Upgrading an intronic TMEM67 variant of unknown significance to likely pathogenic through RNA studies and community data sharing.

FETAL PHENOTYPE: A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome. GENETIC DIAGNOSTIC TEST PERFORMED, RESULT, AND INTERPRETATION: Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic. IMPLICATIONS AND NOVELTY: This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies.

A New BCl6 Transcriptional Corepressor Variant Mosaicism in a Fetus with Severe Fetal-Eye Anomalies.

We present the prenatal imaging of a fetus with severe eye anomalies diagnosed as carrying a new variant mosaicism on the BCOR gene.

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.

Evaluación del cerebro fetal: nuevas herramientas / Fetal brain assessment: new tools

RESUMEN La evaluación del cerebro fetal es un punto imprescindible en el ultrasonido obstétrico, por la gran cantidad de malformaciones que pueden ser diagnosticadas. La guía de ISUOG nos brinda los cortes elementales para la sospecha de la patología cerebral; pero, podemos ampliar y mejorar nuestro ultrasonido con la visualización de estructuras fácilmente reproducibles, tales como el complejo anterior, cuerpo calloso, cisura de Silvio y el cuarto ventrículo. Presentamos algunas herramientas para complementar la evaluación del cerebro fetal.

ABSTRACT The evaluation of the fetal brain is an essential point in obstetric ultrasound due to the large number of malformations that can be diagnosed. The ISUOG guide provides us with the elementary sections for the suspicion of brain pathology; but we can extend and improve our ultrasound with the visualization of easily reproducible structures, such as the anterior complex, corpus callosum, Sylvian fissure and the fourth ventricle. We present some tools to complement the assessment of the fetal brain.

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.

A practical approach to prenatal diagnosis of malformations of cortical development.

Malformations of cortical development (MCD) can frequently be diagnosed at multi-disciplinary Fetal Neurology clinics with the aid of multiplanar neurosonography and MRI. The patients are usually referred following prenatal sonographic screening that raises the suspicion of a possible underlying MCD. These indirect findings include, but are not limited to, ventriculomegaly (lateral ventricles larger than 10 mm), asymmetric ventricles, commissural anomalies, absent cavum septum pellucidum, cerebellar vermian and/or hemispheric anomalies, abnormal head circumference (microcephaly or macrocephaly), multiple CNS malformations, and associated systemic defects. The aim of this paper is to suggest a practical approach to prenatal diagnosis of malformations of cortical development utilizing dedicated neurosonography and MRI, based on the current literature and our own experience. We suggest that an MCD should be suspected in utero when the following intracranial imaging signs are present: abnormal development of the Sylvian fissure; delayed achievement of cortical milestones, premature appearance of sulcation; irregular ventricular borders, abnormal cortical thickness (thick, thin); abnormal shape and orientation of the sulci and gyri; irregular, abnormal, asymmetric, and enlarged hemisphere; simplified cortex; non continuous cortex or cleft; and intraparenchymal echogenic nodules. Following the putative diagnosis of fetal MCD by neurosonography and MRI, when appropriate and possible (depending on gestational age), the imaging diagnosis is supplemented by genetic studies (CMA and trio whole exome sequencing). In some instances, no further studies are required during pregnancy due to the clear dire prognosis and then the genetic evaluation can be deferred after delivery or termination of pregnancy (in countries where allowed).

A unique brain germinal matrix involvement in cytomegalovirus infected fetuses: A retrospective neurosonographic analysis with outcome correlation.

