Total anomalous pulmonary venous connection: Influence of heterotaxy and venous obstruction on outcomes.

BACKGROUND: Previous studies have demonstrated increased early mortality and pulmonary vein reintervention for patients with total anomalous pulmonary venous connection (TAPVC) and heterotaxy syndrome (HTX+) compared with patients with TAPVC without heterotaxy syndrome (HTX-). We aimed to evaluate the longitudinal risk of pulmonary vein reintervention and mortality in HTX + patients. METHODS: A retrospective review was performed to identify longitudinal interventions in patients with TAPVC seen at a single center from 1995 to 2019. The mean cumulative interventions were described for all patients using the Nelson-Aalen estimator. Survival with TAPVC was described using Kaplan-Meier estimates. RESULTS: A total of 336 patients were identified with TAPVC, of whom 118 (35%) had heterotaxy syndrome. Functional single ventricles were identified in 106 of these 118 HTX + patients (90%) and in 14 of 218 HTX- patients (6%) (P < .001). Obstructed TAPVC (OBS+) was present in 49 of 118 HTX + patients (42%) and in 87 of 218 HTX- patients (40%) (P = .89). The median duration of follow-up was 6.5 years. Five-year survival was 69% for HTX+/OBS + patients, 72% for HTX+/OBS- patients, 86% for HTX-/OBS + patients, and 95% for HTX-/OBS- patients (P < .0001, log-rank test). The mean number of pulmonary vein interventions at the median follow-up time was greater in the HTX+/OBS + patients compared with HTX+/OBS- patients (mean, 2.0 vs 1.1; P = .030), HTX-/OBS + patients (mean, 1.3; P = .033), and HTX-/OBS- patients (mean, 1.3; P = .029). CONCLUSIONS: Among the 4 cohorts, HTX+ was associated with a higher rate of mortality, and HTX+/OBS+ was associated with a greater number of pulmonary vein interventions. This may be due in part to the high prevalence of single ventricle physiology in the HTX + cohort.

The development of a quality improvement project to improve infection prevention and management in patients with asplenia or hyposplenia.

Asplenia and hyposplenia (a/hyposplenia) are associated with increased morbidity and mortality from complications including infection. The recommended measures to reduce the risks associated with infection include patient education, vaccination and early initiation of antibiotic therapy for fever. Despite these recommendations, there is poor adherence to best practice management of patients with asplenia or hyposplenia (PWA/H). We present the development methodology and pilot data of a quality improvement project that explored whether a programme involving a novel medical alert card together with a patient and healthcare provider educational booklet increased vaccination rates and improved awareness and understanding of the infectious implications of a/hyposplenia. Our aim was to increase the proportion of those appropriately vaccinated and the proportion of patients with proper understanding of fever management by twofold in 18 months. Questionnaires were used locally as a root-cause-analysis to confirm the need for education and evaluate the effectiveness of the programme, as well as patient satisfaction. An interdisciplinary team developed a toolkit composed of a medical alert card and booklet. The toolkit was distributed to PWA/H who presented for a haematology clinic visit at a tertiary care centre. A separate set of questionnaires was then used to evaluate satisfaction and obtain feedback from patients and practitioners receiving the toolkit for the first time. Changes suggested by patients and practitioners with unanimous agreement among study investigators were made to the toolkit. The pilot study showed an increase in vaccination rates and awareness of vaccination status and appropriate fever management. The majority of the patients and practitioners found the information provided by the toolkit helpful. Given these promising single-centre findings, the intervention is being extended to another tertiary care centre with a large red blood cell disorders programme to evaluate its generalisability. The next step will be to expand the scope to paediatric PWA/H.

CRT in a congenital heart disease patient with interventricular dyssynchrony due to an RV conduction delay.

We encountered a unique pattern of cardiac dyssynchrony in a patient with complex congenital heart disease (heterotaxy syndrome) with a biventricular physiology and systemic left ventricle (LV). On speckle tracking echocardiography, dyssynchrony was not detected within the LV, but was noted in an interventricular fashion between the LV and right ventricle (RV). An electrophysiologic study revealed a conduction delay in the subpulmonary RV. Cardiac resynchronization therapy provided reverse cardiac remodeling and an excellent result in our patient by placing the pacing leads around the dyssynchronous lesion.

