Late gestation predictors of a postnatal biventricular circulation after fetal aortic valvuloplasty.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) for severe aortic stenosis (AS) has shown promise in averting progression to hypoplastic left heart syndrome. After FAV, predicting which fetuses will achieve a biventricular (BiV) circulation after birth remains challenging. Identifying predictors of postnatal circulation on late gestation echocardiography will improve parental counseling. METHODS: Liveborn patients who underwent FAV and had late gestation echocardiography available were included (2000-2017, n = 96). Multivariable logistic regression and classification and regression tree analysis were utilized to identify independent predictors of BiV circulation. RESULTS: Among 96 fetuses, 50 (52.1%) had BiV circulation at the time of neonatal discharge. In multivariable analysis, independent predictors of biventricular circulation included left ventricular (LV) long axis z-score (OR 3.2, 95% CI 1.8-5.7, p < 0.001), LV ejection fraction (OR 1.3, 95% CI 1.0-1.8, p = 0.023), anterograde aortic arch flow (OR 5.0, 95% CI 1.2-20.4, p = 0.024), and bidirectional or right-to-left foramen ovale flow (OR 4.6, 95% CI 1.4-15.8, p = 0.015). CONCLUSION: Several anatomic and physiologic parameters in late gestation were found to be independent predictors of BiV circulation after FAV. Identifying these predictors adds to our understanding of LV growth and hemodynamics after FAV and may improve parental counseling.

Early hemodynamic changes after fetal aortic stenosis valvuloplasty predict biventricular circulation at birth.

OBJECTIVE: To describe the early hemodynamic changes after fetal aortic valvuloplasty (FAV) for evolving hypoplastic left heart syndrome due to mid-gestational aortic stenosis and to assess whether these early changes predict biventricular (BiV) circulation at neonatal discharge. METHOD: We retrospectively reviewed all technically successful FAV cases resulting in live birth between 2000 and 2015 (n = 93, 45% BiV circulation at neonatal discharge). Paired testing methods were used to compare pre-intervention and post-intervention measures of left ventricular hemodynamics. Logistic regression was used to determine whether these changes were predictive of post-natal outcome. RESULTS: Measures of left heart physiology were markedly abnormal pre-FAV and improved significantly post-FAV. No subjects had systolic antegrade transverse aortic arch flow pre-FAV and 65% of subjects had antegrade flow post-FAV. The number of subjects with abnormal left-to-right patent foramen ovale flow decreased, and the number with biphasic mitral valve inflow increased. The median left ventricular ejection fraction improved after intervention. Amongst the pre-post changes, gaining partially or exclusively antegrade systolic arch flow was the most significant independent predictor of BiV circulation (OR 9.80 and 19.83, respectively, both P < 0.001). CONCLUSION: Technically successful FAV is associated with immediate improvements in left heart physiology that are predictive of BiV circulation at neonatal discharge.

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines.

BACKGROUND: We aimed to examine clinical features and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z-score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z-score (absolute regression); (3) a reduction ≥15% of the MLVWT z-score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2-12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%-100%) 1 year after presentation and 80.9% (95% CI, 70.1%-90.7%) at 5 years. Patients with MLVWT z-score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6-7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.

An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism.

BACKGROUND: During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay. METHODS: Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. RESULTS: The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion. CONCLUSION: Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.

Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome.

