Publications by authors named "Malinger Gustavo"

70 Publications

Prenatal Diagnosis of Snijders Blok-Campeau Syndrome in a Fetus with Macrocephaly.

Fetal Diagn Ther 2021 17;48(5):407-410. Epub 2021 May 17.

The Danek Gertner Institute of Human Genetics, The Chaim Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel.

We present the prenatal imaging and whole exomics sequencing with the newly described Snijders Blok-Campeau macrocephaly syndrome.
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http://dx.doi.org/10.1159/000514326DOI Listing
May 2021

Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations.

Eur J Hum Genet 2021 Apr 9. Epub 2021 Apr 9.

Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.
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http://dx.doi.org/10.1038/s41431-021-00880-3DOI Listing
April 2021

Monogenic Causes of Apparently Idiopathic Perinatal Intracranial Hemorrhage.

Ann Neurol 2021 04 16;89(4):813-822. Epub 2021 Feb 16.

Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH.

Methods: We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance.

Results: Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, Von Willebrand factor [VWF], FGA, and F7; n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in 1 case (4%). Fifty-five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families.

Interpretation: Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. ANN NEUROL 2021;89:813-822.
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http://dx.doi.org/10.1002/ana.26033DOI Listing
April 2021

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

Prenat Diagn 2021 Jun 5;41(7):877-883. Epub 2021 Feb 5.

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1002/pd.5888DOI Listing
June 2021

Neurodevelopmental outcome of children born with an isolated atretic cephalocele.

Childs Nerv Syst 2021 Apr 6;37(4):1295-1300. Epub 2021 Jan 6.

Pediatric Neurology Institute, The Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, 6423906, Tel Aviv, Israel.

Purpose: The existing data on the neurodevelopmental outcome of children born with an isolated atretic cephalocele (IAC) are scant. We aimed to expand upon these data by describing our experience with affected children, as well as assist parents and clinicians in deciding how to proceed when an IAC is diagnosed prenatally.

Methods: A follow-up study was conducted on nine children who were born with an IAC. Evaluations were performed by pediatric neurologists and child development specialists. Developmental outcomes were based on a global development evaluation that assessed gross and fine motor skills, receptive and expressive language levels, activities of daily living, communication skills, and social domains. Adaptive skills were estimated by the Adaptive Behavior Assessment System, Second Edition.

Results: None of the nine children (median age 4 years and 6 months) had abnormal findings on neurological examination. Six children had age-appropriate developmental milestones, two had a mild motor delay, and one had mild expressive language delay (catchup was achieved by all of the latter three by ~ 3.5 years of age). The mean general adaptive composite score was 105 ± 11.7 (normal = 100). None of the children had behavioral, social, or communication problems.

Conclusions: Children diagnosed with an IAC with/without a falcine sinus and devoid of coexisting intracranial abnormalities seem to have a normal neurodevelopmental outcome. Continuation of pregnancy may be recommended when an IAC is detected prenatally, and reassurance if detected postnatally.
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http://dx.doi.org/10.1007/s00381-020-04997-6DOI Listing
April 2021

Obstetric and perinatal outcomes in cases of congenital Zika syndrome.

Prenat Diagn 2020 12 27;40(13):1732-1740. Epub 2020 Oct 27.

Instituto de Pesquisa Professor Amorim Neto (IPESQ), Campina Grande, Brazil.

Objective: To describe obstetric and perinatal outcomes in cases of congenital Zika syndrome (CZS).

Methods: A dual prospective and retrospective cohort study involving 102 pairs of mothers and fetuses/children with CZS whose infection was confirmed by testing for the Zika virus in amniotic fluid, umbilical cord blood, and fragments from the placenta of the newborn infant (confirmed CZS), or by intrauterine imaging tests (neurosonography), and/or postnatal computed tomography (presumed CZS).

Results: Suspicion of CZS was investigated by ultrasonography during pregnancy in 52.9% of cases. The principal prenatal imaging findings were ventriculomegaly (43.1%) and microcephaly (42.2%). Median gestational age at delivery was 39 weeks, with 15.7% being premature. Mean head circumference at birth was 30.0 ± 2.3 cm, with 66% of cases being classified as having microcephaly. Arthrogryposis was found in 10 cases (9.8%). There were no fetal deaths; however, nine neonatal deaths were recorded, and three autopsies were performed.

