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Stacy Goergen

Head, Obstetric MRI Program and Obstetric ImagingMonash Imaging, Monash Health

Professor, Medical Imaging, Monash University School of Clinical SciencesMelbourne, Australia

From Images to Genes: the Role of

Prenatal MRI in Fetal PhenotypingTOP

Request?review

committee

SecondOpinion

T2 Ultrasound

Cell FreeDNA

?TOP

MicroarrayTertiary

Ultrasound

T1 Ultrasound

Multi -disciplinary

Team

Fetal Therapy

Follow up

T2 Ultrasound

Chromosome Testing

Diagnosis, prognostication, recurrence prediction for fetal CNS anomalies is multidisciplinary in

2019

Information Obtained at

Initial Screening

Additional Information Obtained at

FDU

Counseling and

Management Decision

MRI

Image: Courtesy Dr. Mark Teoh

2014 ISUOG Survey of 60 international fetal diagnosis / MFM centres

When would you perform fetal MRI ?

Fetal MRI for Suspected CNS abnormality

Funded by Medicare Australia from 1 May 2019

Apparently isolated VM• Ganglionic eminences• Sulcation / opercularisation• Subependymal heterotpia• Polymicrogyria

Absent septal leaflets• Perforation vs failed formation

The small cerebellum / posterior fossa “cyst”• Brainstem and cerebellar size and shape

Accurate Fetal Phenotyping with MR:Diagnosis, Prognosis, Recurrence

Isolated severe ventriculomegaly 36/40 neurosonogram

PVNH due to X linked Filamin A mutation

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CLICK TO EDIT MASTER TITLE STYLEIsolated bilateral >15mm VM at 32 weeks

neurosonogramPVNH – Filamin A mutation

Filamin A mutation – Mother of affected female child

23.5/40 – Posterior fossa cyst? Abn cerebellum?

US: Mega cisterna magna or Posterior fossa arachnoid cyst

cyst?Filamin A mutation

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• Diagnosis: Filamin A (FLNA) genetic variant

• Prognosis: Epilepsy/ aortic dissection / intracranial aneurysms / cardiac valvular dysplasia – monitoring and BP control important

• Recurrence: 50% in females50% in utero fatality in males, 50% unaffected

• Other:• Head MRI of mother – 50% denovo mutation, 50% inherited• If mother carrier – risk of same cardiovascular complications as fetus• Preimplantation diagnosis possible

Both pregnancies continued based on change of counselling from “severe VM” and PF abnormality” to specific diagnosis

Severe VM

22+2 G3P0 – 40 y.o. IVF pregnancySevere bilateral ventriculomegaly

?Intraventricular mass - haemorrhage?

22+2w Ultrasound15mm bilateral VM

Reduced TCD, Thin CC – hypogenetic?Thin CC

Normal 23/40 DWI

Enlarged GEunderopercularisation DWI

Lissencephaly – which one?

23/40 MRI

CC too thin – hypogenesisGE too large

Normal 23/40

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TCD 20mm: – 3SD below mean for 23/40 25/40 Follow upPersistent enlarged GE

No opercularisation

Normal 25 / 40

25/40 Cerebellar biometry still - 3SD

Hypogenesis of CC + cerebellar hypoplasia + lissencephaly

Prenatal Dx = tubulinopathy

TOP – selective genetic testing for tubulin gene variantsDiagnosis – Tubulinopathy due to

c.74G>T (p.Cys25Phe) in exon 2 of TUBA1A gene

Severe VM + callosal hypogenesis + cerebellar hypoplasia• Diagnosis – Tubulinopathy

• Prognosis – severe neurodevelopmental abnormality, seizures

• Recurrence – de novo mutation – likelihood of recurrence very low

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23yoG1P0

External tertiary neurosonogram 28/40Isolated fetal ventriculomegaly 14 mm

BPD, HC, AC > 99th centile

Mild (12mm) VMCerebral Hemispheres and TCD +6 SD > mean for GA

Source: Kline – Fath, Fetal Imaging, Wolter – Kluwers 2016

Enlarged GE, Abnormal opercularisation

Normal 28 week DWI

Abnormal opercularisationBilateral perisylvian polymicrogyria

Normal 28 / 40

US same day as MRI

Courtesy Dr. Lufee Wong

Postaxial polydactyly

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Provisional Diagnosis – Megalencephaly, polydactyly, polymicrogyria hydrocephalus (MPPH) syndrome

