Seasonal Variation of Congenital Diaphragmatic Hernia: A Review of the Literature and Database Report from the United States and Canada.

INTRODUCTION: The etiology of congenital diaphragmatic hernia (CDH) remains unknown and only 10 to 30% of patients have a genetic cause. Seasonal variation is known to contribute to the development of some congenital anomalies. Our aim was to investigate whether CDH births have seasonal variation. MATERIALS AND METHODS: A literature review was conducted for CDH and seasonality. Moreover, data from the CDH International Patient Registry Database were collected for infants with due dates between 2008 and 2014. Due dates were used to determine seasonal distribution of births. Birth rates per month in the United States and Canada were extracted from publicly available databases. Data were analyzed using analysis of variance and contingency tables. RESULTS: First, the literature review revealed 11 articles, of which 3 were eligible for inclusion. These studies reported conflicting results on seasonality of CDH. Second, we extracted due dates from the CDH International Patient Registry Database (1,259 patients) and found that there were fewer due dates in winter months (12.1 ± 4 patients/month) than in summer (16.7 ± 6 patients/month; p = 0.011) and fall months (16.3 ± 5 patients/month; p = 0.022). Although this trend was similar to that of all births in the United States and Canada, a lower incidence was observed in winter for CDH infants (20.2%) than for the general population (24.1%, p = 0.0012). CDH survival rate did not vary by season. CONCLUSION: This study provides evidence for a seasonal variation of CDH births. No causative link was established between CDH development and seasonality. Population-based studies with a focus on exposome data are needed to explain seasonal variation in CDH.

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia.

BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Maternal cigarette smoking and alcohol consumption and congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs when abnormal diaphragm development allows herniation of abdominal organs into the thoracic cavity. Its etiopathogenesis is not well understood, but cigarette smoking and alcohol exposure may impact diaphragm development. Using data from a large, population-based case-control study, we examined associations between maternal cigarette smoking and alcohol consumption and CDH in offspring. METHODS: We analyzed maternal interview reports of cigarette smoking and alcohol consumption during early pregnancy for 831 children with CDH and 11,416 children without birth defects with estimated dates of delivery during 1997-2011. Generalized linear mixed effects models with a random intercept for study site were used to estimate associations between measures of exposure to smoking (any, type, frequency, duration) and alcohol (any, quantity, frequency, variability, type) for all CDH combined and selected subtypes (Bochdalek and Morgagni). RESULTS: Mothers of 280 (34.0%) case and 3,451 (30.3%) control children reported early pregnancy exposure to cigarette smoking. Adjusted odds ratios for all CDH were increased for any (1.3; 95% confidence interval 1.1-1.5), active (1.3, 1.0-1.7), and passive (1.4, 1.1-1.7) smoking. Early pregnancy alcohol consumption was reported by mothers of 286 (34.9%) case and 4,200 (37.0%) control children; odds were near the null for any consumption (0.9, 0.8-1.1) and consumption with (0.9, 0.7, 1.1) or without (0.9, 0.8, 1.1) binging. Estimates for smoking and alcohol tended to be higher for Bochdalek CDH and Morgagni CDH than those for all CDH. CONCLUSIONS: Findings suggest that maternal early pregnancy exposure to cigarette smoking, but less so to alcohol consumption, contributes to CDH. These findings need to be replicated in additional large studies that use systematic case ascertainment and classification, detailed exposure assessment, and examine subtype-specific associations.

Parental risk factors for congenital diaphragmatic hernia - a large German case-control study.