Conclusion: Neonatal mortality was high, almost 10%. Regarding the abnormalities of CZS, microcephaly, although common, was not present in all cases and intracranial findings need to be taken into consideration for diagnosis. Therefore, ultrasound screening during pregnancy should be systematized and expanded in endemic zones.
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http://dx.doi.org/10.1002/pd.5831DOI Listing
December 2020

The early pattern of human corpus callosum development: A transvaginal 3D neurosonographic study.

Prenat Diagn 2020 09 2;40(10):1239-1245. Epub 2020 Jun 2.

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: To provide an in-vivo description of early corpus callosum (CC) development.

Methods: We reviewed 3D US volumes acquired transvaginally (TVUS) through the anterior fontanelle, between 14 to 17 weeks. The following landmarks were recognized: tela-choroidea (TC), foramina of Moro, early CC and the evolving cavum septi pellucidi. The following measurements were taken: total, anterior and posterior sections, and height of the CC (referenced to the anterior TC border). All measurements were correlated to both the gestational age and the transverse cerebellar diameter (TCD).

Results: Eighty nine volumes were included in the study (mean 15.1 weeks ± 0.84, TCD range, 13.1-18.4 mm) with high inter and intra observer correlation of the measurements. We found high correlation between CC length and height, and TCD. The anterior segment of the CC appear earlier than the posterior one, and growth continues bi-directionally. Initially, the posterior elongation is significantly larger than the anterior one. Association of all CC measurements with TCD remained significant when co-varying for maternal age and fetal sex.

Conclusions: imaging the fetal CC is feasible from 14 weeks by TVUS, by following the suggested insonation approach. The early CC develops bi-directionally, and the posterior elongation is more significant than the anterior one.
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http://dx.doi.org/10.1002/pd.5735DOI Listing
September 2020

Bypassing physiological puberty, a novel procedure of oocyte cryopreservation at age 7: a case report and review of the literature.

Fertil Steril 2020 08 5;114(2):374-378. Epub 2020 May 5.

Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.

Objective: To report the first successful oocyte cryopreservation in a prepubertal girl.

Design: Case report and review of the literature.

Setting: Tertiary medical center.

Patient(s): A 7-year-old prepubertal girl with Turner syndrome mosaicism (45,X[37]/47,XXX[15]) who underwent a novel fertility preservation procedure after fertility preservation counseling and informed decision of the parents.

Intervention(s): Controlled ovarian hyperstimulation with daily administration of 100 IU recombinant human follicle-stimulating and 50 IU recombinant human luteinizing hormone per milliliter, injection of 250 μg human chorionic gonadotropin was given 36 hours before the follicular aspiration procedure, and oocytes retrieved by a transabdominal ultrasound guided approach.

Main Outcome Measure(s): Mature oocyte cryopreservation.

Result(s): The first cryopreservation cycle with use of a gonadotropin-releasing hormone agonist trigger failed to yield oocytes. The second cycle with human chorionic gonadotropin trigger was successful. Six oocytes were retrieved, and all were mature metaphase 2. The patient was discharged in good condition with no complications.

Conclusion(s): This novel procedure bypasses the timely physiologic progression of pubertal maturation of the hypothalamic-pituitary-ovarian axis to directly target the ovaries and achieve mature ovarian follicles. This innovative approach offers a new treatment modality for prepubertal girls who need fertility preservation such as in Turner syndrome or in cases that ovarian tissue cryopreservation is contraindicated.
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http://dx.doi.org/10.1016/j.fertnstert.2020.03.009DOI Listing
August 2020

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

Prenat Diagn 2020 07 6;40(8):931-941. Epub 2020 May 6.

Fetal Neurology Clinic-Ultrasound in ObGyn Unit, Wolfson Medical Center, Holon, Israel.

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.
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http://dx.doi.org/10.1002/pd.5704DOI Listing
July 2020

Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

Eur J Paediatr Neurol 2020 May 4;26:46-60. Epub 2020 Mar 4.

Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Objective: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome.

Methods: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses.

Results: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal.

Conclusions: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.
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http://dx.doi.org/10.1016/j.ejpn.2020.03.001DOI Listing
May 2020

Agenesis of the septum pellucidum: Prenatal diagnosis and outcome.

