Truncating variants in PAPSS2 gene: A cause of early prenatal onset brachyolmia?

Brachyolmia is a rare form of skeletal dysplasia characterized by a wide genetic and clinical heterogeneity. This condition is usually diagnosed postnatally, and very few cases of prenatal diagnosis have been described so far. Here, we report a case of a pregnant woman at 20 weeks' gestation referred to our center because of fetal short long bones. On targeted ultrasound, mild bowing of the femurs and fibulae and mild micrognathia were also observed. Exome sequencing analysis showed the presence in compound heterozygosity of two pathogenic variants-both truncating variants-in the 3-prime-phosphoadenosine 5-prime-phosphosulfate synthase 2 (PAPSS2) gene, known to cause brachyolmia type 4 (OMIM #612847). Of note, all of the few cases reported prenatally have indeed truncating variants. Hence, we speculate this kind of variant is likely responsible for a complete loss of function of the protein leading to an earlier and more severe phenotype.

Learning-based keypoint registration for fetoscopic mosaicking.

PURPOSE: In twin-to-twin transfusion syndrome (TTTS), abnormal vascular anastomoses in the monochorionic placenta can produce uneven blood flow between the two fetuses. In the current practice, TTTS is treated surgically by closing abnormal anastomoses using laser ablation. This surgery is minimally invasive and relies on fetoscopy. Limited field of view makes anastomosis identification a challenging task for the surgeon. METHODS: To tackle this challenge, we propose a learning-based framework for in vivo fetoscopy frame registration for field-of-view expansion. The novelties of this framework rely on a learning-based keypoint proposal network and an encoding strategy to filter (i) irrelevant keypoints based on fetoscopic semantic image segmentation and (ii) inconsistent homographies. RESULTS: We validate our framework on a dataset of six intraoperative sequences from six TTTS surgeries from six different women against the most recent state-of-the-art algorithm, which relies on the segmentation of placenta vessels. CONCLUSION: The proposed framework achieves higher performance compared to the state of the art, paving the way for robust mosaicking to provide surgeons with context awareness during TTTS surgery.

Placental vessel segmentation and registration in fetoscopy: Literature review and MICCAI FetReg2021 challenge findings.

Fetoscopy laser photocoagulation is a widely adopted procedure for treating Twin-to-Twin Transfusion Syndrome (TTTS). The procedure involves photocoagulation pathological anastomoses to restore a physiological blood exchange among twins. The procedure is particularly challenging, from the surgeon's side, due to the limited field of view, poor manoeuvrability of the fetoscope, poor visibility due to amniotic fluid turbidity, and variability in illumination. These challenges may lead to increased surgery time and incomplete ablation of pathological anastomoses, resulting in persistent TTTS. Computer-assisted intervention (CAI) can provide TTTS surgeons with decision support and context awareness by identifying key structures in the scene and expanding the fetoscopic field of view through video mosaicking. Research in this domain has been hampered by the lack of high-quality data to design, develop and test CAI algorithms. Through the Fetoscopic Placental Vessel Segmentation and Registration (FetReg2021) challenge, which was organized as part of the MICCAI2021 Endoscopic Vision (EndoVis) challenge, we released the first large-scale multi-center TTTS dataset for the development of generalized and robust semantic segmentation and video mosaicking algorithms with a focus on creating drift-free mosaics from long duration fetoscopy videos. For this challenge, we released a dataset of 2060 images, pixel-annotated for vessels, tool, fetus and background classes, from 18 in-vivo TTTS fetoscopy procedures and 18 short video clips of an average length of 411 frames for developing placental scene segmentation and frame registration for mosaicking techniques. Seven teams participated in this challenge and their model performance was assessed on an unseen test dataset of 658 pixel-annotated images from 6 fetoscopic procedures and 6 short clips. For the segmentation task, overall baseline performed was the top performing (aggregated mIoU of 0.6763) and was the best on the vessel class (mIoU of 0.5817) while team RREB was the best on the tool (mIoU of 0.6335) and fetus (mIoU of 0.5178) classes. For the registration task, overall the baseline performed better than team SANO with an overall mean 5-frame SSIM of 0.9348. Qualitatively, it was observed that team SANO performed better in planar scenarios, while baseline was better in non-planner scenarios. The detailed analysis showed that no single team outperformed on all 6 test fetoscopic videos. The challenge provided an opportunity to create generalized solutions for fetoscopic scene understanding and mosaicking. In this paper, we present the findings of the FetReg2021 challenge, alongside reporting a detailed literature review for CAI in TTTS fetoscopy. Through this challenge, its analysis and the release of multi-center fetoscopic data, we provide a benchmark for future research in this field.

