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BackgroundDespite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders.ObjectiveThe objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts.MethodsCandidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems.ResultsHomozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction.ConclusionsWe report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

On October 24, 2017, in Chicago, the Society of Radiologists in Ultrasound convened a panel of specialists in contrast-enhanced ultrasound (CEUS) to arrive at a white paper regarding the use of CEUS in noncardiac applications in North America. Recommendations are based on analysis of the current literature and common practice strategies. They represent a reasonable approach to introduce the advantages of this safe and noninvasive technique for the benefit of our patients. Characterization of liver nodules with CEUS, as the approval indication worldwide, is the major focus of this endeavor. In addition, many off label uses are reviewed and literature supporting these indications provided.Key Points(1) Contrast-enhanced ultrasound (CEUS) allows cross-sectional imaging of the liver, kidneys and multiple other solid and hollow viscera, providing excellent characterization of identified focal mass lesions.(2) Performed with the injection of a microbubble contrast agent, CEUS provides a safe and readily available imaging technique which requires no ionizing radiation, making it appropriate for use in all ages, in those with renal insufficiency and when a portable examination is needed.(3) The CEUS can be considered in abdominal imaging whenever blood flow information is of value to diagnosis.(4) Dynamic real-time acquisition and the use of a purely intravascular contrast agent are the 2 most essential technical aspects of CEUS imaging which distinguish it from both computed tomography and magnetic resonance scan.

The Society of Radiologists in Ultrasound convened a panel of specialists in contrast-enhanced ultrasound (CEUS) to produce a white paper on noncardiac CEUS in North America. The panel met in Chicago, Illinois, on October 24 and 25, 2017. The recommendations are based on analysis of current literature and common practice strategies and are thought to represent a reasonable approach to introduce the advantages of this safe and noninvasive technique for the benefit of our patients. Characterization of liver nodules, and pediatric vascular and intravesicular applications comprise the approved indications for CEUS in the United States. They, along with the very successful off-label use of CEUS for the kidney, are included in this publication.Other off-label uses are presented with emphasis on their value and literature support in the online version.

Significance Thyroid hormone deficiencies are the most common preventable causes of intellectual disability. We report that mutations in the thyroid hormone receptor α1 gene (THRA) that result in intellectual disability also reduce brain size. Using human THRA mutation stem cell models, we studied the impact of THRA mutations on human brain development by combining quantitative lineage analysis, gene expression analyses, and novel assays of neuroepithelium formation. We found that THRA regulates the balance between progenitor self-renewal and neurogenesis, and thus overall brain size. Importantly, these in vitro results are consistent with in vivo evidence from magnetic resonance imaging of people with these mutations, advancing our understanding of thyroid hormone action in human brain development., Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Current descriptions of ultrasound evaluations, including use of the term "point-of-care ultrasound" (POCUS), are imprecise because they are predicated on distinctions based on the device used to obtain images, the location where the images were obtained, the provider who obtained the images, or the focus of the examination. This is confusing because it does not account for more meaningful distinctions based on the setting, comprehensiveness, and completeness of the evaluation. In this article, the Society of Radiologists in Ultrasound and the members of the American College of Radiology Ultrasound Commission articulate a map of the ultrasound landscape that divides sonographic evaluations into four distinct categories on the basis of setting, comprehensiveness, and completeness. Details of this classification scheme are elaborated, including important clarifications regarding what ensures comprehensiveness and completeness. Practical implications of this framework for future research and reimbursement paradigms are highlighted.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Highlights • We studied manual function in patients exposed to neonatal hypoxia-ischaemia. • Patients had preserved function in motor adaptation learning, and in speed and accuracy of handwriting. • Manual coordination was impaired on a timed pegboard task. • Motor impairment was associated with bilaterally reduced volumes of the caudate nuclei. • Early basal ganglia damage may lead to persistent deficits in fine manual control., Acute sentinel hypoxia-ischaemia in neonates can target the hippocampus, mammillary bodies, thalamus, and the basal ganglia. Our previous work with paediatric patients with a history of hypoxia-ischaemia has revealed hippocampal and diencephalic damage that impacts cognitive memory. However, the structural and functional status of other brain regions vulnerable to hypoxia-ischaemia, such as the basal ganglia, has not been investigated in these patients. Furthermore, it is not known whether there are any behavioural sequelae of such damage, especially in patients with no diagnosis of neurological disorder. Based on the established role of the basal ganglia and the thalamus in movement coordination, we studied manual motor function in 20 participants exposed to neonatal hypoxia-ischaemia, and a group of 17 healthy controls of comparable age. The patients’ handwriting speed and accuracy was within the normal range (Detailed Assessment of Speed of Handwriting), and their movement adaptation learning (Rotary Pursuit task) was comparable to the control group’s performance. However, as a group, patients showed an impairment in the Grooved Pegboard task and a trend for impairment in speed of movement while performing the Rotary Pursuit task, suggesting that some patients have subtle deficits in fine, complex hand movements. Voxel-based morphometry and volumetry showed bilateral reduction in grey matter volume of the thalamus and caudate nucleus. Reduced volumes in the caudate nucleus correlated across patients with performance on the Grooved Pegboard task. In summary, the fine movement coordination deficit affecting the hand and the wrist in patients exposed to early hypoxic-ischaemic brain injury may be related to reduced volumes of the caudate nucleus, and consistent with anecdotal parental reports of clumsiness and coordination difficulties in this cohort.