OBJECTIVE: To study the clinical significance of brain germinal matrix (GM) changes in cytomegalovirus (CMV) infected fetuses. METHOD: This is a retrospective analysis. Group A; isolated GM finding, with or without lenticulostriatal vasculopathy (LSV). Group B; non-isolated lesion. Amniocentesis, urinalysis, postnatal US and developmental assessment, were obtained. RESULTS: Group A and B included 18 and four fetuses, respectively. In group A, mean fetal age at diagnosis was 34.3 weeks (31-38 weeks). In 15/18 (83.3%), the lesion was bilateral and LSV was present in 8/18 (44.4%). Small cysts appeared inside the lesion in 5/18 (27.7%). MRI was normal in 8/18 (44.4%). Subtle or inconclusive findings were reported in the remaining fetuses. Brain ultrasound was normal in 10/18 (55.5%) of newborns. In the remaining, caudothalamic cyst with or without LSV, or isolated LSV were found. All newborns are developing normally at a mean follow-up age of 33.3 months (+/- 19.6 moths). In group B, all four patients requested for termination of pregnancy. CONCLUSION: Fetal CMV infection may cause focal GM changes, frequently accompanied by LSV, late in pregnancy. These changes may be isolated, or as part of a more generalized brain damage. When isolated, favorable prognosis is expected.

Improving renal phenotype and evolving extra-renal features of 17q12 deletion encompassing the HNF1B gene.

BACKGROUND: HNF1B deletion/intragenic mutations are the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) suggested by fetal ultrasound findings such as: parenchymal hyperechogenicity, overt cystic changes or gross morphological urinary system (UT) abnormalities. The postnatal evolution of these 17q12 deletions encompassing the HNF1B gene-associated findings has not been assessed in depth. METHODS: In this observational study, we present postnatal follow-up findings in 5 of 6 cases (one pregnancy was terminated on parental request) of fetal-onset cystic/hyperechogenic kidneys eventually diagnosed with 17q12 microdeletion encompassing the HNF1B gene between 2009 and 2017. RESULTS: Complete normalization of kidney parenchymal abnormalities and of depressed neonatal renal function was observed in 4/5 and 5/5 patients within 2-4.9 years and 1.5-8 months, respectively. All 5 patients had preserved normal renal function at 3-11 years of follow-up. The evolving later-onset renal features included: hypomagnesemia, hyperuricemia, urinary tract infection (UTI), and bilateral grade 3-4 vesicoureteral reflux and bladder diverticula in 3, 3, 2, and 1 patient, respectively. HNF1B gene deletion-associated extra-renal manifestations with delayed presentation were global developmental delay/autistic spectrum disorder (ASD), rolandic-type seizures, overweight, and borderline fasting hyperglycemia observed in 1-2 patients each. Family history was positive for small-size or asymptomatic cystic kidneys with normal function, diabetes mellitus, seizures, and mental/psychiatric problems in 3/6 cases. CONCLUSIONS: Fetal-onset HNF1B deletion-associated kidneys' parenchymal abnormalities confirmed postnatally with initially depressed renal function might undergo complete resolution within several years and few months, respectively. However, later-onset urinary tract, metabolic, and neurodevelopmental features of this mutation might appear over years. Therefore, genetic molecular evaluation/diagnosis and continuous follow-up for evolving features are mandatory in affected children.

Periventricular pseudocysts of noninfectious origin: Prenatal associated findings and prognostic factors.

OBJECTIVE: The purpose of this study was to establish prognostic factors in fetuses diagnosed with periventricular pseudocysts (PVPCs) without known congenital infection, between 28 and 37 weeks of gestation. METHODS: This retrospective study included cases of fetal PVPC from 2008 to 2018. PVPCs were classified according to location, number, extension, morphology, and size. Additional findings, MRI and genetic studies were recorded. Pregnancy outcome, postnatal, or postmortem results were obtained. Images from patients with normal (Group 1) and abnormal postnatal development (Group 2) were compared for analysis of factors predictive of outcome. RESULTS: One-hundred and fifteen pseudocysts were observed in 59 patients. In 34 fetuses (57%), the PVPC was an isolated finding. Thirty-nine patients delivered live newborns, 27% opted for termination of pregnancy, and 4 patients were lost to follow-up. Eighty-four percent of the liveborns had normal development. When assessing for the influence of pseudocyst characteristics, a wide CSP, or large head circumference, neither of these affected the outcome. The presence of additional anomalies was the only positive predictor for abnormal development regradless of specific PVPC characteristics (P = .002). CONCLUSIONS: In fetuses with PVPCs, the presence of additional anomalies was the only predictor for adverse postnatal outcome. No association between cystic characteristics and adverse outcome was observed.

