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The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4 and CD8 T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased β-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.

Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals is a complex congenital heart defect that includes a heterogeneous subgroup of patients. Variation in the sources of pulmonary blood flow contributes to the complexity of the lesion and the diversity of approaches to its management. Unifocalization and rehabilitation focus on mobilization of collateral arteries and growth of native pulmonary arteries, respectively, with the ultimate surgical goal of achieving separated systemic and pulmonary circulations with the lowest possible right ventricular pressure. Regardless of the strategy, outcomes have altered the natural history of the disease, with a complete repair rate of approximately 80% and low early and late mortality rates. Given this heterogeneity of pulmonary vasculature, a tailored approach should be adopted for each patient, using all diagnostic methods currently offered by technical developments.

Double-outlet left ventricle (DOLV) is an abnormal ventriculo-arterial connection characterized by the origin of both great arteries from the morphological left ventricle. The aim of our paper is to describe the morphological and imaging features of DOLV and to assess the prevalence of the associated malformations and their surgical outcomes. METHODS From 2011 to 2022, we retrospectively reviewed the electronic case records of patients diagnosed with DOLV at the Bambino Gesu Children’s Hospital. A systematic search was developed in MEDLINE, Web of Science, and EMBASE databases to identify reports assessing the morphology and outcomes of DOLV between 1975 and 2023. RESULTS: Over a median follow-up of 9.9 years (IQR 7.8–11.7 y), four cases of DOLV were identified at our institution. Two patients were diagnosed with (S,D,D) DOLV subaortic VSD and pulmonary stenosis (PS): one patient had (S,D,D) DOLV with doubly committed VSD and hypoplastic right ventricle, and another patient had (S,D,L) DOLV with subaortic VSD and PS (malposition type). Pulmonary stenosis was the most commonly associated lesion (75%). LITERATURE REVIEW: After systematic evaluation, a total of 12 reports fulfilled the eligibility criteria and were included in our analysis. PS or right ventricular outflow tract obstruction was the most commonly associated lesion (69%, 95% CI 62–76%). The most common locations of VSD were subaortic (pooled prevalence: 75%, 95% CI 68–81), subpulmonary (15%, 95% CI 10–21), and doubly committed (7%, 95% CI 4–12). The position of the great arteries showed that d-transposition of the aorta was present in 128 cases (59% 95% CI 42–74), and l-transposition was present in 77 cases (35%, 95% CI 29–43).

Objective Children undergoing Ross operation were expected to have longer autograft, but shorter homograft durability compared with adults. In order to define the outcome in the second decade after Ross operation in children, a nationwide review of 23 years of experience was undertaken. Methods 305 children underwent Ross operation in 11 paediatric units between 1990 and 2012. Age at surgery was 9.4±5.7 years, indication aortic stenosis in 103 patients, regurgitation in 109 and mixed lesion in 93. 116 (38%) patients had prior procedures. Root replacement was performed in 201 patients, inclusion cylinder in 14, subcoronary grafting in 17 and Ross–Konno in 73. Results There were 10 (3.3%) hospital and 12 late deaths (median follow-up 8.7 years). Survival was 93±2% and 89±3% and freedom from any reoperation was 76±3% and 67±6% at 10 and 15 years. 34 children had autograft 37 reoperations (25 replacement, 12 repair): three required transplantation after reoperation. Freedom from autograft reoperation was 86±3% and 75±6% at 10 and 15 years. 32 children had right heart redo procedures, and only 25 (78%) conduit replacements (15-year freedom from replacement, 89±4%). Prior operation (p=0.031), subcoronary implant (p=0.025) and concomitant surgical procedure (p=0.004) were risk factors for left heart reoperation, while infant age (p=0.015) was for right heart. The majority (87%) of late survivors were in NYHA class I, 68% free from medication and six women had pregnancies. Conclusions Despite low hospital risk and satisfactory late survival, paediatric Ross operation bears substantial valve-related morbidity in the first two decades. Contrary to expectation, autograft reoperation is more common than homograft.

An intrapericardial vacuolated mass compressing and displacing the heart was diagnosed by echocardiography in a foetus of 22 weeks gestation. The birth was induced for early signs of foetal distress at 29 weeks and, after two initial pericardial evacuation procedures, the tumour was resected radically 7 days after birth at a weight of 1.55 kg. Mass histology showed teratoma associated with yolk sac tumour. We comment on the overall approach adopted after foetal diagnosis and the histopathological features of the tumour, and try to draw conclusions on patient outcome data.

Aim: This study evaluates the risk factors associated with right ventricular (RV) dilation and dysfunction leading to pulmonary valve replacement (PVR) or adverse cardiac events in repaired Tetralogy of Fallot (rToF) patients. Methods: Data from all rToF patients who underwent magnetic resonance imaging (MRI) evaluation at our hospital between February 2007 and September 2020 were collected. Results: Three hundred and forty-two patients (60% males, 42% older than 18 years), with a median age of 16 years (IQR 13–24) at the time of MRI, were included. All patients underwent complete repair at a median age of 8 months (IQR 5–16), while palliation was performed in 56 patients (16%). One hundred and forty-four patients (42%) subsequently received pulmonary valve replacement (PVR). At the multivariate analysis, male gender was an independent predictor for significant RV dilation, RV and left ventricular (LV) dysfunction. Transventricular ventricular septal defect (VSD) closure and previous palliation significantly affected LV function and RV size, respectively. Male gender and the transventricular VSD closure were independent predictors for PVR. Conclusions: Male gender and surgical history (palliation, VSD closure approach) significantly affected the long-term outcomes in rToF patients and should be taken into consideration in the follow-up management and in PVR timing in this patient population.

Right ventricular (RV) evaluation represents one of the major clinical tasks in the follow-up of repaired tetralogy of Fallot patients (rToF) with pulmonary valve regurgitation, as both severe RV dilatation and dysfunction are key factors in defining the need of pulmonary valve replacement. The aim of our study was to report the diagnostic accuracy of echocardiography in the identification of rToF patients with severely dilated and/or depressed RV as compared to cardiac magnetic resonance (CMR). Among our patients with rToF, a subgroup of 95 (17.6 ± 6.8 years; 60% male), who underwent right ventricular qualitative and quantitative evaluation with CMR following echocardiographic suspicion of severe dilation/dysfunction, were included in the analysis. When comparing echocardiographic RV functional parameters to CMR findings, we found no association between CMR-ejection fraction (EF) and either tricuspid annulus plane systolic excursion (TAPSe) nor tissue Doppler systolic tricuspid excursion velocity (all p = ns). In contrast RVFAC was strongly associated with CMR-EF (r = 0.44; p < 0.01) as well as to longitudinal components of RV mechanics including tissue Doppler s′ (r = 0.40; p < 0.01) and TAPSE (r = 0.36; p < 0.01). When comparing echocardiographic and CMR structural parameters of the RV, we found that CMR RV volume was strongly related to echocardiographic measurements of RV end diastolic area (from the 4 chamber apical view) and with proximal parasternal short axis right ventricle outflow-dimension. Accordingly a regression model was derived from multiple regression analysis, which allows a more accurate estimate of CMR RV volume from echocardiography (r2 = 0.59, p < 0.001). Our study demonstrates a significant, although imperfect, correlation between echocardiographic and CMR RV functional and geometrical parameters. Combining echocardiographic measures of RV inflow and RV outflow, we deliver a simple formula to estimate CMR-RV volume, improving the echocardiographic accuracy in RV volume quantification.