Spectrum of brain malformations in fetuses with mild tubulinopathy.

OBJECTIVE: To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. METHODS: This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. RESULTS: Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17-33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23-34) weeks and that at MRI was 30.2 (range, 24-35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. CONCLUSIONS: Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Exome sequencing as first-tier test for fetuses with severe central nervous system structural anomalies.

OBJECTIVE: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly. METHODS: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs). RESULTS: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs. CONCLUSIONS: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly.

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) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Biallelic constitutional mutations in DNA mismatch repair genes cause a distinct syndrome, constitutional mismatch repair deficiency syndrome (CMMRD), characterized by cancers from multiple organs, most commonly brain tumors, during childhood. Surveillance protocols include total and brain MR imaging among other modalities to enable early detection of tumors. Brain surveillance scans revealed prominent brain developmental venous anomalies (DVAs) in some patients. DVAs are benign vascular anomalies, and their incidence in the general population is 2.6%-6.4%. Most developmental venous anomalies are asymptomatic and are found incidentally. Our purpose was to assess the prevalence of DVAs in CMMRD patients and describe their phenotype. MATERIALS AND METHODS: A retrospective descriptive analysis of brain MR imaging studies from 10 patients from 3 families with CMMRD was performed. Analysis included the number of developmental venous anomalies, location, draining vessels, and associated vascular anomalies (ie, cavernomas), with clinical correlation of symptoms and tumors. RESULTS: All 10 patients had ≥2 developmental venous anomalies, and 2 had, in addition, non-therapy-induced cavernomas. There was no clinically symptomatic intracranial bleeding from developmental venous anomalies. Six patients had malignant brain tumors. The location of brain tumors was not adjacent to the developmental venous anomalies. No new developmental venous anomalies developed during follow-up. CONCLUSIONS: The occurrence of multiple developmental venous anomalies in all our patients with CMMRD suggests that developmental venous anomalies may be a characteristic of this syndrome that has not been previously described. If confirmed, this quantifiable feature can be added to the current scoring system and could result in early implementation of genetic testing and surveillance protocols, which can be life-saving for these patients.

T1-weighted MR imaging of bone marrow pattern in children with adolescent idiopathic scoliosis: a preliminary study.

PURPOSE: Distinct normal physiological patterns of fat conversion in vertebrae were described both for children and adults. Our aim was to evaluate the T1-weighted bone marrow pattern of the vertebral bodies in various sites along the scoliotic spine of children with adolescent idiopathic scoliosis (AIS). METHODS: We retrospectively evaluated spine MRI studies of children with AIS. Scoliosis radiographs were assessed for type of curvature according to the Lenke classification. A paediatric neuroradiologist assessed the T1-weighted signal of vertebral bodies in comparison with the adjacent disc and distinct patterns of fatty conversion within the apical and stable vertebral bodies. Statistical assessment was performed. RESULTS: MRI study of the spines of 75 children with AIS were assessed, 59 (79%) of whom were female, with an age range of nine to 19 years. The relative overall T1-weighted signal intensity of the vertebral body bone marrow relative to the intervertebral disc was hyperintense in 76% and isointense in 24%. Fatty conversion grade of the stable vertebra was higher than the apex vertebra (p = 0.0001). A significant tendency to have more advanced fat conversion patterns in the apex vertebra up to age 13.5 years old compared with adolescents above that (p = 0.015) was seen. CONCLUSION: This preliminary study suggests a different pattern of bone marrow conversion in AIS from the normal physiologic pattern described in the literature. Whether these changes are secondary to the biomechanics of the curved spine or may suggest that bone marrow maturation rate and content have a role in the pathogenesis of AIS remains to be further researched. LEVEL OF EVIDENCE: Level III (Diagnostic Study).

Spinal and Paraspinal Plexiform Neurofibromas in Patients with Neurofibromatosis Type 1: A Novel Scoring System for Radiological-Clinical Correlation.