OBJECTIVE: To describe a group of children with co-incident pulmonary vein stenosis and Smith-Lemli-Opitz syndrome and to generate hypotheses as to the shared pathogenesis of these disorders. DESIGN: Retrospective case series. PATIENTS: Five subjects in a pulmonary vein stenosis cohort of 170 subjects were diagnosed with Smith-Lemli-Opitz syndrome soon after birth. RESULTS: All five cases were diagnosed with Smith-Lemli-Opitz syndrome within 6 weeks of life, with no family history of either disorder. All cases had pathologically elevated 7-dehydrocholesterol levels and two of the five cases had previously reported pathogenic 7-dehydrocholesterol reductase mutations. Smith-Lemli-Opitz syndrome severity scores ranged from mild to classical (2-7). Gestational age at birth ranged from 35 to 39 weeks. Four of the cases were male by karyotype. Pulmonary vein stenosis was diagnosed in all cases within 2 months of life, earlier than most published cohorts. All cases progressed to bilateral disease and three cases developed atresia of at least one vein. Despite catheter and surgical interventions, all subjects' pulmonary vein stenosis rapidly recurred and progressed. Three of the subjects died, at 2 months, 3 months, and 11 months. Survival at 16 months after diagnosis was 43%. CONCLUSIONS: Patients with pulmonary vein stenosis who have a suggestive syndromic presentation should be screened for Smith-Lemli-Opitz syndrome with easily obtainable serum sterol tests. Echocardiograms should be obtained in all newly diagnosed patients with Smith-Lemli-Opitz syndrome, with a low threshold for repeating the study if new respiratory symptoms of uncertain etiology arise. Further studies into the pathophysiology of pulmonary vein stenosis should consider the role of cholesterol-based signaling pathways in the promotion of intimal proliferation.

Growth in children with congenital heart disease.

OBJECTIVE: We sought to describe growth in young children with congenital heart disease (CHD) over time. METHODS: We performed a retrospective matched cohort study, identifying children with CHD in a large primary care network in Pennsylvania, New Jersey, and Delaware and matching them 10:1 with control subjects. The primary endpoint was the difference in mean World Health Organization z score for cases and controls for weight-for-age (WFAZ), length-for-age (LFAZ), weight-for-length (WFLZ), and head circumference-for-age (HCFAZ) at traditional ages for preventive visits, stratified by CHD category. RESULTS: We evaluated 856 cases: 37 with single ventricle (SV) physiology, 52 requiring complex repair (CR), 159 requiring simple repair (SR), and 608 requiring no repair. For children in the SV, CR, and SR categories, large, simultaneous, and statistically significant (Student's t test P < .05) decreases in WFAZ and LFAZ appeared within the first month of life, peaked near 4 months, and persisted through 24 or 36 months. There were fewer and smaller decreases in the no-repair group between 2 and 18 months. HC data were available between 1 week and 24 months; at those ages, decreases in mean HCFAZ generally paralleled decreases in WFAZ and LFAZ in the SV, CR, and SR groups. CONCLUSIONS: Children with CHD experience early, simultaneous decreases in growth trajectory across weight, length, and head circumference. The simultaneous decrease suggests a role for altered growth regulation in children with CHD.

Changes in vitamin D and parathyroid hormone metabolism in incident pediatric Crohn's disease.

BACKGROUND: Prior studies of vitamin D metabolism in Crohn's disease (CD) did not include controls or examine changes following diagnosis. This study examined associations among 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) levels in incident pediatric CD, compared with controls, and following diagnosis. METHODS: Serum vitamin D and PTH were measured at diagnosis (n = 78), 6, 12, and a median of 43 months (n = 52) later in CD participants, and once in 221 controls. Multivariate regression was used to examine baseline associations and quasi-least squares regression to assess subsequent changes. RESULTS: At diagnosis, 42% of CD participants were 25(OH)D-deficient (<20 ng/mL). The odds ratio for deficiency was 2.1 (95% confidence interval [CI]: 1.1, 3.9; P < 0.05) vs. controls, adjusted for age, race, and season. 1,25(OH)(2)D was lower in CD vs. controls (P < 0.05), adjusted for 25(OH)D, tumor necrosis factor alpha (TNF-α), and PTH. TNF-α was associated with lower 1,25(OH)(2)D (P < 0.05), and the positive association between PTH and 1,25(OH)(2)D in controls was absent in CD (interaction P = 0.02). Among participants with 25(OH)D <30 ng/mL, CD was associated with lower PTH (P < 0.05) vs. controls. Following diagnosis, 25(OH)D and 1,25(OH)(2)D improved (P < 0.001). At the final visit, 3% were 25(OH)D-deficient, PTH was no longer low relative to 25(OH)D, and 1,25(OH)(2)D was significantly elevated (P < 0.001) compared with controls. CONCLUSIONS: Incident CD was associated with 25(OH)D and 1,25(OH)2D deficiency and a relative hypoparathyroidism that resolved following diagnosis. Inflammatory cytokine suppression of PTH and renal 1-α-hyroxylase may contribute to these alterations.