We would like to bring to your attention recent original research we performed in relation to measuring head circumference on MRI brain studies in the paediatric population. Occipitofrontal head circumference (OFC) is a routine component of the paediatric clinical examination and the gold standard is to use a tape measure. While reading paediatric MRI brain studies, often a recent measurement is not available, and an attempt is made to assess the head size by estimating the craniofacial ratio which is subjective. It would be of benefit to know if the head circumference can reliably be estimated using measurements from the MRI scan. A recent study by Rau et al used an ovoid region of interest on a single axial image to obtain the head circumference. Obtaining a circumference from this region of interest is not available on our Picture Archiving and Communication System and therefore likely not available to many radiologists worldwide. The head is often considered to be an ellipse for calculation purposes and the simplest formula for the circumference of an ellipse is (long axis+short axis)/2 multiplied by π. We performed a prospective study to compare head circumference calculated from MRIs (MRC) with the measured OFC performed on the same day in an unselected consecutive series of 120 children aged under 8 years attending for MRI brain scans. Two reviewers independently and blinded to the other’s measurements recorded the largest transverse diameter (T) on an axial T2weighted image and the largest occipitofrontal diameter (OFD) on a midline sagittal T1 image (figure 1). These sequences were chosen as they are performed as standard in most routine MRI brain study protocols. Estimated head circumference, MRC, was calculated from the MRI scans using the formula: MRC=(OFD+T)×1.57, where 1.57=π/2. Our study showed an extremely high correlation of MRC with OFC; intraclass correlation coefficient=0.99 (95% CI 0.97 to 0.99) for both reviewers. The 95% confidence limits of agreement of reviewer 1 (R1) were −1.3 cm to +2.7 cm and of reviewer 2 (R2) were −1.6 cm to +2.4 cm. The mean interobserver difference of MRC was 2.8 mm. The most common way to express systematic error inherent to all studies that involve anthropometric measurements is to calculate the technical error of measurement (TEM). We calculated TEM between MRC and OFC; for R1, the absolute TEM was 0.6 mm and relative TEM was 0.12%; for R2, the absolute TEM was 0.5 mm and relative TEM was 0.11%. This compares with absolute TEM range of 0.47–0.75 and relative TEM range of 1.0%–1.6% in the study by Rau et al. A relative TEM <2% is considered ‘acceptable’. We conclude that calculation of head circumference on brain MRI scans is reliable, and this is of benefit to the radiologist when interpreting MRI studies in the paediatric population.

AbstractPurposeTo describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib.MethodsWe report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively.ResultsSubjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy.ConclusionTrametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

Alexander Disease (AD) is a rare and ultimately lethal leukodystrophy, typically presenting in infants who exhibit developmental delay, macrocephaly, seizures, spasticity and quadriparesis. Classic infantile forms are generally due to sporadic mutations in GFAP that result in the massive deposition of intra-astrocytic Rosenthal fibres, particularly in the frontal white matter. However, phenotypic manifestations are broad and include both juvenile and adult forms that often display infratentorial pathology and a paucity of leukodystrophic features. We describe the unique case of an 8.5 year old female who presented with an 8 month history of progressively worsening vomiting and cachexia, whose extensive multidisciplinary systemic workup, including GI biopsies, proved negative. Neuroimaging ultimately revealed bilaterally symmetric and anterior predominant supratentorial signal alterations in the white matter plus a 1.7 x 1.2 x 0.7 mm right dorsal medullary mass. Biopsy of this presumed low-grade glioma revealed features in keeping with AD, which was later confirmed on whole exome sequencing. The proband exhibited a pathogenic p.Arg239Cys heterozygous missense mutation in GFAP, which was apparently inherited from her asymptomatic mother (1% mosaicism in the mother’s blood). Germline mosaic inheritance patterns of young-onset AD, particularly those presenting with a tumor-like mass of the brainstem, are scarcely reported in the literature and serve to expand the clinicopathologic spectrum of AD. LEARNING OBJECTIVES This presentation with enable the learner to: 1. Recognize an uncommon clinical presentation of AD. 2. Describe the underlying genetics of AD, including a rare familial juvenile onset form featuring germline mosaicism.

Abstract OBJECTIVE Refractory symptomatic plexiform neurofibromas (PNF) and inoperable refractory low grade gliomas (LGG) pose a clinical challenge that may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition with selumetinib in inoperable PNF and LGG have demonstrated promising results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has been completed, publication is pending. Thus we have treated a series of children on a compassionate basis with extensive PN or LGG refractory disease with trametinib, as this is available in Canada. METHODS We have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been IRB approved. RESULTS Two young patients were treated for indication of life threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae, eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects these two patients remain on treatment due to clear benefit from therapy including: improved respiratory compromise, hearing and dysphagia. We will present the data of additional patients treated with trametinib. CONCLUSION Trametinib is an effective therapy for life threatening PNF by changing the natural history of tumor growth in young children. Further data is required in terms of tolerance, efficacy and durability of response in such patients in the setting of clinical trials.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

BACKGROUND:Tubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature.CASE PRESENTATIONS:Both patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features.CONCLUSION:This report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.

