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Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.

To assess whether microcephaly with pontine and cerebellar hypoplasia (MICPCH) could manifest in the prenatal period in patients with calcium/calmodulin-dependent serine protein kinase (CASK) gene disorders.In this international multicentre retrospective study, we contacted a CASK parents' social media group and colleagues with expertise in cerebellar malformations and asked them to supply clinical and imaging information. Centiles and standard deviations (SD) were calculated according to age by nomograms.The study consisted of 49 patients (44 females and 5 males). Information regarding prenatal head circumference was available in 19 patients; 11 out of 19 had a fetal head circumference below -2SD (range -4.1SD to -2.02SD, mean gestational age at diagnosis 20 weeks). Progressive prenatal deceleration of head circumference growth rate was observed in 15 out of 19. At birth, 20 out of 42 had a head circumference below -2SD. A total of 6 out of 15 fetuses had a TCD z-score below -2 (range -5.88 to -2.02).This study expands the natural history of CASK-related disorders to the prenatal period, showing evidence of progressive deceleration of head circumference growth rate, head circumference below -2SD, or small TCD. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements and genetic studies are advised in the presence of progressive deceleration of head circumference growth rates or small TCD.

Background Among all of the studied potential causes of autism, vaccines have received some of the most scrutiny and have been the topic of many evidence-based studies. These efforts have led the great majority of scientists, physicians, and public health researchers to refute causation between vaccines and autism. Rationale This presumed association and concern has been a major contributor to parents’ refusal to immunize their children and has become a major threat to public health in secluded populations over the last two decades, even prior to the COVID-19 pandemic. With the emergence of COVID-19 immunizations, sentiments towards this topic were addressed as a public health concern that may influence the ability to overcome the Corona virus worldwide. Scientific review of data Despite the overwhelming data demonstrating that there is no link between vaccines and autism, many parents are hesitant to immunize their children because of the alleged association. Other contributing factors to the myths and conspiracy theories surrounding the association between vaccines and autism include the fact that the diagnosis of autism is typically made after the age of receiving the main childhood immunizations, as well as the occasional occurrence of regression after the age of first year vaccinations. In spite of vast evidence that the main contribution to the increase in incidence is from improvement of the diagnostic process, this rapid and publicized rise in autism diagnoses feeds parental concerns regarding any medical intervention that may be associated with the health of their children. Recommendations It is plausible that with more evidence-based studies linking autism to specific etiologies the myth will diminish and disappear eventually. In an era where conspiracy theories are prevalent on social media, it is critical that evidence-based studies relating autism to specific etiologies be made public, and that information concerning autism diagnosis and causes be made more readily available through social media and parental organizations.

ObjectivePerampanel, an antiseizure drug with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of gamma-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. MethodsThis multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. ResultsA total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 +/- 9.9 years), were enrolled. The mean dosage was 6.45 +/- 2.47 mg, and treatment period was 2.0 +/- 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% +/- 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity. SignificancePerampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.

Inborn errors of metabolism (IEM) are genetic disorders due to a defective metabolic pathway. The incidence of each disorder is variable and depends on the respective population. Some disorders such as urea cycle disorders (UCD) and organic acidurias, pose a high risk for a metabolic crisis culminating in a life-threatening event, especially during infections; thus, vaccines may play a crucial role in prevention. However, there are different triggers for decompensations including the notion that vaccines themselves can activate fever and malaise. Additionally, many of the IEM include immunodeficiency, placing the patients at an increased risk for infectious diseases and possibly a weaker response to immunizations. Since metabolic crises and vaccine regimens intersect in the first years of life, the question whether to vaccinate the child occupies parents and medical staff. Many metabolic experts hesitate to vaccinate IEM patients, disregarding the higher risk from the direct infections. In this paper we summarize the published data regarding the safety and recommendations for vaccinations in IEM patients, with reference to the risk for decompensations and to the immunogenic component.

OBJECTIVE: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations. METHODS AND RESULTS: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients’ charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development. CONCLUSIONS: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.

Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.

