05/01/20 “Cerebellar Syndrome” • Cerebellar ataxia • Hypotonia • Asthenia and fatigue • Superior cognitive function deficits Patients with posterior fossa Midbrain-hindbrain malformations malformations typically present with Andrea Rossi, MD psychomotor/developmental delay Neuroradiology Unit Istituto Giannina Gaslini Children’s Hospital - Genoa, Italy [email protected] Desmond JE et al., J Neurosci 1997 2 months, nystagmus, apnea 5-mm study 3D 1 mm normal Molar tooth malformation Anterior vs posterior vermis: ≈ 1:1:5 Midbrain/medulla vs Pons ≈ 1:1.5 Primary fissure Primary fissure T Ex vacuo enlargement ≠ megacisterna magna! Inferior vermis hypoplasia Brainstem dysplasia (early AP patterning) 1 05/01/20 DWI b 700 T1 21 W normal 21 W 28 W > 24W Be careful with early diagnoses of vermian hypoplasia/DWM! 4 v BPC < 24W Global cerebellum: cerebellar agenesis, RES, PCH Vermis: DWM, BPC/MCM, vermis hypoplasia Hemisphere: UCH, cortical dysgenesis Brainstem: molar tooth, PTCD, HGPPS 2 05/01/20 CEREBELLAR AGENESIS DIABETES MELLITUS, PERMANENT NEONATAL, WITH CEREBELLAR AGENESIS PTF1A: 10p12.3 Global cerebellum: cerebellar agenesis, RES, PCH Vermis: DWM, BPC/MCM, vermis hypoplasia Hemisphere: UCH, cortical dysgenesis Brainstem: molar tooth, PTCD, HGPPS RHOMBENCEPHALOSYNAPSIS Absence of the vermis with midline fusion of the cerebellar hemispheres, dentate nuclei, and cerebellar peduncles normal 22 W PCH PONTOCEREBELLAR HYPOPLASIA PCH PONTOCEREBELLAR HYPOPLASIA PCH type 1 (with spinal anterior horn degeneration) (Barth, type 1) (VRK1, EXOSC3 mutations) PCH type 1 (with spinal anterior horn degeneration) (Barth, type 1) (VRK1, EXOSC3 mutations) PCH type 2 (with extrapyramidal features) (Barth, type 2) (TSEN54, TSEN2, TSEN34 mutations) PCH type 2 (with extrapyramidal features) (Barth, type 2) (TSEN54, TSEN2, TSEN34 mutations) PCH type 3 (with optic atrophy, 7q11-21, gene unknown) MRI: PCH type 3 (with optic atrophy, 7q11-21, gene unknown) MRI: PCH type 4 (fatal infantile OPCH) (TSEN54 mutations) PCH type 4 (fatal infantile OPCH) (TSEN54 mutations) PCH type 5 (with hypocellular vermis and fetal seizures) (TSEN54 mutations) PCH type 5 (with hypocellular vermis and fetal seizures) (TSEN54 mutations) PCH type 6 (multiple respiratory chain defects and mutations in the mt RARS2 gene) PCH type 6 (multiple respiratory chain defects and mutations in the mt RARS2 gene) PCH type 7 (with primary hypogonadism) PCH type 7 (with primary hypogonadism) PCH type 8 (with joint contractures and growth retardation) (CHMP1A mutations) PCH type 8 (with joint contractures and growth retardation) (CHMP1A mutations) PCH type 9 (with profound microcephaly) (AMPD2 mutations) PCH type 9 (with profound microcephaly) (AMPD2 mutations) PCH type 10 (with delayed myelination) (CLP1 mutations) PCH type 10 (with delayed myelination) (CLP1 mutations) PCH type 11 (malformative) (CASK mutations) the “dragonfly” sign PCH type 11 (malformative) (CASK mutations) the “dragonfly” sign 3 05/01/20 The CASK - RELN pathway Lissencephaly The Reelin pathway Lissencephaly The Reelin pathway + + Cerebellar Cerebellar Hypoplasia Hypoplasia © Manto & Jissendi, 2012 © Boycott KM, 2005 CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME 1; CAMRQ1 RELN CASK TSEN54 • Consequence of extreme prematurity with a birth weight <1500 g • Proposed mechanisms: - Selective vulnerability at 24-30 weeKs - Presence of hemosiderin At birth (28 W) 