An unusual presentation of de novo RAC3 variation in prenatal diagnosis.

Pathogenic variants in RAC3 cause a neurodevelopmental disorder with brain malformations and craniofacial dysmorphism, called NEDBAF. This gene encodes a small GTPase, which plays a critical role in neurogenesis and neuronal migration. We report a 31 weeks of gestation fetus with triventricular dilatation, and temporal and perisylvian polymicrogyria, without cerebellar, brainstem, or callosal anomalies. Trio whole exome sequencing identified a RAC3 (NM_005052.3, GRCh38) probably pathogenic de novo variant c.276 T>A p.(Asn92Lys). Eighteen patients harboring 13 different and essentially de novo missense RAC3 variants were previously reported. All the patients presented with corpus callosum malformations. Gyration disorders, ventriculomegaly (VM), and brainstem and cerebellar malformations have frequently been described. The only previous prenatal case associated with RAC3 variant presented with complex brain malformations, mainly consisting of midline and posterior fossa anomalies. We report the second prenatal case of NEDBAF presenting an undescribed pattern of cerebral anomalies, including VM and polymicrogyria, without callosal, cerebellar, or brainstem malformations. All neuroimaging data were reviewed to clarify the spectrum of cerebral malformations.

Reversed cortico-medullary differentiation in the fetal and neonatal kidneys: an indicator of poor prognosis?

BACKGROUND: Bilateral reversed cortico-medullary differentiation is rarely observed on fetal or neonatal renal ultrasound and is therefore a diagnostic challenge. OBJECTIVE: Our purpose was to widen the differential diagnoses of fetal and neonatal nephropathies introducing reversed cortico-medullary differentiation as a clue either on obstetric US or during follow-up of hyperechoic kidneys in order to improve the management of such rare clinical situations. MATERIALS AND METHODS: We retrospectively reviewed the US images of 11 patients showing bilateral reversed cortico-medullary differentiation on prenatal examination or in which this pattern developed postnatally in the follow-up of fetal hyperechoic kidneys. For each patient, a precise diagnosis was established either on clinical assessment or, when available, on histological or genetic findings. RESULTS: Six fetuses displayed bilateral reversed cortico-medullary differentiation on obstetric examination, and the pattern persisted throughout pregnancy. In the five other fetuses, the kidneys appeared initially homogeneously hyperechoic; this evolved into reversed cortico-medullary differentiation during the third trimester in two cases and shortly after birth in three cases. Two pregnancies were terminated because of estimated poor prognosis. In the nine surviving neonates, four died of renal failure in the post-natal period. The clinical evolution was more favorable in the remaining five newborns. CONCLUSIONS: Six different diagnoses were established in patients presenting with a reversed cortico-medullary differentiation renal pattern. This finding was associated with poor outcome in six cases. An acute prenatal diagnosis of reversed cortico-medullary differentiation improves pre- and postnatal work-up and guides counseling and genetic testing.

Prenatal imaging of the normal and abnormal spinal cord: recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee.

Spinal dysraphisms are amenable to diagnosis in utero. The prognosis and the neonatal management of these conditions differ significantly depending on their types, mainly on the distinction between open and closed defects. A detailed evaluation not only of the fetal spine, but also of the brain, skull, and lower limbs is essential in allowing for the right diagnosis. In this article, recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee will be presented. The aim of this paper is to review the imaging features of the normal and abnormal fetal spinal cord, to clarify the prenatal classification of congenital spinal cord anomalies and to provide guidance in their reporting.

TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly.

Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.

Fetal uropathies: pre- and postnatal imaging, management and follow-up.

Congenital uropathies are the most common fetal anomalies. They include a wide spectrum of anomalies ranging from mild pelvis dilation to complex urinary tract malformations. Prenatal imaging not only allows for their diagnosis but, in experienced hands, it can differentiate obstructive from refluxing or malformative uropathies. Such precise prenatal information allows for intervention before birth in select cases or for adapting the postnatal workup to provide a better long-term outcome. For the different types of congenital uropathies, we describe their prenatal presentations on US and the complementary role of fetal MRI where indicated. We correlate these findings with postnatal workup and summarize the updated neonatal diagnostic and clinical/surgical management.

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.

Exploration of the fetal skeleton by ultra-low-dose computed tomography: guidelines from the Fetal Imaging Task Force of the European Society of Paediatric Radiology.