TOPPathogenic PI3K variant on WES

Ventriculomegaly + Head >99th centileDiagnosis : MPPH

Prognosis: Very poor prognosisSeizuresMajor developmental delay

Recurrence:• De novo somatic mutation in majority – no recurrence• Small risk of germline mutation with N parental phenotype• Preimplantation Dx possible

32yoG2P1

P1 macrosomicNormal 20/40 morphology G2

T3 US for growth assessment @32/40

“Incidental” US findings on T3 growth scan

• EFW 9th centile • HC, AC, FL 13th – 19th centile• 15mm, 11mm atria – otherwise N brain• Echogenic enlarged kidneys – 1 cyst 3mm• Talipes

Abnormal opercularisation @33 weeksFrontal lobes smaller than temporal

àPerisylvian PMG, temporal lobe overgrowth in FGFR mutations (Apert’s, thanatophoric dysplasia)

perisylvian polymicrogyria

Talipes Enlarged kidneys

Perisylvian PMG + cystic kidneys + growth restriction = Zellweger syndrome

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Cystic kidneys, talipes, moderate asymmetric VM (11,15mm)

Prenatal diagnosis: Zellweger syndrome (peroxisomal disorder)

Prognosis: Fatality during infancy usualhypotonia, respiratory /multiorgan failure)

Recurrence: AR, 1:4, pre – implantation diagnosis possible Zellweger syndrome: Baby died with respiratory failure +

pneumonia @ 1/12

Enlarged dysplasitckidneys with cysts

21/40 G1P0GDM – poor control

Severe ventriculomegalyNo septal leaflets Small cerebellum

Dx ? holoprosencephalyCardiac: Parallel Ao / Pulm outflow

tracts + VSD = TGA

Absent Septal LeafletsPerforated vs Not Formed

PERFORATIONSevere VM

Heart shaped roof of “fused” hornsNo forniceal fusion

Dx: aqueductal obstruction

FAILED FORMATIONNo – mild VM

Flat roof fused hornsFused fornices

Dx: Isolated / SOD in 10%

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9 % of all paediatric cases of aqueductal stenosis have RESRES associations: VACTERL, poorly controlled GDM

Severe VM, no septal leaflets ?HPE, cerebellar hypoplasia

Diagnosis: RES with AS due to VACTERL sequence associated with poor GDM control

Prognosis: Variable and dependent on • severity of AS• presence of Gomez Lopez Hernandez syndrome

Recurrence: Unlikely with good control of GDM

*Tan TY, McGillivray G, Goergen SK, White SM. Prenatal magnetic resonance imaging in Gomez-Lopez-Hernandez syndrome and review of the literature. American Journal of Medical Genetics Part A. 2005 Nov 1;138(4):369-73

US 22/40 – Dandy Walker Malformation? The most likely diagnosis is:

1. Dandy – Walker malformation2. Persistent Blake’s pouch cyst3. PHACE(S)4. Isolated vermian hypoplasia5. Cerebellar hemispheric infarction

Leibowitz et al 2018 Eur J Paediatric Neurol“tilted telephone receiver sign”

PHACE(S) – Neurocutaneous disorderPosterior fossa malformations

Dandy – WalkerUnilateral hemispheric hypoplasia

Haemangioma (facial +/- neck, chest, limbs) – typically not be present antenatally / early newborn

Arterial anomalies (head and neck stenoses, occlusions, moya moya, dural AVF, aneurysms)

Cardiac (aortic coarctation, anomalous great vessels, septal defects, tetralogy of Fallot, dextrocardia)

Eye (1/3 have one or more coloboma, buphthalmos / microphthalmia, glaucoma, morning glory on fundoscopy / many ophthalmoplegia, other clinical eye abnormalities)

Sternal cleft (prenatal US), supraumbilical raphe

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Leibowitz et al 2018 Eur J Paediatric Neurol –“tilted telephone receiver sign” pathognomonic for

PHACE(S) = 11/11 cases

Day 20

Day 4

PHACE syndrome

MR and US working together in fetal neurology can be a marriage made in heaven

• Contemporary diagnosis of fetal cerebral anomalies is multidisciplinary

• Knowledge of obstetric US, paediatricneuroradiology, genetics needs to be integrated

• Close interdisciplinary co-operation and communication are challenging but essential