Prenat Diagn 2020 05 31;40(6):674-680. Epub 2020 Mar 31.

Division of Ultrasound in Obstetrics & Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Israel and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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.
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http://dx.doi.org/10.1002/pd.5663DOI Listing
May 2020

Subtle findings on fetal brain imaging in CMV infected pregnancies: What is the clinical significance? A retrospective analysis with outcome correlation.

Prenat Diagn 2020 03 24;40(4):447-453. Epub 2020 Feb 24.

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: To describe the prognosis of subtle findings on fetal brain imaging in pregnant women with primary CMV infection during pregnancy.

Methods: This was a retrospective study. The data included: timing of infection, amniocentesis results, imaging findings, obstetric outcome, and developmental assessment.

Results: For the 27 included patients, the time of infection was: periconception, first, second, third trimesters or unknown in 14.8%, 29.7%, 40.7%, 7.4%, and 7.4%, respectively. Seventy-four percent had only MRI findings; white matter hyperintense T2 signal (HT2) (51.8%), mild ventriculomegaly (18.5%), HT2 and temporal cyst (7.4%), dilated occipital horn (7.4%), Periventricular pseudo cyst (PVPC) with dilated occipital horn (3.7%), isolated PVPC (7.4%), choroid plexus cyst (3.7%). In 26% of fetuses, additional ultrasound findings were observed: Lenticulostriatal vasculopathy (LSV) (11.1%), LSV with PVPC (3.84%), isolated PVPC (3.84%), mild ventriculomegaly (3.84%), and bilateral temporal cysts (3.84%). In 66.6%, the MRI had false-positive findings (due to noninfected neonates). All children are developing normally, and one has a hearing deficit. Postnatal ultrasound (US) was normal in 21/27, with LSV in five, and a resolving subependymal cyst in one patient.

Conclusion: Subtle imaging findings are more common on MRI than US and the prognosis is most likely favorable. Performing amniocentesis will significantly reduce the false-positive rate.
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http://dx.doi.org/10.1002/pd.5634DOI Listing
March 2020

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

J Neurosurg Pediatr 2019 Jul 26:1-5. Epub 2019 Jul 26.

4Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

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.
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http://dx.doi.org/10.3171/2019.5.PEDS19142DOI Listing
July 2019

Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.

Prenat Diagn 2019 05 1;39(6):420-430. Epub 2019 Apr 1.

Department "Woman-Mother-Child", Lausanne University Hospital, Materno-Fetal and Obstetrics Research Unit, Lausanne, Switzerland.

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http://dx.doi.org/10.1002/pd.5446DOI Listing
May 2019

Fetal Neurology.

Eur J Paediatr Neurol 2018 11;22(6):895-897

Fetal Neurology Clinic, Obstetrics-Gynecology Ultrasound Unit, and Pediatric Neurology Unit, Wolfson Medical Center, Holon, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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http://dx.doi.org/10.1016/j.ejpn.2018.11.004DOI Listing
November 2018

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

Am J Med Genet A 2019 01 4;179(1):78-84. Epub 2018 Dec 4.

Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.

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.
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http://dx.doi.org/10.1002/ajmg.a.6DOI Listing
January 2019

Ultrasound imaging of the fetal secondary palate: Methodological description of a two-dimensional approach and a case series.

Prenat Diagn 2018 12;38(13):1049-1054

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: The study aims to describe our two-dimensional (2D) ultrasound approach to visualize the fetal secondary palate and plot its growth curve and to describe and demonstrate its clinical implementation.

Methods: This is a two parts retrospective study. First, we measured the antero-posterior length of the bony secondary palate, from the soft to hard palate interface (SHPI) line to the alveolar ridge, blindly by two operators during routine scans of low-risk fetuses, and plot a longitudinal growth curve. In the second part, we describe four cases of prenatal diagnosis of secondary palate cleft.

Results: Sixty-eight fetuses were included: 14 to 15 weeks (n = 20), 21 to 24 weeks (n = 32), and 29 to 35 weeks (n = 16). The bony secondary palate elongates along gestation from a mean of 5.3 mm (+/-0.46 mm) at 14 to 15 weeks to 15.9 mm (+/-1.7 mm) at 29 to 35 weeks. We found high intraobserver and interobserver correlation between measurements. All four cases diagnosed by this approach were confirmed postnatally.