Toward a navigation framework for fetoscopy.

PURPOSE: Fetoscopic laser photocoagulation of placental anastomoses is the most effective treatment for twin-to-twin transfusion syndrome (TTTS). A robust mosaic of placenta and its vascular network could support surgeons' exploration of the placenta by enlarging the fetoscope field-of-view. In this work, we propose a learning-based framework for field-of-view expansion from intra-operative video frames. METHODS: While current state of the art for fetoscopic mosaicking builds upon the registration of anatomical landmarks which may not always be visible, our framework relies on learning-based features and keypoints, as well as robust transformer-based image-feature matching, without requiring any anatomical priors. We further address the problem of occlusion recovery and frame relocalization, relying on the computed features and their descriptors. RESULTS: Experiments were conducted on 10 in-vivo TTTS videos from two different fetal surgery centers. The proposed framework was compared with several state-of-the-art approaches, achieving higher [Formula: see text] on 7 out of 10 videos and a success rate of [Formula: see text] in occlusion recovery. CONCLUSION: This work introduces a learning-based framework for placental mosaicking with occlusion recovery from intra-operative videos using a keypoint-based strategy and features. The proposed framework can compute the placental panorama and recover even in case of camera tracking loss where other methods fail. The results suggest that the proposed framework has large potential to pave the way to creating a surgical navigation system for TTTS by providing robust field-of-view expansion.

Second trimester fetal MRI of the brain: Through the ground glass.

Fetal MRI is an important tool for the prenatal diagnosis of brain malformations and is often requested after second-trimester ultrasonography reveals a possible abnormality. Despite the immature state of the fetal brain at this early stage, early suggestive signs of the presence of brain malformations can be recognized. To differentiate between the normal dynamics of the growing brain and the developing pathological conditions can be challenging and requires extensive knowledge of normal central nervous system developmental stages and their neuroradiological counterparts at those different stages. This article reviews the second-trimester appearances of some commonly encountered brain malformations, focusing on helpful tricks and subtle signs to aid in the diagnosis of such conditions as rhombencephalosynapsis, various causes of vermian rotation, molar tooth spectrum anomalies, diencephalic-mesencephalic junction dysplasia, ganglionic eminence anomalies, and the most common malformations of cortical development.

Prenatal diagnosis of Aicardi syndrome based on a suggestive imaging pattern: A multicenter case-series.

OBJECTIVES: To characterize a suggestive prenatal imaging pattern of Aicardi syndrome using ultrasound and MR imaging. METHODS: Based on a retrospective international series of Aicardi syndrome cases from tertiary centers encountered over a 20-year period (2000-2020), we investigated the frequencies of the imaging features in order to characterize an imaging pattern highly suggestive of the diagnosis. RESULTS: Among 20 cases included, arachnoid cysts associated with a distortion of the interhemispheric fissure were constantly encountered associated with complete or partial agenesis of the corpus callosum (19/20, 95%). This triad in the presence of other CNS disorganization, such as polymicrogyria (16/17, 94%), heterotopias (15/17, 88%), ventriculomegaly (14/20, 70%), cerebral asymmetry [14/20, 70%]) and less frequently extra-CNS anomaly (ocular anomalies [7/11, 64%], costal/vertebral segmentation defect [4/20, 20%]) represent a highly suggestive pattern of Aicardi syndrome in a female patient. CONCLUSION: Despite absence of genetic test to confirm prenatal diagnosis of AS, this combination of CNS and extra-CNS fetal findings allows delineation of a characteristic imaging pattern of AS, especially when facing dysgenesis of the corpus callosum.

Consensus on Training and Assessment of Competence in Performing Chorionic Villus Sampling and Amniocentesis: An International Delphi Survey.