Skeletal anomalies are rare, requiring a systematic ultrasound (US) examination of each skeletal part when there is suspicion of a skeletal dysplasia. Although US examination can provide good evaluation of the fetal bones and cartilage, ultra-low-dose three-dimensional (3-D) multi-detector computed tomography (CT) is a useful complementary tool that can significantly improve prenatal diagnostic accuracy in select cases. Given that ultra-low-dose fetal CT remains an irradiating technique, indications should result from a multidisciplinary consensus, acquisition protocols should be optimized and the reporting standardized. In this paper we discuss guidelines from the Fetal Imaging Task Force of the European Society of Paediatric Radiology for indications, protocols and reporting of ultra-low-dose fetal CT.

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts.

PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.

Fetal magnetic resonance imaging at 3 Tesla - the European experience.

BACKGROUND: The Fetal Imaging Taskforce was established in 2018 by the European Society of Paediatric Radiology. The first survey on European practice of fetal imaging published in 2020 revealed that 30% of fetal magnetic resonance imaging (MRI) is performed at 3 tesla (T). The purpose of this second survey was to identify the impact of 3-T fetal MRI with an emphasis on image quality, diagnostic yield, and technical challenges and artifacts at higher field strengths. OBJECTIVE: To describe the prenatal imaging practice at 3-T MRI units in various centres in Europe and to prepare recommendations on behalf of the Fetal Imaging Taskforce. MATERIALS AND METHODS: A survey was sent to all members performing 3-T fetal MRI. Questions included practitioner experience, magnet brand, protocols, counselling, artifacts and benefits of imaging at higher field strengths. RESULTS: Twenty-seven centres replied and reported improved spatial resolution and improved signal-to-noise ratio when performing fetal MRI at 3 T. Shading and banding artifacts and susceptibility to motion artifacts were common problems identified by practitioners at the higher field strength. For all neurological indications, practitioners reported a benefit of imaging at 3 T, most marked for posterior fossa evaluation and parenchymal lesions. CONCLUSION: The use of 3-T magnets in fetal MRI has improved the availability and quality of advanced imaging sequences and allowed for better anatomical evaluation. There remain significant challenges to minimize the impact of artifacts on image quality. This paper includes guidelines for clinical practice and imaging at 3 T.

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

Fetal central nervous system MRI is a well-established method to complement a high-quality fetal ultrasound and to clarify sonographically detected abnormalities in complex pregnancies. However, there is still worldwide heterogeneity and confusion regarding the indications of fetal central nervous system MRI, which has roots in differences among countries regarding the performance of ultrasound examinations and legislation on pregnancy termination. The purpose of this article is to clarify the indications for fetal central nervous system MRI by focusing on the ultrasound findings that guide further investigation with MRI and highlight the strengths and the weaknesses of each modality on imaging the fetal central nervous system.

European overview of current practice of fetal imaging by pediatric radiologists: a new task force is launched.

A new task force dedicated to prenatal imaging was created in 2018 by the European Society of Pediatric Radiology. In order to establish a network of European prenatal imaging practice, we sent a questionnaire to radiologists practicing prenatal imaging in Europe. The questions were related to the type of institution, the local legislation for termination of pregnancy, the type of imaging modality and the following items regarding magnetic resonance imaging (MRI): magnetic field, gestational age at which it is performed, use of maternal sedation, number of examinations per year, proportion of cerebral versus body indications and proportion of repeated examinations. We collected responses from 20 European countries, 52 cities and 67 institutions (82% public). In most countries, the upper gestational age limit for termination of pregnancy is 24 weeks of gestation. In some countries, it is earlier and in other countries, there is no limit. Very few radiologists practice fetal ultrasonography and computed tomography. In some countries, fetal MRI is mainly performed before 24 weeks of pregnancy, while in others, it is mainly performed in the third trimester. Neurological indications are by far predominant and 30% of the institutions have access to a 3-tesla (T) unit for fetal MRI. Maternal sedation is rarely used. The number of scans per year is highly variable with an average of 140, which is not necessarily correlated to the size of the population.

Prenatal ultrasonography of autosomal dominant polycystic kidney disease mimicking recessive type: case series.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. This pathology has been increasingly diagnosed in utero and several sonographic patterns are well described in the literature. OBJECTIVE: To present a series of fetuses with an unusual imaging pattern of ADPKD, mimicking autosomal recessive polycystic kidney disease (ARPKD). MATERIALS AND METHODS: We retrospectively reviewed second-line ultrasound (US) scans performed for suspicion of fetal kidney pathology between 2006 and 2018. Inclusion criteria were (1) proven ADPKD on the basis of a known family history and/or of genetic testing and (2) US features suggestive of ARPKD. We recorded the clinical, imaging, genetic and pathological findings in cases with pregnancy termination. RESULTS: Three out of 12 patients with proven ADPKD diagnosed in utero presented with US features suggestive of ARPKD. Furthermore, an additional patient observed at another institution was added to the series. History of familial ADPKD was present in three cases. US showed enlarged kidneys with increased cortical echogenicity, decreased corticomedullary differentiation, multiple medullary cysts and decreased amniotic fluid in all four cases. Pregnancy was terminated in two cases (histology confirmed features in keeping with ADPKD), one premature neonate died (histology in progress) and one child is alive. Genetic testing showed a homozygous mutation of the PKD1 gene in two patients, a heterozygous mutation of the PKD1 gene in one patient and was not performed in the remaining patient. CONCLUSION: This series describes an unusual sonographic prenatal presentation of ADPKD, not yet well described in the radiologic literature, mimicking ARPKD.