OBJECTIVE: Impairment of speech repetition following injury to the dorsal language stream is feature of conduction aphasia - a well-described 'disconnection syndrome' in adults. The impact of similar lesions sustained in infancy has not been established. METHODS: We compared language outcomes in term-born individuals with confirmed neonatal stroke (n=30; age: 7-18 years, left-sided lesions in 21 cases) to matched controls (n=40). Injury to the dorsal and/or ventral language streams was assessed using T1- and T2-weighted MRI and diffusion tractography. Language lateralization was determined using functional MRI. RESULTS: At the group level, left dorsal language stream injury was associated with selective speech repetition impairment for non-words (p=0.021) and sentences (p

Objective:To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use.Methods:A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared.Results:The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab–negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab–associated disease, and antibody-negative RDS.Conclusions:Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab–positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab–associated disease), included in a new diagnostic algorithm.

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B 6 , functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B 6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC , which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (Δ YggS ) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

Indeterminate cystic kidney lesions found incidentally are an increasingly prevalent diagnostic challenge. Standard workup includes Bosniak classification with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, these tests are costly and not without risks. Contrast-enhanced ultrasound (CEUS) is a relatively new technique with lower risk of adverse events than iodine-containing contrast or gadolinium. In our review of the evidence for characterization of cystic kidney lesions with CEUS, CEUS displayed sensitivity (89%-100%) and negative predictive value (86%-100%) comparable to contrast-enhanced CT or MRI, with no decrease in specificity compared with CT and only a slight decrease compared with MRI.

BACKGROUND AND PURPOSE: It has been hypothesized that skull marrow signal alteration may represent an early disease manifestation of Sturge-Weber syndrome before development of its intracranial manifestations. We alternatively hypothesized that intraosseous changes are associated with the overlying port-wine stain rather than the intracranial stigmata of Sturge-Weber syndrome and hence are not a predictor of brain involvement. MATERIALS AND METHODS: MR imaging of children presenting with port-wine stain and/or Sturge-Weber syndrome between 1998 and 2017 was evaluated by 2 pediatric neuroradiologists for marrow signal abnormality and pial angioma and other Sturge-Weber syndrome features: ocular hemangioma, atrophy, and white matter changes (advanced myelination). Groups were divided into port-wine stain–only (without intracranial Sturge-Weber syndrome features) and Sturge-Weber syndrome (the presence of cerebral pial angioma). The χ(2) test was performed to evaluate the association between port-wine stain and bone marrow changes and between osseous change and pial angioma. RESULTS: We reviewed 139 cases: 40 with port-wine stain–only and 99 with Sturge-Weber syndrome with pial angioma. Fifteen of 99 cases of Sturge-Weber syndrome had no port-wine stain. In the port-wine stain–only cohort, 78% had ipsilateral bony changes and 17% had no intraosseous changes. In the Sturge-Weber syndrome cohort, 84/99 had associated port-wine stain, 91% (P < .01) had bony changes ipsilateral to the port-wine stain or had no bone changes in the absence of port-wine stain, and 77% (P = .27) had bony changes ipsilateral to a cerebral pial angioma. Eighty percent of patients with Sturge-Weber syndrome who lacked a port-wine stain also lacked marrow changes. Five patients with bilateral port-wine stain and bilateral marrow changes had only a unilateral pial angioma. CONCLUSIONS: Intraosseous marrow changes are strongly associated with facial port-wine stain; no significant association was found between pial angioma and bone marrow changes.