Background: Congenital mirror movements are involuntary movements of a side of the body imitating intentional movements on the opposite side, appearing in early childhood and persisting beyond 7 years of age. Congenital mirror movements are usually idiopathic but have been reported in association with various brain malformations. Methods: We describe clinical, genetic, and radiologic features in 9 individuals from 5 families manifesting congenital mirror movements. Results: The brain malformations associated with congenital mirror movements were: dysplastic corpus callosum in father and daughter with a heterozygous p.Met1* mutation in DCC; hypoplastic corpus callosum, dysgyria, and malformed vermis in a mother and son with a heterozygous p.Thr312Met mutation in TUBB3; dysplastic corpus callosum, dysgyria, abnormal vermis, and asymmetric ventricles in a father and 2 daughters with a heterozygous p.Arg121Trp mutation in TUBB; hypoplastic corpus callosum, dysgyria, malformed basal ganglia and abnormal vermis in a patient with a heterozygous p.Glu155Asp mutation in TUBA1A; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, and cerebellar cysts in a patient with a homozygous p.Pro312Leu mutation in POMGNT1. Conclusion: DCC, TUBB3, TUBB, TUBA1A, POMGNT1 cause abnormal axonal guidance via different mechanisms and result in congenital mirror movements associated with brain malformations.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

Acyl‐CoA dehydrogenase family member 9 (ACAD9) is an enzyme essential for the assembly of mitochondrial respiratory chain complex I. ACAD9 deficiency can cause lactic acidosis, myopathy, cardiomyopathy, intellectual disability, and early demise. We present a patient with mitochondrial myopathy, hypertrophic cardiomyopathy, and epilepsy due to recessive ACAD9 mutations. A muscle biopsy depicted ragged red fibers, and decreased activity of complex I of the respiratory chain. Treatment with riboflavin was initiated at the age of 4 years due to complex I deficiency (before the genetic diagnosis), resulting in symptomatic improvement of the cardiomyopathy, exercise intolerance, and lactate levels. A novel homozygous ACAD9 mutation was found: c.398G>A; p.Ser133Asn at the age of 23 years. Three years later she sustained a normal pregnancy, and gave birth to a healthy baby girl delivered by an elective Cesarean section. To the best of our knowledge, this is the first description of a successful pregnancy and delivery in a patient with this rare mitochondrial disease.

Iron-sulfur cluster assembly 2 (ISCA2)-related multiple mitochondrial dysfunction syndrome 4 (MMDS4) is a fatal autosomal recessive mitochondrial leukoencephalopathy. The disease typically manifests with rapid neurodevelopmental deterioration during the first months of life leading to a vegetative state and early death. MRI demonstrates a demyelinating leukodystrophy. We describe an eleven-year-old boy with a milder phenotype of ISCA2 related disorder manifesting as: normal early development, acute infantile neurologic deterioration leading to stable spastic quadriparesis, optic atrophy and mild cognitive impairment. The first MRI demonstrated a diffuse demyelinating leukodystrophy. A sequential MRI revealed white matter rarefaction with well-delineated cysts. The patient harbors two novel bi-allelic variants (p.Ala2Asp and p.Pro138Arg) in ISCA2 inherited from heterozygous carrier parents. This report expands the clinical spectrum of ISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation.

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.

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.

Epilepsy and intracranial pressure (ICP) can be interrelated. While shunt malfunction is recognized as a cause of seizures, shunt over-drainage is seldom reported as such. We report a child who had undergone ventriculoperitoneal shunt insertion at the age of 6 months following an excision of a left ventricle choroid plexus papilloma, who developed refractory epilepsy since the age of 3 years. An MRI showed small ventricles. The child presented with acute hydrocephalus due to proximal shunt malfunction at the age of 11 years and was treated with an endoscopic third ventriculostomy. Following the procedure, the seizures abated. Our case suggests that intractable epilepsy may be related to intracranial hypotension. Potential treatments for shunt over-drainage may be indicated even in the absence of classic over-drainage symptoms, in the presence of refractory epilepsy.

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-related phenotypes. We discuss the possible pathophysiology in view of PTEN function.

The chromosome alignment maintaining phosphoprotein 1 (CHAMP1) gene has a key role in neurodevelopment. It is involved in kinetochore-microtubule attachment and in the regulation of chromosomes alignment during mitosis. So far, 17 cases of CHAMP1 mutations have been reported with a common clinical picture of developmental delay and intellectual disability, dysmorphic facial features, hypotonia and/or spasticity, and microcephaly. Four patients had epilepsy of whom three had focal seizures and one had generalized epilepsy. We report two new cases, which have in addition to developmental delay, refractory myoclonic epilepsy. These cases suggest that the phenotypic spectrum of CHAMP1 mutations may be broader and includes refractory myoclonic epilepsy as well.

