Irene A.L. Groenenberg

Phenotypic variability of atypical 22q11.2 deletions not including TBX1

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.

Using virtual reality for evaluation of fetal ambiguous genitalia

The utility of a virtual reality system was examined in the visualization of three‐dimensional (3D) ultrasound images of fetal ambiguous genitalia.

Doppler flow velocity waveforms in the fetal cardiac outflow tract reproducibility of waveform recording and analysis

Reproducibility of flow velocity waveform recording and analysis was studied at fetal cardiac level (ductus arteriosus, pulmonary artery and ascending aorta) in 42 normal pregnancies. The flow velocity parameters studied were the peak systolic velocity (PSV), acceleration time (ACT), acceleration velocity (ACV), average velocity (AV) and flow velocity integral (FVI). In each patient, two consecutive measurements were performed (time delay 15 min) and of each measurement two hardcopies were analysed. A high reproducibility was achieved for the PSV, AV and FVI in all vessels studied; the coefficients of variation between readings of hardcopies were less than or equal to 3%, and the coefficients of variation between tests within patients were less than or equal to 7%. A moderate reproducibility was achieved for the ACT in the ascending aorta and pulmonary artery; the variation between tests was large for the ductus arteriosus. The reproducibility of the ACV was poor.

Reproducibility of echocardiographic measurements of human fetal left ventricular volumes and ejection fractions using four-dimensional ultrasound with the spatio-temporal image correlation modality.

OBJECTIVES To determine the reproducibility, both reliability and agreement, of measurements of fetal left ventricular parameters from volumes obtained by spatio-temporal image correlation (STIC) acquisition applying virtual organ computer-aided analysis (VOCAL) and Simpsons rule (method of discs). Furthermore the success rate of STIC acquisition was determined. STUDY DESIGN In 84 pregnancies between 20 and 34 weeks of gestation the fetal heart was scanned using the STIC modality. An optimal four-chamber view in end-diastole and end-systole was obtained. Left ventricular end-diastolic volume, left ventricular end-systolic volume, stroke volume and ejection fraction were determined. For calculations based on Simpsons rule only one plane was traced, whereas for VOCAL six planes were traced. To quantify the reliability intraclass correlation coefficients were calculated for both intra- and inter-observer measurements. Agreement of measurements was evaluated by Bland-Altman plots. RESULTS The STIC volumes of 54 women (64%) were excluded from the study because of poor quality, leaving 30 volumes for further analysis. Intraclass correlation coefficients for intra-observer reliability for VOCAL and Simpson were 0.99 and 0.99 for left ventricular end-diastolic volume, 0.95 and 0.92 for left ventricular end-systolic volume, 0.98 and 0.97 for stroke volume, 0.76 and 0.77 for ejection fraction, respectively. Intraclass correlation coefficients for inter-observer reliability for VOCAL and Simpson were 0.97 and 0.86 for left ventricular end-diastolic volume, 0.97 and 0.86 for left ventricular end-systolic volume, 0.95 and 0.81 for stroke volume, 0.68 and 0.63 for ejection fraction, respectively. According to Bland-Altman plots, the mean percentage difference and 95% limits of intra- and inter-observer agreement for left ventricular stroke volume measurements using VOCAL were -0.2 (-25.1, 24.7)% and 2.8 (-34.2, 39.8)%, respectively. For left ventricular stroke volume measured with Simpson versus VOCAL the mean percentage difference and 95% limits of agreement were -1.8 (-22.1, 18.5)%. CONCLUSIONS 4D STIC enables reproducible measurements of left ventricular volumes. Reliability of the VOCAL mode is not essentially different from the single-plane method used in Simpsons rule. The large percentage of poor quality STIC volumes and the wide limits of inter-observer agreement would create obstacles for the clinical applicability of this technique.

