De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops.

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.

Growth, body composition, and endocrine-metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies.

Mendelian neurodevelopmental disorders caused by variants in genes encoding chromatin modification can be categorized as Mendelian disorders of the epigenetic machinery (MDEMs). These disorders have significant overlap in molecular pathways and phenotypes including intellectual disability, short stature, and obesity. Among the MDEMs is Kleefstra syndrome (KLFS), which is caused by haploinsufficiency of EHMT1. Preclinical studies have identified metabolic dysregulation and obesity in KLFS models, but proper clinical translation lacks. In this study, we aim to delineate growth, body composition, and endocrine-metabolic characteristics in a total of 62 individuals with KLFS. Our results revealed a high prevalence of childhood-onset overweight/obesity (60%; 28/47) with disproportionately high body fat percentage, which aligns perfectly with previous preclinical studies. Short stature was common (33%), likely due to advanced skeletal maturation. Endocrine-metabolic investigations showed thyroid dysregulation (22%; 9/41), elevated triglycerides, and decreased blood ammonia levels. Moreover, hand radiographs identified decreased bone mineralization (57%; 8/14) and negative ulnar variance (71%; 10/14). Our findings indicate a high (cardio)metabolic risk in KLFS. Therefore, we recommend monitoring of weight and endocrine-metabolic profile. Supporting a healthy lifestyle and screening of bone mineralization is advised. Our comprehensive results support translational research and contribute to a better understanding of MDEM-associated phenotypes.

Feasibility and repeatability of ultrasound-guided surface electroenterography to measure colonic slow wave motility in healthy adults.

Surface electroenterography is a potential non-invasive alternative to current diagnostics of colonic motility disorders. However, electrode positioning in electroenterography is often based on general anatomy and may lack generalizability. Furthermore, the repeatability of electroenterography measurements is unknown. This study aimed to evaluate ultrasound-guided electrode positioning for electroenterography measurements and to determine the repeatability of those measurements. In ten healthy adults, two electroenterography procedures were performed, consisting of fasting, ultrasound-guided electrode localization and two 20-minute electroenterography recordings separated by a meal. The dominant frequency, the mean power density (magnitude of colonic motility) and the power percent difference (relative pre- to postprandial increase in magnitude) were determined. Repeatability was determined by Lin's concordance correlation coefficient. The results demonstrated that the dominant frequency did not differ between pre- and postprandial recordings and was 3 cpm, characteristic of colonic motility. The mean power density increased between the pre- and postprandial measurements, with an average difference of over 200%. The repeatability of both the dominant frequency and power density was poor to moderate, whereas the correlation coefficient of the power percent difference was poor. Concluding, ultrasound-guided surface electroenterography seems able to measure the gastrocolic reflex, but the dissatisfactory repeatability necessitates optimization of the measurement protocol.

Imaging and Interventions for Lymphatic and Lymphatic-related Disorders.

The lymphatic system is critical in fluid balance homeostasis. Yet, until recently, lymphatic imaging has been outside of mainstream medicine due to a lack of robust imaging and interventional options. However, during the last 20 years, both clinical lymphatic imaging and interventions have shown dramatic advancement. The key to imaging advancement has been the interstitial delivery of contrast agents through lymphatic-rich tissues. These techniques include intranodal lymphangiography and dynamic contrast-enhanced MR lymphangiography. These methods provide the ability to image and recognize lymphatic anatomy and pathologic conditions. Percutaneous thoracic duct catheterization and embolization became the first widely accepted interventional technique for the management of chyle leaks. Advances in interstitial lymphatic embolization, as well as liver and mesenteric lymphatic interventions, have broadened the scope of possible lymphatic interventions. Also, recent techniques of lymphatic decompression allow for the treatment of a variety of lymphatic disorders. Finally, immunologic studies of central lymphatic fluid reveal the potential of lymphatic interventions on immunity. These advances herald an exciting new chapter for lymphatic imaging and interventions in the coming years.

Clinical and radiological assessment of scoliosis in Koolen-de Vries syndrome.

