Anton H. J. Koning

Cohort Profile: The Rotterdam Periconceptional Cohort (Predict Study)

Cohort Profile: The Rotterdam Periconceptional Cohort (Predict Study) Régine PM Steegers-Theunissen,* Jennifer JFM Verheijden-Paulissen, Evelyne M van Uitert, Mark F Wildhagen, Niek Exalto, Anton HJ Koning, Alex J Eggink, Johannes J Duvekot, Joop SE Laven, Dick Tibboel, Irwin Reiss and Eric AP Steegers Department of Obstetrics and Gynaecology, Research Office Sophia Sophia, Department of Bioinformatics, Intensive Care and Department of Pediatric Surgery and Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Huvariome: a web server resource of whole genome next-generation sequencing allelic frequencies to aid in pathological candidate gene selection

BackgroundNext generation sequencing provides clinical research scientists with direct read out of innumerable variants, including personal, pathological and common benign variants. The aim of resequencing studies is to determine the candidate pathogenic variants from individual genomes, or from family-based or tumor/normal genome comparisons. Whilst the use of appropriate controls within the experimental design will minimize the number of false positive variations selected, this number can be reduced further with the use of high quality whole genome reference data to minimize false positives variants prior to candidate gene selection. In addition the use of platform related sequencing error models can help in the recovery of ambiguous genotypes from lower coverage data.DescriptionWe have developed a whole genome database of human genetic variations, Huvariome, determined by whole genome deep sequencing data with high coverage and low error rates. The database was designed to be sequencing technology independent but is currently populated with 165 individual whole genomes consisting of small pedigrees and matched tumor/normal samples sequenced with the Complete Genomics sequencing platform. Common variants have been determined for a Benelux population cohort and represented as genotypes alongside the results of two sets of control data (73 of the 165 genomes), Huvariome Core which comprises 31 healthy individuals from the Benelux region, and Diversity Panel consisting of 46 healthy individuals representing 10 different populations and 21 samples in three Pedigrees. Users can query the database by gene or position via a web interface and the results are displayed as the frequency of the variations as detected in the datasets. We demonstrate that Huvariome can provide accurate reference allele frequencies to disambiguate sequencing inconsistencies produced in resequencing experiments. Huvariome has been used to support the selection of candidate cardiomyopathy related genes which have a homozygous genotype in the reference cohorts. This database allows the users to see which selected variants are common variants (> 5% minor allele frequency) in the Huvariome core samples, thus aiding in the selection of potentially pathogenic variants by filtering out common variants that are not listed in one of the other public genomic variation databases. The no-call rate and the accuracy of allele calling in Huvariome provides the user with the possibility of identifying platform dependent errors associated with specific regions of the human genome.ConclusionHuvariome is a simple to use resource for validation of resequencing results obtained by NGS experiments. The high sequence coverage and low error rates provide scientists with the ability to remove false positive results from pedigree studies. Results are returned via a web interface that displays location-based genetic variation frequency, impact on protein function, association with known genetic variations and a quality score of the variation base derived from Huvariome Core and the Diversity Panel data. These results may be used to identify and prioritize rare variants that, for example, might be disease relevant. In testing the accuracy of the Huvariome database, alleles of a selection of ambiguously called coding single nucleotide variants were successfully predicted in all cases. Data protection of individuals is ensured by restricted access to patient derived genomes from the host institution which is relevant for future molecular diagnostics.

Human embryonic growth and development of the cerebellum using 3-dimensional ultrasound and virtual reality.

The aim of our study was to evaluate the first trimester cerebellar growth and development using 2 different measuring techniques: 3-dimensional (3D) and virtual reality (VR) ultrasound visualization. The cerebellum measurements were related to gestational age (GA) and crown-rump length (CRL). Finally, the reproducibility of both the methods was tested. In a prospective cohort study, we collected 630 first trimester, serially obtained, 3D ultrasound scans of 112 uncomplicated pregnancies between 7 + 0 and 12 + 6 weeks of GA. Only scans with high-quality images of the fossa posterior were selected for the analysis. Measurements were performed offline in the coronal plane using 3D (4D view) and VR (V-Scope) software. The VR enables the observer to use all available dimensions in a data set by visualizing the volume as a “hologram.” Total cerebellar diameter, left, and right hemispheric diameter, and thickness were measured using both the techniques. All measurements were performed 3 times and means were used in repeated measurements analysis. After exclusion criteria were applied 177 (28%) 3D data sets were available for further analysis. The median GA was 10 + 0 weeks and the median CRL was 31.4 mm (range: 5.2-79.0 mm). The cerebellar parameters could be measured from 7 gestational weeks onward. The total cerebellar diameter increased from 2.2 mm at 7 weeks of GA to 13.9 mm at 12 weeks of GA using VR and from 2.2 to 13.8 mm using 3D ultrasound. The reproducibility, established in a subset of 35 data sets, resulted in intraclass correlation coefficient values ≥0.98. It can be concluded that cerebellar measurements performed by the 2 methods proved to be reproducible and comparable with each other. However, VR—using all three dimensions—provides a superior method for the visualization of the cerebellum. The constructed reference values can be used to study normal and abnormal cerebellar growth and development.