Agenesis of the septum pellucidum: Prenatal diagnosis and outcome.

OBJECTIVE: The purpose of this study is to describe the imaging findings in a group of fetuses with suspected agenesis of the septum pellucidum (ASP) and to evaluate their clinical outcome. METHODS: This is a retrospective multicenter study on a cohort of fetuses diagnosed with suspected ASP, between 2008 and 2017. The records of each patient, including ultrasound (US) and magnetic resonance studies, were reviewed and compared with the postnatal findings. RESULTS: Forty-seven patients were included in the study at a mean gestational age of 26.6 weeks. In 17 patients, the ASP was considered isolated. Fourteen patients delivered live-born, and all 14 are developing normally. Three were lost to follow-up. Twenty-four patients had associated malformations involving the central nervous system (CNS); 13 were delivered (normal development [5], abnormal [6] and no follow-up [2]). Nine patients opted for termination, and two pregnancies were lost to follow-up. Six patients had non-CNS associated findings, two were delivered with normal neurological development and four had a termination. CONCLUSIONS: Isolated ASP is usually associated with a favorable outcome; but in the presence of associated malformations, there is at least a 50% risk of abnormal development. Current imaging techniques can provide an accurate prognosis in cases when ASP appears isolated.

Mature teratoma splitting the brainstem in a newborn: case report.

Mature teratomas (MTs) of the posterior fossa are extremely rare. The authors present a case of a prenatal diagnosis of an MT splitting the brainstem. Representative images as well as the clinical and surgical course are presented. Literature regarding "split brainstem" and MT of the posterior fossa is discussed.

Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.

Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter.

OBJECTIVE: To construct prenatal age-specific reference intervals for sonographic measurements of the optic nerve sheath diameter (ONSD) during gestation in normal fetuses. MATERIALS AND METHODS: Prospective cross-sectional study of fetuses assessed in antenatal ultrasound units between 2010 and 2014. The examination was based on a technique for the sonographic assessment of ONSD previously published by our group. The mean values and SDs of the ONSD were modeled as a function of the gestational week by curve estimation analysis based on the highest adjusted R2 coefficient. Repeatability tests were performed to assess intraobserver variability and interobserver agreement. RESULTS: During the study period 364 healthy fetuses were enrolled. The mean values for the ONSD varied from 0.6 mm at 15-16 weeks to 2.8 mm at 37-38 weeks. The ONSD grows in a linear fashion throughout gestation, with a quadratic equation providing an optimal fit to the data (adjusted R2 = 0.957). CONCLUSION: Sonographic age-specific references for the fetal ONSD are presented. This data may assist in the decision-making process in fetuses with a suspected increase in intracranial pressure, or anomalies affecting the development of optic stalks, such as optic hypoplasia and septo-optic dysplasia.

The cerebellar "tilted telephone receiver sign" enables prenatal diagnosis of PHACES syndrome.

