O. Bar-Yosef

Multiple congenital skull fractures as a presentation of Ehlers–Danlos syndrome type VIIC†

We describe a newborn infant with multiple congenital skull fractures and intracranial hemorrhage. He also had multiple skin folds suggesting a connective tissue abnormality. Electron microscopy of the skin biopsy showed collagen abnormalities with a “hieroglyphic appearance.” The analysis of the synthesis of collagen in the cultured dermal fibroblasts demonstrated an accumulation of procollagen I. Molecular analysis found a nonsense mutation Q225X in ADAMTS2 gene, which encodes procollagen I N‐terminal proteinase. All these findings confirmed the diagnosis of Ehlers–Danlos syndrome type VIIC (MIM 225410). Family studies suggested a founder effect in Ashkenazi Jews originating from Belarus. Prenatal diagnosis in the subsequent pregnancy reassured the parents that the fetus was an unaffected carrier.

Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: Further delineation of a new chaperone-mediated tubulinopathy

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co‐chaperones required for assembly and disassembly of α/β‐tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re‐polymerization. Morpholino‐mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone‐associated tubulinopathy, and provide insights into the phenotype of this disorder.

Neurodevelopmental outcome of isolated ventriculomegaly: a prospective cohort study

Data regarding the neurodevelopmental outcome of children diagnosed in utero with isolated ventriculomegaly (IVM) are limited and principally founded on ultrasound‐based studies. Here, we endeavored to assess the outcome of such cases in a large‐scale, magnetic resonance imaging (MRI)‐based study.

Fetal Brain Anomalies Associated with Ventriculomegaly or Asymmetry: An MRI-Based Study.

BACKGROUND AND PURPOSE: Fetal lateral ventriculomegaly is a relatively common finding with much debate over its clinical significance. The purpose of this study was to examine the association between ventriculomegaly and asymmetry and concomitant CNS findings as seen in fetal brain MR imaging. MATERIALS AND METHODS: Fetal brain MR imaging performed for various indications, including ventriculomegaly, with or without additional ultrasound findings, was assessed for possible inclusion. Two hundred seventy-eight cases found to have at least 1 lateral ventricle with a width of ≥10 mm were included in the study. Ventriculomegaly was considered mild if the measurement was 10–11.9 mm; moderate if, 12–14.9 mm; and severe if, ≥15 mm. Asymmetry was defined as a difference of ≥2 mm between the 2 lateral ventricles. Fetal brain MR imaging findings were classified according to severity by predefined categories. RESULTS: The risk of CNS findings appears to be strongly related to the width of the ventricle (OR, 1.38; 95% CI, 1.08–1.76; P = .009). The prevalence of associated CNS abnormalities was significantly higher (P = .005) in symmetric ventriculomegaly compared with asymmetric ventriculomegaly (38.8% versus 24.2%, respectively, for all CNS abnormalities and 20% versus 7.1%, respectively, for major CNS abnormalities). CONCLUSIONS: In this study, we demonstrate that the rate of minor and major findings increased with each millimeter increase in ventricle width and that the presence of symmetric ventricles in mild and moderate ventriculomegaly was a prognostic indicator for CNS abnormalities.

Normal Fetal Posterior Fossa in MR Imaging: New Biometric Data and Possible Clinical Significance

BACKGROUND AND PURPOSE: Posterior fossa malformations are a common finding in prenatal diagnosis. The objectives of this study are to re-evaluate existing normal MR imaging biometric data of the fetal posterior fossa, suggest and evaluate new parameters, and demonstrate the possible clinical applications of these data. MATERIALS AND METHODS: This was a retrospective review of 215 fetal MR imaging examinations with normal findings and 5 examinations of fetuses with a suspected pathologic posterior fossa. Six previously reported parameters and 8 new parameters were measured. Three new parameter ratios were calculated. Interobserver agreement was calculated by using the intraclass correlation coefficient. RESULTS: For measuring each structure, 151–211 MR imaging examinations were selected, resulting in a normal biometry curve according to gestational age for each parameter. Analysis of the ratio parameters showed that vermian lobe ratio and cerebellar hemisphere ratio remain constant with gestational age and that the vermis-to-cisterna magna ratio varies with gestational age. Measurements of the 5 pathologic fetuses are presented on the normal curves. Interobserver agreement was excellent, with the intraclass correlation coefficients of most parameters above 0.9 and only 2 parameters below 0.8. CONCLUSIONS: The biometry curves derived from new and existing biometric data and presented in this study may expand and deepen the biometry we use today, while keeping it simple and repeatable. By applying these extensive biometric data on suspected abnormal cases, diagnoses may be confirmed, better classified, or completely altered.