Diagnostic techniques and criteria for first-trimester conjoined twin documentation: a review of the literature illustrated by three recent cases.

Objectives Conjoined twins are rare. High-quality imaging techniques are essential for proper first-trimester diagnosis. Technological development leads to new imaging techniques such as 3-dimensional virtual embryoscopy. The aim of this review was to explore imaging techniques used in the first-trimester diagnosis of conjoined twins and provide a systematic diagnostic table for making this diagnosis. Design A PubMed literature search was performed using the terms ultrasound, Doppler, MRI, and CT combined with first-trimester and conjoined twins. Three recent cases at our department are reviewed and examined additionally using 3-dimensional virtual embryoscopy. Results The different types of conjoined twins are summarized in a table for practical use during ultrasound examination. In evaluating conjoined twins, 2-dimensional ultrasound is the criterion standard. Three-dimensional and Doppler ultrasounds add anatomical and prognostic information. Virtual embryoscopy imaging reveals additional findings in our 3 cases not seen with routine 2-dimensionalultrasound examination. Conclusions Each case of conjoined twins is unique and should be evaluated with the best possible imaging techniques. Three-dimensional and Doppler ultrasound should be added to the systematic diagnostic evaluation of conjoined twins. Virtual embryoscopy imaging may contribute to earlier, more appropriate counseling and management of these pregnancies. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to differentiate between the different types of conjoined twins and their prognosis, compare the different imaging techniques used for the evaluation of conjoined twins to decide whether additional diagnostic imaging techniques are useful in an individual case, and evaluate complex cases, such as conjoined twins, using new imaging techniques.

Abdominal rectus muscle atrophy and midline shift after colostomy creation

INTRODUCTIONnIncisional hernia (IH) can be attributed to multiple factors. The presence of a parastomal hernia has shown to be a risk factor for IH after midline laparotomy. Our hypothesis is that this increased risk of IH may be caused by changes in biomechanical forces, such as midline shift to the contralateral side of the colostomy owing to decreased restraining forces at the site of the colostomy, and left abdominal rectus muscle (ARM) atrophy owing to intercostal nerve damage.nnnMETHODSnPatients were selected if they underwent end-colostomy via open operation between 2004 and 2011. Patients were eligible if computed tomography (CT) had been performed postoperatively. If available, preoperative CTs were collected for case-control analyses. Midline shift was measured using V-scope application in the I-space, a CAVE-like virtual reality system. For the ARM atrophy hypothesis, measurements of ARM were performed at the level of colostomy, and 3 and 8 cm cranial and caudal of the colostomy.nnnRESULTSnPostoperative CT were available for 77 patients; of these patients, 30 also had a preoperative CT. Median follow-up was 19 months. A mean shift to the right side was identified after preoperative and postoperative comparison; from -1.3 ± 4.6 to 2.1 ± 9.3 (P = .043). Furthermore, during rectus muscle measurements, a thinner left ARM was observed below the level of colostomy.nnnDISCUSSIONnCreation of a colostomy alters the abdominal wall. Atrophy of the left ARM was seen caudal to the level of the colostomy, and a midline shift to the right side was evident on CT. These changes may explain the increased rate of IH after colostomy creation.

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).

Evaluation of First-Trimester Physiological Midgut Herniation Using Three-Dimensional Ultrasound

Introduction: The aim of this study was to investigate the development of midgut herniation in vivo using three-dimensional (3D) ultrasonographic volume and distance measurements and to create reference data for physiological midgut herniation in ongoing pregnancies in a tertiary hospital population. Materials and Methods: The transvaginal 3D ultrasound volumes of 112 women, seen weekly during the first trimester of pregnancy, were obtained and subsequently analysed in a virtual reality environment. The width of the umbilical cord insertion, the maximum diameter of the umbilical cord, and the volume of midgut herniation were measured from 6 until 13 weeks gestational age (GA). Results: All parameters had a positive relation with GA, crown-rump length, and abdominal circumference. In approximately 1 of 10 volumes no midgut herniation could be observed at 9 and 10 weeks GA. In 5.0% of the fetuses the presence of midgut herniation could still be visualised at 12 weeks GA. Conclusion: Reference charts for several dimensions of physiological midgut herniation were created. In the future, our data might be used as a reference in the first trimester for comparison in case of a suspected pathological omphalocele.