Aim To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. Materials and methods Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort ( n = 400) of fetuses ( n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. Results Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. Conclusions PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic–ischaemic brain injury, and may not detect rarer disorders not encountered in this study.

Item does not contain fulltext Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years ( n = 63) was 1.52:1 ( p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Conclusions: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

We report the case of a young girl who presented with hemiparesis, seizures, and subtle features consistent with a linear form of facial morphea (en coup de sabre). She was treated with pulsed parenteral steroids and oral steroids and started on methotrexate. Magnetic resonance imaging results and neurologic problems improved after 6 months. Switching off inflammation early in the course of disease seemed to reverse some of the central nervous system changes. Assessment of children with unexplained hemiparesis and seizures should include careful examination of the face and scalp, looking for subtle signs of skin change and asymmetry. This is one of the few reported cases of neuroradiologic improvement after immunosuppressive treatment in a child with en coup de sabre.

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

Summary Purpose: Most published data on infants presenting with epilepsy originate from hospital/specialist clinic settings and may therefore not be representative of the general population. We carried out a population-based study to estimate the incidence of epilepsy onset in infants, to characterize the range of phenotypes and associated structural brain abnormalities, and to determine whether specific epilepsy diagnoses could be established at onset. Methods: Children between 1 and 24 months of age with new-onset epilepsy were ascertained over 13 months from the residents in 15 boroughs of North London. Classification based on clinical information, electroencephalography (EEG), and neuroimaging data was undertaken independently by two pediatric neurologists. Neuroimages were reviewed by two neuroradiologists blinded to clinical details. Key Findings: A total of 57 children were enrolled giving an ascertainment-adjusted incidence of 70.1 (95% CI [56.3, 88.5])/100,000 children ≤2 years of age/year (ascertainment 76%). The incidence was highest among Asian children. An electroclinical syndrome was identified in 24 (42%) cases of which 21 were epileptic encephalopathies. Magnetic resonance (MR) images of 51 cases (89% of the total cohort) were reviewed. These demonstrated positive findings in 37 (72%) of 51 cases, of which 26 (51%) of 51 were etiologically relevant, and included developmental malformations in 11 (21%) of 51. Significance: In a population setting infantile onset epilepsy presents mostly with complex phenotypes commonly associated with structural brain abnormalities. Routine MR imaging at presentation is therefore justified. However, identification of specific electroclinical syndromes remains difficult at onset.

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age=15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

