Mitral Annular Disjunction and Its Progression during Childhood in Marfan Syndrome.

BACKGROUND: Data on mitral annular disjunction (MAD) in children with Marfan syndrome (MFS) are sparse. OBJECTIVES: To investigate the diagnostic yield of MAD by echocardiography and cardiac magnetic resonance imaging (CMR), its prevalence and progression during childhood. METHODS: We included patients <21 years old with MFS, defined by 2010 Ghent criteria and a pathogenic FBN1 variant or ectopia lentis. Two readers measured systolic separation between the mitral valve (MV) posterior hinge point and left ventricular (LV) myocardium on initial and subsequent imaging. MAD was defined as MV-LV separation ≥2 mm, MV prolapse (MVP) as atrial displacement ≥2 mm. Kappa coefficients evaluated echocardiogram-CMR agreement. Bland-Altman and intraclass correlation coefficients (ICC) assessed interrater and intermodality reliability. Univariable mixed-effects linear regression was used to evaluate longitudinal changes of MAD. RESULTS: MAD was detected in 60% (110/185) eligible patients. MVP was present in 48% (53/110) of MAD and MAD in 90% (53/59) of MVP. MAD detection by CMR and echocardiography had 96% overall agreement (Kappa = 0.89, p < 0.001) and a 0.32-mm estimate bias (95%CI 0.00, 0.65). ICC by echocardiography, CMR, and between modalities were 0.97 (95%CI 0.93, 0.98), 0.92 (95%CI 0.79, 0.97), and 0.91 (95%CI 0.85, 0.94), respectively. MAD was associated with aortic root dilation (p < 0.001). MAD was found in children of all ages, increased +0.18 mm/year (95%CI +0.14, + 0.22) during a median duration of 5.5 years (IQR 3.1, 7.5 years). MAD indexed by height yielded a constant value +0.0002 mm/m/year (95%CI -0.0002, + 0.0005 mm/m/year). CONCLUSIONS: MAD was common in pediatric MFS and was associated with aortic root dilation. MAD detection by echocardiography and CMR was highly reliable, suggesting that routine assessment in MFS is feasible. MAD was present in neonates and progressed over time but remained constant when indexing by height. Further studies are needed to evaluate MAD as a biomarker for clinical outcomes in pediatric MFS.

Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome.

BACKGROUND: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS). METHODS AND RESULTS: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score <-2.0, or (3) sinotubular junction Z score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille syndrome (3 JAG1), neurofibromatosis (1 NF1), and homozygous familial hypercholesterolemia (1 LDLR1). Overall, sequencing was diagnostic in 29 of 47 (62%). CONCLUSIONS: When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the ELN gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.

Scientific impact of the National Birth Defects Prevention Network multistate collaborative publications.

BACKGROUND: Given the lack of a national, population-based birth defects surveillance program in the United States, the National Birth Defects Prevention Network (NBDPN) has facilitated important studies on surveillance, research, and prevention of major birth defects. We sought to summarize NBDPN peer-reviewed publications and their impact. METHODS: We obtained and reviewed a curated list of 49 NBDPN multistate collaborative publications during 2000-2022, as of December 31, 2022. Each publication was reviewed and classified by type (e.g., risk factor association analysis). Key characteristics of study populations and analytic approaches used, along with publication impact (e.g., number of citations), were tabulated. RESULTS: NBDPN publications focused on prevalence estimates (N = 17), surveillance methods (N = 11), risk factor associations (N = 10), mortality and other outcomes among affected individuals (N = 6), and descriptive epidemiology of various birth defects (N = 5). The most cited publications were those that reported on prevalence estimates for a spectrum of defects and those that assessed changes in neural tube defects (NTD) prevalence following mandatory folic acid fortification in the United States. CONCLUSIONS: Results from multistate NBDPN publications have provided critical information not available through other sources, including US prevalence estimates of major birth defects, folic acid fortification and NTD prevention, and improved understanding of defect trends and surveillance efforts. Until a national birth defects surveillance program is established in the United States, NBDPN collaborative publications remain an important resource for investigating birth defects and informing decisions related to health services planning of secondary disabilities prevention and care.

Quality of Life Among Caregivers of Children with Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder: A Cross Sectional Study.

Caregivers of children with attention deficit-hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) experience more stress than caregivers of typically developing children but there is limited research evaluating caregivers' quality of life (QoL). This study aimed to describe the association of caregiver QoL in children with ASD and/or ADHD. This study included patients with ADHD and/or ASD seen in one pediatric specialty clinic between September 2018-August 2020. Caregivers were classified as those caring for children with ASD-only, ADHD-only, or youth with both conditions (ADHD + ASD). An adapted version of the PedsQL Family Impact Module was used to measure caregiver QoL. The sample included caregivers of 931 children. The majority of these children were male (74.7%), non-Hispanic white (63.3%), and aged 6 to 12 years (57.8%). Across the groups, significant differences were observed in patient age (p < 0.0001), preferred language (p = 0.005), and insurance (p = 0.001). Caregivers of non-Hispanic Black children had 4-times the odds of reporting feeling isolated from others (OR 4.36, 95% CI 1.19-16.00 p = 0.03). Those caring for children with ADHD-only had significantly lower odds of reporting helplessness or hopelessness (OR 0.45, 95% CI 0.26-0.80, p = 0.004), and difficulty talking about their child's health with others (OR 0.30, 95% CI 0.17-0.54, p < 0.0001). Similarly, caregivers of children who had ADHD + ASD reported higher odds of difficulty making decisions together as a family (OR 14.18, 95% CI 1.15-17.91, p=0.04) and difficulty solving family problems together (OR 45.12, 95% CI 2.70-752.87), p = 0.008). Caring for children with ADHD and/or ASD may affect caregiver QoL.

Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h ≥15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P=0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Clinical Predictors of Recurrent Supraventricular Tachycardia in Infancy.

BACKGROUND: Data regarding recurrence risk among infants with supraventricular tachycardia (SVT) are limited. OBJECTIVES: The purpose of this study was to determine incidence and factors associated with SVT recurrence. METHODS: This was a retrospective single-center study (1984-2020) with prospective phone follow-up of infants with structurally normal hearts diagnosed at age ≤1 year with re-entrant SVT. Primary outcome was first SVT recurrence after hospital discharge. Classification and regression tree analysis was performed to determine a risk algorithm. RESULTS: Among 460 infants (62% male), 87% were diagnosed at ≤60 days of age (median 13 days; IQR: 1-31 days). During a median follow-up of 5.2 years (IQR: 1.8-11.2 years), 33% had recurrence. On multivariable analysis, factors associated with recurrence included: fetal or late (>60 days) diagnosis (HR: 1.90; 95% CI: 1.26-2.86; and HR: 1.73; 95% CI: 1.07-2.77, respectively), Wolff-Parkinson-White (WPW) syndrome (HR: 2.46; 95% CI: 1.75-3.45), and need for multi-antiarrhythmic or second-line therapy (HR: 2.08; 95% CI: 1.45-2.99). Based on the classification and regression tree analysis, WPW incurred the highest risk. Among those without WPW, age at diagnosis was the most important factor predicting risk. Fetal or late diagnosis incurred higher risk, and if multi-antiarrhythmic or second-line therapy was also required, risk nearly doubled. Infants without WPW, who were diagnosed early (0-60 days), and who were discharged on propranolol were at lowest recurrence risk. CONCLUSIONS: Infants with SVT are most likely to be diagnosed at ≤60 days and be male. Risk factors for recurrence (occurred in 33%), present at time of diagnosis, include WPW, fetal or late diagnosis, and multi-antiarrhythmic or second-line therapy. Infants with early diagnosis, without WPW, and discharged on first-line monotherapy are at lowest recurrence risk.

Evaluating perinatal and neonatal outcomes among children with vascular Ehlers-Danlos syndrome.

PURPOSE: Birth outcomes data for patients with vascular Ehlers-Danlos syndrome (VEDS) are limited. METHODS: Patients with a pathogenic or likely pathogenic COL3A1 variant were included. Outcomes included gestational age (GA), birthweight (BW), and maternal complications. Birth outcomes were first compared with that of US population data, then compared by sex, maternal affected status, and COL3A1 genotype. RESULTS: A total of 41 children were included (70.7% male), including 32 with high-risk (missense and splice site) variants. Preterm birth (<37 weeks) was more common in patients with VEDS than in the US population (48.8% vs 12.2%, P < .0001). Low BW (<2.5 kg) was also more common in patients with VEDS than in the US population (P < .0001), although, it was appropriate after GA adjustment (median GA-adjusted z-score 0.01 vs z-score 0.0, P = .26). No differences in GA or BW were observed by sex or maternal affected status. Those with high-risk variants were more likely to be born preterm than those with haploinsufficient variants, although this did not meet significance criteria (53% vs 33%, P = .35). Of the 6 affected mothers, 5 had perinatal complications. CONCLUSION: Preterm birth is more common in children with VEDS than in the general population. Maternal affected status is not associated with preterm birth, suggesting that risk is conferred by the fetal VEDS diagnosis alone.

Cardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises.

BACKGROUND: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking. OBJECTIVE: The purpose of this study was to describe TDD-related cardiac crises. METHODS: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises. RESULTS: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504-600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. CONCLUSION: TDD-related cardiac crises are associated with a high risk of arrhythmias, cardiomyopathy, cardiac arrest, and death. Although further studies are needed, early recognition and appropriate treatment are critical. Acutely, intravenous magnesium, isoproterenol, atrial pacing, and ECMO as a last resort seem to be the best current treatment options, and early initiation of feeds may prevent VT events.

The Utility of Self-Determination Theory in Predicting Transition Readiness in Adolescents With Special Healthcare Needs.

PURPOSE: Adolescents and young adults with chronic health conditions must learn skills to successfully manage their health as they prepare to transition into adult-based care. Self-determination theory (SDT), an empirically based theory of human motivation, posits that competence (feeling effective), autonomy (volition to perform behaviors), and relatedness (support for autonomy from others) influence behavioral change. This study evaluates the utility of SDT constructs in predicting transition readiness among adolescents and young adults recruited into an intervention to promote successful healthcare transition. METHODS: Baseline assessments were completed by 137 patients aged 17-23 years recruited from pediatric renal, gastroenterology, or rheumatology clinical services. Surveys measured transition readiness (Transition Readiness Assessment Questionnaire) as well as SDT constructs, including competence (Patient Activation Measure); provider relatedness and parent autonomy support (Health Care Climate Questionnaire); and health care-related autonomy (Treatment Self-Regulation Questionnaire). Relationships between SDT constructs and transition readiness were evaluated using linear regression. RESULTS: Between 44 and 48 participants were recruited from each service. Bivariate correlation coefficients between transition readiness and SDT constructs were competence (r = .44), autonomous autonomy (r = .34), controlled autonomy (r = .27), provider relatedness (r = .46), and parental autonomy support (r = .35) (p < .01). Age positively correlated with transition readiness (r = .47, p < .001). After controlling for age, gender, and clinical service, competence (p < .001) and provider relatedness (p = .008) successfully predicted transition readiness (R2 = .423; F change; p < .001). CONCLUSIONS: Findings from this cross-sectional study support the utility of SDT constructs in promoting transition readiness among adolescents and young adults with chronic conditions, underscoring the importance of building competence and provider support for autonomy during this critical period.