INTRODUCTION: The aim of this study was to obtain expert consensus on the content of a curriculum for learning chorionic villus sampling (CVS) and amniocentesis (AC) and the items of an assessment tool to evaluate CVS and AC competence. METHODS: We used a 3-round iterative Delphi process. A steering committee supervised all processes. Seven international collaborators were identified to expand the breadth of the study internationally. The collaborators invited fetal medicine experts to participate as panelists. In the first round, the panelists suggested content for a CVS/AC curriculum and an assessment tool. The steering committee organized and condensed the suggested items and presented them to the panelists in round 2. In the second round, the panelists rated and commented on the suggested items. The results were processed by the steering committee and presented to the panelists in the third round, where final consensus was obtained. Consensus was defined as support by more than 80% of the panelists for an item. RESULTS: Eighty-six experts agreed to participate in the study. The panelists represented 16 countries across 4 continents. The final list of curricular content included 12 theoretical and practical items. The final assessment tool included 11 items, systematically divided into 5 categories: pre-procedure, procedure, post-procedure, nontechnical skills, and overall performance. These items were provided with behavioral scale anchors to rate performance, and an entrustment scale was used for the final overall assessment. CONCLUSION: We established consensus among international fetal medicine experts on content to be included in a CVS/AC curriculum and on an assessment tool to evaluate CVS/AC skills. These results are important to help transition current training and assessment methods from a time- and volume-based approach to a competency-based approach which is a key step in improving patient safety and outcomes for the 2 most common invasive procedures in fetal medicine.

L1CAM variants cause two distinct imaging phenotypes on fetal MRI.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.

The Human Fetal and Adult Stem Cell Secretome Can Exert Cardioprotective Paracrine Effects against Cardiotoxicity and Oxidative Stress from Cancer Treatment.

Cardiovascular side effects are major shortcomings of cancer treatments causing cardiotoxicity and late-onset cardiomyopathy. While doxorubicin (Dox) has been reported as an effective chemotherapy agent, unspecific impairment in cardiomyocyte mitochondria activity has been documented. We demonstrated that the human fetal amniotic fluid-stem cell (hAFS) secretome, namely the secreted paracrine factors within the hAFS-conditioned medium (hAFS-CM), exerts pro-survival effects on Dox-exposed cardiomyocytes. Here, we provide a detailed comparison of the cardioprotective potential of hAFS-CM over the secretome of mesenchymal stromal cells from adipose tissue (hMSC-CM). hAFS and hMSC were preconditioned under hypoxia to enrich their secretome. The cardioprotective effects of hAFS/hMSC-CM were evaluated on murine neonatal ventricular cardiomyocytes (mNVCM) and on their fibroblast counterpart (mNVFib), and their long-term paracrine effects were investigated in a mouse model of Dox-induced cardiomyopathy. Both secretomes significantly contributed to preserving mitochondrial metabolism within Dox-injured cardiac cells. hAFS-CM and hMSC-CM inhibited body weight loss, improved myocardial function, reduced lipid peroxidation and counteracted the impairment of mitochondrial complex I activity, oxygen consumption, and ATP synthesis induced by Dox. The hAFS and hMSC secretomes can be exploited for inhibiting cardiotoxic detrimental side effects of Dox during cancer therapy, thus ensuring cardioprotection via combinatorial paracrine therapy in association with standard oncological treatments.

A shape-constraint adversarial framework with instance-normalized spatio-temporal features for inter-fetal membrane segmentation.

BACKGROUND AND OBJECTIVES: During Twin-to-Twin Transfusion Syndrome (TTTS), abnormal vascular anastomoses in the monochorionic placenta can produce uneven blood flow between the fetuses. In the current practice, this syndrome is surgically treated by closing the abnormal connections using laser ablation. Surgeons commonly use the inter-fetal membrane as a reference. Limited field of view, low fetoscopic image quality and high inter-subject variability make the membrane identification a challenging task. However, currently available tools are not optimal for automatic membrane segmentation in fetoscopic videos, due to membrane texture homogeneity and high illumination variability. METHODS: To tackle these challenges, we present a new deep-learning framework for inter-fetal membrane segmentation on in-vivo fetoscopic videos. The framework enhances existing architectures by (i) encoding a novel (instance-normalized) dense block, invariant to illumination changes, that extracts spatio-temporal features to enforce pixel connectivity in time, and (ii) relying on an adversarial training, which constrains macro appearance. RESULTS: We performed a comprehensive validation using 20 different videos (2000 frames) from 20 different surgeries, achieving a mean Dice Similarity Coefficient of 0.8780±0.1383. CONCLUSIONS: The proposed framework has great potential to positively impact the actual surgical practice for TTTS treatment, allowing the implementation of surgical guidance systems that can enhance context awareness and potentially lower the duration of the surgeries.

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.

Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species.

Inter-foetus Membrane Segmentation for TTTS Using Adversarial Networks.