BACKGROUND AND PURPOSE: Neurofibromatosis type 1 is a common tumor predisposition syndrome. The aim of this study was to characterize the radiologic presentation of patients with neurofibromatosis type 1 with widespread spinal disease and to correlate it to clinical presentation and outcome. MATERIALS AND METHODS: We conducted a historical cohort study of adult patients with neurofibromatosis type 1 with spinal involvement. Longitudinal clinical evaluation included pain and neurologic deficits. Radiologically, spinal involvement was classified according to a novel classification system, and a radiologic risk score was calculated. RESULTS: Two hundred fifty-seven adult patients with neurofibromatosis type 1 are followed in our center. Thirty-four of these patients qualified for inclusion in this study. Three independent factors were found to be associated with increased risk for neurologic deficit: 1) bilateral tumors at the same level in the cervical region that approximated each other, 2) paraspinal tumors at the lumbar region, and 3) intradural lesions. On the basis of these factors, we calculated a combined risk score for neurologic deficits for each patient. We found a clear correlation between patient status and the calculated radiologic risk score. Patients with neurologic deficits were found to have a higher risk score (9 ± 8.3) than patients without neurologic deficits (2.5 ± 2.9, P < .05). Patients who progressed during the follow-up period had significantly higher scores at presentation than patients with stable conditions (9.9 ± 8.73 versus 3.9 ± 5.3, respectively; P < .05). CONCLUSIONS: In this series, neurologic deficit is correlated with tumor burden and subtype. We found no direct correlation with tumor burden and pain. Our novel radiologic classification scoring system may be used to predict increased risk for neurologic morbidity.

Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero.

OBJECTIVE: To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. METHODS: A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. RESULTS: In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R(2) = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean - 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: -3.85 ± 0.96 SD and -1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive value (PPV) was 56%. Combination of the HC and FCD criteria raised the PPV to 78%, decreasing the number of false positives from 11 to four, without missing any of the 14 micB cases. CONCLUSIONS: Fetal vertical cranial biometric assessment in the mid-sagittal plane is feasible and correlates well with gestational age. In our series, a vertical cranial deformation was a frequent cause of a false Fmic diagnosis made on the basis of HC alone. Combination of the new vertical cranial biometric measurement with HC measurement can exclude these cases and thus improve diagnostic accuracy for Fmic. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis?

OBJECTIVE: To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. METHODS: Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH-21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. RESULTS: Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non-significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false-negative results. The deviation of the HC from the mean, by all references, was significantly larger compared with the actual deviation of the OFC at birth, with mean differences between the corresponding Z-scores of -1.15, -1.95 and -0.74 for the Jeanty, INTERGROWTH and Israeli references, respectively. CONCLUSIONS: The evaluated reference ranges all result in considerable over-diagnosis of fetal microcephaly. The use of the two new HC reference ranges did not significantly improve micB prediction compared with that of Jeanty et al., whilst use of additional characteristics and stricter HC cut-offs could improve the PPV with an increase in false negatives. The postnatal OFC deviates significantly less from the mean compared with the prenatal HC, and we propose that adjustment for this would enable better prediction of the actual OFC deviation at birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Tumor burden evaluation in NF1 patients with plexiform neurofibromas in daily clinical practice.

BACKGROUND: Existing volumetric measurements of plexiform neurofibromas (PNs) are time consuming and error prone, as they require delineation of PN boundaries, a procedure that is not practical in the typical clinical setting. The aim of this study is to assess the Plexiform Neurofibroma Instant Segmentation Tool (PNist), a novel semi-automated segmentation program that we developed for PN delineation in a clinical context. PNist was designed to greatly simplify volumetric assessment of PNs through use of an intuitive user interface while providing objectively consistent results with minimal interobserver and intraobserver variabilities in reasonable time. MATERIALS AND METHODS: PNs were measured in 30 magnetic resonance imaging (MRI) scans from 12 patients with neurofibromatosis 1. Volumetric measurements were performed using PNist and compared to a standard semi-automated volumetric method (Analyze 9.0). RESULTS: High correlation was detected between PNist and the semi-automated method (R(2) = 0.996), with a mean volume overlap error of 9.54 % and low intraobserver and interobserver variabilities. The segmentation time required for PNist was 60 % of the time required for Analyze 9.0 (360 versus 900 s, respectively). PNist was also reliable when assessing changes in tumor size over time, compared to the existing commercial method. CONCLUSIONS: Our study suggests that the new PNist method is accurate, intuitive, and less time consuming for PN segmentation compared to existing commercial volumetric methods. The workflow is simple and user-friendly, making it an important clinical tool to be used by radiologists, neurologists and neurosurgeons on a daily basis, helping them deal with the complex task of evaluating PN burden and progression.

Isolated mild white matter signal changes in preterm infants: a regional approach for comparison of cranial ultrasound and MRI findings.

OBJECTIVE: To compare echogenicity detected using cranial ultrasound (cUS) and diffuse excessive high signal intensity (DEHSI) detected using magnetic resonance imaging (MRI) by identical region-based scoring criteria in preterm infants. To explore the association between these white matter (WM) signal changes with early neurobehavior. STUDY DESIGN: Forty-nine pre-selected premature infants with only echogenicity on a first routine cUS1 underwent MRI and a repeated cUS2 at term equivalent age. Echogenicity and DEHSI were graded in various brain areas and diffusivity values were calculated. Neurobehavior was assessed using the Rapid Neonatal Neurobehavioral Assessment Procedure. RESULT: WM signal changes were significantly higher on cUS1 than cUS2; and higher in MRI than cUS2 in posterior regions. Infants with DEHSI demonstrated reduced tissue integrity. Imaging findings were not correlated with early neurobehavior. CONCLUSION: Echogenicity and DEHSI likely represent the same phenomenon. Reduction of over-interpretation of WM signal changes may help define criteria for the judicious use of imaging in routine follow-up of premature infants.

