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Patient Y.D. Clinicopathologic Conference (CPC) 12/18/15 Neurology Resident: Natalia Gonzalez Pathologist: Ronald Hamilton History HPI: Y.D. was a male infant born at 37 weeks via elective C-section. A second trimester prenatal ultrasound was concerning for ventriculomegaly, a dilated left renal pelvis with hydroureter, a small VSD, and a two vessel cord. At delivery, the infant was limp with poor respiratory effort requiring intubation. A VPS shunt was placed. The infant passed at 2 weeks of age from cardiorespiratory failure after life support was withdrawn. FH: Mother was 33yo, G3P2. Family is from Mexico. Patient has a healthy 17 yo brother and 8 yo sister. Physical Examination Vitals: Birth weight was 6.6 lbs. OFC 41cm (97 %ile). HEENT: Macrocephaly. Large anterior and posterior fontanelles. Microphthalmia. Low set and posteriorly rotated ears. Right iris coloboma. Slit lamp: anomolous iris b/l with multiple vessels and persistent pupillary membranes. Dense cataracts. Anterior and posterior fetal vasculature. Derm: Tuft of hair over sacral region (ultrasound normal underneath) Ext: Single palmar creases. Digitalized right thumb. Bilateral 5th clinodactyly. Neuro: Responds to stimulus with flexion of ext. Otherwise no movements. Pupils unreactive bilaterally. + oculovestibular response. Decreased axial tone. Normal tone in extremities. DTRs elicited in patella bilaterally. Babinski and plantar grasp present. Fetal ventriculomegaly (ventricle width > 10mm) 1. Obstructive 1. Dysgenesis 1. Destructive Obstructive - Ventricles are typically smooth-walled. Ventricle orientation is normal. Cortex is intact, but compressed. Posterior fossa structures may be abnormal. If normal, consider aqueductal stenosis. Cavum septum pellucidum may be absent if severe. The falx is present. Dysgenesis - Ventricle shape and position is abnormal Ventricles are typically smooth-walled Cavum septum pellucidum is abnormal Falx may be abnormal Other CNS abnormalities may be visible (e.g. fused frontal horns) Destructive - infarcts, bleeds, infections, trauma - Ventricle position is normal Thinning/loss of cerebral cortex in a patchy asymmetric distribution Midline structures are normal Posterior fossa structures are normal Falx is present MRI Brain Workup Metabolic workup - normal peroxisomal panel and sterol panel CPK ranged from 2,000 to 23,280 Sent microarray for congenital muscular dystrophy panel… Pt homozygous for POMT1 gene - for a sequence variant causing a frame-shift mutation - located on 9q34.13 - Defective glycosylation of alpha-dystroglycan complex (in skeletal muscle works as a transmembrane linkage between extracellular matrix and the cytoskeleton. In brain, impairs interaction of migrating neurons with matrix elements, causing malformations of cortical development. - Dystroglycan also found in other tissues including kidneys and retina Walker-Warburg Syndrome - AKA Muscle-Eye-Brain Disease - Autosomal recessive - 25% chance of having another child with WWS - Life expectancy 4 months (but variable phenotypes and severities depending on exact mutation) - Can include macro or microcephaly, eye malformations (retinal dysplasia, ocular colobomas, cataracts), brain malformations (hydrocephalus, lissencephaly type II, Dandy-Walker, cerebellar malformations, encephalocele, agenesis of the corpus callosum), congenital muscular dystrophy Expected pathology - Gross pathology: CNS structural abnormalities including cobblestoning of lissencephaly type II - Micro: Type II lissencephaly: Chaotic neuronal organization, interrupted glia, allowing passage of neurons into subarachnoid space - Muscle biopsy usually shows dystrophic changes. Immunohistochemistry shows deficient alpha-dystroglycan with normal dystrophin References http://www.omim.org http://neuropathology-web.org http://www.nextprot.org UpToDate Radiopaedia.org http://brain.oxfordjournals.org/content/brain/early/2012/02/09/brain.awr357.full.pdf Virtual Microscopy Cortex Slide A H&E NeuN Cortex Slide B H&E NeuN Cerebellum Slide F H&E NeuN Spinal Cord Slide J H&E