ObjectiveRecent studies have suggested that mutations in genes encoding several hypothalamo-pituitary (H-P) transcription factors result in hypopituitarism [isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD)], which may in turn be related to the neuroanatomy revealed by magnetic resonance (MR) imaging. Although studies have focused on patients with either optic nerve hypoplasia (ONH) or isolated hypopituitarism with normal optic nerves, few studies have compared the two groups. We aimed to relate the clinical phenotype of a large cohort (n = 170) of children with congenital hypopituitarism including septo-optic dysplasia (SOD) attending a single centre to the neuroradiological and genetic findings.DesignClinical, biochemical, MR imaging and molecular data were analysed retrospectively in 170 patients with or 'at-risk' (with ONH) of hypopituitarism to determine predictors of hypopituitarism.ResultsThe presence of ONH was significantly associated with an absent septum pellucidum [odds ratio (OR) 31 center dot 5, 95% confidence intervals (CI) 7 center dot 3-136 center dot 6, P < 0 center dot 001], an abnormal corpus callosum (OR 10 center dot 5, 95% CI 3 center dot 8-28 center dot 6, P < 0 center dot 001) and stalk abnormalities (OR 2 center dot 3, 95% CI 1 center dot 2-4 center dot 2, P = 0 center dot 009). The risk of hypopituitarism was 27 center dot 2 times greater in patients with an undescended posterior pituitary (95% CI 3 center dot 6-205 center dot 1, P < 0 center dot 001). Anterior pituitary hypoplasia (OR 3 center dot 1, 95% CI 1 center dot 3-7 center dot 0, P = 0 center dot 006) and an absent pituitary stalk (P < 0 center dot 001) were also significantly associated with hypopituitarism. With respect to the type or severity of hypopituitarism, CPHD was more often associated with an abnormal corpus callosum (OR 6 center dot 1, 95% CI 1 center dot 4-27 center dot 4, P = 0 center dot 008) and stalk abnormalities (OR 2 center dot 8, 95% CI 1 center dot 3-6 center dot 1, P = 0 center dot 006). Male to female ratio was significantly greater in patients with normal optic nerves (3 center dot 3:1) as compared with those with ONH (1 center dot 2:1). The prevalence of diabetes insipidus, thyrotrophin and ACTH deficiencies was significantly greater in patients with ONH as compared with 'idiopathic' hypopituitarism. Mutations in pituitary transcription factors and genes regulating GH secretion were rare (5/170) in this cohort of patients with sporadic hypopituitarism.ConclusionOur data suggest that individuals presenting with ONH are at high risk for neuroradiologic and endocrine abnormalities. The neuroradiologic features are predictive not only of the presence, but also of the type, of hypopituitarism. The association of midline abnormalities with hypopituitarism in this cohort suggests a common developmental origin for these features, the aetiology of which remains unidentified in the majority of cases.

To compare quantitative T2 relaxometry of cerebral white matter (WM) with qualitative assessment of conventional T2-weighted magnetic resonance (MR) images, to assess the relationship between cerebral WM T2 and region-specific apparent diffusion coefficient (ADC), and to examine WM T2 regional variation in preterm infants at term.The local ethical committee granted ethical permission for this study; informed parental consent was obtained for each infant. Sixty-two preterm infants born at less than 32 weeks gestation and nine control infants were examined at 1.5 T; T2-weighted fast spin-echo MR images, T2 relaxometry data, and diffusion-weighted MR images were acquired. Conventional T2-weighted MR images were assessed by a pediatric neuroradiologist for diffuse excessive high signal intensity (DEHSI) in WM. Regions of interest were positioned in frontal WM, central WM, and posterior WM at the level of the centrum semiovale.In preterm infants at term, T2 was longer in all WM regions than in control infants; in infants with DEHSI, T2 was longer than in infants without DEHSI and control infants, with posterior WM T2 being longer than central or frontal WM T2. In control infants, T2 was similar in all WM regions. Frontal and posterior WM ADCs were higher in preterm infants at term than in control infants.Cerebral WM T2 is an objective quantitative measurement that can easily and rapidly be obtained during clinical MR imaging in preterm infants at term.

To determine the clinical value of motor functional magnetic resonance imaging (fMRI) in the presurgical evaluation of a large group of children and adolescents with epilepsy caused by lesions close to the central sulcus., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Ultrasound of the right upper quadrant is one of the most commonly performed sonographic studies. Sonography is the first-line imaging modality for evaluation of the patient who has right upper quadrant abdominal pain. It is accurate, quick, easy to perform, does not use ionizing radiation, and can be done in at the patient's bedside. This article describes the sonographic evaluation of right upper quadrant pain.

The neuropsychological and clinical histories of three male siblings affected by pyridoxine-dependent seizures with known homozygous antiquitin mutations are presented. Neuropsychological evaluation is reported from when the siblings were 11, 9, and 7 years of age. Two of the siblings had received early pyridoxine treatment (antenatal, 2-4 wks into pregnancy) and one had received late treatment (2mo postnatal). However, there was no differential effect on cognitive outcome, with all three siblings having moderate to severe learning disability. Unlike previously reported cases that received early postnatal treatment, none of the siblings had relatively preserved non-verbal cognitive skills. Equally, their intellectual performance over time did not increase above the 1st centile despite high maintenance doses of vitamin B6 (range 16-26 mg/kg/d), and mild sensory neuropathy was reported on nerve conduction studies. The findings in these siblings challenge assumptions that early and high dose pyridoxine treatment can benefit cognition in this population and suggest routine electromyography monitoring may be beneficial.

