[Congenital brain malformations]. / Angeborene Hirnfehlbildungen.

CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

SAMHD1 compound heterozygous rare variants associated with moyamoya and mitral valve disease in the absence of other features of Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also been associated with a spectrum of cerebrovascular diseases, including moyamoya disease (MMD). In this report, we describe a 31-year-old male referred to genetics for MMD since childhood who lacked the hallmark features of AGS patients but was found to have compound heterozygous SAMHD1 variants. He later developed mitral valve insufficiency due to recurrent chordal rupture and ultimately underwent a heart transplant at 37 years of age. Thus, these data suggest that SAMHD1 pathogenic variants can cause MMD without typical AGS symptoms and support that SAMHD1 should be assessed in MMD patients even in the absence of AGS features.

Lissencephaly With Cerebellar Hypoplasia Due To a New RELN Mutation.

Lissencephaly with cerebellar hypoplasia (LCH) is a rare variant form of lissencephaly, its distinctive neuroradiological phenotype being an important investigation clue regarding the potential involved genes, including variants in RELN gene. We report on a case of LCH whose clinical and neuroradiological features led to the identification of a homozygous pathogenic variant in RELN gene that has not been previously reported in the scientific literature.

The role of routine first-trimester ultrasound screening for central nervous system abnormalities: a longitudinal single-center study using an unselected cohort with 3-year experience.

BACKGROUND: To evaluate the role of a standardized first-trimester scan in screening different kinds of central nervous system malformations and to report a 3-year experience from a tertiary center using an unselected cohort. METHODS: This was a retrospective analysis of prospectively collected data from a single center evaluating first-trimester scans with predesigned standardized protocols performed between 1 May 2017 and 1 May 2020, involving 39,526 pregnancies. All pregnant women underwent a series of prenatal ultrasound scans at 11-14, 20-24, 28-34 and 34-38 weeks of gestation. Abnormalities were confirmed by magnetic resonance imaging, postmortem examination or trained ultrasound professionals. Pregnancy outcomes and some postnatal follow-up were obtained from maternity medical records and telephone calls. RESULTS: A total of 38,586 pregnancies included in the study. The detection rates of CNS anomalies by ultrasound in the first, second, third and late third trimester were 32%, 22%, 25%, and 16%, respectively. And there were 5% of CNS anomalies missed by prenatal ultrasound. In the first-trimester scan, we diagnosed all cases of exencephaly, anencephaly, alobar holoprosencephaly and meningoencephalocele, and some cases of posterior cranial fossa anomalies (20%), open spina bifida (67%), semilobar holoprosencephaly (75%) and severe ventriculomegaly (8%). Vein of Galen aneurysmal malformation, closed spina bifida, lobar holoprosencephaly, intracranial infection, arachnoid cyst, agenesis of the corpus callosum, cysts of the septum pellucidum and isolated absence of the septum pellucidum were never detected during the first trimester. The abortion rates of fetal CNS anomalies detected by first-trimester scan, second-trimester scan, and third- trimester scan were 96%, 84% and 14%, respectively. CONCLUSIONS: The study showed that almost 1/3 of central nervous system anomalies were detected by the standard first-trimester scan and these cases were associated with a high rate of abortion. Early screening for fetal abnormalities gives parents more time for medical advice and safer abortion if needed. It is therefore recommended that some major CNS anomalies should be screened in the first trimester. The standardized anatomical protocol, consisting of four fetal brain planes, were recommended for routine first trimester ultrasound screening.

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies.

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities. METHODS: This was a retrospective cohort study of fetuses identified to have CNS abnormality on prenatal ultrasound and/or magnetic resonance imaging. All fetuses were first analyzed by chromosomal microarray analysis (CMA). Fetuses with a confirmed aneuploidy or causal pathogenic copy-number variant (CNV) on CMA did not undergo pES analysis and were excluded, while those with a negative CMA result were offered pES testing. RESULTS: Of the 167 pregnancies included in the study, 42 (25.1%) were identified to have a pathogenic or likely pathogenic (P/LP) variant. The diagnostic rate was significantly higher in fetuses with a non-isolated CNS abnormality than in those with a single CNS abnormality (35.7% (20/56) vs 14.5% (8/55); P = 0.010). Moreover, when a fetus had three or more CNS abnormalities, the positive diagnostic rate increased to 42.9%. A total of 25/42 (59.5%) cases had de-novo mutations, while, in the remaining cases, mutations were inherited and carried a significant risk of recurrence. Families whose fetus carried a P/LP mutation were more likely to choose advanced pregnancy termination than those with a variant of uncertain significance, secondary/incidental finding or negative pES result (83.3% (25/30) vs 41.3% (38/92); P < 0.001). CONCLUSION: pES improved the identification of genetic disorders in fetuses with CNS anomalies without a chromosomal abnormality or CNV identified on CMA, regardless of the number of CNS anomalies and presence of extracranial abnormality. We also demonstrated that pES findings can significantly impact parental decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Postmortem MR in termination of pregnancy for central nervous system (CNS) anomalies.

