical and basic research studies is essential to further improve survival and the quality of life from childhood to adulthood of patients with trisomy 21.

A single-center experience with 12 consecutive cases of pregnancy among patients with membranous ventricular septal aneurysm.

BACKGROUND: Membranous ventricular septal aneurysm (MVSA) is a rare cardiac anomaly that can occur as an isolated entity or being associated with other cardiac malformations. Complications of MVSA include thromboembolism, arrhythmia, rupture, bacterial endocarditis, right ventricular outflow tract obstruction, and atrioventricular valve diseases.The success rate of pregnancy and delivery in patients with MVSA has not been reported in the literature. This study was to assess the clinical implications of this condition from our center's experience. METHODS: This was a retrospective study for consecutive 12 pregnancies in women with MVSA, who delivered at a tertiary care center in west China between May 2008 and March 2015. RESULTS: All patients with MVSA delivered via caesarian section. One patient with severe pulmonary arterial hypertension expired from pulmonary infection and heart failure after delivery. One patient terminated pregnancy in the second trimester- necessitated by cardiogenic shock. The other mothers had varying degrees of cardiac morbidity, but survived. Ten of thirteen newborns survived. Congenital heart disease and small-for-gestational-age (SGA) of newborn occurred in two cases (one twin and one single gestation). Two of these babies expired. CONCLUSIONS: Maternal and neonatal risk appeared associated with heart functional classifications, pulmonary hypertension and histories of cardiac events such as serious cardiac arrhythmia. Accurate diagnosis and care by a multidisciplinary team is recommended for pregnant woman with MVSA.

Genetic Origins of Tetralogy of Fallot.

Due to improved survival and clinical outcomes, congenital heart disease (CHD) is an area of growing importance within the medical community. As these patients reach adulthood and have children, there has been a growing appreciation for the increased risk of CHD among their offspring, strongly implying a genetic element. Given the growing wealth of genetic data available and these clinical implications, this review serves to reexamine the role of genetics within CHD, using Tetralogy of Fallot as a model pathology. Tetralogy of Fallot (TOF) is one of the oldest documented CHDs, with a growing prevalence of adult patients, and thus serves as an excellent model for this review. Given the complex nature of cardiac development, it is not surprising that multiple transcription factors and signaling molecules responsible for cardiogenesis have been implicated in TOF, with additional, previously nonimplicated genes being routinely reported within the literature. This review focuses on the well-characterized genes gata4, nkx2.5, jag1, foxc2, tbx5, and tbx1, which have been previously implicated in TOF. Furthermore, this article will attempt to summarize the specific clinical implications associated with the affected genes, such as right-sided aortic arches, associated syndromic presentations, and parental carrier states.

Effect of Concomitant Birth Defects and Genetic Anomalies on Infant Mortality in Tetralogy of Fallot.

BACKGROUND: A substantial proportion of infants born with tetralogy of Fallot (TOF) die in infancy. A better understanding of the heterogeneity associated with TOF, including extracardiac malformations and chromosomal anomalies is vital to stratifying risk and optimizing outcomes during infancy. METHODS: Using the North Carolina Birth Defects Monitoring Program, infants diagnosed with TOF and born between 2003 and 2012 were included. Kaplan-Meier survival curves were used to estimate cumulative 1-year mortality, stratified by the presence of concomitant birth defects (BDs) and chromosomal anomalies. Multivariable logistic regression was used to estimate the direct effect of each concomitant BD, after adjusting for all others. RESULTS: A total of 496 infants with TOF were included, and 15% (n = 76) died. The number of concomitant BD systems was significantly associated with the risk of death at 1-year, p < 0.0001. Specifically, the risk of mortality was 8% among infants with TOF with or without additional cardiac defects, 16% among infants with TOF and 1 extracardiac BD system, 19% among infants with 2 extracardiac BD systems, and 39% among infants with ≥ 3 extracardiac BD systems. After adjustment, concomitant eye and gastrointestinal defects were significantly associated increased with 1-year mortality, odds ratio 2.83 (95% confidence interval, 1.08-7.32) and odds ratio 4.43 (95% confidence interval, 1.57, 12.45), respectively. Infants with trisomy 13 or trisomy 18 were also significantly more likely to die, p < 0.0001. CONCLUSION: Both concomitant BDs and genetic anomalies increase the risk of mortality among infants with TOF. Future studies are needed to identify the underlying genetic and socioeconomic risk factors for high-risk TOF infants. Birth Defects Research 109:1154-1165, 2017. © 2017 Wiley Periodicals, Inc.

