Cameron Thomas

Regions of homozygosity identified by SNP microarray analysis aid in the diagnosis of autosomal recessive disease and incidentally detect parental blood relationships

Purpose:The purpose of this study was to document the ability of single-nucleotide polymorphism microarray to identify copy-neutral regions of homozygosity, demonstrate clinical utility of regions of homozygosity, and discuss ethical/legal implications when regions of homozygosity are associated with a parental blood relationship.Methods:Study data were compiled from consecutive samples sent to our clinical laboratory over a 3-year period. A cytogenetics database identified patients with at least two regions of homozygosity >10 Mb on two separate chromosomes. A chart review was conducted on patients who met the criteria.Results:Of 3,217 single-nucleotide polymorphism microarrays, 59 (1.8%) patients met inclusion criteria. The percentage of homozygosity ranged from 0.9 to 30.1%, indicating parental relationships from distant to first-degree relatives. First-degree kinship was suspected in the parents of at least 11 patients with regions of homozygosity covering >21.3% of their autosome. In four patients from two families, homozygosity mapping discovered a candidate gene that was sequenced to identify a clinically significant mutation.Conclusion:This study demonstrates clinical utility in the identification of regions of homozygosity, as these regions may aid in diagnosis of the patient. This study establishes the need for careful reporting, thorough pretest counseling, and careful electronic documentation, as microarray has the capability of detecting previously unknown/unreported relationships.Genet Med 2013:15(1):70–78

The Evaluation and Management of Pediatric Syncope

Syncope is a common problem in children and adolescents. It is typically caused by benign neurally mediated hypotension, but other, more concerning, etiologies of syncope must be considered. In most instances, the underlying cause of syncope in the pediatric patient can be determined by obtaining a thorough history and physical examination. Attention to the cardiac, neurological, and psychological history and examination can rule out more rare causes of loss of consciousness. Most individuals with neurally mediated hypotension can be treated with lifestyle measures including aggressive hydration, dietary salt, and an exercise program. In instances where lifestyle modification fails, medications may offer symptomatic improvement.

Levetiracetam for the Treatment of Seizures in Neonatal Hypoxic Ischemic Encephalopathy

The objective of this study was to determine the efficacy and safety of levetiracetam in treatment of neonatal seizures due to hypoxic ischemic encephalopathy. Seizures often persist in neonates with hypoxic ischemic encephalopathy despite phenobarbital. A retrospective single-center study was conducted in neonates ≥36 weeks gestation with hypoxic ischemic encephalopathy. A total of 127 neonates were identified born 2008-2015. Clinical seizures occurred in 83 infants. Fifty-one neonates (61%) had cessation of seizures with only phenobarbital. Thirty-two neonates received levetiracetam after phenobarbital, and the seizures stopped in 27 of these neonates. The mean total loading dose of levetiracetam was 63 mg/kg. Mean maintenance dose of levetiracetam was 65 mg/kg/d. We found no negative side effects in neonates following levetiracetam use. Our study finds that levetiracetam is an efficacious medication in treatment of seizures in the setting of neonatal hypoxic ischemic encephalopathy. Future prospective studies should explore its use as a first-line medication.

A Retrospective Analysis of the Utility of Head Computed Tomography and/or Magnetic Resonance Imaging in the Management of Benign Macrocrania.