Optic nerve sheath diameter on MR imaging: establishment of norms and comparison of pediatric patients with idiopathic intracranial hypertension with healthy controls.

BACKGROUND AND PURPOSE: IIH is a disorder associated with increased intracranial pressure with no clinical, laboratory, or radiologic evidence of an intracranial space-occupying lesion. The aim of this study was to establish ONSD standards of healthy pediatric subjects and compare the normal measurements with those of patients with IIH. MATERIALS AND METHODS: One hundred fifteen MR imaging studies of children 4 months to 17 years of age were blinded and reviewed by a pediatric neuroradiologist. A total of 230 optic nerves were measured. Eighty-six MR imaging examinations were performed in apparently healthy subjects. This control group included subjects who underwent MR imaging for various reasons, and their MR imaging findings were interpreted as normal. Twenty-nine MR imaging examinations were performed in patients with documented IIH. The ONSD was measured 1 cm anterior to the optic foramina on an axial T2 sequence. For statistical analysis, both patients and controls were stratified into 4 age groups (I, 0-3 years; II, 3-6 years; III, 6-12 years; IV, 12-18 years). RESULTS: The mean ONSD of the control group in all age groups (I, 3.1 mm; II, 3.41 mm; III, 3.55 mm; IV, 3.56 mm) was significantly smaller than the mean ONSD of patients (I, 4.35 mm; II, 4.37 mm; III, 4.25 mm; IV, 4.69 mm). A positive correlation between age and ONSD (r = 0.414, P < .01) was found in the control group. CONCLUSIONS: According to our study, in pediatric patients with IIH, the ONSD is significantly larger than that in healthy controls regardless of age group and sex. This measurement might prove to be an auxiliary tool in the diagnosis of increased intracranial pressure in pediatric patients.

Automatic segmentation, internal classification, and follow-up of optic pathway gliomas in MRI.

This paper presents an automatic method for the segmentation, internal classification and follow-up of optic pathway gliomas (OPGs) from multi-sequence MRI datasets. Our method starts with the automatic localization of the OPG and its core with an anatomical atlas followed by a binary voxel classification with a probabilistic tissue model whose parameters are estimated from the MR images. The method effectively incorporates prior location, tissue characteristics, and intensity information for the delineation of the OPG boundaries in a consistent and repeatable manner. Internal classification of the segmented OPG volume is then obtained with a robust method that overcomes grey-level differences between learning and testing datasets. Experimental results on 25 datasets yield a mean surface distance error of 0.73 mm as compared to manual segmentation by experienced radiologists. Our method exhibits reliable performance in OPG growth follow-up MR studies, which are crucial for monitoring disease progression. To the best of our knowledge, this is the first method that addresses automatic segmentation, internal classification, and follow-up of OPG.

Fetal optic nerve sheath measurement as a non-invasive tool for assessment of increased intracranial pressure.

OBJECTIVES: To describe the sonographic technique for assessment of the fetal optic nerve sheath and to report on three fetuses with intracranial lesions and enlarged optic nerve sheath diameter (ONSD) compared with normal controls matched for gestational age (GA). METHODS: In this cross-sectional study ONSD was measured sonographically in three fetuses (aged 23, 24 and 35 gestational weeks) with intracranial findings associated with increased intracranial pressure (ICP; dural thrombosis and intracranial tumors) as well as 42 healthy controls matched for GA ± 1 week (aged 22-25 and 34-36 weeks). For fetal eye assessment, transabdominal and transvaginal routes and high-resolution transducers were used for optimal visualization depending on fetal position. Measurements were made using an axial view at the level of the orbits, with the fetal face positioned towards the transducer. The ONSD was measured 1.5 or 2 mm behind the papilla (depending on GA) in all fetuses. Mean ± 2 SD ONSD of controls were calculated for each GA and compared with data from the three fetuses with intracranial pathology. RESULTS: In the 42 normal fetuses, ONSD increased from 1.2 mm at 23 weeks to 2.6 mm at 36 weeks. The measurements at 36 weeks correlated well with those observed in newborns. ONSD measurements of the three cases were above mean + 2 SD of values obtained from healthy controls at the same GA and also exceeded values of fetuses that were 1 week older. CONCLUSIONS: Fetal ONSD measurement is feasible using a technique similar to that used in adults and children. ONSD enlargement was observed in all three fetuses with intracranial lesions and may be an early tool with which to diagnose increased ICP.