PAX6 encodes a transcriptional regulator that is essential for brain morphogenesis. Heterozygous PAX6 mutation is associated with aniridia and abnormalities of the interhemispheric pathway in humans. We present the case of a 12 year old boy with a known mutation of the PAX6 gene. There were parental concerns regarding his hearing, but repeated pure-tone audiograms were normal. He had a battery of standard central auditory tests, which gave abnormal results in tests which required auditory interhemispheric transfer (dichotic digits and pattern tests). A speech and language assessment, which yielded age-appropriate scores for speech, receptive and expressive language, revealed impaired verbal working memory. These test results were interpreted as indicating impaired auditory sensory and higher order interhemispheric transfer, consistent with reported findings in adults with mutations in PAX6, and correlated with his parent-reported hearing difficulties. This is the first report of central auditory and verbal working memory deficits in a child with a PAX6 mutation. Further research is needed to assess how these deficits impact on academic performance particularly in childhood.

Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus-tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (chi2; p = 0.045), but abnormal structural MRI (chi2; p = 0.7) or magnetic resonance angiography (chi2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease-associated seizures.

The ability of a child to remain sufficiently immobile for painless imaging depends upon their behaviour and the imaging itself. Anaesthesia allows imaging to be optimised but it is expensive, scarce and inappropriate for many situations. Fortunately, sedation and behavioural techniques are sufficiently successful for the majority of scanning, and success rates are high provided that suitable children are selected. Sedation, however, administered by non-anaesthetists, may have catastrophic complications such as airway obstruction. Current UK recommendations demand that any sedation technique has a 'wide margin of safety', but in addition to this, safety is dependent on trained, skillful and experienced staff. Magnetic resonance imaging frightens many children and special planning is necessary for sedation and anaesthesia. When planning an imaging service for children, all the management techniques should be considered in order to achieve maximum efficiency, quality and safety.

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

In this case report, severe encephalitis with no established cause developed in a child with SCID. Through deep sequencing, human coronavirus OC43 was identified in brain tissue.

Objective: To ascertain whether posterior circulation stroke in children has distinctive clinical or radiologic features. Methods: Patients were identified retrospectively from two pediatric neurology centers. Clinical details were ascertained by chart review, and radiologic data were reviewed by three neuroradiologists. Results: Twenty-two cases were identified (17 boys). Twenty children had evidence of vertebrobasilar arterial abnormalities, which were multifocal in 12. The etiology of these was vertebral artery dissection in 10 cases and unclear in the remaining 10. Cardiac abnormalities were rare (n = 4). Other risk factors for stroke in childhood were hypertension (n = 9), the thermolabile methylene tetrahydrofolate reductase gene mutation (n = 4), and the factor V Leiden mutation (n = 2). Two children had subluxation of the upper cervical spine at the extreme of normal limits. In follow-up for 6 months to 11 years (median 4 years), five patients had further strokes and seven had TIA. Overall, 12 patients had no residual neurologic deficits. Conclusions: The male preponderance, frequency of arterial dissection, rarity of cardiac embolism, and >20% recurrence were notable. Cerebral angiography is usually indicated if a definitive diagnosis is not made on MRI. Additional investigations should include echocardiography and cervical spine radiography in flexion and extension.

Nat. Genet. 49, 223–237 (2017); published online 19 December 2016; corrected after print 20 April 2017 Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process.

AIM To establish the prevalence of central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) in a population of children with congenital melanocytic naevi (CMN) over the head and/or spine, and to compare this with clinical findings. METHODS Forty three patients identified from outpatient clinics underwent MRI of the brain and/or spine. These were reported by a paediatric radiologist and findings compared with the clinical picture. RESULTS Nine patients had abnormal clinical neurology, seven had abnormal findings on MRI, and six had both abnormal clinical and radiological findings. Only three of the abnormal MRIs showed features of intracranial melanosis. Three others showed structural brain abnormalities: one choroid plexus papilloma, one cerebellar astrocytoma, and one posterior fossa arachnoid cyst; the first two of these have not previously been described in association with CMN. The last abnormal MRI showed equivocal changes requiring reimaging. CONCLUSIONS The prevalence of radiological CNS abnormality in this group of children was 7/43. Six of these developed abnormal clinical neurological signs within the first 18 months of life, but two did not do so until after the MRI. Two of the CNS lesions were operable; for this reason we support the routine use of early MRI in this group.

