Hydrocephalus associated with a molar tooth sign: A distinct subtype of Joubert syndrome.

Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or potentially signifies a new phenotypic subtype. The databases of Wolfson Medical Center, Sourasky Medical Center, and EB's personal collection were reviewed. Records from an additional family were obtained from RG. The patients' medical records, prenatal ultrasounds, and magnetic resonance imaging were assessed. In addition, we reviewed the medical literature for the association of ventriculomegaly/hydrocephalus (VM/HC) in JBTS. Only seven cases (from five families) were found with prenatal onset of VM/HC, diagnosed during the second trimester; three pregnancies were terminated, one was stillborn and three were born, of which one died within a week, and another died at the age of 6 years. Additional central nervous system findings included dysgenesis of the corpus callosum, delayed sulcation, polymicrogyria, and pachygyria. We found 16 publications describing 54 patients with JBTS and VM/HC: only five were diagnosed at birth and three were diagnosed prenatally. Hydrocephalus is extremely rare in JBTS. The recurrence of this association, reported in several publications in multiple family members, suggests that it might represent a new phenotypic subtype of JBTS possibly associated with specific genes or variants. Further genetic studies are needed to confirm this hypothesis. WHAT THIS PAPER ADDS: The association of fetal hydrocephalus with Joubert-Boltshauser syndrome (JBTS) is very rare but not a chance association. This association represents a new phenotypic subtype of JBTS possibly linked to specific genes or variants.

Diagnosis of fetal cortical abnormalities by new reference charts for assessment of sylvian fissure biometry.

OBJECTIVE: To develop novel fetal reference ranges for the characterization of the normal appearance of the Sylvian fissures (SF) along gestation and to apply them to fetuses with cortical abnormalities affecting the SF. METHODS: In this cross-sectional study, we used three-dimensional sonographic multiplanar reformatting (3D-MPR) to examine the fetal SF. Normal development was assessed in the second and third trimesters. SF parameters were evaluated in predefined axial and coronal planes: insular height and length, SF depth, and the extent of the coverage of the insula by the frontal and temporal lobes. Intra-observer variability and inter-rater reliability for the studied parameters were evaluated. The new reference charts were applied to 19 fetuses with cortical abnormalities involving the SF who had appropriate sonographic volumes for 3D-MPR analysis. Their diagnoses were confirmed by autopsy, fetal or postnatal MRI, genetic findings related to cortical malformations, or an abnormal cortical imaging pattern with similar MRI findings in an affected sibling. We applied the two previously published references for the evaluation of fetal SF development to these cases and compared the ability of the references to correctly detect SF abnormalities. RESULTS: The study included 189 fetuses of low-risk singleton pregnancies between 24 and 34 gestational weeks. The insular length or height increased with gestational age in the axial and coronal planes with adjusted R2  = 0.621, p < 0.0001 and R2  = 0.384, p < 0.0001, respectively. The SF depth also increased with gestational age in the axial and coronal planes with adjusted R2  = 0.695, p < 0.0001 and R2  = 0.219, p = 0.008, respectively. The extent of the coverage of the insula by the frontal and temporal lobes in the coronal plane increased with gestational age (adjusted R2  = 0.627, p < 0.0001 and R2  = 0.589, p < 0.0001, respectively). The interclass correlation coefficients of the intra- and inter-rater reliability of the studied parameters ranged between 0.71 and 0.97. The cortical anomalies in the 19 fetuses were polymicrogyria (7), simplified gyral pattern (3), dysgyria (3), lissencephaly (2), cortical malformation related to tubulinopathy (1), brain atrophy (1), cortical dysplasia (1), and cobblestone malformation (1). Three of the fetuses had multiple cortical anomalies. In 17 of 19 (89%) cases, at least one of our 6 SF parameters was found to be out of the normal range. In the coronal plane, SF height and depth were measured below 2SD in 9 (47%) and 4 (21%) cases, respectively. In the axial plane, SF length and depth were out of the normal ranges in six (31.5%) and four (21%), correspondingly. In the coronal plane, the opercular coverage by the frontal and temporal lobes was below 2 SD in 10 (52%) and 11 (57%), respectively. The scoring of the SF operculization by Quarello et al. was abnormal in 8 cases (42%). The measurement of the SF angle according to Poon et al. was abnormal in 14 cases (74%). CONCLUSIONS: The fetal SF is a complex developing structure that can be reliably characterized by sonographic parameters. One abnormal parameter is sufficient to raise the suspicion of SF malformation. Our new SF parameters might facilitate the detection of prenatal cortical abnormalities affecting the SF.