Proportion of selected congenital heart defects attributable to recognized risk factors.

PURPOSE: To assess the contribution of multiple risk factors for two congenital heart defects-hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). METHODS: We used data from the National Birth Defects Prevention Study (1997-2011) to estimate average adjusted population attributable fractions for several recognized risk factors, including maternal prepregnancy overweight-obesity, pregestational diabetes, age, and infant sex. RESULTS: There were 594 cases of isolated simple HLHS, 971 cases of isolated simple TOF, and 11,829 controls in the analysis. Overall, 57.0% of HLHS cases and 37.0% of TOF cases were estimated to be attributable to risk factors included in our model. Among modifiable HLHS risk factors, maternal prepregnancy overweight-obesity accounted for the largest proportion of cases (6.5%). Among modifiable TOF risk factors, maternal prepregnancy overweight-obesity and maternal age of 35 years or older accounted for the largest proportions of cases (8.3% and 4.3%, respectively). CONCLUSIONS: Approximately half of HLHS cases and one-third of TOF cases were estimated to be attributable to risk factors included in our models. Interventions targeting factors that can be modified may help reduce the risk of HLHS and TOF development. Additional research into the etiology of HLHS and TOF may reveal other modifiable risk factors that might contribute to primary prevention efforts.

Early onset intellectual disability in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation.

Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects.

BACKGROUND: Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects. METHODS: During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy. RESULTS: Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy. CONCLUSION: Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect.

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome.

Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD.

Myocardial cardiotrophin-1 is differentially induced in congenital cardiac defects depending on hypoxemia.

AIM: Cardiotrophin-1 (CT-1) is upregulated by hypoxemia and hemodynamic overload and is characterized by potent hypertrophic and protective properties on cardiac cells. This study aimed to investigate whether CT-1 is differentially induced in the myocardium of infants with congenital cardiac defects depending on hypoxemia. METHODS & RESULTS: Infants with Tetralogy of Fallot (n = 8) or with large nonrestrictive ventricular septal defect (n = 8) undergoing corrective surgery were investigated. Expression of CT-1 was assessed at mRNA and protein levels in the right atrial and ventricular myocardium. The activation of the STAT-3 and VEGF were measured. Degradation of cardiac troponin-I served as a marker of myocardial damage. CT-1 was detected in all patients with levels negatively correlating to the arterial oxygen saturation. Higher CT-1 expression in Tetralogy of Fallot patients was associated with activation of the JAK/STAT pathway and higher cardiac troponin-I degradation. CONCLUSION: CT-1 may mediate myocardial hypertrophy and dysfunction in infants with congenital cardiac defects, particularly in those with hypoxemia.

Tetralogy of Fallot with absent pulmonary valve syndrome, right aortic arch, and disconnected left pulmonary artery.

We present a rare case of a two-week-old infant with tetralogy of Fallot , absent pulmonary valve syndrome , right aortic arch, and disconnected left pulmonary artery (LPA) whose origin was from ductal ligament adjacent to the left subclavian artery. One-stage surgical correction, including closure of ventricular septal defect (VSD), LPA reconstruction and reconnection to the pulmonary trunk, reduction in size of the right pulmonary artery (RPA), and right ventricular outflow tract reconstruction with valved conduit, was successfully performed with good clinical mid-term outcome.

The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation.

STUDY QUESTION: Are the risks of hypoplastic left heart syndrome, transposition of great arteries, tetralogy of Fallot (TOF) and coarctation of the aorta increased in infants conceived by different assisted reproductive techniques (ARTs)? STUDY ANSWER: ARTs, and particularly intracytoplasmic sperm injection (ICSI), are specifically associated with a higher risk of TOF. WHAT IS ALREADY KNOWN: ARTs are associated with an increase in the overall risk of birth defects. The risk for congenital heart defects (CHDs) associated with ARTs has been evaluated as a whole but there is limited information on the risks for specific CHDs. STUDY DESIGN, MATERIAL AND METHODS: We conducted a case-control study using population-based data from the Paris registry of congenital malformations for the period 1987-2009 and a cohort study of CHD (EPICARD) on 1583 cases of CHDs and 4104 malformed controls with no known associations with ARTs. ARTs included ovulation induction only, IVF and ICSI. RESULTS: Exposure to ARTs was significantly higher for TOF than controls (6.6 versus 3.5%, P = 0.002); this was not the case for the other three CHDs. ARTs (all methods combined) were associated with a 2.4-fold higher odds of TOF after adjustment for maternal characteristics, paternal age and year of birth [adjusted odds ratios (OR): 2.4, 95% confidence interval (CI): 1.5-3.7] with the highest risk associated with ICSI (adjusted OR: 3.0, 95% CI: 1.0-8.9). No statistically significant associations were found for the other CHDs. LIMITATIONS: Our study cannot disentangle to what extent the observed associations between the risk of TOF and ARTs are due to causal effects of ARTs and/or the underlying infertility problems of couples who conceive following ART. IMPLICATIONS: The developmental basis of the specific association between the risk of TOF and ARTs need to be further investigated.

Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder. We report three patients with WHIM syndrome who are affected by Tetralogy of Fallot (TOF). This observation suggests a possible increased risk of TOF in WHIM syndrome and that birth presentation of TOF and neutropenia should lead to suspect WHIM syndrome.

Could submicroscopical chromosomal imbalances cause cono-truncal malformations in twins?

The course of normal heart formation in the embryo has been known for decades, but little is known about the genes that control its development. To further improve our understanding of the molecular and genetic mechanisms involved in congenital heart disease, we screened for submicroscopic chromosomal aberrations using bacterial artificial chromosome-based array comparative genomic hybridization analysis in two Danish twin pairs, one pair of monozygotic twins with tetralogy of Fallot, and one twin pair of unknown zygosity with pulmonary valve stenosis. We did not find any major chromosome defects, although a number of submicroscopic copy number variations were present. The question of whether these submicroscopic chromosomal imbalances alone or in conjunction with unknown intrauterine factors causes the observed cono-truncal malformations remains unanswered.

Clinical profile of patients with tetralogy of Fallot admitted for surgery at a cardiac surgical centre.

INTRODUCTION: Tetralogy of Fallot (TOF), a conotruncal defect, has been documented to be associated with chromosome abnormalities, single gene syndrome (22q11 microdeletion), known teratogens, with the rest associations being multifactorial. This study was carried out to determine the clinical profile and associated risk factors in patients with TOF admitted for surgical repairs. METHODS: Case files of all patients admitted for Tetralogy of Fallot over a period of one year were retrieved from the Medical Records Department and reviewed. Data on the patients' and their family history and associated cardiac anomalies were noted. RESULTS: There were 54 patients, 37 males and 17 females, with a mean age of 6.8 years +/- 7.1. Sixty percent were born between July and December, 81.5% as full term and 44% as first born. Twenty-six percent were born into consanguineous marriages. Five patients had dysmorphic features. Associated cardiac anomalies included right aortic arch, pulmonary atresia, dextrocardia and left superior vena cavae. CONCLUSION: The associated risk factors noted in this study were male sex, birthdates between July and December, first born and increased paternal age. Other risk factors were consanguinity and specific patterns of cardiovascular diseases associated with 22q 11 deletions. This suggests a multifactorial etiology for TOF.

Epidemiology of nonsyndromic conotruncal heart defects in Texas, 1999-2004.

INTRODUCTION: Congenital heart defects (CHDs) are the most common structural birth defects, yet their etiology is poorly understood. As there is heterogeneity within the group of CHDs, epidemiologic studies often focus on subgroups, of conditions, such as conotruncal heart defects (CTDs). However, even within these subgroups there may be etiologic heterogeneity. The aim of the present study was to identify and compare maternal and infant characteristics associated with three CTDs: truncus arteriosus (TA), dextro-transposition of the great arteries (d-TGA), and tetralogy of Fallot (TOF). METHODS: Data for cases with nonsyndromic TA (n = 78), d-TGA (n = 438), and TOF (n = 529) from the Texas Birth Defects Registry, 1999-2004, were used to estimate crude and adjusted prevalence ratios, separately for each condition, using Poisson regression. Polytomous logistic regression was used to determine whether the observed associations were similar across the two largest case groups (d-TGA and TOF). RESULTS: In Texas, 1999-2004, the prevalence of nonsyndromic TA, d-TGA, and TOF was 0.35, 1.98, and 2.40 per 10,000 live births, respectively. There was evidence of a significant linear increase in the risk of each condition with advancing maternal age (p < 0.01). Significant associations were observed for TA and maternal residence on the Texas-Mexico border; d-TGA and infant sex, maternal race/ethnicity, history of previous live birth, and birth year; and TOF and maternal race/ethnicity and education. Further, the associations with some, but not all, of the study variables were significantly different for d-TGA and TOF. CONCLUSION: These findings add to our limited understanding of the epidemiology of CTDs.