Objective To assess whether computed tomography (CT), magnetic resonance imaging (MRI), and neurosurgical evaluations altered the diagnosis or management of children diagnosed with benign macrocrania of infancy by ultrasonography (US). Study design We queried our radiology database to identify patients diagnosed with benign macrocrania of infancy by US between 2006 and 2013. Medical records of those with follow‐up CT/MRI were reviewed to determine clinical/neurologic status and whether or not CT/MRI imaging resulted in diagnosis of communicating hydrocephalus or required neurosurgical intervention. Results Patients with benign macrocrania of infancy (n = 466) were identified (mean age at diagnosis: 6.5 months). Eighty‐four patients (18.0%) received subsequent head CT/MRI; of these, 10 patients had neurologic abnormalities before 2 years of age, of which 3 had significant findings on MRI (temporal lobe white matter changes, dysmorphic ventricles, thinned corpus callosum). One patient without neurologic abnormalities had nonspecific white matter signal abnormality (stable over 6 months) but no change in management. None required neurosurgical intervention. Another 9/84 patients had incidental findings including Chiari I (3), small subdural bleeds (2), arachnoid cyst (1), small cavernous malformation (1), frontal bone dermoid (1), and a linear parietal bone fracture after a fall (1). Conclusions Children diagnosed with benign macrocrania of infancy on US without focal neurologic findings do not require subsequent brain CT/MRI or neurosurgical evaluation. Decreasing unnecessary imaging would decrease costs, minimize radiation and sedation exposures, and increase clinic availability of neurology and neurosurgery specialists.

Prenatal aqueduct stenosis: Association with rhombencephalosynapsis and neonatal outcome

To examine prenatal MRI and postnatal imaging in fetuses with congenital aqueductal stenosis (CAS) to determine the frequency of association of rhombencephalosynapsis (RES) and how it may affect neonatal intensive care unit (NICU) course.

Congenital aqueduct stenosis: Progressive brain findings in utero to birth in the presence of severe hydrocephalus

To evaluate the effects of progressive hydrocephalus on the developing brain in a cohort of fetuses diagnosed with congenital aqueduct stenosis by comparing prenatal magnetic resonance imaging and postnatal imaging.

Outcome of Isolated Absent Septum Pellucidum Diagnosed by Fetal Magnetic Resonance Imaging (MRI) Scan

Improved fetal imaging has resulted in increased diagnosis of isolated absent septum pellucidum without other intracranial abnormalities. There is little literature regarding outcomes for these fetuses. This study hypothesized the majority of infants diagnosed by fetal magnetic resonance imaging (MRI) with isolated absent septum pellucidum would retain this diagnosis postnatally. Specifically, in the absence of postnatal endocrine or ophthalmologic abnormalities, postnatal imaging would find no additional related findings, and fetuses would be at low risk for developmental delay. Two of 8 subjects met postnatal criteria for septo-optic dysplasia; remaining subjects had normal postnatal endocrine and ophthalmologic evaluations and no significant related findings on postnatal MRI. One subject without septo-optic dysplasia had delays on developmental screening; all others had normal screening (range of follow-up 8-72 months). Our study questions the necessity of postnatal imaging for prenatally diagnosed isolated absent septum pellucidum. Majority of fetuses with isolated absent septum pellucidum retained this diagnosis postnatally.

Conventional MRI scan and DTI imaging show more severe brain injury in neonates with hypoxic-ischemic encephalopathy and seizures

BACKGROUND Neonates with hypoxic-ischemic encephalopathy (HIE) and seizures have poorer outcome for undetermined reasons. AIMS Our aim was to determine if brain imaging was more abnormal in neonates with HIE and electrographically confirmed seizures and whether this was impacted by seizure burden. STUDY DESIGN Single center retrospective review. SUBJECTS Forty-eight term neonates with HIE (with and without seizures) underwent MRI brain scans before age 14 days between the years 2008 and 2013. OUTCOME MEASURES Images were rated using a MRI injury score and fractional anisotropy (FA) values were extracted from diffusion tensor imaging (DTI). RESULTS The seizure group (n = 25) had significantly more injury within white matter, basal ganglia, posterior limb of internal capsule, and watershed areas compared to the group without seizures (n = 23). The severity of injury in all measured areas increased with increasing seizure severity. The seizure group also had lower FA values in posterior limb of the internal capsule and the splenium of corpus callosum. CONCLUSIONS Neonates with HIE and seizures had more brain injury that occurred in areas typically affected by HIE and was greater with higher seizure burden. Seizures may be a marker of more severe brain injury or seizures themselves may amplify brain damage from HIE.