The Koolen-de Vries syndrome (KdVS) is a multisystem disorder characterized by developmental delay, intellectual disability, characteristic facial features, epilepsy, cardiovascular and urogenital malformations, and various musculoskeletal disorders. Scoliosis is a common feature. The aim of this study is to fill the gap in the current knowledge about scoliosis in individuals with KdVS and to provide recommendations for management and follow-up. In total, 54 individuals with KdVS were included in the study, with a mean age of 13.6 years (range 1.9-38.8 years). Spine radiographs, MR scans, and corresponding radiology reports were analyzed retrospectively for scoliosis and additional anomalies. The presence of scoliosis-related clinical conditions was assessed in participants' medical records and by use of a parent survey. Scoliosis was present in 56% of the participants (30/54) with a mean age of onset of 10.6 years and curve progression during the growth spurt. Prevalence at age 6, 10, and 18 years was, respectively, 9%, 41%, and 65%. Most participants were diagnosed with a single curve (13/24, 54%), of which five participants had a long C-curve type scoliosis. No significant risk factors for development of scoliosis could be identified. Severity was mostly classified as mild, although 29% (7/24) of the curves were larger than 30° at last follow-up. Bracing therapy was received in 13% (7/54), and surgical spinal fusion was warranted in 6% (3/54). Remarkably, participants with scoliosis received less often physical therapy compared to participants without scoliosis (P = 0.002). Scoliosis in individuals with KdVS should be closely monitored and radiologic screening for scoliosis and vertebrae abnormalities is recommended at diagnosis of KdVS, and the age of 10 and 18 years.

Oral sialic acid supplementation in NANS-CDG: Results of a single center, open-label, observational pilot study.

NANS-CDG is a congenital disorder of glycosylation (CDG) caused by biallelic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. It presents with intellectual developmental disorder (IDD), skeletal dysplasia, neurologic impairment, and gastrointestinal dysfunction. Some patients suffer progressive intellectual neurologic deterioration (PIND), emphasizing the need for a therapy. In a previous study, sialic acid supplementation in knockout nansa zebrafish partially rescued skeletal abnormalities. Here, we performed the first in-human pre- and postnatal sialic-acid study in NANS-CDG. In this open-label observational study, 5 patients with NANS-CDG (range 0-28 years) were treated with oral sialic acid for 15 months. The primary outcome was safety. Secondary outcomes were psychomotor/cognitive testing, height and weight, seizure control, bone health, gastrointestinal symptoms, and biochemical and hematological parameters. Sialic acid was well tolerated. In postnatally treated patients, there was no significant improvement. For the prenatally treated patient, psychomotor and neurologic development was better than two other genotypically identical patients (one treated postnatally, one untreated). The effect of sialic acid treatment may depend on the timing, with prenatal treatment potentially benefiting neurodevelopmental outcomes. Evidence is limited, however, and longer-term follow-up in a larger number of prenatally treated patients is required.

Indications for magnetic resonance imaging of the fetal body (extra-central nervous system): recommendations from the European Society of Paediatric Radiology Fetal Task Force.

The indications for fetal body MRI are amplifying because of the expanding possibilities of fetal and perinatal therapy. However, huge heterogeneity regarding the indications for fetal body MRI is seen among different European countries that is mostly related to local use of US, but also to local fetal MRI expertise and legislation on pregnancy termination. The purpose of this article is to summarize the precise indications for fetal MRI, excluding the central nervous system. MRI indications arise from the sonographic findings, based on the operator's experience and the various practices in the countries and institutions represented on the European Society of Paediatric Radiology Fetal Task Force. We also highlight the strengths and weaknesses of fetal US and MRI of the fetal body.

Current and future funding streams for paediatric postmortem imaging: European Society of Paediatric Radiology survey results.