BACKGROUND: Evidence for periconceptional or prenatal environmental risk factors for the development of congenital diaphragmatic hernia (CDH) is still scarce. Here, in a case-control study we investigated potential environmental risk factors in 199 CDH patients compared to 597 healthy control newborns. METHODS: The following data was collected: time of conception and birth, maternal BMI, parental risk factors such as smoking, alcohol or drug intake, use of hairspray, contact to animals and parental chronic diseases. CDH patients were born between 2001 and 2019, all healthy control newborns were born in 2011. Patients and control newborns were matched in the ratio of three to one. RESULTS: Presence of CDH was significantly associated with maternal periconceptional alcohol intake (odds ratio = 1.639, 95% confidence interval 1.101-2.440, p = 0.015) and maternal periconceptional use of hairspray (odds ratio = 2.072, 95% confidence interval 1.330-3.229, p = 0.001). CONCLUSION: Our study suggests an association between CDH and periconceptional maternal alcohol intake and periconceptional maternal use of hairspray. Besides the identification of novel and confirmation of previously described parental risk factors, our study underlines the multifactorial background of isolated CDH.

Evidence that FGFRL1 contributes to congenital diaphragmatic hernia development in humans.

Fibroblast growth factor receptor-like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf-Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf-Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left-sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome.

Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X-linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L-related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L-related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus.

Update on Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a rare developmental defect of the diaphragm, characterized by herniation of abdominal contents into the chest that results in varying degrees of pulmonary hypoplasia and pulmonary hypertension (PH). Significant advances in the prenatal diagnosis and identification of prognostic factors have resulted in the continued refinement of the approach to fetal therapies for CDH. Postnatally, protocolized approaches to lung-protective ventilation, nutrition, prevention of infection, and early aggressive management of PH have led to improved outcomes in infants with CDH. Advances in our understanding of the associated left ventricular (LV) hypoplasia and myocardial dysfunction in infants with severe CDH have allowed for the optimization of hemodynamics and management of PH. This article provides a comprehensive review of CDH for the anesthesiologist, focusing on the complex pathophysiology, advances in prenatal diagnosis, fetal interventions, and optimal postnatal management of CDH.

Diaphragmatic Hernia Associated With Absent Ductus Venosus and Anomalous Connection of an Obliterated Umbilical Vein to the Coronary Sinus.

Umbilical vein anomalies are a rare congenital defect, which have been associated with absent ductus venosus, with few cases also involving a congenital diaphragmatic hernia. We describe a case of postnatal development of an anterior diaphragmatic hernia of Morgagni in a four-year-old patient diagnosed prenatally with mesocardia, absent ductus venosus with a large umbilical vein, a large secundum atrial septal defect, and patent ductus arteriosus.

Tandem mass tag (TMT) proteomic analysis of fetal lungs revealed differential expression of tight junction proteins in a rat model of congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is a common and often lethal birth defect characterized by congenital lung malformation, which severely affects neonate prognosis and mortality. This study aimed to investigate differences in protein expression in order to elucidate the mechanism of CDH-associated pulmonary hypoplasia during the early stage of lung development using tandem mass tag (TMT) quantitative proteomics. METHODS: Nitrofen was administered orally to establish a rat CDH model, and pathological changes were evaluated through hematoxylin-eosin (H&E), PCNA, and Ki67 staining at the pseudoglandular stage. Fetal lungs were then collected, pooled before TMT labeling, and subjected to mass spectrometry. Immunohistochemistry (IHC), Western blotting, and Q-PCR were used to further validate the candidate proteins. RESULTS: A total of 79 differentially expressed proteins (DEPs) were identified when CDH and control lungs were compared, and further bioinformatics analysis showed that these proteins play important roles in tight-junctions, phospholipase D signaling, and the HIF-1 signaling pathway. Three differentially expressed proteins, Cldn3, Magi1, and Myh9 are involved in the tight-junction pathway (P < 0.05), and their differential expressions were confirmed by IHC, Western blotting, and Q-PCR. CONCLUSION: These findings indicate that alterations of tight-junction protein expression may play an important role in the pathogenesis of abnormal lung development in CDH. Further studies are warranted to verify the mechanism by which these tight-junction proteins influence the pathogenesis of CDH-associated pulmonary hypoplasia.

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside.

Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

Maternal exposure to ambient cadmium levels, maternal smoking during pregnancy, and congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare musculoskeletal birth defect with a prevalence of 2.61 per 10,000 in the United States. There is limited evidence for ambient air pollutants in the etiology of CDH in humans. OBJECTIVES: We investigated the role of maternal exposure to ambient cadmium as a risk factor for CDH (overall and stratified by isolated and non-isolated subtypes) in Florida and whether maternal smoking during pregnancy was an effect modifier of this association. METHODS: We conducted a population-based, retrospective cohort study using data from the 1999-2012 Florida Birth Defects Registry linked to the National Air Toxic Assessment database. Analyses included chi-square tests; multilevel Poisson regression models to calculate measures of association between cadmium and CDH; and stratified analyses to examine effect modification by maternal smoking status. RESULTS: The study population consisted of 2,591,395 live births including 840 CDH cases. We did not find evidence for an association between maternal exposure to ambient cadmium concentration and CDH. We observed a 24% increased risk of CDH among isolated cases in the highest quartile of cadmium exposure (95% confidence interval [CI]: 1.00, 1.55). Although we were limited by small sample size for CDH cases, we found that among mothers who smoked during pregnancy, exposure to the highest quartile of cadmium was associated with more than two times higher risk for CDH among overall (95%CI: 1.04, 4.39) and isolated (95%CI: 1.07, 5.57) cases. CONCLUSIONS: Additional research is needed to elucidate the mechanism by which maternal ambient cadmium exposure may increase the risk of CDH in offspring, and the extent to which maternal smoking during pregnancy modifies this association.

Heterogeneous Pulmonary Response After Tracheal Occlusion: Clues to Fetal Lung Growth.

BACKGROUND: Understanding inconsistent clinical outcomes in infants with severe congenital diaphragmatic hernia (CDH) after tracheal occlusion (TO) is a crucial step for advancing neonatal care. The objective of this study is to explore the heterogeneous airspace morphometry and the metabolic landscape changes in fetal lungs after TO. METHODS: Fetal lungs on days 1 and 4 after TO were examined using mass spectrometry-based metabolomics, fluorescence lifetime imaging microscopy (FLIM), the number of airspaces, and tissue-to-airspace ratio (TAR). RESULTS: Two morphometric areas were identified in TO lungs compared with controls (more small airspaces at day 1 and a higher number of enlarged airspaces at day 4). Global metabolomics analysis revealed a significant upregulation of glycolysis and a suppression of the tricarboxylic acid cycle in day 4 TO lungs compared with day 1 TO lungs. In addition, there was a significant increase in polyamines involved in cell growth and proliferation. Locally, FLIM analysis on day 1 TO lungs demonstrated two types of heterogeneous zones-similar to control and with increased oxidative phosphorylation. FLIM on day 4 TO lungs demonstrated appearance of zones with enlarged airspaces and a metabolic shift toward glycolysis, accompanied by a decrease in the FLIM "lipid-surfactant" signal. CONCLUSIONS: In normal fetal lungs, we report a novel temporal pattern of varied morphometric and metabolic changes. Initially, there is formation of zones with small airspaces, followed by airspace enlargement over time. Metabolically day 1 TO lungs have zones with increased oxidative phosphorylation, whereas day 4 TO lungs have a shift toward glycolysis in the enlarged airspaces. Based on our observations, we speculate that the "best responders" to tracheal occlusion should have bigger lungs with small airspaces and normal surfactant production.

Intra-amniotic Sildenafil Treatment Modulates Vascular Smooth Muscle Cell Phenotype in the Nitrofen Model of Congenital Diaphragmatic Hernia.

