Phenotipic identification of neurological malformations:

Neuroradiology of Syndromes

Morning SeminarsMorning SeminarsThursday October 7Thursday October 7

F. TriulziF. TriulziDept. of Radiology and NeuroradiologyDept. of Radiology and Neuroradiology

Children’s Hospital “V. Buzzi”Children’s Hospital “V. Buzzi”Milan, ItalyMilan, Italy

SyndromeSyndrome (σύνδρομος - "run together”) (σύνδρομος - "run together”)

“association of several clinically recognizable features, signs, symptoms, phenomena or characteristics that often occur together “

Syndromes Neurological Neurological signs & symptomssigns & symptoms

CNSCNSanomaliesanomalies

NEURORADIOLOGY OF SYNDROMESSYNDROMES

David W Smith 1926-1981

Syndromology Syndromology DysmorphologyDysmorphology

Hooshang Taybi 1919-2006

Radiology of SyndromesRadiology of Syndromes

MIM ID #180849 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. Initiated in the early 1960s by Dr. Victor A. McKusickMcKusick as a catalog of as a catalog of mendelian traits and disorders, entitled mendelian traits and disorders, entitled Mendelian Inheritance in Man Mendelian Inheritance in Man

(MIM).(MIM).

http://www.ncbi.nlm.nih.gov/omim

•Nomenclature •Animal Model•History•Clinical Synopsis•References•Contributors•Creation Date•Edit History

NRX role in the diagnostic NRX role in the diagnostic evaluation of Syndromes with evaluation of Syndromes with

CNS involvement CNS involvement

A.A. Highly suggestiveHighly suggestive Can be in some rare case Can be in some rare case pathognomonicpathognomonicB.B.Suggestive

But never pathognomonicBut never pathognomonicC.DoubtfulC.Doubtful “ “Minor anomalies”Minor anomalies”D.Normal NRX studiesD.Normal NRX studies Rule out somethingRule out something

A number of definite anomalies A number of definite anomalies that can suggest a syndrome with that can suggest a syndrome with an high level of confidencean high level of confidence

A.A.Highly Highly suggestivesuggestive

Type AExamples

- AicardiAicardi- Delleman Delleman - De Morsier- De Morsier- Frontonasal dysplasia- Frontonasal dysplasia- Kallmann- Kallmann- Lhermitte-Duclos (Cowden Sy)Lhermitte-Duclos (Cowden Sy)- Walker-WarburgWalker-Warburg

FAKOMATOSISFAKOMATOSIS- NF 1- NF 1- NF 2- NF 2- Tuberous SclerosisTuberous Sclerosis- Sturge WeberSturge Weber- Encephalocraniocutaneous - Encephalocraniocutaneous lipomatosislipomatosis

Gene map locus: Xp22

AICARDI SYNDROME

•callosal agenesis•infantile spasms•chorioretinal lacunae•female

MIM ID %304050

Corpus callosum agenesisin a female

Intracranial cystsCortical anomalies

Subependymal heterotopia

*

*

Aicardi Syndrome

Aicardi Syndrome Corpus callosum agenesis XX

Intracranial cystsCortical anomalies

Subependymal heterotopia

23 GW female, US: CC agenesisMR: Aicardi Syndrome?

22.5 GW female, US: CC agenesisMR: Aicardi Syndrome?

MIM ID #182230

SEPTOOPTIC DYSPLASIADE 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 agenesisPituitary hypoplasiaOptic 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 #236670

WALKER-WARBURG SYNDROME

Gene map locus: 14q24.3, 9q34.1 genes encoding protein O-mannosyltransferase-1 (POMT1; 607423) and -2 (POMT2; 607439).

•hydrocephalus (H)•agyria (A),•retinal dysplasia (RD)•with or without encephalocele (+/-E).

Walker-Walker-WarburgWarburg

Walker-WarburgWalker-Warburg

Fetal MR

ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS MIM ID %613001

•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 sideArachnoid cystLipomaMeningeal calcificationsVentricular dilatationCortical malformation

Encephalocraniocutaneous Lipomatosis

Evidence of one or more anomalies Evidence of one or more anomalies that are mandatory to define a that are mandatory to define a syndrome, but remain non specificsyndrome, but remain non specific

B.SuggestivB.Suggestivee

Type BGeneric Anomalies

Corpus callosum agenesisCerebellar hypoplasiaMalformations of cortical develpmentWhite matter hypoplasiaMicrocephaly

Type BExamples

- Andermann- Andermann- Atassia-- Atassia-teleangectasiateleangectasia- CHARGE- CHARGE- Cockayne- Cockayne- Ehlers-Danlos- Ehlers-Danlos- Nevo epidermico- Nevo epidermico- Fragile X- Fragile X- Hypomelanosis of Ito- Hypomelanosis of Ito- Incontinentia - Incontinentia pigmentipigmenti- Klippel-Trenaunay- Klippel-Trenaunay- Marinesco-Sjogren- Marinesco-Sjogren- Miller-Dieker- Miller-Dieker

- Moebius- Moebius- Goldenhar- Goldenhar- Pallister-Hall- Pallister-Hall- PEHO- PEHO- Rendu-Osler- Rendu-Osler- Rubistein-Taybi- Rubistein-Taybi- Stoll-Charrow-Poznanski- Stoll-Charrow-Poznanski- Toriello-CareyToriello-Carey- Trichothiodystrophy- Von Hippel-Lindau- Von Hippel-Lindau- WolframWolfram- Wolf-HirschornWolf-Hirschorn

MILLER-DIEKER LISSENCEPHALY SYNDROME MIM ID #247200

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 Miller DiekerDieker lissencephaly

TRICHOTHIODYSTROPHY MIM ID #601675

Gene map locus: 6q25.3, 2q21,

•brittle hair and nails•ichthyotic skin•physical and mental retardation•hypomyelination

HypomyelinationHypomyelinationTrichothiodystrophy

HypomyelinationHypomyelination

Cerebellar Cerebellar atrophyatrophy

HypodontiaHypodontia

Corpus callosum agenesis

Minor subtle anomalies, that Minor subtle anomalies, that can however suggest a can however suggest a syndrome in case of a positive syndrome in case of a positive clinical hystoryclinical hystory

C.DoubtfC.Doubtfulul

Type C

Corpus callosumCerebellum-brainstemCortical gyri

Minor dysmorphic features of:

Corpus callosum is not partly or totally absent…

…But DYSMORPHIC

BorjesonBorjesonForssmanForssmanLehmannLehmann

•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-upKabuki make-upsyndromesyndrome

•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 #147920mutation in the MLL2 geneon chromosome 12q12-q14.

Pallister-KillianMIM ID #601803

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

CostelloMIM ID #218040

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 months 3 5

6 6,5 8 8,5

9,5 11 12,5 15

4

Normal corpus callosum development

2 3 5

6 6,5 8 8,5

9,5 11 12,5 15

4

Genu Body

Hystmus Splenium

4 years 5 6 8

10 12 14 18

Normal corpus callosum development…

…and Syndromes

Band thick to thin

short and thickhumpty dumpty

Short and irregular

Minor dysmorphismsin Syndromes

Very frequent

Minor dysmorphismsin Syndromes

Very low specificityDifferent Syndromes – Same anomalies

“Cerebral phenotype”

Needs quantitation

Voxel based morphometry??DTI??

Williams syndromes Marenco et al PNAS 2007;104:15117-22

Connectivity in Syndromes

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Thank you for your attention