BACKGROUND: Perinatal and childhood postmortem imaging has been accepted as a noninvasive alternative or adjunct to autopsy. However, the variation in funding models from institution to institution is a major factor prohibiting uniform provision of this service. OBJECTIVE: To describe current funding models employed in European and non-European institutions offering paediatric postmortem imaging services and to discuss the perceived barriers to future postmortem imaging service provision. MATERIALS AND METHODS: A web-based 16-question survey was distributed to members of the European Society of Paediatric Radiology (ESPR) and ESPR postmortem imaging task force over a 6-month period (March-August 2021). Survey questions related to the radiologic and autopsy services being offered and how each was funded within the respondent's institute. RESULTS: Eighteen individual responses were received (13/18, 72.2% from Europe). Only one-third of the institutions (6/18, 33.3%) have fully funded postmortem imaging services, with the remainder receiving partial (6/18, 33.3%) or no funding (5/18, 27.8%). Funding (full or partial) was more commonly available for forensic work (13/18, 72%), particularly where this was nationally provided. Where funding was not provided, the imaging and reporting costs were absorbed by the institute. CONCLUSION: Increased access is required for the expansion of postmortem imaging into routine clinical use. This can only be achieved with formal funding on a national level, potentially through health care commissioning and acknowledgement by health care policy makers and pathology services of the value the service provides following the death of a fetus or child. Funding should include the costs involved in training, equipment, reporting and image acquisition.

Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

OBJECTIVE: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. MATERIAL AND METHODS: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols. We performed two-dimensional single-slice tumor delineation. Areas of necrosis or hemorrhage were delineated to be excluded in the primary analysis. Mean, median and 5th and 95th apparent diffusion coefficient (ADC) were extracted. RESULTS: Of 134 included patients, 82 had measurable tumor at diagnosis and response and DW-MRI scans of adequate quality and were included in the analysis. Technical heterogeneity in scan acquisition protocols and scanners was observed. Mean ADC at diagnosis was 1.1 (95% confidence interval [CI]: 1.1-1.2) (all ADC expressed in * 10-3 mm2/s), versus 1.6 (1.5-1.6) at response assessment. The 5th percentile ADC was 0.8 (0.7-0.9) at diagnosis and 1.1 (1.0-1.2) at response. Absolute change in mean ADC after neoadjuvant chemotherapy was 0.4 (0.3-0.5). Exploratory analyses for association between ADC and clinical parameters showed a significant difference in mean ADC at diagnosis for alveolar versus embryonal histology. Landmark analysis at nine weeks after the date of diagnosis showed no significant association (hazard ratio 1.3 [0.6-3.2]) between the mean ADC change and event-free survival. CONCLUSION: A significant change in the 5th percentile and the mean ADC after chemotherapy was observed. Strong heterogeneity was identified in DW-MRI acquisition protocols between centers and in individual patients.

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study.

Noonan syndrome (NS) has been associated with an increased risk of lymphatic anomalies, with an estimated prevalence of 20%. The prevalence of lymphatic anomalies seems to differ between pathogenic variants. Therefore, this study aims to describe the clinical presentation, prevalence and genotype-phenotype correlations of lymphatic anomalies during life in patients with NS. This retrospective cohort study included patients (n = 115) who were clinically and genetically diagnosed with NS and visited the Noonan expertise Center of the Radboud University Medical Center between January 2015 and March 2021. Data on lymphatic anomalies during lifetime were obtained from medical records. Lymphatic anomalies most often presented as an increased nuchal translucency, chylothorax and/or lymphedema. Prenatal lymphatic anomalies increased the risk of lymphatic anomalies during infancy (OR 4.9, 95% CI 1.7-14.6). The lifetime prevalence of lymphatic anomalies was 37%. Genotype-phenotype correlations showed an especially high prevalence of lymphatic anomalies during infancy and childhood in patients with a pathogenic SOS2 variant (p = 0.03 and p < 0.01, respectively). This study shows that patients with NS have a high predisposition for developing lymphatic anomalies during life. Especially patients with prenatal lymphatic anomalies have an increased risk of lymphatic anomalies during infancy. Genotype-phenotype correlations were found in pathogenic variants in SOS2.