Neurofibromatosis type 2 (NF2) is a neurocutaneous disorder caused by mutations in the NF2 gene. 1 Trofatter JA MacCollin MM Rutter JL et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993; 75 (PubMed PMID: 8242753): 826 Abstract Full Text PDF PubMed Scopus (3) Google Scholar In children, the clinical presentation of NF2 is much more varied compared to adults. Seizures and epilepsy are rarely described in NF2, but have been reported occasionally in pediatric case series. 2 Anand G Vasallo G Spanou M et al. Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population. Arch Dis Child. 2018 March 13; (PubMed PMID: 29535107) Crossref PubMed Scopus (18) Google Scholar , 3 Evans DG Birch JM Ramsden RT Paediatric presentation of type 2 neurofibromatosis. Arch Dis Childhood. 1999; 81 (PubMed PMID: 10569966; PubMed Central PMCID: PMC1718148): 496-499 Crossref PubMed Scopus (154) Google Scholar , 4 Ruggieri M Gabriele AL Polizzi A et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics. 2013; 14 (PubMed PMID: 23377185): 89-98https://doi.org/10.1007/s10048-013-0354-0 Crossref PubMed Scopus (53) Google Scholar We present an 8.5-year-old girl with seizures electrographically localized to an area of probable focal cortical dysplasia (FCD) who went on to have whole exome sequencing (WES) demonstrating a disease causing mutation in the NF2 gene.

Background High-dose steroid administration is no longer recommended in the treatment of acute traumatic brain injury (TBI) as it failed to prove beneficial in improving patients’ outcome. However, a masked benefit of steroid administration in TBI management was that it provided corticosteroid replacement therapy in patients with TBI-related central adrenal insufficiency. Case presentation We report the case of a 12-year-old boy who suffered a severe TBI from a motor vehicle accident that resulted in complete deficiency of anterior pituitary function. Central adrenal insufficiency was not ruled out by a near normal response to a low-dose ACTH test performed on D11. Conclusion Consideration should be given to the empirical treatment of TBI pediatric patients with stress doses of corticosteroids if injury to the hypothalamus or pituitary gland is possible until a formal assessment of the hypothalamic—pituitary—adrenal axis can be made.

Primary V-pattern strabismus is frequently presumed to be due to bilateral superior oblique palsy. Such strabismus is often seen in the context of craniofacial disorders where excyclorotation of the orbital contents has been observed. We wished to assess the anatomical contribution to A- and V-pattern strabismus in patients without a recognised craniofacial disorder.

Objective: Establishing the prevalence of semicircular canal dehiscence in a pediatric population using temporal bone CT imaging.Study design: Retrospective analysis of all temporal bone CT scans during a 5-year period (2007-2012).Methods: CT scan images were reformatted in the plane of the canals and assessed by two independent reviewers with a third to resolve disagreement. Detailed chart review was performed for those found to have dehiscence. Superior and posterior canals were classified as "dehiscent", "possibly dehiscent", "thin" or "normal" for each case.Results: 649 temporal bones were assessed from 334 children (under 18 years of age). The prevalence rate of superior canal dehiscence (SCD) was 1.7% (3.3% of individuals). Posterior canal dehiscence (PCD) was present in 1.2% (2.1% of individuals). There were no cases of bilateral SCD, and one case of bilateral PCD. Age under 3 years was associated with a higher prevalence of thinning but not dehiscence. Congenital inner ear malformation was not related to a higher probability of dehiscence. The superior petrosal sinus was associated with the SCD in three cases (27.3%). Retrospective chart review highlighted possible vestibular symptoms in 3/11 patients with SCD (27.3%).Conclusions: This forms the largest pediatric study of canal dehiscence to date. This study's prevalence rate is significantly lower than previous reports. The identified association with overlying venous structures may reflect the etiological process involved. The occurrence in children supports the hypothesis of a congenital predisposition for development of canal dehiscence syndrome. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: Creatine transporter (SLC6A8) deficiency is an X-linked inborn error of metabolism characterized by cerebral creatine deficiency, behavioral problems, seizures, hypotonia, and intellectual developmental disability. A third of patients are amenable to treatment with high-dose oral creatine, glycine, and L-arginine supplementation. METHODS: Given the limited treatment response, we initiated an open-label observational study to evaluate the effect of adjunct S-adenosyl methionine to further enhance intracerebral creatine synthesis. RESULTS: Significant and reproducible issues with sleep and behavior were noted in both male patients on a dose of 50/mg/kg. One of the two patients stopped S-adenosyl methionine and did not come for any follow-up. A safe and tolerable dose (17 mg/kg/day) was identified in the other patient On magnetic resonance spectroscopy, this 8-year-old male did not show an increase in intracerebral creatine. However, significant improvement in speech/language skills, muscle mass were observed as well as in personal outcomes as defined by the family in activities related to communication and decision making. DISCUSSION: Further research is needed to assess the potential of S-adenosyl methionine as an adjunctive therapy for creatine transporter deficiency patients and to define the optimal dose. Our study also illustrates the importance of pathophysiology-based treatment, individualized outcome assessment, and patient/family participation in rare diseases research.