Relationship between fetal cardiac and extra-cardiac Doppler flow velocity waveforms and neonatal outcome in intrauterine growth retardation

In a total of 42 consecutive pregnancies with intrauterine growth retardation (IUGR), Doppler velocimetry was related to neonatal outcome as determined by Apgar score at 1 min, umbilical artery acid-base status and PO2, number of nucleated red blood cells (NRBC), duration of ventilatory support, and sonographic appearance of cerebral leukomalacia. Doppler flow velocity waveforms were obtained from the ascending aorta (AO), pulmonary artery (PA), internal carotid artery (ICA) and umbilical artery (UA) at 2-3 day intervals until delivery. At cardiac level the peak systolic velocity (PSV) and time-averaged velocity (AV), and at peripheral level the pulsatility index (PI) was determined. As all Doppler parameters were significantly related to gestational age at birth, gestational age was taken into account in the analysis. There was no relationship between Apgar score, acid-base status and Doppler parameters. Low AVAO was related to a low umbilical artery PO2. Significant correlations were established between PSVPA, AVPA and PIUA, and the duration of neonatal ventilatory support. Infants who died within 22 days after admission to the neonatal intensive care unit (n = 7) displayed a significantly higher PIUA than those who remained alive. The PIUA was also related to the absolute and relative number of NRBCs. No relationship existed between the Doppler parameters and degree of leukomalacia. The present study demonstrates that from all Doppler parameters, the PIUA is most clearly related to neonatal outcome in IUGR.

The predictive value of Doppler flow velocity waveforms in the development of abnormal fetal heart rate traces in intrauterine growth retardation: a longitudinal study

In a longitudinal, blinded study design the predictive value of Doppler velocimetry for the development of an abnormal fetal heart rate trace was assessed in 42 cases of intrauterine growth retardation. Doppler velocity waveform recordings were obtained at 2- to 3-day intervals and characterized by the standard deviation score of the pulsatility index in the umbilical artery and internal carotid artery, and the peak systolic and time-averaged velocity in the ascending aorta and pulmonary artery. Twenty-seven patients did not display an abnormal fetal heart rate trace on the day of entry into the study. During follow-up of these patients, the pulsatility index in the umbilical artery and internal carotid artery were the most predictive parameters for the development of an abnormal fetal heart rate trace. The resulting prognostic index was found to have an acceptable discriminative power in the prediction of abnormal fetal heart rate traces as established in a second group of growth-retarded fetuses.

Growth trajectories of the human embryonic head and periconceptional maternal conditions

STUDY QUESTION Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? SUMMARY ANSWER Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. WHAT IS KNOWN ALREADY Fetal growth is influenced by periconceptional maternal conditions. STUDY DESIGN, SIZE, DURATION We selected 149 singleton pregnancies with a live born non-malformed fetus from the Rotterdam periconception cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. MAIN RESULTS A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! ρ = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! ρ = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. WIDER IMPLICATIONS OF THE FINDINGS Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. STUDY FUNDING/COMPETING INTERESTS This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

First-trimester diagnosis of thrombocytopenia-absent radius syndrome using virtual reality.

Introduction Thrombocytopenia-absent radius (TAR) syndrome is a rare condition characterized by hypomegakaryocytic thrombocytopenia and bilateral absence of the radius with presence of both thumbs. Thrombocytopenia is often symptomatic in the neonatal period and improves over time (Hall, 1987). A microdeletion of chromosome 1q21.1 is found in all investigated patients with TAR syndrome (Klopocki et al., 2007). However, the recessive inheritance pattern of TAR syndrome requires an additional causative allele that until recently was unknown. A low-frequency single-nucleotide polymorphism (SNP) in the RBM8A gene is detected as the second causative allele in the origination of TAR syndrome (Albers et al., 2012).

Differentiation of early first-trimester cranial neural tube defects

Neural tube defects (NTDs) are one of themost commonly reported birth defects and are the result of failure of primary neurulation, the folding and fusion of the neural plate1. We report on three early first-trimester cases with different types of cranial neural tube defects (NTD) not previously reported in ultrasound studies. Previously, it was believed that the process of neural tube closure occurred in a ‘zipper-like’ fashion, starting at one point and proceeding in both cranial and caudal directions. However, neural tube closure is a more complex process. More recently, Nakatsu et al. described three different closure initiation sites of the human neural tube after studying miscarried embryos2. Following from this closure model six different types of cranial NTDs were distinguished, based on location of the closure defect (Figure S1)2. Survival rates significantly decreased if the

Prenatal influence of congenital heart defects on trajectories of cortical folding of the fetal brain using three-dimensional ultrasound

The objective of the study is to investigate the prenatal influence of congenital heart defects (CHD) on trajectories of fetal cortical folding using three‐dimensional ultrasound (3D US).