Prenatal Evaluation, Imaging Features, and Neurodevelopmental Outcome of Prenatally Diagnosed Periventricular Pseudocysts

BACKGROUND AND PURPOSE: Periventricular pseudocysts are cystic cavities that lack the ependymal cell lining found in true cysts. The aim of this study was to characterize periventricular pseudocysts and related findings and their neurodevelopmental outcome. MATERIALS AND METHODS: This was a retrospective study of periventricular pseudocysts detected prenatally on fetal MR imaging in 26 fetuses. The fetuses were divided into group A (n = 8), which included cases with isolated periventricular pseudocysts, and group B (n = 18), which included cases of periventricular pseudocysts with additional findings. Cases were further subdivided into connatal cysts and subependymal pseudocysts. Data collected included prenatal history, MR imaging features, sonographic follow-up, and neurodevelopmental outcome. RESULTS: All cases in group A (n = 8) had a normal outcome. In group B (n = 18), 6 pregnancies were terminated and 2 had an abnormal outcome. Both cases with an abnormal outcome involved patients with subependymal pseudocysts. No significant association was found between the morphologic features on MR imaging and the neurodevelopmental outcome. CONCLUSIONS: Neurodevelopmental outcome in cases of isolated periventricular pseudocysts detected prenatally appears to be normal. A detailed evaluation should be performed to rule out additional brain findings, chromosomal aberration, and fetal malformation. This evaluation should include the following: maternal TORCH status, detailed fetal sonographic anatomic evaluation, fetal echocardiogram, fetal brain MR imaging, amniocentesis and karyotyping/comparative genomic hybridization, and genetic counseling. Additional findings on MR imaging, including mild-to-moderate dilated ventricles, asymmetric ventricles, or T2 hyperintense signal in the white matter without other findings or major fetal abnormality, appear to be benign. Connatal cysts appear to be benign.

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

BackgroundRhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms.MethodsWe employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established.ResultsUsing WES, we identified causative mutations in candidate genes in nine of the 21 families (43%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY).ConclusionsOur findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

P11.02: Neurodevelopmental outcome of fetuses with isolated ventricular asymmetry without dilation: Poster discussion hub abstracts

Study group: Cases referred to fetal brain MRI as part of the investigation of IVA without ventriculomegaly (≤10 mm), identified during routine US examinations Sonographic measurement of the fetal lateral ventricles in the axial transventricular plane Measurement of the fetal lateral ventricles in a T2weighted MRI (coronal plane) at the level of the ventricles Control group: normal cases without IVA

Neurodevelopmental outcome of fetal isolated ventricular asymmetry without dilation: a cohort study

Fetal isolated ventricular asymmetry (IVA) is a relatively common finding in pregnancy, but data regarding its effect on neurodevelopmental outcome are scarce and founded principally on ultrasound‐based studies. The purpose of this study was to assess the neurodevelopmental outcome of IVA cases in a magnetic resonance imaging (MRI)‐based study.

Apparent Diffusion Coefficient Levels and Neurodevelopmental Outcome in Fetuses with Brain MR Imaging White Matter Hyperintense Signal

BACKGROUND AND PURPOSE: One of the perplexing findings of fetal brain MR imaging is white matter T2 hyperintense signal. The aims of our study were initially to determine the main etiologies associated with white matter T2 hyperintense signal, then to examine whether the different etiologies have different ADC values, and, last, to assess the association of white matter T2 hyperintense signal with developmental outcome. MATERIALS AND METHODS: This was a prospective cohort study of 44 MR imaging scans of fetal brains obtained for suspected brain pathologies at a tertiary medical center during 2011–2015. Clinical data were collected from electronic medical charts. ADC values were measured and averaged in the frontal, parietal, occipital, and temporal lobes. Neurodevelopmental assessments were performed with the Vineland Adaptive Behavior Scales II. RESULTS: Half of the cases of MRI hyperintense T2 signal of the fetal brain were associated with congenital cytomegalovirus infection. The other half were mainly idiopathic. Thus, the study group was divided to subgroups positive and negative for cytomegalovirus. Both groups had hyperintense signal in the temporal lobe. The group positive for cytomegalovirus had involvement of the parietal lobe. Only this group had increased ADC values in the temporal and parietal lobes. There was no association between the neurodevelopment outcome and the etiologies or ADC values. CONCLUSIONS: T2 hyperintense signal in fetal brain MRI associated with positive cytomegalovirus infection has increased ADC values in the temporal and parietal lobes, suggestive of brain edema in these areas. However, the association between this finding and neurodevelopment outcome requires further evaluation.