Phenotipic identification of neurological malformations: Neuroradiology of Syndromes Morning Seminars Thursday October 7 F. Triulzi Dept. of Radiology and Neuroradiology Childrens Hospital V. Buzzi Milan, Italy Syndrome ( - "run together) association of several clinically recognizable features, signs, symptoms, phenomena or characteristics that often occur together Syndromes Neurological signs & symptoms CNSanomalies SYNDROMES NEURORADIOLOGY OF SYNDROMES David W Smith Syndromology Dysmorphology Hooshang Taybi Radiology of Syndromes MIM ID # RUBINSTEIN-TAYBI SYNDROME; RSTS Gene map locus: 16p13.3, 22q13 Clinical Features Inheritance Cytogenetics Diagnosis Clinical Management Molecular Genetics Genotype/Phenotype Correlations Population Genetics Initiated in the early 1960s by Dr. Victor A. McKusick as a catalog of mendelian traits and disorders, entitled Mendelian Inheritance in Man (MIM).Nomenclature Animal Model History Clinical Synopsis References Contributors Creation Date Edit History NRX role in the diagnostic evaluation of Syndromes with CNS involvement A.Highly suggestive Can be in some rare case pathognomonic B. B.Suggestive But never pathognomonic But never pathognomonic C.Doubtful Minor anomalies Minor anomalies D.Normal NRX studies Rule out something Rule out something A number of definite anomalies that can suggest a syndrome with an high level of confidence A.Highly suggestive Type A Examples - Aicardi - Delleman - De Morsier - Frontonasal dysplasia - Kallmann - Lhermitte-Duclos (Cowden Sy) - Walker-Warburg FAKOMATOSIS FAKOMATOSIS - NF 1 - NF 2 - Tuberous Sclerosis - Sturge Weber - Encephalocraniocutaneous lipomatosis - Aicardi - Delleman - De Morsier - Frontonasal dysplasia - Kallmann - Lhermitte-Duclos (Cowden Sy) - Walker-Warburg FAKOMATOSIS FAKOMATOSIS - NF 1 - NF 2 - Tuberous Sclerosis - Sturge Weber - Encephalocraniocutaneous lipomatosis Gene map locus: Xp22 AICARDI SYNDROME callosal agenesis infantile spasms chorioretinal lacunae female MIM ID %304050 Corpus callosum agenesis in a female Intracranial cysts Cortical anomalies Subependymal heterotopia * * Aicardi Syndrome Corpus callosum agenesis XX Intracranial cysts Cortical anomalies Subependymal heterotopia 23 GW female, US: CC agenesis MR: Aicardi Syndrome? 22.5 GW female, US: CC agenesis MR: Aicardi Syndrome? MIM ID # SEPTOOPTIC DYSPLASIA DE MORSIER SYNDROME Gene map locus: 3p21.2-p21.1 optic nerve hypoplasia pituitary gland hypoplasia septum pellucidum agenesis mutation in the homeobox gene HESX1 (601802). Septum pellucidum agenesis Pituitary hypoplasia Optic nerves hypoplasia Normal chiasm & pituitary De Morsier Syndrome (septo-optic dysplasia) Pituitary dwarfs + DSO P.R.,m. 20m SOD + polymicrogyria P.R.,m. 20m SOD + polymicrogyria I.R.J.C.,m. 11 a SOD + schizencephaly I.R.J.C.,m. 11 a SOD + schizencephaly MIM ID # WALKER-WARBURG SYNDROME Gene map locus: 14q24.3, 9q34.1 genes encoding protein O-mannosyltransferase-1 (POMT1; ) and -2 (POMT2; ). hydrocephalus (H) agyria (A), retinal dysplasia (RD) with or without encephalocele (+/-E). Walker-Warburg Walker-Warburg Fetal MR ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS MIM ID % profound mental retardation early onset of seizures unilateral temporofrontal lipomatosis ipsilateral cerebral and leptomeningeal lipomatosis cerebral malformation and calcification lipomas of the skull, eye, and heart Affected side Arachnoid cyst