The etiology of pulmonary vascular abnormalities in CDH is incompletely understood. Studies have demonstrated improvement in pulmonary vasculature with prenatal therapy in animal models. We hypothesize that prenatal sildenafil may attenuate defective pulmonary vascular development via modulation of vSMC phenotype from undifferentiated, proliferative phenotype to differentiated, contractile phenotype. We utilized the nitrofen model of CDH to examine the effect of IA sildenafil on pulmonary vSMC phenotype during lung development. Timed-pregnant CD-1 mice were gavage fed 25 mg nitrofen or olive oil (control) at E8.5 of gestation. Single IA injections of Sildenafil (Revatio; 10 µL of 4 mg/4 ml solution) or dextrose control were performed at E12.5. Mice were sacrificed on various gestational days for embryonic lung harvest. Markers of vSMC development of undifferentiated and differentiated phenotypes were analyzed by immunostaining and western blot. Across all time points in gestation, nitrofen-treated embryonic lungs demonstrated increased vSMC expression of NOTCH3, Hes-5, PDGFR-ß, desmin and α-SMA and decreased expression of calponin and SMMHC, compared to oil controls. IA dextrose treatment had no effect on expression levels. However, IA Sildenafil treatment resulted in down-regulation of NOTCH3, Hes-5, PDGFR-ß, desmin and α-SMA and upregulation of calponin and SMMHC, comparable to oil controls. In the nitrofen model, vSMC express markers consistent with more undifferentiated proliferative phenotype, resulting in hypermuscularization of intrapulmonary arterioles in CDH. A single dose of IA Sildenafil treatment early in gestation, results in sustained normalization of vSMC phenotype. Pharmacologic modulation of the vSMC phenotype at key gestational points may have therapeutic potential.

Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia 1.

PURPOSE: To evaluate the vascular ventilatory response in different stages of lung development and to compare them to the neonates with congenital diaphragmatic hernia (CDH) in a rabbit model. METHODS: New Zealand rabbits were divided into 8 groups (n=5): E25, E27, E30, and CDH. All groups were ventilated on a FlexiVent (Scireq, Montreal, QC, Canada), compounding the other 4 groups. The CDH surgery was performed at E25 and the harvest at E30. Dynamic compliance (CRS), dynamic elastance (ERS) and dynamic resistance (RRS) were measured every 4 min/24 min. Median wall thickness (MWT) and airspace were measured. ANOVA Bonferroni tests were used to perform statistical analysis. Significance was considered when p<0.05. RESULTS: CRS was higher in E30 compared to all other groups (p<0.05). CRS and RRS of CDH and E27 were similar and were higher in E25 (p<0.05). MWT was decreased according to the gestational age, was increased in E27V and E30V (p<0.05) and decreased in CDHV (p<0.05), airspace was decreased in E25 and increased in all ventilated groups (p<0.05). CONCLUSIONS: The ventilation response of congenital diaphragmatic hernia is like the pseudoglandular stage of the lung development. These findings add information about the physiology of pulmonary ventilation in CDH.

Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia.

INTRODUCTION: Extensive vascular remodeling causing pulmonary hypertension (PH) represents a major cause of mortality in patients with congenital diaphragmatic hernia (CDH). The chemokine monocyte chemoattractant protein-1 (MCP-1) is a biomarker for the severity of PH and its activation is accompanied by pulmonary influx of monocytes and extensive vascular remodeling. MCP-1 activation can be reversed by application of rosiglitazone (thiazolidinedione). We performed this study to evaluate the role of MCP-1 for the pathogenesis of PH in experimental CDH. We hypothesized that vascular remodeling and MCP-1 activation is accompanied by pulmonary influx of fetal monocytes and can be attenuated by prenatal treatment with rosiglitazone. METHODS: In a first set of experiments pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blot (WB), and immunohistochemistry (IHC) were used to evaluate MCP-1 expression, activation, and localization. Quantification and localization of pulmonary monocytes/macrophages were carried out by IHC. In a second set of experiments nitrofen-exposed dams were randomly assigned to prenatal treatment with rosiglitazone or placebo on D18+D19. Fetal lungs were harvested on D21, divided into control, CDH+rosiglitazone, and CDH+placebo and evaluated by WB as well as IHC. RESULTS: Increased thickness of pulmonary arteries of CDH fetuses was accompanied by increased systemic and perivascular MCP-1 protein expression and significantly higher amounts of pulmonary monocytes/macrophages compared to controls (p<0.01). These effects were reversed by prenatal treatment with rosiglitazone (p<0.01 vs. CDH+P; control). CONCLUSION: Prenatal treatment with rosiglitazone has the potential to attenuate activation of pulmonary MCP-1, pulmonary monocyte influx, and vascular remodeling in experimental CDH. These results provide a basis for future research on prenatal immunomodulation as a novel treatment strategy to decrease secondary effects of PH in CDH.

Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia

Abstract Purpose: To evaluate the vascular ventilatory response in different stages of lung development and to compare them to the neonates with congenital diaphragmatic hernia (CDH) in a rabbit model. Methods: New Zealand rabbits were divided into 8 groups (n=5): E25, E27, E30, and CDH. All groups were ventilated on a FlexiVent (Scireq, Montreal, QC, Canada), compounding the other 4 groups. The CDH surgery was performed at E25 and the harvest at E30. Dynamic compliance (CRS), dynamic elastance (ERS) and dynamic resistance (RRS) were measured every 4 min/24 min. Median wall thickness (MWT) and airspace were measured. ANOVA Bonferroni tests were used to perform statistical analysis. Significance was considered when p<0.05. Results: CRS was higher in E30 compared to all other groups (p<0.05). CRS and RRS of CDH and E27 were similar and were higher in E25 (p<0.05). MWT was decreased according to the gestational age, was increased in E27V and E30V (p<0.05) and decreased in CDHV (p<0.05), airspace was decreased in E25 and increased in all ventilated groups (p<0.05). Conclusions: The ventilation response of congenital diaphragmatic hernia is like the pseudoglandular stage of the lung development. These findings add information about the physiology of pulmonary ventilation in CDH.

Mortality factors in infants with congenital diaphragmatic hernia: A systematic review.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a malformation of the diaphragm accounting for 8% of all major congenital anomalies. Although many clinical factors of survival in children with CDH have been established, limited research exists on the role of sociodemographic and other factors. We aimed to systematically identify and summarize all available international literature, published from January 2000 to July 2017, evaluating specific mortality factors for children with prenatally diagnosed, isolated, left-sided CDH. METHODS: MEDLINE, PROSPERO, EMBASE, Scopus, The Cochrane Library databases, and the table of contents for the past 5 years for relevant journals were searched systematically. The risk factors of interest were as follows: birth weight, gestational age (GA) at diagnosis, GA at birth, infant sex, maternal age, ethnicity, socioeconomic status (SES), and plurality. The primary outcome measure was survival. Data were extracted on study design, study quality, participant data, and survival-related effect estimates. RESULTS: Seven studies fulfilled the inclusion criteria. In total, 347 children were included in the review. Birth weight, GA at diagnosis, and GA at birth were evaluated in five studies each, infant sex in two, and maternal age in one. None of these factors were significantly associated with survival. No studies evaluated the influence of plurality, ethnicity or SES. CONCLUSION: Although the factors of interest showed no significant association with survival, more evidence is required to confirm these findings. Understanding whether sociodemographic factors are associated with survival may help inform the development of public health interventions to improve survival rates for children with CDH.

Scimitar syndrome associated with aberrant right subclavian artery, diaphragmatic hernia, and urinary anomalies - case report and review of the literature.

Scimitar syndrome is a form of a partially or totally right pulmonary venous return to the inferior vena cava, which may associate variably right lung hypoplasia, right pulmonary artery hypoplasia, pulmonary sequestration together with the presence of aortopulmonary collaterals from the descending aorta towards the right lung. In many cases, there are also other cardiac anomalies associated. We present a unique association of a partially anomalous pulmonary venous return to the inferior vena cava with other vascular and thoracic anomalies: inferior sinus venosus and secundum atrial septal defect, retroesophageal right subclavian artery, obstructed accessory right bronchus, diaphragmatic hernia with ectopic liver, "S"-type thoracic scoliosis and malformations of the urinary tract (duplication of the right ureter and of the left basinet). The patient had a reimplantation of the "scimitar" vein to the left atrium and closure of the inferior sinus venosus and secundum atrial septal defect.