Helmut Singer

First successful implantation of a biodegradable metal stent into the left pulmonary artery of a preterm baby

Stent implantation in the youngest patients with a congenital heart disease implicates limitations concerning further vessel growth, the need of staged redilation, and later surgical removal. The search to overcome these restrictions led to open stent designs, with a wide adaptability to the vessel growth and recently to the development of bioabsorbable stent materials. A preterm baby born at 26 weeks of gestation was referred to our clinic following inadvertent ligation of the left pulmonary artery. Despite efficient debanding, the left lung perfusion was absent. Implantation of a biodegradable 3 mm magnesium stent was performed in a hybrid procedure when the baby weighed 1.7 kg. Reperfusion of the left lung was established and persisted throughout the 4‐month follow‐up period during which the gradual degradation process of the stent completed. Additional interventions, should they become necessary, seem not to be limited. Despite the small size of the baby, the degradation process was clinically well tolerated. The mechanical and degradation characteristics of the magnesium stent proved to be adequate to secure reperfusion of the previously occluded left pulmonary artery. Bioabsorbable stents with different diameters may help develop new strategies in the therapy of vessel stenosis in pediatric patients.

Systematic assessment of atypical deletions reveals genotype–phenotype correlation in 22q11.2

Introduction: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients. Methods: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR. Results: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls. Discussion: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region.

Prenatal findings in patients with prolonged QT interval in the neonatal period

OBJECTIVE: To describe prenatal abnormalities of cardiac rhythm in patients with prolonged QT interval in the neonatal period. DESIGN: A retrospective analysis of the results of fetal echocardiography and the outcome in patients with prolonged QT interval in the neonatal period who had been referred for prenatal evaluation. SETTING: Two university hospitals. PATIENTS: Nine patients with prolonged QT interval in the neonatal period who had been referred for prenatal evaluation. Fetal echocardiograms were obtained from 24 to 40 weeks of gestation. Indications were fetal bradycardia (five patients), a family history of long QT syndrome (two patients), and complex arrhythmias (two patients). RESULTS: Seven fetuses had persistent sinus bradycardia without ventricular arrhythmias (heart rates 70-120 beats/ min). Five patients were treated with propranolol, after the diagnosis had been established by postnatal electrocardiogram (ECG). One of these patients died suddenly at the age of 3 weeks, after the treatment had been stopped because of profound bradycardia. One of the remaining two patients who did not receive propranolol had a syncope at the age of 6 weeks. Two fetuses presented with frequent runs of ventricular tachycardia and intermittent bradycardia caused by intermittent, functional second degree atrioventricular block. Both patients died on the first day of life despite treatment with propranolol and transvenous temporary pacing. CONCLUSIONS: Sinus bradycardia in an otherwise normal fetus may be a symptom of long QT syndrome. Postnatal ECGs and a family examination are strongly recommended in these children. In fetuses with frequent runs of ventricular tachycardia and intermittent second degree atrioventricular block long QT syndrome should be suspected prenatally. These high risk patients should be delivered in centres with a paediatric cardiology unit.

Comprehensive genotype–phenotype analysis in 230 patients with tetralogy of Fallot

Background Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype–phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated. Methods and results 230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. Conclusion This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.

A Novel 22q11.2 Microdeletion in DiGeorge Syndrome

We thank the family for their cooperation and patience, and we thank Silke Appel (Berlin) for help with the BAC screening.

Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch.

