The importance of genetic counseling and screening for people with pathogenic SMARCE1 variants: A family study.

Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.

Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Perceived fatigue in children and young adults with neurofibromatosis type 1.

AIM: This study describes the prevalence and severity of perceived fatigue in a young neurofibromatosis type 1 (NF1) population. METHODS: Ethical approval was obtained and NF1 affected Individuals aged 2-18 years from the Manchester's NF1 clinic invited along with any unaffected siblings. The PedsQL Multidimensional Fatigue Scale Parental and child report was used. This validated measure explores cognitive, physical and sleep/rest domains on a 0-100 scale. Higher scores indicate less fatigue. Fatigue scores in affected children were compared to unaffected siblings after adjusting for age, sex and Index of Multiple Deprivation and with published population standards using z-scores. RESULTS: A total of 286 families were invited and 75 affected and 16 siblings participated. There were significant differences between NF1 and controls in the aggregated fatigue core (child report 55 ± 19 vs. 75 (14), P < 0.001; parent 54 ± 20 vs. 73 ± 18, P = 0.001) and the three sub-domains: cognitive (child 48 ± 27 vs. 75 ± 23, P < 0.001), physical (child 59 ± 19 vs. 82 ± 14, P < 0.001) and sleep/rest (child 59 ± 19 vs. 71 ± 15, P = 0.018). Similar differences were seen when compared with published controls (aggregated child z-score -1.9 ± 1.4, P < 0.001; parent -3.2 ± 1.8, P < 0.001). Prevalence of severe fatigue indicated by scores <2 standard deviation below published means for healthy controls were also higher for children with NF on both parent and child reports. Agreement between child and parent reports were limited as is frequently seen in the literature. CONCLUSION: This study suggests that children with NF1 are affected by perceived fatigue when compared with healthy children who do not have NF1.

Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2.

BACKGROUND: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. METHODS: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. RESULTS: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. DISCUSSION: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

Quantification of structural changes in the corpus callosumin children with profound hypoxic-ischaemic brain injury.

BACKGROUND: Birth-related acute profound hypoxic-ischaemic brain injury has specific patterns of damage including the paracentral lobules. OBJECTIVE: To test the hypothesis that there is anatomically coherent regional volume loss of the corpus callosum as a result of this hemispheric abnormality. MATERIALS AND METHODS: Study subjects included 13 children with proven acute profound hypoxic-ischaemic brain injury and 13 children with developmental delay but no brain abnormalities. A computerised system divided the corpus callosum into 100 segments, measuring each width. Principal component analysis grouped the widths into contiguous anatomical regions. We conducted analysis of variance of corpus callosum widths as well as support vector machine stratification into patient groups. RESULTS: There was statistically significant narrowing of the mid-posterior body and genu of the corpus callosum in children with hypoxic-ischaemic brain injury. Support vector machine analysis yielded over 95% accuracy in patient group stratification using the corpus callosum centile widths. CONCLUSION: Focal volume loss is seen in the corpus callosum of children with hypoxic-ischaemic brain injury secondary to loss of commissural fibres arising in the paracentral lobules. Support vector machine stratification into the hypoxic-ischaemic brain injury group or the control group on the basis of corpus callosum width is highly accurate and points towards rapid clinical translation of this technique as a potential biomarker of hypoxic-ischaemic brain injury.

Enlarged Vestibular Aqueduct: Disease Characterization and Exploration of Potential Prognostic Factors for Cochlear Implantation.

OBJECTIVES: There is an unmet need to match the anticipated natural history of hearing loss (HL) in enlarged vestibular aqueduct (EVA) with clinical management strategies. The objectives of this study are therefore to provide a detailed case characterization of an EVA cohort and explore the relationship between candidate prognostic factors and timing of cochlear implant (CI) surgery. STUDY DESIGN: A multicenter retrospective review of patients diagnosed with EVA. SETTING: Patient data recruitment across three CI centers in the UK. PATIENTS: One hundred fifty patients with a radiological diagnosis of EVA from January 1995 to January 2021. MAIN OUTCOME MEASURES: Age at audiological candidacy for CI and age at first implant surgery. RESULTS: EVA was predominately a bilateral condition (144/ 150) with increased prevalence in women (M:F, 64:86). 51.7% of patients failed new-born hearing screening, with 65.7% having HL diagnosed by 1 year. Initial moderate to severe and severe to profound HL were reported most frequently. In 123 patients, median age that audiological candidacy for CI was met for at least one ear was 2.75 years. Median age at first CI was 5 years (140/150).Pendred syndrome (confirmed in 73 patients) and ethnicity, were not significantly associated with earlier CI surgery. Multivariate linear regression demonstrated that male patients have first CI surgery significantly earlier than females (coefficient -0.43, 95% CI [-0.82, -0.05), p-value = 0.028). CONCLUSIONS: This large UK EVA cohort provides evidence that patients should be closely monitored for CI candidacy within the first 3 years of life. Significantly, male gender is emerging as an independent prognostic factor for earlier assessment and first CI surgery.

Endoscopic third ventriculostomy: predicting outcome with phase-contrast MR imaging.