Reply to "Can we avoid rectus abdominis muscle atrophy and midline shift after colostomy creation?".

markdownabstractWe read with interest the letter to the editor by Stephenson et al regarding our article “Abdominal rectus muscle atrophy and midline shift after colostomy creation.” Any attempt to decrease the risk of parastomal herniation should be applauded, because its incidence of greater than 50% remains unacceptably high. Transrectus vs pararectal stoma placement has been subject to discussion for quite some time, is retrospective in nature, and thus the level of evidence is low. The most recent Cochrane review concludes that the poor quality of the included evidence did not allow a robust conclusion. In addition, no difference could be discovered after we pooled all studies, which comprised a total number of 761 patients. Furthermore, the authors describe in their letter that they could not observe a midline shift in their trial; however, as we mention in our study, we could only determine the true midline by using the I-Space, a CAVE-like virtual reality system and V-scope software, so we are interested as to how the authors determined a midline without these tools. nnApplying new techniques to prevent this complication seems highly relevant, because the impact of parastomal hernia on the quality of life of patients should not be underestimated (unpublished results). Placement of the stoma lateral to the rectus muscles could possibly decrease the rate of parastomal hernia, as is suggested by the retrospective study of Stephenson et al. The intercostal nerves are less segmented lateral to the stoma and could be easier to detect and preserve. Randomized, controlled trials, however, are needed to evaluate the effect of this technique. A possible technique for parastomal hernia prevention is the use of primary mesh augmentation. A meta-analysis focusing on primary mesh augmentation showed a decrease in parastomal hernia with a risk ratio of 0.23. Interestingly, no mesh infections were reported in any of the randomized controlled trials, but the use of prosthetic material in potentially contaminated areas are still a subject of debate. Possibly, the long-term results of the PREVENT trial could give us more information regarding this prevention method.

OP21.01: Early pregnancy placental bed and foetal vascular volume measurements using three dimensional virtual reality

A 15 year old female diagnosed with Klippel Trenaunay Syndrome, a congenital vascular disorder, initially presented with continuous bleeding following menarche at age 11. Her symptoms were controlled with Depoprovera for 2.5 years. The patient returned with 6 month duration of dysfunctional uterine bleeding. MRI and ultrasound were performed prior to hysteroscopy with removal of clot from the uterus. She was placed on a GnRh agonist with no improvement in her bleeding pattern. She required blood transfusions prior to undergoing definitive therapy. Following further imaging evaluation with MRI, CT, and serial ultrasounds for identification of abnormal vasculature in the pelvis and uterus, a total abdominal hysterectomy was performed. MRI, CT, and ultrasound demonstrated the abnormal vasculature in the pelvis and associated with the uterus. Ultrasound and MRI were excellent at evaluating myometrial thickness. Ultrasound was a safe, noninvasive, and less expensive imaging modality for monitoring and preoperative evaluation of this patient compared to MRI and CT as ultrasound does not require intravenous contrast administration or utilize radiation. Additionally, serial imaging studies are necessary in these patients as myometrial compression by endometrial contents appears to alter visualization and localization of small venous abnormalities associated with this disease process.

OP38.02: Diagnostic techniques and criteria for first trimester conjoined twin evaluation

Normal first-trimester fetuses display a characteristic gap between the right and left body of the mandible in this view (the ‘‘mandibular gap’’). The presence or absence of this gap was evaluated and measured prospectively during real-time scanning (n = 100) and retrospectively by analyzing three-dimensional (3D) volume datasets (n = 50) in normal first-trimester fetuses undergoing screening for aneuploidy at 11–13 weeks of gestation. 3D volume datasets from 12 fetuses with suspected micrognathia were also collected and examined retrospectively for the same features. Results: The mandibular gap was identified in all 150 normal fetuses and measured between 2.2–3.7 mm (mean, 2.8) with no significant differences between measurements obtained by two-dimensional ultrasound and 3D off-line analysis. Among fetuses with suspected micrognathia, 3 3D volume datasets were excluded from analysis because of poor image quality in 1 and the diagnosis of a normal chin in 2. In the remaining 9 fetuses, the mandibular gap was absent and was replaced by a bony structure representing the receding chin in 7 (78%) cases and not visualized due to severe retrognathia in the remaining 2 (22%) cases. All fetuses with micrognathia had associated anomalies, including 5 with aneuploidy, 2 with skeletal dysplasias, and 2 with a genetic syndrome. Conclusions: The RNT view may be a helpful technique to detect severe micrognathia in the first trimester. The absence of the mandibular gap or failure to identify the mandible in this view is highly suggestive of micrognathia and should prompt a targeted ultrasound to assess for other anomalies. Further research is needed to determine the false positive and negative rates of this technique.