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15/01/2021 1 MICROCEPHALY AND MEGALENCEPHALY Fabio Triulzi University of Milan Dept of Neuroradiology, Cà Granda Foundation Ospedale Maggiore Policlinico, Milan , IT MICROCEPHALY - Definition A reduction of head circumference of more than two (microcephaly) or three (severe microcephaly) standard deviations (SDs) Congenital Postnatal Congenital «prenatal» Microcephaly Genetic Microcephaly Primary Hereditary MCPH Primary microcephaly and dwarfism FOXG1-related congenital microcephaly Syndromic static microcephaly Clastic Hypoxic-Ischemic-Haemorrhagic Infective Toxic Deprivational Clastic-genetic Metabolic Degenerative Congenital «prenatal» Microcephaly Genetic Microcephaly Primary Hereditary MCPH Primary microcephaly and dwarfism FOXG1-related congenital microcephaly Syndromic static microcephaly Clastic Hypoxic-Ischemic-Haemorrhagic Infective Toxic Deprivational Clastic-genetic Metabolic Degenerative 1 MCPH MicroCephaly Primary Hereditary Prevalence: 1:30.000 - 1:250.000 – SEVERE MICROCEPHALY 35 cm 29 cm 26 cm Very frequent Simplified Gyral Pattern (SGP) A minority with focal cortical anomalies (PMG) High variability Cerebellum relatively less affected Cellular mitosis MCPH From the first MCPH gene discovered in 1998 – 18 genes up to now

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Page 1: three(severe microcephaly) MICROCEPHALY AND …

15/01/2021

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MICROCEPHALY AND

MEGALENCEPHALY

Fabio Triulzi University of Milan

Dept of Neuroradiology, Cà Granda Foundation

Ospedale Maggiore Policlinico, Milan , IT

MICROCEPHALY - Definition

A reduction of head circumference of more than two (microcephaly)

or three (severe microcephaly) standard deviations (SDs)

Congenital

Postnatal

Congenital «prenatal» Microcephaly

Genetic Microcephaly Primary Hereditary MCPH

Primary microcephaly and dwarfism

FOXG1-related congenital microcephaly

Syndromic static microcephaly

Clastic Hypoxic-Ischemic-Haemorrhagic

Infective

Toxic

Deprivational

Clastic-genetic Metabolic

Degenerative

Congenital «prenatal» Microcephaly

Genetic Microcephaly Primary Hereditary MCPH

Primary microcephaly and dwarfism

FOXG1-related congenital microcephaly

Syndromic static microcephaly

Clastic Hypoxic-Ischemic-Haemorrhagic

Infective

Toxic

Deprivational

Clastic-genetic Metabolic

Degenerative

1 MCPH MicroCephaly Primary HereditaryPrevalence: 1:30.000 - 1:250.000 – SEVERE MICROCEPHALY

35 cm 29 cm 26 cm

• Very frequent Simplified Gyral

Pattern (SGP)

• A minority with focal cortical

anomalies (PMG)

• High variability

• Cerebellum relatively less affected

Cellular mitosisMCPHFrom the first MCPH gene discovered

in 1998 – 18 genes up to now

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MCPH7

MCPH5

MCPH8

MCPH9

MCPH14

MCPH3

MCPH2

Centrosome Mitotic spindle

Cellular mitosisMCPH MCPH5 - ASPM

The MOST frequent MCPH, nearly 60% of all cases, with high variability

Abnormal spindle-like microcephaly-associated

Simplified gyral pattern with small frontal lobes

Hypoplastic corpus callosum (86%), small pons (63%), small vermis (47%)

Polymicrogyria in

some cases

MCPH5 - ASPM variability 2 Primary Microcephalies and DwarfismPrimordial dwarfism syndromes PD

• Microcephalic osteodysplastic primordial

dwarfism type Majewski II (MOPD-II)

• Seckel syndrome

• Taiby-Linder syndrome type (MOPD I-III)

“Primordial dwarfisms: the growth deficit begins before birth”

• Meier-Gorlin syndrome

Seckel syndrome

Autosomal recessive disorder

Short stature

Severe microcephaly and mental retardation

Typical 'bird-head' facial appearance

Centrosomal protein CEP152 is a regulator of

genomic integrity impairment of DNA damage

response pathways.