OBJECTIVES: To describe a unique posterior fossa neuroimaging characteristic of prenatal PHACES syndrome (PS): unilateral cerebellar hypoplasia (UCH) and ipsilateral posterior fossa (PF) cyst communicating with an asymmetrically distended 4th ventricle. METHODS: The registries of seven prenatal diagnosis centers were searched for cases with PF findings and a postnatal diagnosis of PS. All records were evaluated for ultrasound and MRI findings and the postnatal outcome. PS was diagnosed after birth according to the consensus statement on diagnostic criteria for PS from 2009. The imaging findings of the PS fetuses were compared to a group of consecutive cases with fetal UCH, whose postnatal diagnosis was not PS. RESULTS: The PS group included 10 fetuses. All were referred due to UCH accompanied by an ipsilateral retrocerebellar cyst. All pregnancies resulted in livebirths, all newborns had a large segmental facial hemangioma. In all PS fetuses the affected cerebellar hemisphere was upwardly displaced by an ipsilateral PF cyst communicating with an asymmetrically distended 4th ventricle. An upwardly rotated and deviated vermis merged with the contralateral cerebellar peduncles forming an elongated oblique connection between the cerebellar hemispheres, resulting in a unique cerebellar shape, "a tilted telephone receiver sign" (TTRS), on the coronal plane through the upper vermis.The non-PS group included 11 fetuses with UCH: clastic cerebellar lesions (8) and a unilateral PF arachnoid cyst (3). The TTRS was not depicted in any of them (p < 0.0005). CONCLUSIONS: The cerebellar TTRS is a specific fetal imaging feature of PHACES syndrome enabling its prenatal diagnosis.

Fetal pericallosal lipomas - Clues to diagnosis in the second trimester.

INTRODUCTION: Pericallosal lipomas (PCL) are congenital soft masses of adipose cells encapsulated by a thin layer of fibrous tissue, appearing adjacent to the corpus callosum (CC). The lipomas are usually diagnosed prenatally during the third trimester. The purpose of this study was to identify 2nd trimester ultrasound findings that may hint to a later diagnosis of PCL and to evaluate their MRI evolution. METHODS: A multicenter study of fetuses diagnosed during the 3rd trimester with a PCL in 7 fetal ultrasound units between 2001 and 2017. We reevaluated the ultrasound and MRI images starting from the referral examination and until the time of diagnosis, searching for clues that could have prompted an earlier diagnosis. Parents were contacted at the end of the study period to obtain information regarding development and neurological examination. RESULTS: Fifteen patients with PCL were diagnosed during the study period; fourteen had second trimester scans. A 2nd trimester diagnosis was established in only 2 (13.3%). Anomalies of the CC were evident in 8/14 patients during the 2nd trimester scan and included: short length (n = 4), increased thickness (n = 1), complete agenesis (n = 2) and partial agenesis (n = 1). Third trimester ultrasound scans were considered diagnostic of PCL in all 12 remaining cases, in eight it was considered an isolated finding. Postnatal neurological evaluation in the isolated cases revealed normal development in all children. One child was diagnosed with attention deficit disorder. CONCLUSIONS: Non visualization of a PCL during the 2nd trimester is common, and should not be considered a diagnostic error. An underlying PCL should be included in the differential diagnosis of CC anomalies during this time period, necessitating further follow up into the 3rd trimester.

Fetal cerebellar disorders.

The embryologic development of the cerebellum extends over a long time period, thus making it vulnerable to a broad spectrum of malformations and disruptions. Knowledge of the main steps of fetal posterior fossa development; the normal imaging patterns at different stages of embryogenesis; the large spectrum of cerebellar malformations; and their clinical presentations enables diagnosis and precise counseling of parents. Sonography is the most important imaging method for the screening of cerebellar malformations since it is noninvasive, widely available, and safe for both mother and child. The ultrasonographic approach for the evaluation of the fetal posterior fossa is based on the classic transabdominal visualization of axial planes with addition when indicated of a more comprehensive, multiplanar transvaginal or transfundal approach, including coronal and sagittal imaging planes. Fetal magnetic resonance imaging (MRI) has become an adjunct to prenatal ultrasound since the 1980s. Good-quality images have been obtained thanks to the implementation of fast and ultrafast MRI sequences. Fetal MRI has higher-contrast resolution than prenatal sonography and may contribute to the differentiation of normal from abnormal tissue. Both prenatal neurosonography and fetal MRI enable accurate prenatal diagnosis of most posterior fossa anomalies.

Unique Imaging Features Enabling the Prenatal Diagnosis of Developmental Venous Anomalies: A Persistent Echogenic Brain Lesion Drained by a Collecting Vein in Contrast with Normal Brain Parenchyma on MRI.