OBJECTIVES: To evaluate the concordance of conventional autopsy (CA) and postmortem magnetic resonance (MR) after termination of pregnancy (TOP) in fetuses with prenatally detected central nervous system (CNS) anomalies. Second, to determine the most informative postmortem investigation in parental counseling. METHODS: All TOPs between 2006 and 2016 with prenatally detected CNS involvement and having a postmortem MR and CA as postmortem examinations were retrospectively analyzed and concordance levels were established. RESULTS: Of 764 TOPs, 255 cases had a CNS anomaly detected prenatally (33.4%). Fetal genetic anomalies (n = 40) and cases without both postmortem MR and CA were excluded, leaving 68 cases for analysis.Disagreement between postmortem MR and CA was observed in 22 cases (32.4%). In eight cases (11.8%), more information was obtained by CA compared with MR. However, only two cases with major additional findings were found when compared with prenatal diagnosis. In 14 cases (20.6%), MR was superior to CA either because of additional cerebral anomalies undetected by CA (n = 5) and/or because of severe autolysis hindering pathology of the CNS (n = 9). CONCLUSIONS: Our data point out that an adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem MR in 97% of the cases.Key PointsAn adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem (PM) magnetic resonance (MR) in the majority of cases.PM MR is an excellent postmortem imaging tool for the brain.In cases with brain autolysis, PM MR is often the only informative PM investigation tool.PM MR is an essential adjunct to CA in the PM evaluation of pregnancies terminated for a central nervous system (CNS) anomaly.

Early arteriopathy in Aicardi-Goutières syndrome 5. Case report and review of literature.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive disease that mimics congenital viral infection and mainly affects the brain, immune system, and skin. The dominant clinical symptom is the subacute onset of severe encephalopathy, which manifests as irritability, loss of ability, slowing of head growth, and poor nutrition. Arteriopathy in AGS is an uncommon manifestation usually associated with mutations in the SAMHD1 gene. We present a rare case of a 3-year-old male due to failure to thrive, global developmental delay, microcephaly, poor vision, upper and lower limbs spasticity, and gastroesophageal reflux disease (GERD), who harbored early stenotic lesions of the large and medium intracranial arteries with ischemic sequelae in the early postnatal life. Performed genetic testing confirmed homozygous gene mutation, SAMHD1 associated with AGS type 5. By reviewing the available literature, we were able to find only one patient whose arterial lesions were diagnosed after 6 months.

Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation.

BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

Fetal agenesis of the septum pellucidum: Ultrasonic diagnosis and clinical significance.

OBJECTIVE: To describe the prenatal ultrasound (US) findings, genetic results, and clinical outcomes of fetuses with suspected agenesis of the septum pellucidum (ASP) in the Chinese population. METHODS: This retrospective, single-center study included a cohort of fetuses with ASP diagnosed by prenatal imaging over a 10-year period. We evaluated US findings, associated anomalies, genetic results, and clinical outcomes. Prenatal and postnatal imaging findings were compared as well as the clinical outcome of delivery. RESULTS: Ninety patients were included, with a median follow-up time of 36 months (1-96 months). Thirty-six fetuses (40%) with isolated ASP were diagnosed by prenatal US or magnetic resonance imaging (MRI); 39 cases (43.3%) had ASP with central nervous system malformations and 15 cases (16.6%) had ASP with non-CNS abnormalities. Additional imaging findings were supplemented with prenatal MRI in 13 cases. Genetic tests were performed on 32 patients, of whom six had abnormalities. Prenatal US results of 40 patients (40/70) diagnosed by referral hospitals did not correspond to our findings. Of the 38 patients with postnatal records, 11 had abnormal neurological development. CONCLUSION(S): The outcome of an isolated ASP is usually favorable; however, neurological developmental delay is commonly observed if it is combined with other malformations.

