Novel biallelic ZNF335 variant causing primary microcephaly: A case report and radiological review.

Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant.

Clinical application of magnetic resonance elastography in pediatric neurological disorders.

Magnetic resonance elastography is a relatively new, rapidly evolving quantitative magnetic resonance imaging technique which can be used for mapping the viscoelastic mechanical properties of soft tissues. MR elastography measurements are akin to manual palpation but with the advantages of both being quantitative and being useful for regions which are not available for palpation, such as the human brain. MR elastography is noninvasive, well tolerated, and complements standard radiological and histopathological studies by providing in vivo measurements that reflect tissue microstructural integrity. While brain MR elastography studies in adults are becoming frequent, published studies on the utility of MR elastography in children are sparse. In this review, we have summarized the major scientific principles and recent clinical applications of brain MR elastography in diagnostic neuroscience and discuss avenues for impact in assessing the pediatric brain.

Abusive Head Trauma Animal Models: Focus on Biomarkers.

Abusive head trauma (AHT) is a serious traumatic brain injury and the leading cause of death in children younger than 2 years. The development of experimental animal models to simulate clinical AHT cases is challenging. Several animal models have been designed to mimic the pathophysiological and behavioral changes in pediatric AHT, ranging from lissencephalic rodents to gyrencephalic piglets, lambs, and non-human primates. These models can provide helpful information for AHT, but many studies utilizing them lack consistent and rigorous characterization of brain changes and have low reproducibility of the inflicted trauma. Clinical translatability of animal models is also limited due to significant structural differences between developing infant human brains and the brains of animals, and an insufficient ability to mimic the effects of long-term degenerative diseases and to model how secondary injuries impact the development of the brain in children. Nevertheless, animal models can provide clues on biochemical effectors that mediate secondary brain injury after AHT including neuroinflammation, excitotoxicity, reactive oxygen toxicity, axonal damage, and neuronal death. They also allow for investigation of the interdependency of injured neurons and analysis of the cell types involved in neuronal degeneration and malfunction. This review first focuses on the clinical challenges in diagnosing AHT and describes various biomarkers in clinical AHT cases. Then typical preclinical biomarkers such as microglia and astrocytes, reactive oxygen species, and activated N-methyl-D-aspartate receptors in AHT are described, and the value and limitations of animal models in preclinical drug discovery for AHT are discussed.

Innominate Artery Compression Syndrome.

Vascular mediated airway compromise is a fairly common clinical scenario. The diagnosis of innominate artery compression may be challenging due to lack of standardized imaging criteria for diagnosis or for surgical intervention.

Advanced Neuroimaging Approaches to Pediatric Brain Tumors.

Central nervous system tumors are the most common pediatric solid tumors; they are also the most lethal. Unlike adults, childhood brain tumors are mostly primary in origin and differ in type, location and molecular signature. Tumor characteristics (incidence, location, and type) vary with age. Children present with a variety of symptoms, making early accurate diagnosis challenging. Neuroimaging is key in the initial diagnosis and monitoring of pediatric brain tumors. Conventional anatomic imaging approaches (computed tomography (CT) and magnetic resonance imaging (MRI)) are useful for tumor detection but have limited utility differentiating tumor types and grades. Advanced MRI techniques (diffusion-weighed imaging, diffusion tensor imaging, functional MRI, arterial spin labeling perfusion imaging, MR spectroscopy, and MR elastography) provide additional and improved structural and functional information. Combined with positron emission tomography (PET) and single-photon emission CT (SPECT), advanced techniques provide functional information on tumor metabolism and physiology through the use of radiotracer probes. Radiomics and radiogenomics offer promising insight into the prediction of tumor subtype, post-treatment response to treatment, and prognostication. In this paper, a brief review of pediatric brain cancers, by type, is provided with a comprehensive description of advanced imaging techniques including clinical applications that are currently utilized for the assessment and evaluation of pediatric brain tumors.

Pearls and Pitfalls in Arterial Spin Labeling Perfusion-Weighted Imaging in Clinical Pediatric Imaging.

Characteristic arterial spin labeling (ASL) perfusion patterns are seen in a wide variety of pediatric brain pathologies, highlighting the potential added value and prognostic role of this magnetic resonance imaging (MRI) perfusion-weighted imaging modality. Our objective is to review the basic clinical physics, technical underpinnings, and artifacts and challenges as we highlight some of the most clinically relevant pathologies to the application of ASL in the pediatric setting.