Current and emerging artificial intelligence applications in chest imaging: a pediatric perspective.

Artificial intelligence (AI) applications for chest radiography and chest CT are among the most developed applications in radiology. More than 40 certified AI products are available for chest radiography or chest CT. These AI products cover a wide range of abnormalities, including pneumonia, pneumothorax and lung cancer. Most applications are aimed at detecting disease, complemented by products that characterize or quantify tissue. At present, none of the thoracic AI products is specifically designed for the pediatric population. However, some products developed to detect tuberculosis in adults are also applicable to children. Software is under development to detect early changes of cystic fibrosis on chest CT, which could be an interesting application for pediatric radiology. In this review, we give an overview of current AI products in thoracic radiology and cover recent literature about AI in chest radiography, with a focus on pediatric radiology. We also discuss possible pediatric applications.

The lymphatic system throughout history: From hieroglyphic translations to state of the art radiological techniques.

A comprehensive lymphatic system is indispensable for a well-functioning body; it is integral to the immune system and is also interrelated with the digestive system and fluid homeostasis. The main difficulty in examining the lymphatic system is its fine-meshed structure. This remains a challenge, leaving patients with uninterpreted symptoms and a dearth of potential therapies. We review the history of the lymphatic system up to the present with the aim of improving current knowledge. Several findings described throughout history have made fundamental contributions to elucidating the lymphatic system. The first contributions were made by the ancient Egyptians and the ancient Greeks. Vesalius obtained new insights by dissecting corpses. Thereafter, Ruysch (1638-1731) gained an understanding of lymphatic flow. In 1784, Mascagni published his illustration of the whole lymphatic network. The introduction of radiological lymphography revolutionized knowledge of the lymphatic system. Pedal lymphangiography was first described by Monteiro (1931) and Kinmonth (1952). Lymphoscintigraphy (nuclear medicine), magnetic resonance imaging, and near-infrared fluorescence lymphography further improved visualization of the lymphatic system. The innovative dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) transformed understanding of the central lymphatic system, enabling central lymphatic flow disorders in patients to be diagnosed and even allowing for therapeutic planning. From the perspective of the history of lymph visualization, DCMRL has ample potential for identifying specific causes of debilitating symptoms in patients with central lymphatic system abnormalities and even allows for therapeutic planning.

Current state of perinatal postmortem magnetic resonance imaging: European Society of Paediatric Radiology questionnaire-based survey and recommendations.

BACKGROUND: Postmortem magnetic resonance imaging (MRI) in perinatal and childhood deaths is increasingly used as a noninvasive adjunct or alternative to autopsy. Imaging protocols vary between centres and consensus guidelines do not exist. OBJECTIVE: Our aim was to develop practical, standardised recommendations for perinatal postmortem MRI. MATERIALS AND METHODS: Recommendations were based on the results of two surveys regarding local postmortem MRI practices sent electronically to all 14 members of the European Society of Paediatric Radiology (ESPR) Postmortem Imaging Task Force and 17 members of the International Society of Forensic Radiology and Imaging Task Force (25 different centres). RESULTS: Overall, 11/14 (78.6%) respondents from different institutions perform postmortem MRI. All of these centres perform postmortem MRI for perinatal and neonatal deaths, but only 6/11 (54.5%) perform imaging in older children. CONCLUSION: We propose a clinical standard for postmortem MRI sequences plus optional sequences for neuroimaging and cardiac anatomy depending on available scanning time and referral indications.

Treatment Outcomes of Embolization for Peripheral Arteriovenous Malformations.