Conclusions: The SHPI, representing the normally developed secondary bony palate, can be imaged in the fetus by direct 2D ultrasound as early as 14 weeks. A gap within or nonvisualization of the SHPI is highly suggestive for a secondary palate cleft.
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http://dx.doi.org/10.1002/pd.5385DOI Listing
December 2018

Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: prospective cohort study in French Guiana.

BMJ 2018 Oct 31;363:k4431. Epub 2018 Oct 31.

Materno-foetal and Obstetrics Research Unit, Obstetric Service, Department "Femme-Mère-Enfant," University Hospital, Lausanne, Switzerland.

Objectives: To estimate the rates of maternal-fetal transmission of Zika virus, adverse fetal/neonatal outcomes, and subsequent rates of asymptomatic/symptomatic congenital Zika virus infections up to the first week of life.

Design: Cohort study with prospective data collection and subsequent review of fetal/neonatal outcomes.

Settings: Referral centre for prenatal diagnosis of the French Guiana Western Hospital.

Participants: Pregnant women at any stage of pregnancy with a laboratory confirmed symptomatic or asymptomatic Zika virus infection during the epidemic period in western French Guiana. The cohort enrolled 300 participants and prospectively followed their 305 fetuses/newborns.

Main Outcome Measures: Rate of maternal-fetal transmission of Zika virus (amniotic fluid, fetal and neonatal blood, urine, cerebrospinal fluid, and placentas); clinical, biological, and radiological outcomes (blindly reviewed); and adverse outcomes defined as moderate signs potentially related to congenital Zika syndrome (CZS), severe complications compatible with CZS, or fetal loss. Associations between a laboratory confirmed congenital Zika virus infection and adverse fetal/neonatal outcomes were evaluated.

Results: Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed.

Conclusion: In cases of a known maternal Zika virus infection, approximately a quarter of fetuses will become congenitally infected, of which a third will have severe complications at birth or fetal loss. The burden of CZS might be lower than initially described in South America and may not differ from other congenital infections.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207920PMC
http://dx.doi.org/10.1136/bmj.k4431DOI Listing
October 2018

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

Eur J Paediatr Neurol 2018 Nov 1;22(6):900-909. Epub 2018 Sep 1.

Fetal Neurology Clinic, Obstetrics-Gynecology Ultrasound Unit, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv-Aviv, Israel.

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.
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http://dx.doi.org/10.1016/j.ejpn.2018.08.006DOI Listing
November 2018

Whole-exome sequencing in fetuses with central nervous system abnormalities.

J Perinatol 2018 10 14;38(10):1301-1308. Epub 2018 Aug 14.

Prenatal Genetic Diagnosis Unit, Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.

Objective: We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result.

Methods: During the study period (2014-2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis.

Results: A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5). Finally, in two fetuses of the same couple (Case #6), a compound heterozygous state was detected, consisting of the NPHP1 gene deletion and a sequence variant of uncertain significance. Two additional cases had normal WES results.

Conclusion: Whole-exome sequencing may improve prenatal diagnosis in fetuses with CNS abnormalities.
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http://dx.doi.org/10.1038/s41372-018-0199-3DOI Listing
October 2018

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

Eur J Paediatr Neurol 2018 Nov 2;22(6):929-934. Epub 2018 Aug 2.

Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1016/j.ejpn.2018.07.011DOI Listing
November 2018

Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter.

Ultraschall Med 2018 Jul 4. Epub 2018 Jul 4.

Affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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http://dx.doi.org/10.1055/a-0643-0490DOI Listing
July 2018

Fetal cerebellar disorders.

Handb Clin Neurol 2018 ;155:3-23

Fetal Neurology Clinic, Ob-Gyn Ultrasound Unit, Lis Maternity Hospital, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1016/B978-0-444-64189-2.00001-9DOI Listing
October 2018

Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter.

Ultraschall Med 2019 Aug 7;40(4):476-480. Epub 2018 Jun 7.

Affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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.
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http://dx.doi.org/10.1055/a-0594-2053DOI Listing
August 2019

The use of fetal neurosonography and brain MRI in cases of cytomegalovirus infection during pregnancy: A retrospective analysis with outcome correlation.