Multimodality Imaging of Pleuropulmonary Blastoma: Pearls, Pitfalls, and Differential Diagnosis.

Pleuropulmonary blastomas are rare, potentially aggressive embryonal cancers of the lung parenchyma and pleural surfaces that account for 0.25%-0.5% of primary pulmonary malignancies in children. Pleuropulmonary blastomas are classified as cystic (type I), mixed cystic and solid (type II), and solid (type III). Pleuropulmonary blastoma occurs in the same age group (0-6 years) as other more common solid tumors such as neuroblastoma and Wilms tumor. Differential diagnosis includes metastasis from Wilms tumor and macrocystic congenital pulmonary airway malformation (CPAM). A key pathologic and genetic discriminator is the DICER1 germline mutation found in patients with pleuropulmonary blastoma. Imaging, histopathologic, and clinical data are important to use in conjunction in order to determine the diagnosis and risk stratification of pleuropulmonary blastomas. Survival varies from poor to good, depending on type. However, the spectrum of pleuropulmonary blastoma is insufficiently understood due to the variable presentation of this rare disease. We present a current review of the literature regarding pleuropulmonary blastomas in this article.

Large aortic pseudoaneurysm after Bentall procedure in a patient with Marfan's syndrome.

An 11-year-old male with Marfan's syndrome and aortic root dilatation underwent an uneventful Bentall procedure to replace his aortic root and valve. Five months later, surveillance echocardiogram revealed a slowly enlarging pseudoaneurysm arising from the ascending aorta. This finding was subsequently confirmed by computed tomographic angiogram. The patient had successful open surgical repair and paraaortic hematoma evacuation.

Radiosynthesis of 1-(2-[18F]Fluoroethyl)-L-Tryptophan using a One-pot, Two-step Protocol.

The kynurenine pathway (KP) is a primary route for tryptophan metabolism. Evidence strongly suggests that metabolites of the KP play a vital role in tumor proliferation, epilepsy, neurodegenerative diseases, and psychiatric illnesses due to their immune-modulatory, neuro-modulatory, and neurotoxic effects. The most extensively used positron emission tomography (PET) agent for mapping tryptophan metabolism, α-[11C]methyl-L-tryptophan ([11C]AMT), has a short half-life of 20 min with laborious radiosynthesis procedures. An onsite cyclotron is required to radiosynthesize [11C]AMT. Only a limited number of centers produce [11C]AMT for preclinical studies and clinical investigations. Hence, the development of an alternative imaging agent that has a longer half-life, favorable in vivo kinetics, and is easy to automate is urgently needed. The utility and value of 1-(2-[18F]fluoroethyl)-L-tryptophan, a fluorine-18-labeled tryptophan analog, has been reported in preclinical applications in cell line-derived xenografts, patient-derived xenografts, and transgenic tumor models. This paper presents a protocol for the radiosynthesis of 1-(2-[18F]fluoroethyl)-L-tryptophan using a one-pot, two-step strategy. Using this protocol, the radiotracer can be produced in a 20 ± 5% (decay corrected at the end of synthesis, n > 20) radiochemical yield, with both radiochemical purity and enantiomeric excess of over 95%. The protocol features a small precursor amount with no more than 0.5 mL of reaction solvent in each step, low loading of potentially toxic 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (K222), and an environmentally benign and injectable mobile phase for purification. The protocol can be easily configured to produce 1-(2-[18F]fluoroethyl)-L-tryptophan for clinical investigation in a commercially available module.

Gunshot-Related Pediatric Left Ventricular Apical Aneurysm.

Penetrating injuries of the thorax and abdomen, such as gunshot and stabbing, are rare in children. We present the case of a pediatric patient with a history of remote gunshot injury presenting with a late aneurysm in the left ventricle. (Level of Difficulty: Intermediate.).

Unravelling neuroinflammation in abusive head trauma with radiotracer imaging.