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.

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.

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations. Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome. In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers. The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.

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).

OBJECTIVES To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD)

Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.

BACKGROUND: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients.OBJECTIVE: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations.MATERIAL AND METHODS: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder.RESULTS: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two.CONCLUSIONS: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

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.

Objective This article elucidates a clinical and genetic approach to pediatric early-onset chorea in patients with normal neuroimaging. Methods We retrospectively studied patients with onset hyperkinetic movement disorders. Only children with onset of chorea in the first 3 years of life were included, those with an abnormal magnetic resonance imaging (MRI) or electroencephalogram (EEG) were excluded.We studied the movement disorder phenotype by clinical examination and by interpretation of videos and compared our data to the literature. Results Four patients, aged 2 to 13 years, were diagnosed. Abnormal involuntary movements appeared between the ages of 6 months to 3 years in association with developmental delay. One patient has a close relative with NKX2.1-related chorea. One patient is from Iraqi-Jewish origin. Facial twitches and nocturnal dyskinetic attacks were observed in one.The unique clinical presentation and family history enabled genetic diagnosis by molecular analysis of a specific mutation in two (NKX2.1, OPA3) and Sanger sequencing of a target gene in one (ADCY5). One patient was diagnosed by whole-exome sequencing (WES) (GNAO1). Conclusion By carefully recording the phenotype and genetic background, a single gene can be suspected in some cases. In the rest, we suggest multigene panels or WES study.

Objective The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway. Methods We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments. Results We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2. Interpretation Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794-806.

Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated. In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy. In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.

Background and Purpose: Postnatal progressive microcephaly, with seizures and brain atrophy (OMIM # 613668) is a rare disorder caused by a homozygous founder missense mutation c.1112T>C (p.L371P) in the MED17 gene on chromosome 11 that was identified in 2010 in Caucasus Jewish families. The present study aimed to delineate the phenotype and developmental outcomes in patients diagnosed with this mutation to date. Methods We conducted a medical charts review to collect the clinical, laboratory and neuroimaging findings in patients from several unrelated families of Caucasus-Jewish origin, who were diagnosed with the same homozygous c.1112T>C MED17 mutation. Results The study cohort, including the previously reported patients, comprised 10 males and 5 females from 11 families. All subjects had at birth a normal head circumference, which steeply declined to -6SD within a few months. None of the patients achieved developmental milestones. All patients had progressive spasticity and were wheelchair bound due to spastic quadriplegia. All of them eventually developed profound intellectual disability. Epilepsy of varied severity was present in all patients. Most patients required enteral feeding due to aspirations. Eight patients died before puberty (age range 2–13 years). Brain MRI showed marked cerebral atrophy and early prominent cerebellar atrophy (vermian > hemispheres) accompanied by pontine ventral flattening. Conclusions The founder c.1112T>C mutation in MED17 gene is expressed by a unique and homogeneous clinical phenotype with distinctive MRI findings. This mutation should be considered in patients of Caucasus-Jewish ancestry presenting with clinical features and a MRI pattern of progressive cerebral and cerebellar atrophy.

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro-rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro-rearrangement syndrome, and a chromosomal microarray analysis should be performed.