Prenatal diagnosis of major aortopulmonary collateral arteries (MAPCA) in fetuses with pulmonary atresia with ventricular septal defect and agenesis of ductus arteriosus.

OBJECTIVE: The aim of this study was to describe the prenatal diagnosis of Major Aortopulmonary Collateral Arteries (MAPCAs), and to present a systematic ultrasound method for evaluating lung vascularity in fetuses with pulmonary atresia with ventricular septal defect (PAVSD) and agenesis of ductus arteriosus (DA). METHOD: This retrospective study evaluated fetuses diagnosed with PAVSD with agenesis of DA, for the presence of the MAPCAs anomaly. Fetal pulmonary vasculature was investigated by 2D and 4D Spatio Temporal Image Correlation (STIC) technology using High Definition Color Doppler. RESULTS: Over a 10 year period, six fetuses were diagnosed with MAPCAs. Prenatal diagnosis was made between 17 w 6 d and 28 w 4 d in five fetuses, with the sixth diagnosed at 37 w 6 d. All six had PAVSD with agenesis DA, four exhibited pulmonic atresia without any arterial outflow, while two fetuses presented with absent left pulmonary artery, and a miniscule right pulmonary artery. In five cases, the parents elected to terminate the pregnancy and the last, although born alive, did not survive an attempt at restorative surgery and died at the age of 5 months. Postnatal CT angiography imaging of this case revealed the subclavian origin of the MAPCAs. Chromosomal micro array analysis of the amniotic fluid revealed that five of the six fetuses were normal and one was lost to follow up. CONCLUSION: MAPCAs should be investigated in cases of PAVSD with agenesis DA. A meticulous ultrasound evaluation using 2D and 4D STIC can permit the prenatal diagnosis of this anomaly and provide the parents with the opportunity for prenatal consultation.

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.

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.

Walker-Warburg syndrome and tectocerebellar dysraphia: A novel association caused by a homozygous DAG1 mutation.

OBJECTIVES: To elaborate the imaging phenotype associated with a homozygous c.743C > del frameshift mutation in DAG1 leading to complete absence of both α- and ß-dystroglycan previously reported in a consanguineous Israeli-Arab family. METHODS: We analyzed prenatal and postnatal imaging data of patients from a consanguineous Israeli-Arab kindred harboring the DAG1 mutation. RESULTS: The imaging studies (fetal ultrasound, CT scan and postnatal MRI) demonstrated: flat cortex (abnormally thick with irregular pebbled cortical-white matter border on MRI), hydrocephalus, scattered small periventricular heterotopia and subependymal hemorrhages and calcifications, z-shaped brainstem, and in addition an occipital encephalocele, vermian agenesis, and an elongated and thick tectum (tectocerebellar dysraphia). CONCLUSIONS: The novel association of cobblestone malformation with tectocerebellar dysraphia as part of WWS is characteristic of the homozygous c.743C > del frameshift mutation in the DAG1 gene.

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.

Added value of 3-dimensional sonography for endometrial evaluation in early puerperium.

OBJECTIVES: The purpose of this study was to examine the uterine cavity within 48 hours of delivery using 2- and 3-dimensional sonography after normal vaginal deliveries, instrumental deliveries, exploration of the uterine cavity, and cesarean deliveries. METHODS: A prospective study was performed in puerperal women with normal clinical examination findings. Measurements of the uterine length and width were taken in the midsagittal and coronal planes. Midsagittal measurements of the endometrium using 2- and 3-dimensional sonography and virtual organ computer-aided analysis were performed. Comparisons were made between normal and surgical vaginal deliveries, cesarean deliveries, and after exploration of the uterine cavity. RESULTS: A total of 123 patients were examined. Seventy-seven patients had normal vaginal deliveries; 21 had assisted vaginal deliveries; and 25 had cesarean deliveries. Thirteen underwent exploration of the uterine cavity. The uterine volume increased significantly as the birth weight increased and after cesarean delivery (P < .05). No correlation was found between the endometrial volume and parity, birth weight, and mode of delivery, including no correlation with exploration. Five cases of placental residua were found in asymptomatic women. All delivered vaginally. None underwent exploration of the uterus. All had irregular echogenic masses in the uterine cavity with positive color Doppler findings. The endometrial thickness and volume were significantly higher in these patients. CONCLUSIONS: Sonography along with Doppler assessment has added value in the clinical evaluation of the puerperal women, being able to also show residua in asymptomatic women. Three-dimensional sonography did not show an advantage over 2-dimensional sonography in the estimation of the puerperal uterus or residua.