PURPOSE: To evaluate treatment outcomes of embolization for peripheral arteriovenous malformations (AVMs) in a tertiary referral center where ethanol is the primary agent of choice. METHODS: A retrospective study was performed of 93 patients (median age, 31 years; range, 2-66 years) with peripheral AVMs treated with embolization (n = 442; median, 2 per patient; range, 1-82) between January 2010 and July 2016. Ethanol was used in most cases (n = 428; 97%). AVMs were classified as type I (n = 3), type II (n = 57), type IIIa (n = 5), type IIIb (n = 15), and type IV (n = 13) according to the Yakes classification system. Effectiveness of embolization was based on AVM devascularization on angiography: 100% (total), 90%-99% (near-total), 70%-90% (substantial), 30%-70% (partial), and 0%-30% (failure). Complications were graded according to the Society of Interventional Radiology classification. RESULTS: In 69% of patients, 70%-100% devascularization was achieved. Total and near-total occlusion of the nidus were more often achieved in AVMs of types I and IIIa (both 100%) than in AVMs of types II, IIIb, and IV (56%, 67%, and 39%, respectively; P = .019). A total of 109 complications were identified: 101 minor (22.9%) and 8 major (1.8%). Major complications included wounds (n = 5), false aneurysm (n = 1), finger contracture (n = 1), and severe pain (n = 1) requiring therapy. The patient complication risk was significantly affected by the number of procedures (relative risk = 2.0; P < .001). Age, AVM location, and angioarchitecture type did not significantly affect complication risk. CONCLUSIONS: AVM embolization resulted in 70%-100% devascularization in 69% of patients, with few major complications. This study indicates that the type of AVM angioarchitecture affects the number of procedures needed and the achievability of AVM devascularization.

Can digital X-ray radiogrammetry be an alternative for dual-energy X-ray absorptiometry in the diagnosis of secondary low bone quality in children?

Bone quality in children is generally measured with dual-energy X-ray absorptiometry (DXA). Digital X-ray radiogrammetry (DXR) uses BoneXpert to measure cortical bone quality on hand radiographs. This prospective study compared DXR and DXA results in children with high probability of secondary low bone quality, defined as DXA of the lumbar spine (DXALS) Z-score ≤ - 2.0. One hundred one children underwent both DXA and DXR assessment. DXALSZ-scores were also adjusted for bone age. DXR Z-scores were compared with both DXALSZ-scores, using Pearson correlations, Bland-Altman analysis, and sensitivity-specificity analysis. Mean bone age, DXR, and both DXA Z-scores were significantly impaired. Pearson correlation coefficients were significant between DXR Z-scores and both DXALSZ-scores 0.507-0.564 (p < 0.001). Bland-Altman analysis showed a mean difference of 0.05-0.48 between DXR and both DXA Z-scores and showed more than 90% similarity for both DXALSZ-scores ≤ - 2.0. DXR had a sensitivity of 67-71% and specificity of 77-83% compared to both DXALSZ-scores.Conclusion: DXR correlates well with as well DXALS as bone age-adjusted DXALSZ-scores and shows good agreement with as well DXALS as bone age-adjusted DXALSZ-scores ≤ - 2.0. DXR shows best results when compared with DXALSZ-scores. What is Known: • Digital X-ray radiogrammetry (DXR) may correlate well with dual-energy X-ray absorptiometry (DXA) in pediatric, adolescent, and adult patients. • DXR is a feasible method for assessment of bone quality in children. What is New: • This is the first prospective study in children with suspected secondary low bone quality that illustrates correlation between DXR and bone age-adjusted DXA Z-scores and that shows good agreement between DXR and DXA as bone age-adjusted DXA Z-scores ≤ -2.0. • Our results suggest DXR to be a good alternative for DXA for determining low bone quality.

Subclinical enthesitis in nail psoriasis patients: a case-control study.