Background: Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial.Methods: We present our systematic literature review (2001-2013) comprising 7 publications (case series/reports), collectively describing 25 patients who met the inclusion criteria, and 3 additional cases treated at our institution. Definitions were established and extracted data analyzed for cognitive ability, psychiatric and behavioral disturbances, epilepsy, and cerebral proton magnetic resonance spectroscopy measurements at pre- and post-treatment.Results: Treatment regimens varied among the 28 cases: 2 patients received creatine-monohydrate supplementation; 7 patients received L-arginine; 2 patients received creatine-monohydrate and L-arginine; and 17 patients received a combination of creatine-monohydrate, L-arginine and glycine. Median treatment duration was 34.6 months (range 3 months-5 years). Level of evidence was IV. A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine, or improved clinical parameters. Seven of the 28 patients had quantified pre- and post-treatment creatine, and it was significantly increased post-treatment. All of the patients with increased cerebral creatine also experienced clinical improvement In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. 90% of the patients who improved were initiated on treatment before nine years of age.Conclusions: Acknowledging the limitations of this systematic review, we conclude that a proportion of CTD patients show amenability to treatment-particularly milder cases with residual brain creatine, and therefore probable residual protein function. We propose systematic screening for CTD in patients with ID, to allow early initiation of treatment, which currently comprises oral creatine, arginine and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects are required in all patients. This study provides effectiveness on currently available treatment, which can be used to discern effectiveness of future interventions (e.g. cyclocreatine). (C) 2014 Elsevier Inc. All rights reserved.

INTRODUCTION:Serial change in ventricular size is recognized as an imperfect indicator of ongoing hydrocephalus in children. Potentially, other radiographic features may be useful in determining the success of hydrocephalus interventions. In this study, optic nerve sheath diameter (ONSD), optic nerve tortuosity, and optic disk bulging were assessed as indicators of hydrocephalus control in children who underwent endoscopic third ventriculostomy (ETV) or posterior fossa tumor resection.METHODS:Sixteen children underwent ETV or tumor resection for treatment of hydrocephalus. T2-weighted axial magnetic resonance images of the orbit were obtained, and the ONSD was measured posterior to the optic globe, pre- and post-intervention. Evidence of optic disk bulging and optic nerve tortuosity was also assessed. Ventricular size was estimated using the frontal and occipital horn ratio (FOR).RESULTS:There was a significant reduction in the ONSD post-ETV (n = 9) and after tumor resection (n = 7). Average preoperative ONSD was 6.21 versus 5.71 mm postoperatively (p = 0.0017).There was also an 88% (p = 0.011) and 60% (p = 0.23) reduction in optic disk bulging and tortuosity, respectively. The FOR normalized in the tumor resection group but not the ETV group. After intervention, all patients showed improvement in signs and symptoms of hydrocephalus.CONCLUSION:In our study population, ONSD decreased in response to measures to reduce hydrocephalus. Optic disk bulging also appears to resolve. Serial reduction in ONSD, and optic disk bulging may be indicators of improved hydrocephalus following pediatric neurosurgical interventions.

