Right-atrial isomerism (RAI) is a heterotaxy syndrome with disturbances of left–right axis development resulting in complex heart malformations and anomalies of the thoracic and abdominal organs. To ...study the outcome of RAI, all data from patients diagnosed with this syndrome at Helsinki University Hospital between January 1976 and December of 2010 were reviewed. The outcomes were studied for 32 patients (38 % girls). The overall survival was 22 % at a median follow-up time of 13.8 years (range 0.1–33). Extracardiac malformations, mostly asplenic, occurred in 91 % of patients. Cardiac defects included dextrocardia in 44 % and common atrioventricular valve in 100 % of patients. Ventriculoarterial discordance or double-outlet ventricle was seen in 56 and 44 % of patients, respectively. Total anomalous pulmonary venous drainage occurred in 75 % and partially anomalous venous drainage in 13 % of patients. Pulmonary outflow-tract obstruction was identified in 91 % of patients. Cardiac arrhythmias were noted in nine patients (28 %), two of them with atrioventricular block. Cardiovascular surgery was performed in 71 % patients (
N
= 25), seven patients were inoperable. Biventricular repair was not possible in any of the patients. During long-term follow-up there was no significant difference between the patients with total, normal, or partially anomalous pulmonary venous drainage (
P
= 0.5). In conclusion, RAI is one of the most severe forms of congenital cardiac diseases. The prognosis remains poor despite modern surgical techniques. When RAI is identified during pregnancy, prenatal counseling, termination, or planning for prompt cardiac treatment after the birth is necessary.
Objective Despite improved survival and neurodevelopmental outcome, children with hypoplastic left heart syndrome and other forms of univentricular heart remain at increased risk for cognitive, ...motor, and other neurologic deficits. Methods We examined 27 children with hypoplastic left heart syndrome or other forms of univentricular heart at a median age of 5.70 years (range 4.99–7.51 years) and performed brain computed tomography or magnetic resonance imaging on 20. Possible risk factors were correlated with outcome. Results Mean full-scale IQ among patients with hypoplastic left heart syndrome was 86.7; that among patients with other forms of univentricular heart was 89.1, with both differing significantly from the expected population mean ( P = .015 and P = .029, respectively). Cerebral palsy was diagnosed in 1 of 7 patients with hypoplastic left heart syndrome and 2 of 20 with other forms of univentricular heart. Brain computed tomography or magnetic resonance imaging revealed ischemic changes and infarcts or atrophy in 5 of 8 patients who had undergone the Norwood procedure and in 2 of 12 of those who had not ( P = .062). Abnormal computed tomographic findings correlated significantly with lower full-scale IQ ( P = .045) and verbal IQ ( P = .02). In the multiple linear regression model, diuresis the third day after the primary operation and cardiopulmonary bypass time in the bidirectional Glenn operation correlated significantly with the primary outcome of full-scale IQ. Conclusion In children with univentricular heart, intellectual and neurologic deficits are common. Perioperative and postoperative risk factors related to the primary phase and bidirectional Glenn operation contribute to these deficits.
Left atrial isomerism includes a complex spectrum of cardiac and extracardiac anomalies. The records of all patients with left isomerism born during the period of 1973–2010 and treated at the ...Children’s Hospital, Helsinki were reviewed. The short- and long-term outcomes were studied. The review included 38 patients (50% females). The overall survival with left atrial isomerism was 63% during a median follow-up time of 16 years (range, 4–30 years). Extracardiac anomalies were noted in 14 (37%) of 38 cases. Cardiac defects included dextrocardia in 26%, partially or totally anomalous pulmonary venous return in 29%, common atrium in 50%, atrioventriculoseptal defect in 73%, single ventricle in 40%, ventriculoseptal defect without atrioventricular defect in 11%, transposition in 21%, double outlet of the right ventricle in 26%, pulmonary stenosis or atresia in 61%, and left ventricular outflow obstruction in 24% of the cases. Cardiac arrhythmias were presented in 71% and pacemaker treatment in 29% of the cases. Of the 38 patients, 33 had cardiac surgery. Simple palliative methods were used in 11 cases, single-ventricle palliation in 12 cases, and operation with a biventricular track in 10 cases. In the groups that had surgery, 3 of 11 patients, 3 of 12 patients, and 3 of 10 patients died, respectively. In this review, 14 deaths occurred, associated with extracardiac anomalies in five cases and with cardiac arrhythmia in four cases. Five postoperative deaths occurred. At this writing, all three patients who had heart transplantation are alive. Complicated heart defects associated with severe arrhythmias and extracardiac anomalies contribute to a high mortality rate with left isomerism. Cardiac transplantation was considered a good option for selected patients.