Lipoma Meningeal calcifications Ventricular dilatation Cortical malformation Encephalocraniocutaneous Lipomatosis Evidence of one or more anomalies that are mandatory to define a syndrome, but remain non specific B.Suggestive Type B Generic Anomalies Corpus callosum agenesis Cerebellar hypoplasia Malformations of cortical develpment White matter hypoplasia Microcephaly Type B Examples - Andermann - Atassia-teleangectasia - CHARGE - Cockayne - Ehlers-Danlos - Nevo epidermico - Fragile X - Hypomelanosis of Ito - Incontinentia pigmenti - Klippel-Trenaunay - Marinesco-Sjogren - Miller-Dieker - Moebius - Goldenhar - Pallister-Hall - PEHO - Rendu-Osler - Rubistein-Taybi - Stoll-Charrow-Poznanski - Toriello-Carey - - Trichothiodystrophy - Von Hippel-Lindau - Wolfram - Wolf-Hirschorn MILLER-DIEKER LISSENCEPHALY SYNDROME MIM ID # Gene map locus: 17p13.3 lissencephaly microcephaly wrinkled skin over the glabella and frontal suture prominent occiput narrow forehead downward slanting palpebral fissures small nose and chin, cardiac malformations hypoplastic male extrenal genitalia growth retardation Miller Dieker lissencephaly TRICHOTHIODYSTROPHY MIM ID # Gene map locus: 6q25.3, 2q21, brittle hair and nails ichthyotic skin physical and mental retardation hypomyelination Hypomyelination Trichothiodystrophy Hypomyelination Cerebellar atrophy Hypodontia Corpus callosum agenesis Minor subtle anomalies, that can however suggest a syndrome in case of a positive clinical hystory C.Doubtful Type C Corpus callosum Cerebellum-brainstem Cortical gyri Minor dysmorphic features of: Corpus callosum is not partly or totally absent But DYSMORPHIC BorjesonForssmanLehmann severe mental defect epilepsy hypogonadism hypometabolism marked obesity swelling of subcutaneous tissue of face narrow palpebral fissure large but not deformed ears Gene map locus: Xq26.3 MIM ID #301900 Kabuki make-up syndrome mental retardation postnatal dwarfism long palpebral fissures broad and depressed nasal tip large prominent earlobes high-arched palate scoliosis short fifth finger persistence of fingerpads radiographic abnormalities of the vertebrae recurrent otitis media in infancy MIM ID # mutation in the MLL2 gene on chromosome 12q12-q14. Pallister-Killian MIM ID # mosaicism for tetrasomy of chromosome 12p. profound mental retardation seizures streaks of hypo- or hyper-pigmentation prominent forehead sparse anterior scalp hair flat occiput, hypertelorism short nose with anteverted nostrils flat nasal bridge short neck.. Pallister-Killian Costello MIM ID # mutations in the HRAS gene (190020) characteristic coarse facies short stature distinctive hand posture and appearance severe feeding difficulty failure to thrive cardiac anomalies developmental disability. Costello Del 1 q Translocation 3y Chromosomopathies Del 1 q Translocation 3y 2 months35 6 6,5 8 8,5 9,51112,515 4 Normal corpus callosum development ,5 8 8,5 9,51112,515 4 GenuBody Hystmus Splenium 4 years Normal corpus callosum development and Syndromes Band thick to thin short and thick humpty dumpty Short and irregular Minor dysmorphisms in Syndromes Very frequent Minor dysmorphisms in Syndromes Very low specificity Different Syndromes Same anomalies Cerebral phenotype Needs quantitationVoxel based morphometry?? DTI?? Williams syndromes Marenco et al PNAS 2007;104: Connectivity in Syndromes Morning Seminars Thursday October 7 Thank you for your attention