Other genes involved: ATR, ATRIP, CENPJ, RBBP8,

CDK5RAP2.

Centrosome

Underdeveloped or missing patellae, genu

recurvatum

Small ears, low-set or rotated backward

Frequent normal intellect

Narrow nose with a high nasal bridge

Meier-Gorlin syndrome

Mutations in one of genes Origin

Recognition Complex (ORC1, ORC4, ORC6,

CDT1, and CDC6) of the pre-replication

complex-proteins.

ORC proteins are essential for initiation of

DNA replication.

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Delayed myelination

Hypoplasia of CC and frontal lobes

Severe intellectual disability

Epilepsy

FOXG1 (14q12) etiology of “congenital variant of Rett syndrome”.

3 FOXG1-related congenital microcephaly*

*high phenotypical variability,

also postnatal microcephaly

reported

FOXG1 gene encodes a

transcriptional repressor

essential for development of

telencephalon.

Later, FOXG1 continues

to be expressed in neurogenetic

zones of the postnatal brain.

2.8-year-old

patient with

FOXG1 mutation

4 Syndromic static microcephaly

Cornelia de Lange

Just two examples:

7 yrs oldNewbornFetus

2 yrs oldFetus

Wolf-Hirschorn 4p-

Congenital «prenatal» Microcephaly

Genetic Microcephaly Primary Hereditary MCPH

Primary microcephaly and dwarfism

FOXG1-related congenital microcephaly

Syndromic static microcephaly

Clastic Hypoxic-Ischemic-Haemorrhagic

Infective

Toxic

Deprivational

Clastic-genetic Metabolic

Degenerative

Sequelae of fetal encephalopathy

25 w 25 w

1 yr

19 w 21 w

Newborn Newborn

Destructive lesions

Congenital infections

Necrotic parenchyma lesions, deep calcifications, multifocal polymicrogyria

CMV infection

Newborn

22w 25w 30w

Newborn Newborn

Congenital «prenatal» Microcephaly

Genetic Microcephaly Primary Hereditary MCPH

Primary microcephaly and dwarfism

FOXG1-related congenital microcephaly

Syndromic static microcephaly

Clastic Hypoxic-Ischemic-Haemorrhagic

Infective

Toxic

Deprivational

Clastic-genetic Metabolic

Degenerative

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“Pseudo-TORCH”Gene based malformative-clastic microencephalies

Hypothesis: vascular mediated disruption of cell proliferarion, migration and organization

Occludin is component of the

tight junction in endothelia

OCLN gene

Am J Hum Genet. 2010

Recessive Mutations in the Gene Encoding the

Tight Junction Protein Occludin Cause Band-like Calcification with

Simplified Gyration and Polymicrogyria

Mary C. O'Driscoll et Al..

Band-like calcifications

Aicardi-Goutieres syndrome (AGS)

Punctate BG calcifications

WM atrophy, hypomyelination

Progressive microcephaly

1.Fronto-temporal pattern 50%

2. Diffuse involvement 41%

Two main patterns

Postnatal Secondary Microcephaly

Genetic Sindromic postnatal microcephaly

Malformation of cortical development

Neonatal Encephalopathy Hypoxic-ischemic-Encephalopathy

Vascular

Infections

Metabolic,

degenerative

Syndromic postnatal microcephaly

- Angelman syndrome

- Rubistein-Taybi syndrome

- MECP2-related disorder (Rett syndrome)

- Cockayne syndrome

- TRAPPC9 defect

- Some FOXG1 related encephalopathy cases

Am J Med Genet C Semin Med Genet. 2014

Genetic disorders associated with postnatal

microcephaly.

Seltzer LE et Al..