Prenatal Evaluation and Postnatal Follow-Up of Ureteral Ectopic Insertion in Multicystic Dysplastic Kidneys.

OBJECTIVE: To emphasize the need for analyzing the pelvis when a unilateral multicystic dysplastic kidney (MCDK) is observed at prenatal ultrasonography (US) because of possible associated ectopic ureteral insertion. METHODS: We performed a retrospective study including prenatal US diagnosis of unilateral MCDK and retrovesical cyst. The following data were recorded: pre- and postnatal US, magnetic resonance imaging (MRI), and voiding cystourethrography (VCUG) findings. The shape of the pelvic cyst was analyzed as well as the visibility of the ureteral insertion into the cyst. RESULTS: Fourteen patients were included (7 females). At prenatal US, the cyst wall was smooth in 8 cases (6 females) and lobulated in 5 cases (4 males). In 1 case it protruded into the bladder. Ectopic ureteral insertion was observed in 2 cases. Prenatal MRI (n = 6) depicted ureteral insertion in 2 more cases. Postnatal US (n = 14) showed the same cyst patterns as prenatally, ectopic ureteral insertion (n = 8), and duplicated uterus (n = 4). Postnatal MRI (n = 7) always depicted the ureteral ectopic insertion into the cyst. VCUG (n = 5) showed indirect findings of ectopic ureteral insertion (n = 3). CONCLUSION: Unilateral MCDK should lead to search for a retrovesical cyst corresponding most commonly to a distended hemivagina or a seminal vesicle. Early diagnosis of this condition leads to better clinical management.

Variable prenatal presentation of Pfeiffer syndrome: Suggested aids to prenatal sonographic diagnosis.

BACKGROUND: Our purpose was to describe and compare the cranial and extracranial abnormalities of Pfeiffer syndrome on prenatal imaging with postnatal or postmortem findings, which may help in prenatal diagnosis of Pfeiffer syndrome (PS). METHODS: Cases of fetuses with a confirmed diagnosis of PS over a 4-year period (2012-2016) were retrospectively reviewed. Prenatal imaging findings, postnatal, or postmortem investigations and genetic test results were analyzed. RESULTS: Four fetuses were ascertained, 3 with prenatal sonographic findings compatible with PS and one only diagnosed at postmortem. Cases were referred between 22 and 24 weeks' gestation. Three of the 4 cases were terminated, and details of postmortem/postnatal examination were available in all. There was variable presentation of features. Craniosynostosis was present in 3 cases, but only detected prenatally in 2. Extracranial signs included abnormalities of thumbs and/or big toes, detected prenatally in 3 of the 4 cases. A sacral appendage and vertebral or coronal clefts were present at postmortem in 3 cases but only detected prenatally in one. A cartilaginous tracheal sleeve was detected at postmortem in all 3 cases but not detected by prenatal ultrasound. Other findings included ventriculomegaly, posterior fossa, and facial anomalies. Molecular testing revealed mutations of the fibroblast growth factor receptor 2 (FGFR2) gene in all cases. CONCLUSION: Pfeiffer syndrome has a highly variable phenotype, and the absence of craniosynostosis on prenatal US does not exclude the diagnosis. Presence of abnormal thumbs and big toes, a sacral appendage, vertebral fusions, and coronal clefts should lead to prenatal molecular testing for PS.

Association of periventricular nodular heterotopia with posterior fossa cyst: a prenatal case series.

OBJECTIVE: The association of periventricular nodular heterotopia (PVNH) with posterior fossa cyst (PFC) is documented after birth. We report this association in a series of fetuses. METHODS: Eleven cases (7 females) of PVNH and PFC diagnosed at prenatal imaging were collected in this retrospective multicenter study. The patients were referred to tertiary centers for targeted ultrasonography (US) and Magnetic Resonance Imaging (MRI) following detection of PFC on routine US. Mutations of the filamin A gene (FLNA) were searched for (n = 6). Maternal brain MRI was performed (n = 8). Post-mortem or postnatal data were recorded. RESULTS: Targeted US was performed at a mean gestational age of 29 (range; 23-35) weeks and identified PVNH in 4 cases. At MRI, performed at a mean gestational age of 31 (range; 29-35) weeks, PVNH and PFC were visible in all cases. Those findings were confirmed by postnatal MRI (n = 3), autopsy (n = 7) and/or post-mortem MRI (n = 2) or US (n = 1). Maternal brain MRI showed PVNH in one case. A de novo FLNA mutation was found in four cases. CONCLUSION: We describe a series of PVNH and PFC in fetuses, which underlines the importance of searching for PVNH when PFC is identified at prenatal US. © 2014 John Wiley & Sons, Ltd.