[Value of chromosomal microarray analysis for the diagnosis of fetuses with anomalies of central nervous system].

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION: Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.

Pathogenic/likely pathogenic copy number variations and regions of homozygosity in fetal central nervous system malformations.

OBJECTIVE: To explore pathogenic/likely pathogenic copy number variations (P/LP CNVs) and regions of homozygosity (ROHs) in fetal central nervous system (CNS) malformations. METHODS: A cohort of 539 fetuses with CNS malformations diagnosed by ultrasound/MRI was retrospectively analyzed between January 2016 and December 2019. All fetuses were analyzed by chromosomal microarray analysis (CMA). Three cases with ROHs detected by CMA were subjected to whole-exome sequencing (WES). The fetuses were divided into two groups according to whether they had other structural abnormalities. The CNS phenotypes of the two groups were further classified as simple (one type) or complicated (≥ 2 types). RESULTS: (1) A total of 35 cases with P/LP CNVs were found. The incidence of P/LP CNVs was higher in the extra-CNS group [18.00% (9/50)] than in the isolated group [5.32% (26/489)] (P < 0.01), while there was no significant difference between the simpletype and complicated-type groups. (2) In the simple-type group, the three most common P/LP CNV phenotypes were holoprosencephaly, Dandy-Walker syndrome, and exencephaly. There were no P/LP CNVs associated with anencephaly, microcephaly, arachnoid cysts, ependymal cysts, or intracranial hemorrhage. (3) Only four cases with ROHs were found, and there were no cases of uniparental disomy or autosomal diseases. CONCLUSION: The P/LP CNV detection rates varied significantly among the different phenotypes of CNS malformations, although simple CNS abnormalities may also be associated with genetic abnormalities.

Malformation of cortical development with abnormal cortex: early ultrasound diagnosis between 14 and 24 weeks of gestation.

OBJECTIVE: To describe neurosonographic findings diagnostic or highly suggestive of the presence of malformations of cortical development involving the cortex that may be identified before 24 weeks of gestation. METHODS: This was a retrospective single-center study of fetuses referred for neurosonography, during 2012-2019, with an abnormal cortical or sulcation pattern diagnosed early in the mid trimester. Stored files were analyzed for demographic data, abnormal brain findings, non-central nervous system abnormalities, final diagnosis and postnatal outcome. RESULTS: The study cohort included 20 fetuses, with a mean gestational age at diagnosis of 18.7 (range, 14.4-23.6) weeks, in 11 of which the diagnosis was made before 20 weeks of gestation. Reasons for referral were: midline anomaly (n = 7), ventriculomegaly (n = 4), infratentorial findings (n = 3), suspected malformation of cortical development (n = 3), 'abnormal brain' (n = 2) and skeletal dysplasia (n = 1). On neurosonography, both the sulcation pattern and the cortical layer were abnormal in four cases, only the sulcation pattern was considered abnormal in seven and only the cortical layer was abnormal in nine. Nineteen fetuses presented with associated central nervous system anomalies and six also had non-central nervous system malformations. One case was recurrent. Eighteen parents opted for termination of pregnancy, including one selective termination in a twin pregnancy, and two fetuses were liveborn. CONCLUSIONS: Familiarity with fetal brain anatomy and its early sonographic landmarks allowed early diagnosis of malformations involving cortical development. These patients are likely to represent the most severe cases and all had associated malformations. The presence of an abnormal cortical layer and/or abnormal overdeveloped sulci appear to be early signs of malformation of cortical development. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic approach to fetal ventriculomegaly.

Ventriculomegaly (VM) is defined as an enlargement of the lateral ventricles of the developing fetal brain. The diagnosis is easily made by measuring the lateral ventricle width at the level of the atrium, which is normally <10 mm. VM is defined as mild when the atrial width is 10-12 mm, moderate 12-15 mm, severe >15 mm. VM is a non-specific sonographic sign which is common to different pathological entities and genetic conditions. When no associated anomaly can be found VM is defined as isolated. Since the prognosis of fetal VM mainly depends on the presence of associated anomalies, a careful diagnostic approach is necessary to rule out CNS and extra- CNS fetal anomalies. Magnetic Resonance Imaging can be a useful diagnostic tool complementary to ultrasound in order to recognize subtle brain anomalies, particularly cortical disorders. In this review the diagnostic approach to fetal VM will be discussed starting from ultrasound screening, moving to neurosonographic and MRI examination and genetic evaluation, in order to recognize the cause of VM and offer the appropriate counselling to the parents.