Normal head at birth, followed by deceleration in head growth

Newborn 4 yrs

Microcephaly ( - 2SD) 59/118

50%

Microcephaly and polymicrogyria Sequelae of neonatal encephalop.Hypoxic-ischemic

encephalopathy

Ischemic/

Hemorragic

infarcts

Neonatal

infections

Metabolic

imbalance

Metabolic

diseases

HIEArterial

infarction

Herpes

encephalitis Hypoglycemia MSUD

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MEGALENCEPHALY - Definition

“Any oversized and overweight brain (>+2 DS)

irrespective of the patient’s neurologic

function” De Myer. Neurology 1972

“Macrocephaly with normal ventricles and

subarachnoid spaces”Gooskens et al. Neuropediatrics 1989

Normal brain weight at birth ≈ 340 g

Normal brain weight in adult male ≈ 1.400 g

Megalencephaly > 1.700 g

Incidence: 2%o-6%o ♂:♀ ≈ 4:1

MEGALENCEPHALY - Classification

AnatomicalIncreased number and/or size

of neurons and/or glial cells

Metabolic1. Storage disease

2. Leukodystrophies

Anatomical1. Isolated

• familial

• sporadic

2. Autism

3. Syndromic

MEGALENCEPHALY - Classification Syndromic Megalencephalies

Megalencephalies with overgrowth

MCAP-MCM

MPPH

Klippel-Trenaunay

Sotos

Weaver

Proteus

Beckwith-Wiedemann

Megalencephalies with cutaneous

anomalies

NF1, Tuberous Sclerosis, Gorlin

Hemimegalencephaly

PTEN-hamartoma tumor syndrome

RASopathies

Noonan

LEOPARD

Costello

Cardio-facio-cutaneous

Others….

Nuclear factor one (NFI)

transcription factors

…..

PI3K/AKT/mTOR Pathway PI3K/AKT/mTOR Pathway

Dysfunction of the

PI3K/AKT/mTORpathway

PI3K-related

megalencephaly

syndromeMegalencephaly- capillary

malformation MCM

Megalencephaly polydactily

polymicrogyria hydrocephalus

MPPH

Tuberous Sclerosis

Neurofibromatosis

Type 1

Mutations in TSC1 or TSC2

NF1 gene mutationDisregulation of mTOR

pathway

Cowden yndrome

Bannayan-Riley-Ruvalcaba syndrome

PTEN hamartoma tumor syndrome

Mutations in PTEN

Proteus syndrome

Mutations of AKT1

CLOVES syndrome

Klippel-Trenaunay syndrome

PIK3CA mutation

Mutations in AKT3

PIK3CA and PIK3R2

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Syndromic Megalencephalies

Megalencephalies with overgrowth

MCAP-MCM

MPPH

Klippel-Trenaunay

Sotos

Weaver

Proteus

Beckwith-Wiedemann

Megalencephalies with cutaneous

anomalies

NF1, Tuberous Sclerosis, Gorlin

Hemimegalencephaly

PTEN-hamartoma tumor syndrome

RASopathies

Noonan

LEOPARD

Costello

Cardio-facio-cutaneous

Others….

Nuclear factor one (NFI)

transcription factors

…..

Megalencephaly - capillary malformation MCMPI3K-related megalencephaly syndrome

Overgrowth Syndrome

Prenatal overgrowth with progressive

megalencephaly

Brain and/or somatic asimmetry,

ventriculomegaly, tonsillar ectopia, Corpus

callosum thickening, WM T2 hyperintesities

Capillary malformation, hemangiomas

Syndactyly, polydactyly

Polymicrogyria

Skin hyperlaxity and articular hypermobility

Capillary malformations:

reticulated or confluent port-wine stains

MCM - Imaging2 days

6 months 6 months post VP shunt

Megalencephaly polydactily polymicrogyria hydrocephalus

MPPHPI3K-related megalencephaly syndrome

• Very close to MCH

• NO vascular malformations

• Polydactily 50% of cases

• PMG 100% of cases

MCM-MPPH-Other?Klippel-Trenaunay Syndrome

PIK3CA mutation

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Sotos syndrome

• Slight ventriculomegaly

• Cavum septi and cavum vergae

• NO cortical malformations

E.M.Z.♂ 1a4m

G.B.D.♀ 1a7mD.M. ♀ 11yrs6mos

Proteus syndromeAKT1 mutation

Connective tissue

overgrowth

Hemimegalencephaly

Beckwith-Wiedemann syndrome

Frequent association with posterior fossa malformations

Syndromic Megalencephalies

Megalencephalies with overgrowth

MCAP-MCM

MPPH

Klippel-Trenaunay

Sotos

Weaver

Proteus

Beckwith-Wiedemann

Megalencephalies with cutaneous

anomalies

NF1, Tuberous Sclerosis, Gorlin

Hemimegalencephaly

PTEN-hamartoma tumor syndrome

RASopathies

Noonan

LEOPARD

Costello

Cardio-facio-cutaneous

Others….

Nuclear factor one (NFI)

transcription factors

…..

«RAS-ophaties»

• Noonan syndrome

• Costello syndrome

• LEOPARD syndrome

• Capillary malformation,

arteriovenous malformation

• Cardio-facio-cutaneous

syndrome

Noonan syndrome

8 months

At birth

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An increased rate of • white matter lesions,

• extracerebral space enlargement

• simplification of the cortical gyrification

• the vermis height of patients was

significantly lower

• tentorial and infratentorial angles were

significantly higher

«RAS-ophaties» - imaging Syndromic Megalencephalies

Megalencephalies with overgrowth

MCAP-MCM

MPPH

Klippel-Trenaunay

Sotos

Weaver

Proteus

Beckwith-Wiedemann

Megalencephalies with cutaneous

anomalies

NF1, Tuberous Sclerosis, Gorlin

Hemimegalencephaly

PTEN-hamartoma tumor syndrome

RASopathies

Noonan

LEOPARD

Costello

Cardio-facio-cutaneous

Others….

Nuclear factor one (NFI)

transcription factors

…..

Gorlin syndrome – nevoid basal cell carcinoma

Neurofibromatosis Tuberous sclerosis

Keratocystic

odontogenic tumorMedulloblastomaNevoid basal cell

carcinomas

PTEN-hamartoma tumor syndromePTEN tumor suppressore gene

• Cowden

• Bannayan-Riley-Rubalcava

• Lhermitte-Duclos

• Autism spectrum disorder with

macrocephaly

Macrocephaly > 94% of cases

Syndromic Megalencephalies

Megalencephalies with overgrowth

MCAP-MCM

MPPH

Klippel-Trenaunay

Sotos

Weaver

Proteus

Beckwith-Wiedemann

Megalencephalies with cutaneous

anomalies

NF1, Tuberous Sclerosis, Gorlin

Hemimegalencephaly

PTEN-hamartoma tumor syndrome

RASopathies

Noonan

LEOPARD

Costello

Cardio-facio-cutaneous

Others….

Nuclear factor one (NFI)

transcription factors

…..

NFIA insufficiency

Nuclear Factor 1 Transcriptor Factor

Megalencephaly

Corpus callosum agenesis

Ventriculomegaly

Craniosynostosis12 months

At birth

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MEGALENCEPHALY - Classification

AnatomicalIncreased number and/or size

of neurons and/or glial cells

Metabolic1. Storage disease

2. Leukodystrophies

MEGALENCEPHALY - Metabolic

Leukodystrophies

Canavan

Alexander

MLC

VWM

Organic acidurias

L2-Hydroxyglutaric aciduria

Glutaric aciduria type I

Lysosomal disorders

Mucopolysaccaridosis

GM2 gangliosidosis

Canavan

Alexander

MLC

VWM

Leukodystrophies Organic acidurias

L2-Hydroxyglutaric aciduria

Glutaric aciduria type I

Lysosomal storage diseases

Mucopolysaccaridosis

GM2 gangliosidosis

Conclusions

Don’t forget to know the head circumference!