Abusive head trauma (AHT) is a leading cause of mortality and morbidity in child abuse, with a mortality rate of approximately 25%. In survivors, the prognosis remains dismal, with high prevalence of cerebral palsy, epilepsy and neuropsychiatric disorders. Early and accurate diagnosis of AHT is challenging, both clinically and radiologically, with up to one-third of cases missed on initial examination. Moreover, most of the management in AHT is supportive, reflective of the lack of clear understanding of specific pathogenic mechanisms underlying secondary insult, with approaches targeted toward decreasing intracranial hypertension and reducing cerebral metabolism, cell death and excitotoxicity. Multiple studies have elucidated the role of pro- and anti-inflammatory cytokines and chemokines with upregulation/recruitment of microglia/macrophages, oligodendrocytes and astrocytes in severe traumatic brain injury (TBI). In addition, recent studies in animal models of AHT have demonstrated significant upregulation of microglia, with a potential role of inflammatory cascade contributing to secondary insult. Despite the histological and biochemical evidence, there is a significant dearth of specific imaging approaches to identify this neuroinflammation in AHT. The primary motivation for development of such imaging approaches stems from the need to therapeutically target neuroinflammation and establish its utility in monitoring and prognostication. In the present paper, we discuss the available data suggesting the potential role of neuroinflammation in AHT and role of radiotracer imaging in aiding diagnosis and patient management.

Birth-related subdural hemorrhage: prevalence and imaging morphology.

BACKGROUND: Birth trauma accounts for 1-2% of the mortality in newborns with significant intracranial injuries presenting in the immediate postnatal period. However, a significant number of asymptomatic neonates harbor birth-related intracranial hemorrhage (ICH), with birth-related subdural hemorrhage (SDH) being a common occurrence on infant brain CT and MRI studies performed as a standard of care for a variety of reasons. Although clinically insignificant, birth-related SDH is frequently brought up in courts as an alternative explanation for SDH in suspected abusive head trauma. OBJECTIVE: The aim of this study was to determine prevalence, imaging morphology and distribution of birth-related SDHs on brain CT and MRI studies obtained as a standard of care in infants up to 1 month old. We further tried to ascertain the relationship of birth-related SDHs with mode of delivery and birth weight. MATERIALS AND METHODS: Infants up to the age of 1 month who had CT or MRI of the brain performed between Jan. 1, 2018, and March 29, 2020, were included in this retrospective observational study. In addition to the imaging data, we reviewed clinical history, birth history including birth weight and mode of delivery, and final diagnoses. RESULTS: Two hundred six infants younger than 30 days (range 0-29 days, mean 11.9 days, median 11 days and standard deviation [SD] 8.4 days) had a CT or MRI study during the study period. Among these, 58 infants were excluded as per the exclusion criteria. Among the included 148 infants, 88 (59.5%) had no imaging evidence of SDH. An additional 56 (37.8%) infants were assessed as having birth-related SDH based on review of clinical data. Within the birth-related SDH cohort (56 infants), only supratentorial SDH was identified in 5 (8.9%), only infratentorial SDH was identified in 14 (25%), while SDHs within both compartments were identified in 37 (66.1%) infants. The most common location for supratentorial birth-related SDH was along the occipital lobes (31/42, 73.8%), with other common locations being along the posterior interhemispheric fissure (30/42, 71.4%) and fronto-parietal convexity (9/42, 21.4%). The distribution of posterior fossa SDH was along the tentorium (38/51, 74.5%), along the cerebellum (38/51, 74.5%) and in both the locations (25/51, 49.0%). The rate of SDH was significantly higher in vaginal delivery group (46/84, 54.7%) as compared to caesarean section group (10/57, 17.5%) (P<0.05). We did not find any statistically significant difference between the birth weights of normal and birth-related SDH cohorts (P>0.05). CONCLUSION: Birth-related SDH is a common occurrence, with our study suggesting a prevalence of 37.8%. The most common distribution of birth-related SDH is within both the supra- and infratentorial compartments (66.1%) followed by infratentorial compartment (25%). The rate of birth-related SDH was significantly higher in vaginal delivery group as compared to caesarean section group.

Monitoring retinal pathology and cerebral injury in sickle cell disease using spectral-domain optical coherence tomography in pediatric patients.

PURPOSE: This study aimed to confirm the correlation between sickle cell disease (SCD) genotype and retinal damage identified by spectral-domain optical coherence tomography (SD-OCT), and examine a potential link between hypoxic ischemic injury in the retina and brain. METHODS: In this prospective, observational case series, 117 patients (56 males) aged 5-20 years with SCD (36 SC, 68 SS, eight Sß+ thalassemia, five Sß0 thalassemia) underwent ophthalmologic examination including funduscopy and SD-OCT imaging. Comparison of SCD genotypes and association between ocular findings and cerebrovascular disease (CVD) in subjects with SS/Sß0 genotype were investigated. RESULTS: Visual acuity ranged from 20/20 to 20/40. On funduscopic exam, 16 of 117 (13.7%) had retinopathy; 69 of 117 (59.0%) showed inner retina thinning on SD-OCT. Patients with SS/Sß0 showed a higher frequency of sickle cell retinopathy (SCR) change (68.5% vs. 47.2%), bilateral SCR (49.9% vs. 25.0%), and foveal involvement (15.1% vs. 0) than the SC genotype. While funduscopic findings in our cohort with SS/Sß0 genotype showed no correlation with CVD, 20 of 21 patients with CVD had abnormal SD-OCT. Elevated reticulocyte percentage and aspartate aminotransferase are associated with SD-OCT changes and CVD. CONCLUSIONS: SD-OCT was better than funduscopy in detecting retinal changes, higher frequency, and more extensive retinal changes in the more severe SCD genotypes SS and Sß0 as compared with SC. The correlation between abnormal SD-OCT and CVD strongly suggests that retinal exam using SD-OCT may aid in detection and monitoring SCD-related CVD. Retinopathy may be another component of the hemolytic subphenotype of SCD.