Can syndromic macrocephaly be diagnosed in utero?

OBJECTIVES: To compare the outcomes of fetuses with apparently isolated macrocephaly and those with associated findings, and to compare prenatal findings with postnatal diagnoses in children with syndromic macrocephaly. METHODS: We reviewed the files of all patients referred for suspected fetal macrocephaly, during a 10-year period from 2000, to a large prenatal diagnosis unit with expertise in fetal neurology counseling. Macrocephaly was defined as head circumference (HC) > 2 SDs of the norm. Patients with confirmed HC > 2 SD were identified and contacted, and their development was evaluated. RESULTS: Adequate data for analysis were available for 98 patients, in 82 of whom the fetal macrocephaly was considered isolated (Group A), and in 16 of whom associated fetal anomalies were identified (Group B). Macrocephaly was diagnosed earlier in Group B patients (28.4 vs. 32.3 weeks, P = 0.069), and the HC in Group B patients was larger (Z-score 2.95 vs. 2.3, P < 0.001). From Group A there were 81 liveborn; one of whom was diagnosed as having infantile autism. From Group B, there were nine liveborn. The associated central nervous system findings, as demonstrated by ultrasound and magnetic resonance imaging, included mild ventriculomegaly, malformations of cortical development, callosal abnormalities, overdeveloped sulcation, large cavum septi pellucidi, large subarachnoid spaces, mega cisterna magna, periventricular pseudocyst, open operculum and vermian dysgenesis. Syndromic diagnosis was made in utero in five fetuses and after birth in three. In eight patients, associated malformations were confirmed after birth but a specific diagnosis was not reached. CONCLUSIONS: When fetal macrocephaly is associated with other brain or systemic anomalies, syndromic macrocephaly can be diagnosed in utero. Fetuses with syndromic macrocephaly have a significantly larger HC, usually > 2.5 SD above the mean. Isolated macrocephaly, particularly when the HC is < 2.5 SD above the norm, may be clinically benign.

Regression of subependymal giant cell astrocytomas with RAD001 (Everolimus) in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes and characterized by slow-growing tumors in multiple organs. Of the affected individuals, 10% display subependymal giant cell astrocytomas (SEGAs), which can lead to substantial neurological morbidity. The TSC1/TSC2 protein complex is a negative regulator of the mTOR pathway. Hence, mutations in these genes in preclinical models are associated with increased mTOR pathway activation and heightened sensitivity to mTOR inhibitors. We hereby report our experience with RAD001 (Everolimus) therapy, a novel mTOR inhibitor, in inducing a dramatic regression of SEGAs. METHODS: A patient with TSC and SEGAs was treated with 10 mg/day oral RAD001. MRIs and neuro-ophthalmological exams were performed before and at regular intervals following the initiation of therapy. RESULTS: The lesions exhibited significant regression in several tumor locations and stabilization in others, accompanied with an improvement of his visual status. Treatment was well tolerated for 11 months but was than discontinued due to hypertension and elevated CPK, without evidence for rhabdomyolysis. Yet, during 9 months following the interruption of therapy, SEGAs remained unchanged. CONCLUSIONS: Oral RAD001 demonstrated preliminary encouraging results as treatment of astrocytomas associated with TSC. These preliminary results were recently supported by the Novartis announcement of the phase II study of RAD001 for SEGAs, which was not published yet. According to their statement, 75% of the patients showed reduction of SEGAs' volume following treatment with RAD001. Based on these results, RAD001 may be an alternative to surgery in selected patients with TSC and SEGAs.

Thick fetal corpus callosum: an ominous sign?

OBJECTIVE: Anomalies of the corpus callosum are frequently diagnosed during pregnancy, but a thick corpus callosum is a rare finding and its significance is not clear. We aimed to assess the significance of thick fetal corpus callosum by reviewing our experience of such cases. METHODS: The records of all fetuses with anomalies of the corpus callosum referred to the prenatal diagnosis units of two university hospitals from 2000 to 2007 were reviewed. Nine fetuses with a thick corpus callosum were identified. RESULTS: In all cases there were associated abnormalities: macrocephaly, ventriculomegaly, vermian agenesis, abnormal sulcation or encephalocele. Four pregnancies were terminated and in each of these cases the autopsy confirmed dysmorphic features and additional brain abnormalities. Five infants were delivered; two died shortly after birth, one suffers from mental retardation, one had neonatal convulsions and one is developing normally. CONCLUSIONS: A thick fetal corpus callosum is usually associated with other brain anomalies and is part of a neurogenetic syndrome in most cases.