4 05/01/20 DANDY-WALKER MALFORMATION 1) Complete or partial agenesis of the vermis with counter-clockwise rotation 2) Cystic dilatation of the fourth ventricle 3) Enlarged posterior fossa with upward displacement of lateral sinuses, tentorium, and torcular 4 v Global cerebellum: cerebellar agenesis, RES, PCH Affected individuals often have motor deficits Vermis: DWM, BPC/MCM, vermis hypoplasia such as delayed motor development, hypotonia, and ataxia; about half have mental retardation Hemisphere: UCH, cortical dysgenesis and some have hydrocephalus Brainstem: molar tooth, PTCD, HGPPS 22 W 2 months 2 years Case courtesy Anna Pichiecchio, Pavia, Italy Anterior Membranous Area 21 W 30 W choroidal fold 5 days 1 year • Counter-clockwise rotation of a hypoplastic vermis with torcular elevation is the key feature indicating a developmental arrest of the anterior membranous area • Flat fastigium • Large ( > 45) brainstem-vermis angle 5 05/01/20 D Dx: Retrocerebellar “cysts” with intact cerebellum Posterior Membranous Area choroidal fold 4 v 4 v Megacisterna Magna Blake’s Pouch Cyst (No hydrocephalus, incidental finding) “persistent” > 25 W !! (macrocrania, raised ICP) Blake’s BP pouch Normal 25 W UNILATERAL CEREBELLAR HYPOPLASIA 3 years 7 days 29 W Global cerebellum: cerebellar agenesis, RES, PCH Affected patients are typically asymptomatic or Vermis: DWM, BPC/MCM, vermis hypoplasia minimally symptomatic and, typically, no associated abnormalities are found elsewhere in the brain Hemisphere: UCH, cortical dysgenesis Brainstem: molar tooth, PTCD, HGPPS Early disruption CEREBELLAR CORTICAL DYSGENESIS HME MEB © Z Rumboldt 6 05/01/20 PBS MDDGA3 normal cortex COBBLESTONE Global cerebellum: cerebellar agenesis, RES, PCH Vermis: DWM, BPC/MCM, vermis hypoplasia Andrea Poretti, 1977 - 2017 Hemisphere: UCH, cortical dysgenesis Brainstem: molar tooth, PTCD, HGPPS “MOLAR TOOTH” MALFORMATION “MOLAR TOOTH” MALFORMATION 20 W Joubert syndrome Joubert syndrome • Abnormal breathing (hyperpnea/apnea) • Abnormal breathing (hyperpnea/apnea) • Ataxia • Ataxia • Abnormal eye movements • Abnormal eye movements • Developmental delay • Developmental delay 7 05/01/20 Molar tooth sign JS –related disorders Joubert-related cerebello-oculo-renal syndromes normal 20 W In JS, the fibers of the pyramidal tract and the superior cerebellar peduncles do not cross, Ophthalmologic and nephrologic evaluation Abdominal US irrespective of the underlying mutation Poretti et al, AJNR 2007 No correlation between molar tooth shape and genotype Poretti A, et al. Joubert Syndrome and Related Disorders: Spectrum of Neuroimaging Findings in 75 Patients. AJNR 2011 Poretti A et al. Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause. J Med Genet 2017 OFD-VI PTCD: PONTINE TEGMENTAL CAP DYSPLASIA (Varadi-Papp s.) “inverted pons” C5ORF42 mutations * * Hypothalamic hamartoma “Coarse” MT sign DORSAL TRANSVERSE AXONAL BAND Jissendi-Tchofo 2009 , Barth 2007 * * PTCD NORMAL Posterior fossa cyst 8 05/01/20 HGPPS HORIZONTAL GAZE PALSY WITH PROGRESSIVE SCOLIOSIS HGPPS HORIZONTAL GAZE PALSY WITH PROGRESSIVE SCOLIOSIS SPLIT PONS SIGN SPLIT PONS SIGN KAL1 Rossi A, AJNR 2003 Rossi A, AJNR 2003 PROK2 L1 ROBO3 PROKR2 CHN1 KIF21A NORMAL HGPPS © Wahl M, 2010 © Engle et al 2010 Global cerebellum: cerebellar agenesis, RES, PCH Vermis: DWM, BPC/MCM, vermis hypoplasia Hemisphere: UCH, cortical dysgenesis Brainstem: molar tooth, PTCD, HGPPS 9.