Prenat Diagn 2017 12;37(13):1335-1342

OB-GYN Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Medical Center, Tel Aviv, Israel.

Objective: To analyze ultrasound (US) and magnetic resonance imaging (MRI) results and developmental outcome in cases of maternal primary cytomegalovirus (CMV) infection during pregnancy.

Methods: We retrospectively reviewed the results of fetal neurosonography and brain MRI of CMV-infected fetuses (Group 1). Cases of maternal infection in which the fetal status was unknown, and subsequently had a negative CMV postnatal urine analysis, were independently analyzed (Group 2). Imaging results were classified as follows: positive, negative, or inconclusive. Developmental landmarks were followed up.

Results: Eighty-one women were included in the study: 48 (59.2%) in Group 1 and 33 (40.8%) in Group 2. In Group 1, termination of pregnancy was performed in 8 cases (16.7%) following the diagnosis of brain abnormalities. Among the remaining cases, concordance rate between US and MRI was 78%. False negative rates for US and MRI were 5.5% and 6.4%, respectively (hearing deficits). For MRI, we found 17.5% of false positive/inconclusive results, while for the US, we found 5% of inconclusive results. In Group 2, false positive rates for US and MRI were 6.5% and 12.9%, respectively.

Conclusions: Adding MRI in CMV-infected cases with a normal neurosonographic follow-up should be weighed against a nonnegligible rate of false positive and inconclusive findings.
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http://dx.doi.org/10.1002/pd.5180DOI Listing
December 2017

New Insights into the Natural History of Congenital Zika Virus Syndrome.

Fetal Diagn Ther 2018 13;44(1):72-76. Epub 2017 Sep 13.

University Maternity Hospital (HUMN), Córdoba National University, Córdoba, Argentina.

We describe the prenatal evolution of the brain findings in a patient with proved Zika virus infection at 8 weeks of gestation showing the very early appearance at 17 weeks of ventriculomegaly and signs of brain parenchymal involvement without microcephaly. The involvement of the brain becomes more evident at 22 and 27 weeks with the apparition of calcifications and microcephaly. Interestingly, the postnatal findings failed to show significant worsening when compared to these prenatal findings.
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http://dx.doi.org/10.1159/000479866DOI Listing
November 2018

Automatic Measurement of Fetal Brain Development from Magnetic Resonance Imaging: New Reference Data.

Fetal Diagn Ther 2018 13;43(2):113-122. Epub 2017 Sep 13.

Functional Brain Center, The Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: Accurate fetal brain volume estimation is of paramount importance in evaluating fetal development. The aim of this study was to develop an automatic method for fetal brain segmentation from magnetic resonance imaging (MRI) data, and to create for the first time a normal volumetric growth chart based on a large cohort.

Subjects And Methods: A semi-automatic segmentation method based on Seeded Region Growing algorithm was developed and applied to MRI data of 199 typically developed fetuses between 18 and 37 weeks' gestation. The accuracy of the algorithm was tested against a sub-cohort of ground truth manual segmentations. A quadratic regression analysis was used to create normal growth charts. The sensitivity of the method to identify developmental disorders was demonstrated on 9 fetuses with intrauterine growth restriction (IUGR).

Results: The developed method showed high correlation with manual segmentation (r2 = 0.9183, p < 0.001) as well as mean volume and volume overlap differences of 4.77 and 18.13%, respectively. New reference data on 199 normal fetuses were created, and all 9 IUGR fetuses were at or below the third percentile of the normal growth chart.

Discussion: The proposed method is fast, accurate, reproducible, user independent, applicable with retrospective data, and is suggested for use in routine clinical practice.
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http://dx.doi.org/10.1159/000475548DOI Listing
August 2018

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.

Fetal Diagn Ther 2018 17;43(1):53-60. Epub 2017 Jun 17.

Fetal Neurology Clinic and Ultrasound in ObGyn Unit, Wolfson Medical Center, Holon, Israel.

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.
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http://dx.doi.org/10.1159/000464247DOI Listing
August 2018

The MERIDIAN trial: caution is needed.

Lancet 2017 05;389(10084):2103

Fetal Medicine Unit, Venere Hospital, Bari, Italy; M Sarcone Hospital, Terlizzi, Bari, Italy.

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http://dx.doi.org/10.1016/S0140-6736(17)31337-5DOI Listing
May 2017