Vermian biometric parameters in the normal and abnormal fetal posterior fossa: three-dimensional sonographic study.

OBJECTIVES: The purposes of this study were to describe a 3-dimensional sonographic technique for evaluation of the fetal vermis and to compare vermian biometric parameters in fetuses with a normal and an abnormal posterior fossa. METHODS: A prospective study was conducted from 2006 through 2008 on 12 fetuses with an abnormal posterior fossa and 73 healthy control fetuses from 18 to 35 weeks' gestation. Three-dimensional scans of the fetal head were performed in the axial plane, using static volume contrast imaging in the C-plane. The vermian perimeter, cross-sectional area, and superoinferior diameter were measured and compared between abnormal and normal fetuses using the Wilcoxon nonparametric test. Linear regression analysis was used to describe trends of the vermis during gestation. The z scores for perimeter, cross-sectional area, and superoinferior diameter measurements in the abnormal posterior fossa group in each 2-week interval were calculated. RESULTS: Twelve fetuses with an abnormal posterior fossa were recruited: 3 with a Blake pouch cyst, 1 vermian cyst, 1 enlarged cisterna magna, 2 Dandy-Walker malformation, 4 partial vermian agenesis, and 1 hemicerebellar hypoplasia. The vermian cross-sectional area was reduced significantly in the fetuses with an abnormal posterior fossa compared with the control fetuses starting at 18 to 19 weeks' gestation (P = .01); the mean vermian superoinferior diameter was lower only from 22 to 23 weeks (P = .01); and the mean vermian perimeter was decreased from 28-29 weeks' gestation (P = .03). Linear regression analysis of the parameters showed that fetuses with an abnormal posterior fossa had a statistically significantly lower growth rate than control fetuses during gestation (P < .001). CONCLUSIONS: Measurements of the cross-sectional area were more useful than those of the perimeter and superoinferior diameter in distinguishing between fetuses with a normal and an abnormal posterior fossa during the early stages of gestation.

Abnormal number of fetal ribs on 3-dimensional ultrasonography: associated anomalies and outcomes in 75 fetuses.

OBJECTIVE: The purpose of this study was to describe the clinical importance of an abnormal number of fetal ribs. METHODS: A retrospective study of all fetuses that were found to have an abnormal number of ribs during routine ultrasonographic examinations was performed. Volume data sets of the fetal ribs were acquired by either static 3- or 4-dimensional volume contrast imaging in plane C. In all cases, a meticulous survey of the fetal anatomy was performed, and prenatal and postnatal records were reviewed. RESULTS: Seventy-five fetuses were found retrospectively to have an abnormal number of ribs. Ultrasonographic examinations were done between 14 and 31 weeks' gestation (mean, 21.8 weeks; median, 23 weeks). More than 24 ribs were found in 28 fetuses (37%), and fewer than 24 ribs were found in 47 (63%). Additional anomalies were found in 22 fetuses (29%). Cardiovascular anomalies were detected in 10 fetuses. Seven fetuses had renal anomalies. Two fetuses had mild ventriculomegaly, and 1 fetus had holoprosencephaly. Lung dysplasia was found in 2 cases. One fetus had enlarged nuchal translucency with wormian bones. Termination of pregnancy was performed in 3 cases because of major malformations. The other 19 fetuses with associated abnormalities and the 53 without associated anomalies were born alive with only minor anomalies. CONCLUSIONS: An abnormal number of fetal ribs is an isolated finding in most cases. It may also be seen with major anomalies; however, more frequently the anomalies are minor, and the overall prognosis is good.