Consent for magnetic resonance imaging under anesthesia in children is complex - it does not fit the usual model of consent for invasive procedures and requires the collaboration of multiple specialists from different disciplines. This article discusses the issues surrounding consent for this procedure, sets out four essential elements of the consent process, and proposes that, of the specialists involved, the referring clinician is best placed to discuss the options with parents and obtain written consent.

Using a 4-echo spin-echo sequence, cerebral T-2 was measured in specific anatomic regions in eleven healthy newborn infants, whose gestational plus postnatal ages (GPAs) lay between 37 and 42 weeks. For a region in the pens, T-2 was 141 +/- 9 ms (mean +/- standard deviation), and no significant dependence upon GPA was seen. In the thalamus mean T-2 was 136 +/- 13 ms, and T-2 demonstrated a significant negative linear dependence upon age (r = 0.690; p < 0.02). In periventricular and frontal regions, mean T-2 were 217 +/- 33, and 228 +/- 32 ms respectively, and more marked negative linear correlations with age were observed (r = 0.833; p < 0.001 and r = 0.722; p < 0.02). For these regions, the rate of T-2 decrease with age appeared to be related to known patterns of myelination. For the parietal region studied, mean T-2 was 204 +/- 34 ms, no significant dependence upon GPA being seen. T-2 shows promise as an objective measure of cerebral development in the perinatal period. (C) 1999 Elsevier Science Inc.

Aim—To investigate the relation between lesion volume, lesion location, and clinical outcome in children with infarction in the territory of the middle cerebral artery (MCA). Patients and methods—Children with MCA territory infarcts were selected retrospectively from a database of children with ischaemic stroke. Lesion volumes were expressed as a percentage of the supratentorial intracranial volume and were categorised as “small”, “moderate”, or “large”. Lesion location was categorised as cortical or purely subcortical. Outcome was ascertained by parental questionnaire and was categorised as “good” or “poor”. Results—38 patients were identified (median age 6 years); 21 patients had lesions that involved cortical tissue. Outcome was good in 12 cases and poor in 26 cases (including 2 children who died). Although there was no significant eVect of lesion size or lesion location on outcome for the group as a whole, all children who had infarcted more than 10% of intracranial volume had a poor outcome. Of note, some children with small subcortical lesions had pronounced residual deficits. Conclusions—Although the outcome after a small infarct in the MCA territory is variable and unpredictable, infarction of more than 10% of intracranial volume is universally associated with a poor outcome. Characterisation of lesion volume and topography might be helpful in identification of such children for participation in future trials of treatments for acute stroke. (Arch Dis Child 1999;81:295‐300)

The aim of this study was to examine the haemodynamic response to seizures in three infants with Sturge-Weber syndrome by measuring regional cerebral blood flow using transcranial Doppler sonography and 99mTc HMPAO SPECT. Time-locked video/digital EEG recording was carried out for ictal studies. MRI was performed in all subjects. SPECT showed hemispheric hypoperfusion interictally in all three patients and also ictally in one of the three; a small region of hyperperfusion was seen on the same ictal scan in the latter, ie. the patient with interictal and ictal hypoperfusion. In the two older children middle cerebral artery velocity (MCAV) was reduced by between 29 and 62% in the middle cerebral artery of the predominantly affected hemisphere compared with the contralateral side. During seizures, increases of 6 to 30% in MCAV were recorded for the clinically seizing hemisphere compared with 24 to 170% for the contralateral side in four of the seizures recorded. In one infant, MCAV fell bilaterally during a seizure that generalized (-18 and -43% in the predominantly affected and contralateral side respectively). Sequential recordings in one infant suggested that, with time, the haemodynamic response to seizures of the unaffected hemisphere may decrease. These findings suggest that the venous malformation in SWS is associated with an impairment of the cerebral haemodynamic response to seizure activity.