Objectives Despite recent advances in the treatment of children with univentricular heart, their neurodevelopmental outcome remains a major concern. Methods This prospective follow-up study evaluated ...the neurodevelopmental outcome of 23 patients with hypoplastic left heart syndrome, 14 with other forms of univentricular heart, and 46 healthy control subjects at a median age of 12.2 months. The Griffiths Developmental Scale and Alberta Infant Motor Scale served for developmental evaluation. Results The mean Griffiths developmental quotient of children with hypoplastic left heart syndrome was significantly less (91.6) than that of control children (106.8, P < .001). Patients with univentricular heart scored significantly lower than control subjects only in the gross motor domain ( P = .001) but not in overall development (100.6). Alberta Infant Motor Scale scores were significantly lower in children with hypoplastic left heart syndrome (37.5, P < .001) and univentricular heart (43.5, P = .011) than in control subjects (53.3). In linear regression a diagnosis of hypoplastic left heart syndrome ( P = .016), a clinical history of seizure ( P = .002), and the highest plasma lactate level after the bidirectional Glenn operation ( P = .045) were significantly associated with the developmental quotient. Conclusions At age 1 year, the level of development of children with univentricular heart was significantly lower than for control subjects only in motor skills, whereas children with hypoplastic left heart syndrome had a more widespread developmental delay. The diagnosis, a clinical seizure history, and increased plasma lactate levels after the bidirectional Glenn operation emerged as risk factors.
To study the autoimmune response in mothers of children with isolated congenital heart block (CHB) and heart block (HB) diagnosed postnatally.
We reviewed the Finnish hospital registries for patients ...born between 1950 and 2000 and diagnosed with isolated HB before the age of 16 years. Clinical data and sera for the determination of autoantibodies were available from 67 mothers of children with CHB and from 37 mothers of children with postnatally diagnosed HB 9.9 years and 22.6 years (mean) after the index delivery, respectively. Maternal antibodies to 52 kDa and 60 kDa SSA and 48 kDa SSB were determined by time-resolved fluoroimmunoassay (TR-FIA) and by immunoblotting. Other marker antibodies for connective tissue diseases (CTD) were determined by immunoblot and/or by immunofluorescence. The control group comprised 136 mothers with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), or other CTD with healthy children.
Sixty of our 67 mothers (90%) of children with CHB had antibodies to SSA or SSB by the methods initially used in this study. When retests and tests performed previously were taken into account, only 3 (4%) of the 67 mothers did not have any autoantibodies. Two (3%) of the 67 mothers had antibodies to dsDNA and one (1%) each to Jo-1/HRS, RNP-70 kDa, and histone proteins. Of 37 mothers of children with postnatally diagnosed HB, only 3 (8%) had any autoantibodies. Increased risk of having a child with CHB was indicated by maternal primary SS and high levels of anti-SSA and anti-SSB by all assays, whereas low risk was indicated by maternal SLE or other CTD and undetectable or low levels of the antibodies. No single anti-SSA or anti-SSB test was clearly superior to others, but in general, immunoblots were more specific than TR-FIA.
Maternal autoimmune disorder is almost always associated with CHB but only rarely with postnatally diagnosed HB. Anti-SSA and anti-SSB are marker antibodies for mothers of children with CHB, and an increased risk of having an affected child is indicated by maternal primary SS and high titer antibodies to SSA and SSB.