Roughly 40 genes have been linked to autosomal recessive (AR) ataxia syndromes. Of these, at least 10 encode gene products localizing to the mitochondrion. tRNA-histidine guanylyltransferase 1 like (THG1L) localizes to the mitochondrion and catalyzes the 3′–5′ addition of guanine to the 5′-end of tRNA-histidine. Previously, three siblings with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy on brain magnetic resonance imaging (MRI) were reported to carry homozygous V55A mutations in THG1L. Fibroblasts derived from these individuals showed abnormal mitochondrial networks when subjected to obligatory oxidative phosphorylation. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes were found in Exac or gnomAD. This variant is reported with an allelic frequency of 0.02% in Exac, and is not listed in gnomAD. A similar phenotype was recently reported for another, homozygous variant p.L294P was reported with a similar, but more severely affected phenotype [Shaheen et al. (2019); Genetics in Medicine 21: 545–552]. Here, we report two additional Ashkenazi Jewish patients, carrying the same homozygous V55A mutation. We present bioinformatic analyses of the V55A mutation demonstrating high conservation in metazoan species. We refine the clinical and radiological phenotype and discuss the uniqueness of the clinical course of this novel mitochondrial AR ataxia in comparison to the diverse molecular etiologies and clinical phenotypes of other known mitochondrial AR ataxias.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Adenylosuccinate lyase deficiency is a rare autosomal recessive disorder of purine metabolism. The disorder manifests with developmental delay, postnatal microcephaly, hypotonia, involuntary movements, epileptic seizures, ataxia and autistic features. Paroxysmal non-epileptic motor events are not a typical presentation of the disease. We describe an 8-year-old boy who presented with an infantile onset of prolonged episodes of multifocal sustained myoclonic tremor lasting from minutes to days on a background of global developmental delay and gait ataxia. Ictal EEG during these episodes was normal. Ictal surface EMG of the involved upper limb showed a muscular activation pattern consistent with cortical myoclonus. Brain MRI showed mild cerebral atrophy. Whole exome sequencing revealed a novel homozygous variant in the ADSL gene: c.1027G > A; p. Glu343Lys, inherited from each heterozygous parent. There was a marked elevation of urine succinyladenosine, confirming the diagnosis of adenylosuccinate lyase deficiency. In conclusion, myoclonic tremor status expands the spectrum of movement disorders seen in adenylosuccinate lyase deficiency.