BACKGROUND: Patients with nail psoriasis have a higher prevalence of psoriatic arthritis; however, the pathogenetic relationship between these two disorders is as yet unclear. Entheses have been suggested as disease epicenter, which might explain the pathogenesis on an anatomical level. OBJECTIVE: To contribute to the elucidation of the hypothesis as regards the anatomical link between nail psoriasis and psoriatic arthritis, with the extensor enthesis of the distal interphalangeal joint as the epicenter. METHODS: We conducted a cross-sectional cohort study, visualizing the distal interphalangeal (DIP) joints entheses of patients with fingernail psoriasis (n = 54), psoriasis patients without nail involvement (n = 32), and healthy controls (n = 32) using three-dimensional ultrasound. Patients with nail psoriasis underwent repeat imaging studies after one year. RESULTS: Individuals with nail psoriasis had significantly thicker radial entheses than psoriasis patients without nail involvement. However, there were no significant differences in entheseal thickness between adjacent nails that were affected and those that were not (1.297 mm vs. 1.253 mm, p = 0.13). Follow-up after one year showed no significant differences in entheseal thickness in correlation with nail psoriasis activity. CONCLUSIONS: The present study provides evidence for subclinical enthesitis at the level of the DIP joint in patients with nail psoriasis. However, an anatomical correlation between nail psoriasis and psoriatic arthritis could not be confirmed.

The radiodensity of cerebrospinal fluid and vitreous humor as indicator of the time since death.

PURPOSE: After death, a series of changes occur naturally in the human body in a fairly regular pattern. These postmortem changes are detectable on postmortem CT scans (PMCT) and may be useful in estimating the postmortem interval (PMI). The purpose of our study is to correlate the PMCT radiodensities of the cerebrospinal fluid (CSF) and vitreous humor (VH) to the PMI. METHODS: Three patient groups were included: group A consisted of 5 donated cadavers, group B, 100 in-hospital deceased patients, and group C, 12 out-of-hospital forensic cadavers. Group A were scanned every hour for a maximum of 36 h postmortem, and the tympanic temperature was measured prior to each scan. Groups B and C were scanned once after death (PMI range 0.2-63.8 h). Radiodensities of the VH and CSF were measured in Hounsfield units. Correlation between density and PMI was determined using linear regression and the influence of temperature was assessed by a multivariate regression model. Results from group A were validated in groups B and C. RESULTS: Group A showed increasing radiodensity of the CSF and VH over time (r (2) CSF, 0.65). PMI overruled the influence of temperature (r = 0.99 and p = 0.000). Groups B and C showed more diversity, with CSF and VH radiodensities below the mean regression line of Group A. The formula of this upper limit indicated the maximum PMI and was correct for >95 % of the cadavers. CONCLUSION: The results of group A showed a significant correlation between CSF radiodensity and PMI. The radiodensities in groups B and C were higher than in group A, therefore the maximum PMI can be estimated with the upper 95 % confidence interval of the correlation line of group A.

Liver parenchyma at the site of hypodense parafissural pseudolesion contains increased collagen.

PURPOSE: To identify a histological substrate explaining the hypodense pseudolesion in the liver at the right side of the falciform ligament and the correlation with CT radiodensity. MATERIALS AND METHODS: Tissue specimens were obtained from the right (pseudolesion) and left (control) side of the falciform ligament at the level of the left portal vein, in deceased adults during autopsy. Radiodensity was measured at the same locations at CT. Digital image analysis determined the amount of collagen and fat in histological sections, and the number of portal triads and central veins were counted. Glycogen content was visually assessed by the area percentage of the histological section. RESULTS: Specimens from 17 patients showed a 39% increase in collagen for the site of the pseudolesion compared to the contralateral side (p = 0.08). No significant differences were found for the amount of fat, glycogen, portal triads, or central veins. In one patient a pseudolesion was visible on CT, and this contained 52% more collagen than the control side. CONCLUSION: The pseudolesion at the right parafissural side in the liver contains more collagen compared to the control left side, while there is no difference in fat or glycogen content or number of portal and hepatic veins. Collagen may be the cause of the pseudolesion.

Normal pediatric postmortem CT appearances.

Postmortem radiology is a rapidly developing specialty that is increasingly used as an adjunct to or substitute for conventional autopsy. The goal is to find patterns of disease and possibly the cause of death. Postmortem CT images bring to light processes of decomposition most radiologists are unfamiliar with. These postmortem changes, such as the formation of gas and edema, should not be mistaken for pathological processes that occur in living persons. In this review we discuss the normal postmortem thoraco-abdominal changes and how these appear on CT images, as well as how to differentiate these findings from those of pathological processes.