PURPOSE: To determine whether phase-contrast magnetic resonance (MR) imaging measurements of preoperative cerebral blood and cerebrospinal fluid (CSF) hydrodynamics can be used as a biomarker of response to endoscopic third ventriculostomy (ETV). MATERIALS AND METHODS: Approval from the local research ethics committee and written informed consent were obtained for this prospective study. Thirteen patients (six female patients, seven male patients; median age, 43 years) with chronic obstructive hydrocephalus, 12 of whom went on to undergo ETV, were imaged with phase-contrast MR imaging at 1.5 T to determine rates of total cerebral blood flow (CBF) and ventriculostomy defect, foramen magnum (FM), and cerebral aqueduct CSF flow. Ten control subjects (10 men; median age, 37 years) were similarly imaged. Correlations between measured values were assessed by means of Pearson correlation coefficients. Measurements were compared between groups with a Mann-Whitney test, and measurements before and after surgical intervention were compared with a Wilcoxon test for paired samples. RESULTS: Rates of CBF (356 mL . min(-1) +/- 73 [standard deviation] vs 518 mL . min(-1) +/- 79, P < .001) and CSF flow in the FM (17.62 mL . min(-1) +/- 13.12 vs 36.35 mL . min(-1) +/- 8, P < .05) were significantly lower in patients than in control subjects. CONCLUSION: ETV induces changes in brain volume and CBF that can be predicted by using simple metrics. These pilot results support a formal trial of these techniques in a larger prospective study.

Does black blood MRA have a role in the assessment of intracerebral aneurysms?

The aim of this study was to assess whether the addition of a black blood (BB) sequence to standard three-dimensional time-of-flight (3D-TOF) imaging yields improved quantitative assessment of intracranial aneurysms. Thirty seven patients with 42 proven intracranial aneurysms underwent intra-arterial digital subtraction angiography, 3D-TOF and BB MRI imaging. This multimodality imaging was used to create a composite reference aneurysm description. The 3D-TOF and BB imaging were graded on a subjective seven-point scale to determine what improvement if any the addition of BB imaging yielded. Comparison of measurements from all imaging modalities demonstrated no significant difference (p < 0.01) in aneurysm length/width or parent vessel width. Aneurysm neck measurements were underestimated on 3D-TOF images although there was still a significant correlation (R(2) = 0.72, p < 0.05). Comparison of TOF and BB examinations to the composite reference using the Wilcoxon signed-rank test showed significant improvement in the demonstration of the aneurysm to parent/branch vessels and the morphology/size of the aneurysm neck, particularly in the setting of local haematoma or slow flow (p < 0.001). We propose the addition of the BB sequence as a useful adjunct to 3D-TOF imaging particularly when detailed aneurysm morphology is required or there is thrombus in subarachnoid space.

Glandular function in Sjögren syndrome: assessment with dynamic contrast-enhanced MR imaging and tracer kinetic modeling--initial experience.

PURPOSE: To prospectively use dynamic contrast material-enhanced magnetic resonance (MR) imaging and a tracer kinetic model to compare parotid gland microvascular characteristics in patients who have Sjögren syndrome (SS) with those in healthy volunteers. MATERIALS AND METHODS: The local research ethics committee approved the study, and written informed consent was obtained from all participants. Twenty-one patients (19 women, two men; age range, 31-73 years) with a diagnosis of SS and 11 healthy volunteers (10 women, one man; age range, 41-68 years) underwent three-dimensional T1-weighted dynamic contrast-enhanced MR imaging of the parotid gland at 1.5 T. A voxel-wise tracer kinetic model and a model-free analysis were applied to the dynamic MR data. Parameter medians and standard deviations were computed to summarize gland microvascular characteristics and gland heterogeneity, respectively. Differences were investigated by using multivariate analysis of variance, t, or U tests. Further investigation was performed by using linear discriminant and receiver operating characteristic analyses. RESULTS: Compared with the healthy volunteers, the patients with SS had highly significant elevations (P << .001) in the model-free parameter initial area under the curve and in tracer kinetic model parameters, including transcapillary contrast agent transfer constant (P < .001) and extracellular extravascular volume (P < .001). Gland heterogeneity was significantly greater (P < .001) in the patients with SS. Parameter medians and standard deviations enabled excellent differentiation (areas under receiver operating characteristic curve, 0.96 and 1.00, respectively) between the patients with SS and the healthy volunteers. CONCLUSION: Dynamic contrast-enhanced MR imaging has the potential to be used in clinical settings to quantify microvascular function in SS and to differentiate between patients with and those without SS.

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging.

OBJECTIVE: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features. METHODS: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined. RESULTS: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC). CONCLUSION: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making. ADVANCES IN KNOWLEDGE: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.

Picture quiz: a case of sudden severe chest pain.

An 18-year-old male with no previous medical history presented to hospital with sudden onset of acute epigastric pain radiating to the anterior chest wall and both shoulders. There was no history of recent trauma and he had not been vomiting.

Percutaneous ultrasound-guided thrombin injection for endoleaks: an alternative.

Endoleaks are now well-recognized complications of endovascular repair of abdominal aortic aneurysm and an incidence of up to 46% has been reported in the literature. These endoleaks can result in rupture of the aneurysmal sac with potentially serious consequences. A type 2 endoleak is the most common type with a feeding vessel reperfusing the aneurysm sac. Radiological treatment of such an endoleak usually involves coil or particle angioembolisation, but sometimes this can be difficult, especially if endovascular access to the feeding vessel is not straightforward. We describe and illustrate percutaneous ultrasound-guided thrombin injection in the treatment of a type 2 endoleak. In appropriate patients, this technique is simple to perform, and has low associated morbidity.