Objectives Depiction of a thick corpus callosum (CC) in utero is rare, and is generally associated with severe brain anomalies. Our aim was to describe a group of fetuses diagnosed during second-trimester ultrasound examination as having an apparently isolated thick CC, which normalized subsequently in the cases followed to term. Methods Among 59 fetuses referred to the Ob-Gyn Ultrasound Division of Lis Maternity Hospital with suspected callosal anomalies between January 2013 and June 2014, we identified nine cases with an apparently isolated thick CC for inclusion in this retrospective cohort study. Length and body thickness of the CC were compared with previously published nomograms. Fetuses with a suspected isolated thick CC were identified and followed until delivery or termination of pregnancy (TOP). Evaluation consisted of chromosomal analysis, at least one magnetic resonance imaging (MRI) examination and repeat ultrasound examinations. Postnatal evaluation included brain ultrasound examination, MRI when indicated and neurodevelopmental assessment through validated pediatric questionnaires. Results The nine fetuses were diagnosed with an apparently isolated thick CC at a mean gestational age of 23 + 5 (range, 21–29) weeks. Eight exhibited a CC body thickness ≥ 2SD above the mean for gestational age and one exhibited only a thickened genu. Six also exhibited a relatively short CC. Two patients opted for TOP but declined autopsy. In five of the seven remaining fetuses, the CC thickness normalized during follow-up. In the remaining two, the increased CC thickness was a variant of the cingulate sulcus. The CC length remained ≤ 2SD in five of the six fetuses with a short CC. Fetal MRI was performed and confirmed the diagnosis in six fetuses. The karyotype was normal in all fetuses. Short-term neurodevelopmental outcome was reported as normal in all six children with complete follow-up. Conclusions Although the number of fetuses in our study is relatively small, it seems that an apparently isolated thick CC is not necessarily associated with poor prognosis. In such cases, a definitive diagnosis should not be reached based on a single measurement and repeat follow-up examinations during the third trimester are recommended. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Objectives Diagnosis of isolated posterior fossa anomalies in children is biased by the fact that only those that are symptomatic are brought to the attention of the appropriate clinical personnel, and the reported rate is often affected by the adoption of different nomenclature, diagnostic criteria, outcome measures, duration of follow-up and neurodevelopmental tools. The aim of this systematic review was to explore the neurodevelopmental outcome of fetuses with a prenatal diagnosis of isolated posterior fossa anomalies. Methods MEDLINE and EMBASE were searched electronically, utilizing combinations of the relevant medical subject heading terms for ‘posterior fossa’ and ‘outcome’. Studies assessing the neurodevelopmental outcome in children with a prenatal diagnosis of isolated posterior fossa malformations were considered eligible. The posterior fossa anomalies analyzed included Dandy–Walker malformation (DWM), mega cisterna magna (MCM), Blake's pouch cyst (BPC) and vermian hypoplasia (VH). Two authors reviewed all abstracts independently. Quality assessment of the included studies was performed using the Newcastle–Ottawa Scale for cohort studies. Meta-analyses of proportions were used to combine data, and between-study heterogeneity was explored using the I2 statistic. Results A total of 1640 articles were identified; 95 were assessed for eligibility and a total of 16 studies were included in the systematic review. The overall rate of abnormal neurodevelopmental outcome in children with a prenatal diagnosis of DWM was 58.2% (95% CI, 21.8–90.0%) and varied from 0–100%. In those with a prenatal diagnosis of MCM, the rate of abnormal neurodevelopmental outcome was 13.8% (95% CI, 7.3–21.9%), with a range of 0–50%. There was no significant association between BPC and the occurrence of abnormal neurodevelopmental delay, with a rate of 4.7% (95% CI, 0.7–12.1%) and range of 0–5%. Although affected by the very small number of studies, there was a non-significant occurrence of abnormal neurodevelopmental delay in children with a prenatal diagnosis of VH, with a rate of 30.7% (95% CI, 0.6–79.1%) and range of 0–100%. Conclusions Fetuses diagnosed with isolated DWM are at high risk of abnormal neurodevelopmental outcome, while isolated MCM or BPC have a generally favorable outcome. The risk of abnormal developmental delay in cases with isolated VH needs to be further assessed. In view of the wide heterogeneity in study design, time of follow-up, neurodevelopmental tests used and the very small number of included cases, further future large prospective studies with standardized and objective protocols for diagnosis and follow-up are needed in order to ascertain the rate of abnormal neurodevelopmental outcome in children with isolated posterior fossa anomalies. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Objective To explore the outcome in fetuses with prenatal diagnosis of posterior fossa anomalies apparently isolated on ultrasound imaging. Methods MEDLINE and EMBASE were searched electronically utilizing combinations of relevant medical subject headings for ‘posterior fossa’ and ‘outcome’. The posterior fossa anomalies analyzed were Dandy–Walker malformation (DWM), mega cisterna magna (MCM), Blake's pouch cyst (BPC) and vermian hypoplasia (VH). The outcomes observed were rate of chromosomal abnormalities, additional anomalies detected at prenatal magnetic resonance imaging (MRI), additional anomalies detected at postnatal imaging and concordance between prenatal and postnatal diagnoses. Only isolated cases of posterior fossa anomalies – defined as having no cerebral or extracerebral additional anomalies detected on ultrasound examination – were included in the analysis. Quality assessment of the included studies was performed using the Newcastle–Ottawa Scale for cohort studies. We used meta-analyses of proportions to combine data and fixed- or random-effects models according to the heterogeneity of the results. Results Twenty-two studies including 531 fetuses with posterior fossa anomalies were included in this systematic review. The prevalence of chromosomal abnormalities in fetuses with isolated DWM was 16.3% (95% CI, 8.7–25.7%). The prevalence of additional central nervous system (CNS) abnormalities that were missed at ultrasound examination and detected only at prenatal MRI was 13.7% (95% CI, 0.2–42.6%), and the prevalence of additional CNS anomalies that were missed at prenatal imaging and detected only after birth was 18.2% (95% CI, 6.2–34.6%). Prenatal diagnosis was not confirmed after birth in 28.2% (95% CI, 8.5–53.9%) of cases. MCM was not significantly associated with additional anomalies detected at prenatal MRI or detected after birth. Prenatal diagnosis was not confirmed postnatally in 7.1% (95% CI, 2.3–14.5%) of cases. The rate of chromosomal anomalies in fetuses with isolated BPC was 5.2% (95% CI, 0.9–12.7%) and there was no associated CNS anomaly detected at prenatal MRI or only after birth. Prenatal diagnosis of BPC was not confirmed after birth in 9.8% (95% CI, 2.9–20.1%) of cases. The rate of chromosomal anomalies in fetuses with isolated VH was 6.5% (95% CI, 0.8–17.1%) and there were no additional anomalies detected at prenatal MRI (0% (95% CI, 0.0–45.9%)). The proportions of cerebral anomalies detected only after birth was 14.2% (95% CI, 2.9–31.9%). Prenatal diagnosis was not confirmed after birth in 32.4% (95% CI, 18.3–48.4%) of cases. Conclusions DWM apparently isolated on ultrasound imaging is a condition with a high risk for chromosomal and associated structural anomalies. Isolated MCM and BPC have a low risk for aneuploidy or associated structural anomalies. The small number of cases with isolated VH prevents robust conclusions regarding their management from being drawn. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.