Prenatal diagnosis of cystinuria with a heterozygous pathogenic variant in SLC7A9 gene associated with isolated hyperechogenic fetal kidneys: A case report.

Cystinuria is suspected antenatally by a hyperechogenic fetal colonic content. We report the first prenatal case of autosomal dominant SLC7A9-related cystinuria associated with isolated hyperechogenic kidneys as the only prenatal sonographic sign.

Fetal kidneys: additional sonographic criteria of normal development.

OBJECTIVE: The aim of this study was to establish objective criteria for the evaluation of cortical echogenicity (CE), cortical thickness (CT), and medullary thickness (MT), as well as the corticomedullary ratio (CMR), throughout gestation. METHOD: In this prospective single-center study, CE, MT, CT, and CMR were evaluated in a group of singleton pregnancies examined by ultrasound during the second and third trimesters. RESULTS: The CE evolved from a hyperechoic pattern compared with the liver or spleen during early second trimester to a hypoechogenic pattern in the third trimester, with no fetus displaying cortical hyperechogenicity after 32 weeks. CT increased from 1.8 to 2.5 mm (p < 0.05) from 21 to 25 to 34 to 37 weeks; MT from 2.7 to 5.1 mm (p < 0.0001), and the CMR decreased from 0.7 to 0.5 (p < 0.001). CONCLUSION: The CE, CT, and MT evolve with gestation. Cortical hyperechogenicity compared with the liver or spleen after 32 weeks or a CMR above 0.7 in the third trimester should raise the suspicion of a fetal nephropathy.

Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dyplasia torrance type in mother and fetus with the same COL2A1 mutation.

We describe a fetus with platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T), a rare skeletal dysplasia characterized by platyspondyly, extremely short limbs, and mild brachydactyly. Mutation analysis of COL2A1 identified a novel in-frame deletion c.4458_4460delCTT (p.Phe1486del) in the C-propeptide region of the molecule, confirming the clinical diagnosis. The phenotype in the mother was compatible with mild spondyloperipheral dysplasia (SPPD). Molecular studies documented somatic mosaicism for the same mutation in the mother. This observation further highlights the causal relationship between PLSD-T and SPPD and emphasizes the importance of evaluating parents when confronted with a skeletal dysplasia in a prenatal setting.

Imaging and classification of congenital cystic renal diseases.

OBJECTIVE: The purpose of this clinical perspective is to describe a decision-tree approach to the finding of hyperechoic kidneys as signs of congenital renal cystic disease in fetuses and children. This approach takes into account the latest classification of inherited renal cystic diseases. The basis of the approach is a detailed sonographic analysis in addition to assessment of clinical data and the familial history. CONCLUSION: With the decision-tree approach, typical sonographic patterns can be described and used for accurate diagnosis of isolated renal cystic diseases and polymalformative syndromes. In some cases, however, the diagnosis is not achieved, and complementary examinations are needed.

Fetal liver iron overload: the role of MR imaging.

OBJECTIVE: To assess the potential role of MR imaging in the diagnosis of fetal liver iron overload. METHODS: We reviewed seven cases of abnormal liver signal in fetuses referred to MR imaging in a context of suspected congenital infection (n = 2), digestive tract anomalies (n = 3) and hydrops fetalis (n = 2). The average GA of the fetuses was 31 weeks. The antenatal diagnoses were compared with histological data (n = 6) and postnatal work-up (n = 1). RESULTS: Magnetic resonance imaging demonstrated unexpected abnormal fetal liver signal suggestive of iron overload in all cases. The iron overload was confirmed on postnatal biopsy (n = 2) and fetopathology (n = 4). The final diagnosis was hepatic hemosiderosis (haemolytic anaemia (n = 2) and syndromal anomalies (n = 2)) and congenital haemochromatosis (n = 3). In all cases, the liver appeared normal on US. CONCLUSIONS: Magnetic resonance is the only imaging technique able to demonstrate liver iron overload in utero. Yet, the study outlines the fundamental role of MR imaging in cases of congenital haemochromatosis. The antenatal diagnosis of such a condition may prompt ante-(in the case of recurrence) or neonatal treatment, which might improve the prognosis.