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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 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!