Potent cytotoxic responses can be mediated by HLA-C both in the context of NK and CD8+ T cells recognition, but with low level cell surface expression and a more restricted peptide binding, this HLA ...distinguishes itself among the class I molecules.3 Interestingly, immunohistology of heart tissue of fetuses deceased from CHB shows CD8+ T cells in the mononuclear cell infiltrates,4 indicating a direct role for HLA class I peptide presentation to CD8+ T cells in the disease pathogenesis. There are many reports of negative DRB1*13 associations in European populations with autoimmune diseases.6 We therefore hypothesise that the protective DRB1*13 association with CHB depends on a general mechanism of protection from inflammation shared among autoimmune diseases, and interpret the observed lack of significantly associated HLA alleles that increase susceptibility to CHB as consistent with the fact that the pathogenic CHB-initiating autoantibodies are generated in the mother. Funding The study was supported by grants from the Swedish Research Council, the Heart-Lung Foundation, the Stockholm County Council, Karolinska Institutet, the Swedish Rheumatism Association, the King Gustaf Vth 80-year Foundation and the Freemason’s in Stockholm Foundation for Children’s Welfare.
Objective: The prevalence and types of various cardiovascular diseases in different age groups as well as the outcomes of cardiac surgery and other interventions were assessed in a population of 75 ...Williams syndrome (WS) patients aged 4 months to 76 years (median 22.7 years). Study design: The diagnosis of WS was in each case confirmed by the clinical phenotype and by a FISH test showing elastin hemizygosity. Clinical and operative data were collected from all hospitals where the patients had been treated. Results: Cardiovascular symptoms were evident in 35 of 75 (47%) WS children at birth. During follow up, 44 of 75 (53%) WS patients were found to have cardiovascular defects. Among them, the definitive diagnosis was made before 1 year of age in 23 (52%) infants, between 1 year and 15 years of age in 14 (32%) children, and older than 15 years of age in 7 (16%) adults. Multiple obstructive cardiovascular diseases were found in six infants. Supravalvular aortic stenosis (SVAS) was diagnosed in 32/44 (73%), pulmonary arterial stenosis (PAS) in 18/44 (41%), aortic or mitral valve defect in 5/44 (11 %) of cases, and tetralogy of Fallot in one (2%) case. Altogether, 17/44 (39 %) underwent surgery or intervention. Surgery was most frequently performed in the infant group (6% v 21% v 0%, p=0.004). After 1 year of age, seven patients underwent SVAS relief and two cases PAS relief. Postoperatively there was no mortality (median follow up time 6.9 years). Arterial hypertension was found in 55% of adults. In three adults, arterial vasculopathy was not diagnosed until necropsy. Conclusions: Our data indicate the following in WS. Cardiac symptoms are common in neonates. Heart disease diagnosed in infancy frequently requires operation. After 1 year of age, PAS tends to improve and SVAS to progress. Life long cardiac follow up is necessary because of the risks of developing vasculopathy or arterial hypertension.
Introduction
Increased nuchal translucency is known to be associated with chromosomal and structural defects and genetic syndromes. Little is known about the overall long‐term outcome of euploid ...children after increased nuchal translucency. The aims of this study were to assess the additional structural defects diagnosed after discharge from the delivery hospital and the long‐term overall outcome of euploid children after increased nuchal translucency and normal second trimester anomaly scan.
Material and methods
All children from singleton euploid pregnancies during 2002–2007 with increased nuchal translucency in the first trimester screening, normal second trimester anomaly scan, and discharged as apparently healthy were included. Data on the structural defects and genetic disorders diagnosed until 2012 were retrieved from hospital databases and national registers. Previously published data of structural defects diagnosed after birth but before discharge and of severe neurodevelopmental impairment and genetic syndromes was added.
Results
The cohort included 733 children. During the follow‐up time (mean 6.5 years), major structural defects were observed in 10 (1.4%), genetic disorders in two (0.3%), and minor defects in 23 (3.1%) children. In addition, there were 42 previously published major structural defects and major neurodevelopmental impairment or genetic disorders. Adding these results together, major health problems were detected in 54 (7%) euploid children with increased fetal nuchal translucency and normal findings in second trimester anomaly scan.
Conclusion
Although only few additional major structural defects are diagnosed during the follow‐up after increased fetal nuchal translucency, 7% of fetuses assumed to be healthy after second trimester anomaly scan have a major health impairment.
Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left–right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and ...abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. Here we identify the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. This finding, supported by the similar phenotype in Gdf1 knockout mouse, provides firm evidence that RAI can occur as a recessively inherited condition, with GDF1 as the culprit gene. The results will shed light on the biological basis of human laterality defects and facilitate molecular diagnosis of RAI.
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