Percutaneous edge-to-edge repair for common atrioventricular valve regurgitation in a patient with heterotaxy syndrome, single ventricle physiology, and unbalanced atrioventricular septal defect.

Congenital heart disease patients, specifically with unbalanced atrioventricular septal defects and common atrioventricular valves requiring single ventricle palliation, have substantial morbidity and mortality. Atrioventricular valve regurgitation (AVVR) is associated with poor outcomes in single ventricle patients, and many of them require surgical treatment of AVVR in their lifetimes. We describe a unique case of transcatheter edge-to-edge valve repair using the MitraClip system (Abbott, Chicago, IL) in a single ventricle patient with severe common AVVR.

Genetic architecture of laterality defects revealed by whole exome sequencing.

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

Transcatheter redirection of hepatic venous blood to treat unilateral pulmonary arteriovenous malformations in a Fontan circulation by short-term total exclusion of the unaffected lung.

Clinically significant unilateral pulmonary arteriovenous malformations (PAVM) can develop in patients with a Fontan circulation when there is unbalanced distribution of hepatic venous (HV) blood flow to the lungs. There are reported surgical and transcatheter techniques to treat PAVMs by rerouting HV return, with promising short-term results. We report a case of a novel, technically simple transcatheter approach to redirect HV blood flow in an adult Fontan patient with polysplenia syndrome and severe unilateral PAVMs. Our patient had a two-stage procedure, the first to redirect all HV blood flow to the affected lung with a single covered stent, and a second to confirm resolution of PAVMs and to reintroduce HV effluent to the unaffected lung. At 10-month follow-up, her oxygen saturations had increased from 75% to 93% with a marked improvement in her functional status.

Complex congenital cardiac anomalies in the setting of right isomerism in a 31-month-old infant: a case report.

BACKGROUND: Congenital cardiac defects are not rare among neonates. Prompt assessment for life-threatening anomalies is essential for rapid management decisions and positive outcomes. Extracardiac anomalies can occur in congenital heart defects, and their presence increases morbidity and mortality in these neonates. CASE PRESENTATION: We report a case of a 31- month-old infant black girl in Tanzania who presented with an on-and-off history of difficulty in breathing, easy fatigability, facial and lower-limb swelling, recurrent respiratory tract infections, and failure to thrive. CONCLUSIONS: Management of patients with heterotaxy syndrome is complex and largely depends on specific anatomy of both cardiac and noncardiac lesions. Cardiac and noncardiac management must be tailored to individual anatomy, including prophylaxis against encapsulated organisms for asplenic patients.

Comparing levocardia and dextrocardia in fetuses with heterotaxy syndrome: prenatal features, clinical significance and outcomes.

BACKGROUND: To investigate the differences in cardiovascular disease, extracardiac anomalies and outcomes between fetuses with levocardia and dextrocardia. METHODS: Clinical demographics, prenatal features, postnatal characteristics and the outcomes of fetuses with levocardia or dextrocardia were recorded and analyzed. RESULTS: Sixty-five fetuses with dextrocardia and thirty-eight fetuses with levocardia were enrolled. Right ventricle outlet obstruction, atrioventricular septal defect and intestinal malrotation were common in both groups. Univentricular physiology, transposition of the great arteries and esophageal atresia were more frequent in fetuses with levocardia, whereas abnormal pulmonary venous connection, double outlet of right ventricle, left ventricle outlet obstruction and brain abnormalities were more frequent in the dextrocardia group. The accuracy of evaluating cardiac malformations was high, but the sensitivity in assessing extracardiac abnormalities was low. CONCLUSIONS: Although the disorders have certain overlapping features, there are several differences between fetuses with levocardia and dextrocardia. These findings might improve patient counseling and perinatal management.

HLX is a candidate gene for a pattern of anomalies associated with congenital diaphragmatic hernia, short bowel, and asplenia.

Isolated congenital diaphragmatic hernia is often a sporadic event with a low recurrence risk. However, underlying genetic etiologies, such as chromosome anomalies or single gene disorders, are identified in a small number of individuals. We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first-cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20-Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could explain the fetal findings.