Twin-to-Twin Transfusion Syndrome is commonly treated with minimally invasive laser surgery in fetoscopy. The inter-foetal membrane is used as a reference to find abnormal anastomoses. Membrane identification is a challenging task due to small field of view of the camera, presence of amniotic liquid, foetus movement, illumination changes and noise. This paper aims at providing automatic and fast membrane segmentation in fetoscopic images. We implemented an adversarial network consisting of two Fully-Convolutional Neural Networks. The former (the segmentor) is a segmentation network inspired by U-Net and integrated with residual blocks, whereas the latter acts as critic and is made only of the encoding path of the segmentor. A dataset of 900 images acquired in 6 surgical cases was collected and labelled to validate the proposed approach. The adversarial networks achieved a median Dice similarity coefficient of 91.91% with Inter-Quartile Range (IQR) of 4.63%, overcoming approaches based on U-Net (82.98%-IQR: 14.41%) and U-Net with residual blocks (86.13%-IQR: 13.63%). Results proved that the proposed architecture could be a valuable and robust solution to assist surgeons in providing membrane identification while performing fetoscopic surgery.

Etiology of non-immune hydrops fetalis: An update.

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases.

Ultrasound assessment of the Essure contraceptive devices: is three-dimensional ultrasound really needed?

STUDY OBJECTIVE: To evaluate the feasibility of 3-dimensional ultrasound (3DUS) for sonographic localization of Essure microinserts, comparing it with 2-dimensional ultrasound (2DUS) insofar as time to visualize the inserts and accuracy in determining their localization. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: University clinic. PATIENTS: Twenty-seven consecutive women undergoing hysteroscopic Essure device placement. INTERVENTIONS: Essure microinserts were inserted in the outpatient hysteroscopy clinic following the manufacturer's recommendations, leaving from 3 to 8 loops of the inserts in the uterine cavity. In all patients, 2DUS and 3DUS were performed 3 months after the procedure. 2DUS was performed first; the device(s) were located, and their position was recorded. Then 3DUS scans were acquired, trying when possible to have both devices at least at a 45-degree angle with the insonation beam for optimal rendering on 3DUS. The OmniView method with volume contrast imaging was used to show the relationships of the microinserts within the uterine cavity when possible. To define the position of the Essure device in relation to the uterus and the salpinges, we used the classification developed by Legendre and colleagues. After sonographic evaluation all women underwent hysterosalpingography to assess the success of sterilization. MEASUREMENTS AND MAIN RESULTS: Hysteroscopic insertion was successful in all patients, with 2 Essure devices placed in 25 patients and 1 device in 2 patients (due to previous salpingectomy performed because of ectopic pregnancy), for a total of 52 devices. One spontaneous late (within 3 months) expulsion of the device occurred; the device had migrated almost completely into the uterine cavity. At 3-month follow-up, all 51 correctly placed devices were easily observed at 2DUS (mean [SD] duration of the procedure, 2.25 [0.8] minutes). At 3DUS in 51 cases, the device was in perfect position (1+2+3) in 21 (41.2%), in position 2+3 in 14 (27.4%), and in position +3 in 16 (31.4%). Both microinserts were observed on 3DUS reconstructed images in 31 of 35 (88.6%) 1+2+3 and 2+3 cases. However, in the 16 cases in which the devices were in position +3 (salpinx only), a single 3D sweep failed to demonstrate both devices in 10 of 16 cases (62.5%), due to substantially different angles of orientation of the inserts. This was because if 1 of the 2 devices was placed at a <30-degree angle with the insonation beam, its identification along the uterine wall was questionable because of concurrent hyperechogenicity of the bowel loops and poor visualization. Time for performance of 3DUS was 14.4 [4.8] minutes. Hysterosalpingography was performed in all patients, and confirmed tubal occlusion in all but 1 case. CONCLUSIONS: On the basis of a limited number of patients, 2DUS is more time-efficient and equivalent to 3DUS in locating Essure contraceptive microinserts. These results should be considered when planning sonographic follow-up of patients with Essure devices.

Pentalogy of Cantrell: embryofetoscopic diagnosis.