OBJECTIVE: To describe the prenatal imaging features enabling diagnosis of developmental venous anomalies (DVA). METHODS: Four fetuses with unexplained persistent echogenic parenchymal brain lesions were studied. The evaluation included dedicated neurosonography, fetal MRI, serology for intrauterine infection, screening for coagulation abnormalities, and chromosomal microarray. Postnatal neurodevelopmental follow-up or autopsy results were assessed. RESULTS: DVA presented as very slowly growing echogenic brain lesions without cystic components, calcifications, or structural changes on otherwise normal neurosonographic scans performed at 2- to 3-week intervals. A specific Doppler feature was a collecting vein draining the echogenic parenchyma. Fetal brain MRI depicted normal anatomy on half-Fourier acquisition single-shot turbo spin-echo and diffusion-weighted imaging. The rest of the evaluation was normal. CONCLUSIONS: In cases with a persistent, parenchymal echogenic lesion without clastic or structural changes, DVA should be considered. Demonstration of a collecting vein draining the lesion and normal brain anatomy on MRI confirm the diagnosis.

Familial Brain Periventricular Pseudocysts.

INTRODUCTION: We report the rare finding of recurrent periventricular pseudocysts (PVPC) in consecutive pregnancies in 4 families and their postnatal outcome. MATERIALS AND METHODS: We reviewed the databases of 3 large ultrasound units searching for the diagnosis of PVPC in 2 pregnancies of the same patient. RESULTS: The first case of recurrent PVPC was diagnosed in 2011 and since then 3 additional families were diagnosed (8 cases of PVPC all in all). All fetuses underwent fetal MRI that confirmed the presence of frontal or frontocaudal PVPC. Amniocentesis, when performed, demonstrated a normal karyotype. Termination of pregnancy was carried out in 2 pregnancies in 2 of 4 families. The remaining 6 pregnancies ended with a term delivery, and to date all babies are developing normally. CONCLUSION: The rare finding of recurrent brain PVPC in consecutive pregnancies raises the possibility of a hereditary etiology as opposed to a sporadic event. As in isolated PVPC, frontocaudal 'familial PVPC' appears to carry a favorable prognosis.

Hemifacial microsomia with spinal and rib anomalies: prenatal diagnosis and postmortem confirmation using 3-D computed tomography reconstruction.

Hemifacial microsomia (OMIM164210) is a condition featuring unilateral ear anomalies and ocular epibulbar dermoids associated with unilateral underdevelopment of the craniofacial bony structures. Other associated anomalies have also been described, especially spinal malformations, and the term oculoauriculovertebral dysplasia spectrum (OVAS) was suggested to include the three predominant systems involved. Both genetic and environmental causes are implied in the pathogenesis of the syndrome, with a 3% recurrence rate according to reports of both vertical transmission and affected siblings. No specific gene was identified, albeit mutations in chromosome 10 and deficiencies of genes in the endothelin pathway in mice exhibited the same clinical features. We hereby describe the first case of prenatal diagnosis of spinal and rib malformations associated to hemifacial microsomia by means of 2-D and 3-D ultrasound in a 23-week fetus. The sonographic study depicted fetal scoliosis due to the presence of hemivertebrae, Sprengel's deformity of the left shoulder, ribs fusion, asymmetric ears with unilateral microtia, mandible unilateral hypoplasia as well as single umbilical artery and a 'golf ball' sign in the left ventricle of the heart. The diagnosis of OVAS was suggested and the family received proper genetic consultation. After termination of the pregnancy, the syndrome was confirmed by postmortem 3-D computed tomography study. In view of the grim outcome, prenatal death rate and high mortality and morbidity when three or more systems are involved, prenatal diagnosis and appropriate counseling are warranted.

A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutiéres syndrome associated with mtDNA deletions.

Aicardi-Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLGα, POLGß, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components.