Interruption of the aortic arch (IAA) is a severe malformation of the heart with known association to DiGeorge syndrome (DGS) and 22q11.2 hemizygosity. The aim of this study was to establish incidence and significance of 22q11.2 hemizygosity in an unbiased sample of patients with IAA. All 15 children with IAA who were referred to our hospital in a 3-year period were tested by chromosome and fluorescence in situ hybridization (FISH) analysis with the probes D22S75, Tuplel, and cHKAD26 and by a set of 10 simple tandem repeat polymorphic (STRP) markers. In nine of 11 children with IAA type B, 22q11.2 hemizygosity was demonstrated by FISH and STRP analysis, but in none of the four children with type A. In all but one child, deletion size was approximately 3 Mb. The girl with the smaller deletion of approximately 1.5 Mb differed because of an Ullrich-Turner syndrome-like phenotype and severe T-cell defect. Additionally, in one patient with phenotypic signs of DGS, a small deletion distal to the known DGS region containing the marker D22S308 was suspected by STRP analysis. One deletion was shown to be inherited from a healthy father and one IAA type A recurred in a sib. T-cell anomalies were evident in eight of the nine children with classical deletion, five of whom suffered also from hypoparathyroidism. With respect to cause and clinical course, IAA type A and B were shown to represent different entities. This study showed that variable symptoms of 22q11.2 hemizygosity may cluster.

Prenatal diagnosis of QT prolongation by magnetocardiography.

Magnetocardiogrciphy constitutes a new tool for monitoring fetal cardiac activity. The fetal magnetocardiogram (FMCG) recorded noninvasively over the maternal abdomen is detectable with high temporal resolution and permits analysis of all parts of the PQRST waveform. In this way measurements of cardiac time intervals, including the QT interval, become possible. The following article constitutes the first report of antenatal detection of QT prolongation in two fetuses by FMCG.

Usefulness of magnetocardiography for the investigation of fetal arrhythmias

The electrical excitation of the heart causes weak magnetic fields that can be recorded without skin contact over the body surface. Cardiac magnetic activity measures in the range of 0.2 to 5 picotesla (pT) in fetuses and 50 pT in adults, thus approximately 1 million times weaker than the static magnetic field of the earth. Therefore, it was not until the introduction of highly sensitive Superconducting Quantum Interference Device detectors and multichannel equipment that sensitive and low-noise registrations of cardiac magnetic fields became feasible in clinical practice. In 1974, the first fetal “magnetocardiogram” was published by Kariniemi and coworkers 1 ; later studies demonstrated the ability of magnetocardiography (MCG) to detect noninvasively fetal cardiac activity with high resolution and success rates from the second trimester onward. 2‐ 4 MCG provides information equivalent to the surface electrocardiogram (ECG), which is obviously unsuccessful in fetuses. Especially in late pregnancy, the signal of the fetal ECG is severely attenuated due to the insulating properties of the vernix caseosa and volume conduction effects. 5 Although Doppler echocardiography constitutes the gold standard for the analysis of fetal arrhythmias, MCG offers insights into electrophysiologic features of prenatal arrhythmias. An increasing number of recent publications emphasize interest in this field. 6‐ 9 In the present study, we investigated the feasibility of MCG in a clinical work routine to

B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavopulmonary connection.

To assess plasma B‐type natriuretic peptide (BNP) levels in patients with univentricular hearts late after volume unloading by total cavopulmonary connection (TCPC).

First biodegradable metal stent in a child with congenital heart disease: Evaluation of macro and histopathology

New developments in stent technology led to the first biodegradable magnesium stents. To overcome the fundamental restrictions of conventional stent implantation, these new stents may improve interventional therapy, also in small children. What remains after complete degradation of a magnesium stent is of particular interest and concern. At the autopsy, 2 months after the projected complete degradation time of the 3.0 × 10 mm2 stent, no solid compounds were detected, and the vessel diameter had increased slightly to 3.7 mm. Histological preparation revealed an amorphous to jelly‐like substitute of the magnesium struts mainly consisting of calcium phosphate covered by fibrotic tissue. Immunological staining revealed no relevant inflammatory reaction to the stent material. Neointima proliferation was detected around the struts with some cellular infiltration of the calcium‐phosphate material. These pathological and histological findings show minimal alteration of the vessel wall and an increase of the arterial diameter after stent degradation. This is an important precondition for further use of biodegradable stents in small infants. Further observations have to prove whether these findings do reproduce in other settings also.