Embryofetoscopy is an endoscopic technique that permits a direct visualization and morphologic study of embryos during the first and early second trimester. We report the early prenatal diagnosis of a case of Pentalogy of Cantrell combining data obtained by 2-dimensional and 3-dimensional ultrasonography and embryofetoscopy. Morphologic examination focused on a large omphalocele protruding from the anterior abdominal wall as an oval pulsating mass, measuring approximately 3 cm. The visualization of an omphalocele with ectopia cordis without other malformations confirmed the diagnosis of Pentalogy of Cantrell (class III). Currently, embryofetoscopy allows direct visualization of the embryo in vivo, enabling accurate diagnosis of developmental defects and yielding additional insights into developmental disorders in the embryo.

Association of cutis laxa and genital prolapse: a case report.

Cutis laxa (CL) is an extremely inherited or acquired connective tissue disorder characterised by a markedly reduced systemic elastin content. Genital abnormalities in patients with CL have been rarely reported. We report such a case in a 48-year-old CL patient affected by genital prolapse, focusing on immunohistological and molecular biology assessment of elastin and collagen type I, III, VI content in the main uterine ligaments. The woman was referred to our department for the onset of a rapidly progressing genital prolapse and urinary incontinence. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and sacrocolpopexy. Punch biopsies from both cardinal and uterosacral ligaments revealed a dramatic reduction in elastin and an increase in collagen type VI content. The present report seems to underline the central role exerted primarily by elastin in the supportive connective tissue and might contribute to the knowledge of extracellular matrix abnormalities at the basis of genital abnormalities in CL patients.

Ultrasound characteristics of different types of adnexal malignancies.

OBJECTIVE: To describe ultrasound characteristics of adnexal malignancies, i.e., borderline ovarian tumors, primary invasive ovarian epithelial cancer stage 1, primary invasive ovarian epithelial cancer stages 2-4, rare types of malignancy, and metastatic tumors. METHODS: In a prospective international study involving nine European ultrasound centers, 1,066 women with a pelvic mass judged to be of adnexal origin underwent transvaginal gray scale and color Doppler ultrasound examination by a skilled examiner before surgery. A standardized examination technique and predefined definitions of ultrasound characteristics were used. RESULTS: Of 1,066 masses, 266 were malignant and are included: 55 ovarian borderline tumors, 144 primary invasive epithelial ovarian cancers (42 stage 1, 102 stages 2-4), 25 rare malignancies, and 42 metastatic tumors. Most (56%) metastatic tumors and most (60%) rare types of tumor were solid and richly vascularized at color Doppler ultrasound examination (on a scale ranging from 1 to 4, color score based on subjective evaluation was 3 or 4 in 88% and 86%, respectively). Borderline ovarian tumors and stage 1 primary invasive ovarian epithelial cancers differed from stages 2-4 primary invasive ovarian epithelial cancers: they were larger (median volume 375 ml and 695 ml vs. 209 ml; P = 0.0213 and 0.0001), a larger proportion contained papillary projections (64% and 67% vs. 41%; P = 0.0072 and 0.0054), they were more often multilocular cysts without solid components (18% and 14% vs. 2%; P < 0.0017 and 0.0204), but they were less often purely solid (5% and 7% vs. 38%; P

Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants.

OBJECTIVE: To evaluate the role of different polymorphic gene variants involved in homocysteine metabolism and plasma levels of homocysteine, folate and vitamin B12 in families from southern Italy with neural tube defects (NTDs). METHODS: Eighteen fathers, 15 NTD children and 60 women who had conceived NTD foetuses were investigated. A group of 100 adults and 43 apparently healthy children was used as control. At the time of blood draw, none were taking vitamin pills or nutritional supplements. RESULTS: Among controls, 79 (55.2%) were heterozygous for C677T MTHFR variant and 26 (18.2%) were TT homozygous. Among the cases, 35 (61.4%) out of 57 mothers and 7 (38.9%) out of 18 fathers carried the T allele; 12 (21.1%) mothers and 2 (11.1%) fathers had the TT genotype. Four (26.7%) out of 15 probands were TT homozygous and 11 (73.3%) were heterozygous (Fisher exact test p = 0.025). No significant difference between groups was observed for the 1298C MTHFR variant and CBS haplotypes. Median homocysteine in NTD children was significantly higher (10.0 micromol/L) than that of controls (median 4.5 micromol/L, Mann-Whitney p < 0.05). Folate and B12 were not different among groups. CONCLUSIONS: The T677 MTHFR allele is significantly associated with the occurrence of NTDs; no significant association has been observed with other genetic determinants analysed. Homocysteine levels in children with NTDs are significantly higher than those of the paediatric population from the same geographical area.