Pneumococcal vaccination and efficacy in patients with heterotaxy syndrome.

BackgroundPneumococcal vaccines, including pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugated vaccine (PCV), are crucial in preventing invasive pneumococcal diseases. We analyzed the pneumococcal vaccination rate, efficacy, and durability in patients with heterotaxy.MethodsAll patients with heterotaxy and CCHD who were followed up at our institution between 2010 and 2015 were included. Pneumococcal vaccine status and geometric mean concentration (GMC) of serotypes 6B, 14, 19F, and 23F were analyzed. Splenic function was considered abnormal when the percentage of IgM memory B cell was less than 1%.ResultsThe GMCs of the four serotypes did not differ significantly between patients with heterotaxy and those with CCHD; the GMCs were also not affected by abnormal splenic function. Most patients had GMCs >0.35 µg/ml (protection level) 4-5 years after either PPV or PCV injection; however, it may decay gradually in some serotypes. In addition, 21.4% of 42 patients with heterotaxy did not receive pneumococcal vaccine, and none completely adhered to the vaccine guidelines.ConclusionsVaccine efficacy was acceptable, even in patients with abnormal splenic function. In some patients, the durability of PPV and PCV decreased with time, highlighting the importance of booster doses. Vaccination rate in patients with heterotaxy is unsatisfactory.

Left isomerism syndrome with total anomalous systemic connection.

We present a case of left isomerism with total anomalous systemic venous connection where the inferior vena cava was absent and all other systemic veins connected abnormally to the left atrium. The right atrium was hypoplastic with an intact atrial septum. Blood flow to the lungs was through a large ventricular septal defect. The diagnosis was made with echocardiography, angiography, and computed tomography. Complete repair was performed successfully, and the 7-year-old patient had an uneventful recovery.

Ivemark Syndrome.

Ivemark syndrome or right atrial isomerism is a rare syndrome of asplenia / hyposplenia with malformation of heart and abnormal arrangement of internal organs of chest and abdomen and is classified under heterotaxy disorder. We describe here the case of a 14 year old boy diagnosed with asplenia, dextrocardia with double outlet right ventricle and midline liver.

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5.

G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5.

Twin Atrioventricular Nodal Reentrant Tachycardia Associated with Heterotaxy Syndrome with Malaligned Atrioventricular Canal Defect and Atrioventricular Discordance.

There are limited data on the experience of transbaffle access for catheter ablation in patients who have undergone a Fontan palliation for complex congenital heart. Nevertheless, these issues will be encountered more frequently, because patients who have undergone Fontan palliation continue to survive into adulthood and develop a variety of arrhythmias that may be refractory to medical therapy.

Cardiac and Non-Cardiac Abnormalities in Heterotaxy Syndrome.

Thoraco-abdominal viscera have unique morphological asymmetry, unlike the body's external organs. Heterotaxy syndrome is a disorder in which there is a loss of normal left to right asymmetry of thoraco-abdominal viscera and their naturally proscribed spatial relationship. It has multiple anatomical alterations, culminating into physiological and hemodynamic consequences. It is divided into two groups on the basis of morphology of the two atrial appendages. These subgroups are - 1) Isomerism of right atrial appendage (asplenia syndrome); 2) Isomerism of left atrial appendage (polysplenia syndrome); Patients from group I, usually have severe cardiac malformations and present early. They may have duct dependent lesions and eventually may undergo Fontan surgery. However, extracardiac anomalies are more common in group II. All the patients must be evaluated in detail to rule out anomalies like gut-malrotation. Patients must be provided with special care for their susceptibility to infection due to absence of spleen or presence of splenic malfunction. Majority of these patients may have genetic link and may present in families. Hence, genetic evaluation is necessary before assuming long term outcome.

Decreased baseline variability on fetal heart rate pattern in a fetus with heterotaxy syndrome.