Idiopathic midaortic syndrome.

Midaortic syndrome (MAS) is characterized by narrowing of the descending aorta between the distal aortic arch and the aortic bifurcation. We present the case of a 4-year-old male presenting with a murmur and diagnosed with MAS. He was treated with a thoracoabdominal bypass graft.

Coronary artery aneurysm in Kawasaki disease.

A 3-year-old male presents to the emergency department with chief complaints of fever and vomiting. He had a positive rapid streptococcus throat test with cervical lymphadenopathy. The patient was started on antibiotics. On examination, there was diffuse erythematous macular rash on the chest. Laboratory tests revealed elevated white cell count and C-reactive protein. Electrocardiogram was notable for prolonged PR interval indicating 1st degree atrioventricular block. Echocardiogram revealed ectasia of the right coronary artery (RCA). A presumptive diagnosis of Kawasaki disease was made and the patient was started on high-dose aspirin and intravenous immunoglobulins. Cardiac computed tomography angiography (CTA) showed an aneurysm of the proximal RCA measuring up to 7.4 mm. The RCA immediately proximal to the aneurysm measured 3 mm in diameter. The Z score was 13.4. Oblique coronal image from cardiac CTA and volume rendered images demonstrated an aneurysm of the proximal RCA. The patient improved with treatment.

Automated production of 1-(2-[18F]fluoroethyl)-l-tryptophan for imaging of tryptophan metabolism.

Automated production of an fluorine-18 labeled tryptophan analogue, 1-(2-[18F]fluoroethyl)-l-tryptophan (1-L-[18F]FETrp) in a current Good Manufacturing Practice facility was achieved. 1-L-[18F]FETrp was produced by a one-pot, two-step strategy with an overall synthesis time of approximately 100 min, a radiochemical yield of 20 ± 5% (decay corrected), radiochemical purity and enantiomeric excess over 90%, and a molar activity of 103 ± 15 GBq/µmol at the end of synthesis (EOS). The dose mass of 1-L-FETrp in four consecutive batches was less than 5 µg. The radiopharmaceutical product met all quality control criteria for clinical use.

Generalized Arterial Calcification of Infancy.

Generalized arterial calcification of infancy (GACI) is a rare genetic disease that affects the circulatory system and the large- and medium-sized arteries throughout the body. GACI usually occurs during fetal development. Babies with GACI are diagnosed early, generally soon after birth and in some cases before birth by fetal ultrasound.

Cervical Spine Deformities in Children With Rhizomelic Chondrodysplasia Punctata.

BACKGROUND: Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology. METHODS: An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP. Records of children within the registry were evaluated, and magnetic resonance images obtained between 2004 and 2015, were available for review. The levels of spinal canal stenosis were recorded and the severity of the stenosis was decided based on adults' parameters. Cord compression and myelomalacia were confirmed on the axial images. Sagittal lumbar spine magnetic resonance images were also evaluated when available, and the presence of tethered cord and fatty filum was recorded. RESULTS: Twenty-six children (15 boys and 11 girls) were identified in the RCDP Registry. Eleven children (6 boys and 5 girls) had sagittal MRI of the cervical spine available for review. Age at the time of MRI study was variable (1 wk to 32 mo). All patients except 1 had stenosis of the cervical spinal canal. Myelomalacia of the cord was noted only in this patient. CONCLUSIONS: This study suggests that, in children with RCDP, cervical spinal stenosis and cord compression are a real risk, and children with this diagnosis should have monitoring for these issues. Tethered cord is also a possible finding that needs to be evaluated. Full sagittal spine MRI is necessary to detect the possible deformities at the cervical and lumbar levels.