Characteristic progeroid features of Petty syndrome include prenatal growth restriction, decreased subcutaneous fat with loose, wrinkled skin, enlarged fontanelles, underdevelopment of the calvarium, coronal synostosis, coarse unruly hair with an abnormal distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and typically normal neurologic development. We describe a case of Petty syndrome in which the antenatal sonographic findings were characteristic and were correlated with postnatal clinical and postmortem examinations. Knowledge of the key phenotypic features may allow the antenatal imaging diagnosis of this rare progeroid condition. A 20-year-old primigravida was referred for fetal anomalies detected on a screening sonographic examination at 20 weeks’ gestation. Maternal serum screening had been declined. Sonography at 27 weeks 4 days identified severe symmetric growth restriction with biometric measurements below the first percentile and moderate polyhydramnios. The anterior fontanelle was extremely large, with widening of the sagittal suture and confluence with the posterior fontanelle (Figure 1A, left panel). The head shape was abnormal, with coronal craniosynostosis, and there was maxillary hypoplasia without hypertelorism. Mild retrognathia was present, with a protruding tongue and abnormal mouth movement (Figure 1A, right panel). The angle between the columella and philtrum was flat (Figure 1A, right panel). The eyebrow hairs were long and on surface-rendered 3dimensional (3D) images appeared hornlike (Figure 1A, left panel). A midline frontal tuft of hair and long eyelashes were also noted. Intracranially, abnormally increased echogenicity of white matter was noted (Figure 1B, left panel). Additional anomalies included an umbilical hernia, bilateral hydronephrosis, and marked sandal gap of the feet. Decompression amniocentesis was performed, and a normal 46,XX karyotype was confirmed with normal array comparative genomic hybridization. The patient declined further investigation. She was admitted at 35 weeks 1 day with severe polyhydramnios and preterm labor. Decompression amniocentesis of 3 L of fluid was performed. A live female neonate was delivered at 35 weeks 4 days. Apgar scores were 8 at 1 minute and 9 at 5 minutes. The umbilical artery pH was normal at 7.20. Birth weight was 1304 g. Weight, length, and head circumference were below the third percentile.

BACKGROUND:Review of children with low-grade cerebellar astrocytoma (LGCA) prior to 1992 showed a 98% rate of gross total resection (GTR) but a concerning incidence of permanent neurological dysfunction. The purpose of this study was to determine the rate of GTR of LGCA since 1992 and frequency of neurologic injury.METHODS:Retrospective review of children with LGCA was performed. CT/MR scans were rereviewed to assess extent of resection. Primary outcomes included incidence of GTR and incidence of permanent new neurological deficits. Other outcomes included late effects severity score (LESS), Bloom score for functional status, and educational assessment.RESULTS:Of 50 LGCA, GTR was achieved in 38 (76%) compared to 43 of 44 (98%) prior to 1992 (p < 0.004). Permanent new neurologic deficits from surgery occurred in 16% compared to 18% in the prior era (p = 0.61). For 35 patients operated on by the 2 surgeons in the prior study, 74% had GTR, with permanent neurological deficits in 8.6%. At latest follow-up, all patients were alive, 16% with residual tumor. LESS was two or less (mild or no deficit) in 94%. Bloom score was one or two (no or mild disability) in 90%. Eighty-six percent attended normal school.CONCLUSIONS:Less aggressive resection of LGCA in children may reduce postoperative neurologic deficits in the hands of the same surgeons as in the prior study but not overall at our institution. The good long-term outcomes suggest that it may be appropriate to do incomplete resection rather than risk additional neurological deficit.

BACKGROUND:To evaluate the predominant pattern of brain injury and the anatomic areas of injury in children with infantile spasms following neonatal hypoxic-ischemic encephalopathy.METHODS:A nested case-control study of infantile spasms in children with term neonatal hypoxic-ischemic encephalopathy was performed. All patients had T1/T2-weighted magnetic resonance imaging with diffusion-weighted imaging performed on the third day of life. Using a validated scoring system, the magnetic resonance imaging was classified as: normal, watershed, basal ganglia/thalamus, total, or focal-multifocal. Two study investigators scored additional anatomic areas of injury (cortical extent, levels of the brainstem, hypothalamus) on T1/T2-weighted magnetic resonance imaging and diffusion-weighted imaging blinded to the outcome. The predominant pattern of brain injury and anatomic areas of injury were compared between patients who developed infantile spasms and randomly selected controls.RESULTS:Eight patients who developed infantile spasms were identified among a cohort of 176 term newborns with hypoxic-ischemic encephalopathy (4.5%). There were no significant differences in the perinatal and neonatal course between newborns who developed infantile spasms and controls who did not. The development of infantile spasms after neonatal hypoxic-ischemic encephalopathy was significantly associated with basal ganglia/thalamus and total brain injury (P = 0.001), extent of cortical injury greater than 50% (odds ratio = 11.7, 95% confidence interval = 1.1-158.5, P = 0.01), injury to the midbrain (odds ratio = 13, 95% confidence interval = 1.3-172, P = 0.007) and hypothalamic abnormalities (P = 0.01).CONCLUSIONS:The development of infantile spasms after hypoxic-ischemic encephalopathy is associated with injury to the basal ganglia and thalami on neonatal magnetic resonance imaging, particularly when extensive cortical injury and/or injury to the midbrain is present.