In a fetus with suspected heterotaxy syndrome, a decreased/absent baseline variability of fetal heart rate pattern developed at gestational week 36(+5) and continued for 5 days until birth at gestational week 37(+2), while repeat biophysical profile scorings with ultrasound were consistently unremarkable. This neonate weighing 2404 g with Apgar scores of 7 (1-min) and 8 (5-min) and umbilical arterial cord blood pH of 7.28 with base deficit of 3.9 mmol/L, showed a heart rate of 120 b.p.m. for 3 h after birth, but subsequently developed sinus bradycardia (84 b.p.m.) unresponsive to crying. Isoproterenol initiated 9 h after birth was effective in the increase of heart rate to 120 b.p.m. in this neonate. Brain magnetic resonance imaging at 16 days of age was unremarkable. The decreased/absent baseline variability of fetal heart rate pattern was speculated to have been caused by sinus node dysfunction, and not by reduced fetal oxygenation in this case.

An adult case of polysplenia syndrome associated with sinus node dysfunction, dextrocardia, and systemic venous anomalies.

A 54-year-old woman was referred to our hospital for symptomatic sinus bradyarrhythmia with a sinus pause of 8 seconds. She was diagnosed with dextrocardia during childhood and discovered to have heterotaxy syndrome when she had an appendectomy during her teenager years. Chest and abdominal examinations by computed tomography showed multiple spleens located on the right side and abnormal drainages of the superior and inferior vena cava. Left isomerism was diagnosed by bilaterally bilobed lungs. Because of a patent bilateral superior vena cava, pacemaker leads were implanted using the right cephalic vein approach. Her fainting symptoms disappeared after pacemaker implantation.

Ivemark syndrome-a rare entity with specific anatomical features.

Ivemark syndrome (IS) is a rare embryological disorder which results from failure of development of the left-right asymmetry of organs. It is often associated with cardiac and other organ abnormalities, which are the usual causes of death in early neonatal life. We report a 3 months old girl with IS with dextrocardia, transposition of the great vessels, atrio-ventricular connection, total anomalous pulmonary venous drainage, a right atrial and right pulmonary isomerism, a midline liver, a midline gallbladder, asplenia, intestinal malrotation and vena cava anomalies. To our knowledge, complete right heterotaxia syndrome has been rarely described in literature. Lateralization defects such as situs inversus, asplenia or polysplenia due to defective left-right axis development are considered as defects of the primary developmental field. Therefore, additional malformations in IS can be synchronic defects in the primary developmental field rather than causally independent malformations.

Ivemark syndrome-a rare entity with specific anatomical features / Síndrome de Ivermark. Informe de un caso

Ivemark syndrome (IS) is a rare embryological disorder which results from failure of development of the left-right asymmetry of organs. It is often associated with cardiac and other organ abnormalities, which are the usual causes of death in early neonatal life. We report a 3 months old girl with IS with dextrocardia, transposition of the great vessels, atrio-ventricular connection, total anomalous pulmonary venous drainage, a right atrial and right pulmonary isomerism, a midline liver, a midline gallbladder, asplenia, intestinal malrotation and vena cava anomalies. To our knowledge, complete right heterotaxia syndrome has been rarely described in literature. Lateralization defects such as situs inversus, asplenia or polysplenia due to defective left-right axis development are considered as defects of the primary developmental field. Therefore, additional malformations in IS can be synchronic defects in the primary developmental field rather than causally independent malformations.

El síndrome de Ivermark es un desorden embriológico raro resultante de una falla en el desarrollo de la asimetría izquierda y derecha de los órganos. Usualmente se asocia con anomalías cardíacas y de otros órganos, que son la causa usual de muerte en la vida neonatal. Presentamos una niña de 3 meses con dextrocardia, trasposición de los grandes vasos, comunicación aurículo-ventricular, drenaje anómalo total de la vena pulmonar, isomerismo de la aurícula y pulmón derecho, hígado y vesícula en la línea media, asplenia, malrotación intestinal y anomalías de la vena cava. Una heterotaxia derecha completa ha sido raramente descrita en la literatura. Los defectos de lateralización como situs inverso, asplenia o poli esplenia causados por defectos en el desarrollo izquierda derecha son considerados como defectos del campo de desarrollo primario. Por lo tanto, las manifestaciones adicionales del síndrome de Ivemark pueden ser defectos sincrónicos del campo de desarrollo primario más que malformaciones causalmente independientes.