Clinical, radiological, and genetic variation in pontocerebellar hypoplasia disorder and our clinical experience.

Pontocerebellar hypoplasia (PCH) constitutes a heterogeneous neurodegenerative/neurodevelopmental disorder of the pons and cerebellum with onset in the prenatal period. Our study aimed to present different clinical and radiological manifestations of our genetically diagnosed PCH patients. METHOD:  Six patients were enrolled in this study from September 2018 to March 2021. All the clinical radiological and genetic investigations were done at Cukurova University Medical School. RESULTS: Five children were diagnosed genetically and categorized under one of the types of PCH (type 10,7,11). Homozygous mutations in CLP1 In PCH type 10, TOE1 in PCH type 7, and TBC1D23 in PCH type 11 were respectively detected. Pateint with PCH type 11 and female patient with PCH type 7 could walk and speak few words. Male patient with PCH type 7 had disorder of sex development. CONCLUSION: According to our study, PCH is a rare neurodegenerative disease, although some types are static as PCH11 male gender and PCH7 female gender. Some clinical features are specific to a definite type. PCH7 express disorders of sex development most apparent in 46 XY. Some ethnic groups could express distinct subtypes. PCH10 is seen in the Turkish population. Radiological imaging is beneficial in pre-diagnosis; all the patients had different pons and cerebellar hypoplasia degrees. Genetic testing like whole exome sequencing -next-generation sequencing is essential in setting the definite diagnosis and determining the type/subtype of PCH.

A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia.

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.

A comparison of the accuracy of fetal magnetic resonance imaging and ultrasonography for the diagnosis of fetal congenital malformations of the spine and spinal cord.

PURPOSE: To determine the diagnostic value of fetal magnetic resonance imaging (MRI) for congenital spine/spinal cord malformations. METHODS: This single-center retrospective study included 120 cases of fetal spine/spinal cord abnormalities detected using fetal ultrasonography (US) and further examined by fetal MRI between 2016 and 2020. Cases were divided into three groups (congenital spine, spinal cord, and spine + spinal cord malformations) based on US assessment. We analyzed the accuracy of fetal US and MRI relative to postnatal imaging. RESULTS: The diagnostic accuracy of fetal MRI for fetal spinal cord, spine, and spine + spinal cord malformations was 86.2% (25/29), 89.4% (42/47), and 86.3% (38/44), respectively, and the corresponding rates for fetal US were 51.7% (15/29), 87.2% (41/47), and 68.2% (30/44). The diagnostic accuracy did not differ between fetal MRI and US for congenital spine malformations (p > 0.05); for congenital spinal cord malformations and congenital spine + spinal cord malformations, the diagnostic accuracy was significantly higher for fetal MRI than for fetal US (p < 0.05). CONCLUSIONS: Fetal MRI is effective in the assessment of congenital spine/spinal cord malformations. It can yield information that supplements US findings, especially for congenital spinal cord malformations, and can improve the accuracy of fetal diagnosis.

Fetal central nervous system anomalies: When should we offer exome sequencing?

OBJECTIVE: To investigate the detection of pathogenic variants using exome sequencing in an international cohort of fetuses with central nervous system (CNS) anomalies. METHODS: We reviewed trio exome sequencing (ES) results for two previously reported unselected cohorts (Prenatal Assessment of Genomes and Exomes (PAGE) and CUIMC) to identify fetuses with CNS anomalies with unremarkable karyotypes and chromosomal microarrays. Variants were classified according to ACMG guidelines and association of pathogenic variants with specific types of CNS anomalies explored. RESULTS: ES was performed in 268 pregnancies with a CNS anomaly identified using prenatal ultrasound. Of those with an isolated, single, CNS anomaly, 7/97 (7.2%) had a likely pathogenic/pathogenic (LP/P) variant. This includes 3/23 (13%) fetuses with isolated mild ventriculomegaly and 3/10 (30%) fetuses with isolated agenesis of the corpus callosum. Where there were multiple anomalies within the CNS, 12/63 (19%) had LP/P variants. Of the 108 cases with CNS and other organ system anomalies, 18 (16.7%) had LP/P findings. CONCLUSION: ES is an important tool in the prenatal evaluation of fetuses with any CNS anomaly. The rate of LP/P variants tends to be highest in fetuses with multiple CNS anomalies and multisystem anomalies, however, ES may also be of benefit for isolated CNS anomalies.