The Common Phakomatoses

Birgit Ertl-Wagner

ECPNR, 10th Cycle, Rome

Nomenclature

• From Greek φακός, phakos – spot,lens

• Named by Jan van der Hoewe in 1920 (Dutch ophtalmologist): “lens-like” changes on fundoscopy in a tuberous sclerosis patient

• Newer nomenclature: neurocutaneous syndromes neuro-oculo-cutaneous syndromes

https://de.wikipedia.org/wiki/Jan_van_der_Hoeve

Many more diagnoses encompassed now • Neurofibromatosis type 1 • Neurofibromatosis type 2 • Tuberous sclerosis • Sturge-Weber syndrome • von Hippel-Lindau disease • Ataxia telangiectasia • Incontinentia pigmenti • Nevoid basal cell carcinoma

syndrome • Wyburn-Mason syndrome (Bonnet–

Dechaume–Blanc syndrome) • And many more…

“The Big Five”

• Neurofibromatosis type 1

• Neurofibromatosis type 2

• Tuberous sclerosis

• Sturge-Weber syndrome

• von Hippel-Lindau disease

3-year old boy with seizures and developmental delay Tuberous Sclerosis Complex • aka M. Bourneville-Pringle • Autosomal dominant • 70% sporadic (de novo

mutations) • 2 genes:

TSC1 on chromosome 9q34 TSC2 on chromosome 16p13.3

• Incidence: 1:8000 live births • Developmental tauopathy (tau

abnormally expressed)

9

16

Van Eeghen et al., 2013 Jansen et al., 2008

Tuberous Sclerosis Complex - Background

• Original „Vogt triad“: • cognitive impairment

• epilepsy

• adenoma sebaceum • 18 to 55% do not suffer from

mental retardation • Adenoma sebaceum usually

only in later childhood / adolescence

Rayer „Traites des maladies de la peau“ 1835

Umeoka et al., 2008

Tuberous Sclerosis Complex - Skin

• Ash Leaf spots –hypomelanotic lesions

• Adenoma sebaceum - angiofibromas in the face

• Koenen tumours of the fingernails

• Dental enamel pits

www.webmd.com;www.ourdermatology.blogspot.com

Tuberous Sclerosis Complex - Extracranial

• Angiomyolipomas • Renal cysts • Rhabdomyomas of the

heart – usually spontaneously regress postnatally

• Lymphangioleiomyo-matosis (LAM) of the lung

• Cystic bone lesions • Giant drusen on

fundoscopy

Tuberous Sclerosis Complex - Tubers • Tuber = swelling; in plants: for

storage of nutrients

• Contain balloon cells large, eosinophilic

• Can be heterotopic or transhemispheric

• Number and location of tubers may play a role in neurocognitive outcome

Kassiri et al., 2011

Tuberous Sclerosis Complex - Tubers • Frontal > parietal > occipital >

temporal > cerebellum

• 50% are calcified by age 10 y

• Signal variable relative to myelin maturation

• FLAIR hyperintense in older children

• 3-4% enhance

• Higher ADC values in more epileptogenic tubers

• AMT (α-11C-methyl-L-tryptophan) PET may identify epileptogenictubers

Manoukian et al., 2015

Cystic Appearing Tubers

• Tubers may appear cyst-like

• High signal intensity T2w, low signal intensity T1w

• More aggressive type of seizures?

Kassiri et al., 2011

Tuber vs. FCD Type IIb

• Focal cortical dysplasia type IIb histologically identical to tuber

• May also have a funnel-shaped migration part

• FCD IIb do not calcify • If in doubt:

• Skin examination with Wood´s light

• Renal ultrasound • Echocardiography

Kassiri et al., 2011

White Matter Radial Migration Lines

• Heterotopic glia with neurons along migration pathways

• Linear to curvilinear • Radial migration

abnormalities correlate with outcome

• Cyst-like structures in white matter possible as well (origin unknown)

Kassiri et al., 2011

Subependymal Nodules

• Subependymal hamartomas • Usually calcify in the course of

time (after one year of age) • Irregularly shaped nodules • Main axis perpendicular to

ventricular wall • Protrude into the ventricles • May enhance • Are NOT isointense to cortex

Subependymal Nodules

Subependymal Giant Cell Astrocytoma - SEGA

• WHO grade I • At Foramen Monroi • In 15-20% of patients with TSC • Round configuration,

pronounced enhancement • May lead to ipsilateral dilatation

of lateral ventricle

Diagnosis based on size and growth

Enlarging, enhancing mass >1.3 cm near foramen Monroi

Subependymal Giant Cell Astrocytoma - SEGA

• CT: may have calcification • T2WI / FLAIR: iso- to

hyperintense, heterogeneous • T1WI: hypo- to isointense • T2* may have low SI from

calcifications • Contrast-enhancement • (Asymmetric) hydrocephalus

SEGA - Treatment

• Mammalian target of rapamycin (mTOR) inhibitors (e.g.Sirolimus, Everolimus)

• normalize the mTOR pathway also in other TSC manifestations(angiomyolipomas,lymphangioleiomyomatosis,epilepsy)

• consider treatment effects when evaluating SEGAs

Jozwiak et al., 2013; Krueger et al., 2013; Lam et al., 2010

Tuberous Sclerosis Complex – Imaging Patterns

Cortical tuber, subependymal nodules, giant cell astrocytomas

6-year old boy with developmental delay Neurofibromatosis Type 1

• Autosomal dominant • Long arm of chromosome 17

(17q11.2) • NF-1 gene (neurofibromin 1)

probably a tumor-suppressor gene

• Incidence: 1:2500 to 1:3300 live births

• About 50% de novo mutations • Neurofibromin inactivated

(negative regulator of RAS protooncogene)

Gutmann et al., 2012

Neurofibromatosis Type 1

• Café-au-lait spots(>5, >25mm, + symptoms)

• Axillary freckling

• Lisch-nodules (hamartomas of the iris)

• Cutaneous / subcutaneous neurofibromas

Gutmann et al., 2012 Pictures: www.de.wikipedia.org

NF-1 – Diagnostic Criteria: 2 or more

• First degree relative with NF-1 • Six or more Cafe-au-lait spots• Axillary or inguinal freckling • Two or more Lisch nodules (iris hamartomas) • Two or more neurofibromas or one or more plexiform

neurofibroma • Optic pathway glioma

• Distinctive bone lesion (e.g. dysplasia of the sphenoid)

Gutmann et al., 2012

NF-1 – FASI (Focal Areas of Signal Intensity) • Also called “UBOs” (unidentified

bright objects) • Transient intramyelin edema • Start in childhood, tend to

disappear in adulthood • 80-90% in pre-teen children with

NF-1 • No mass effect • In cerebral white matter / internal

capsule / corpus callosum, may also involve thalamus, pallidum,cerebellum, brainstem

Ferraz-Filho et al., 2013; Barbier et al., 2011; Chabernaud et al., 2009

NF-1 – FASI (Focal Areas of Signal Intensity)

• Hyperintense on T2WI, isointense on T1WI

• No edema, no swelling • DTI decreased FA • MRS decreased NAA/Cr &

NAA/Cho (thalamic)

Ferraz-Filho et al., 2013; Barbier et al., 2011; Chabernaud et al., 2009

NF-1 – Location of Tumors NF 1 Location of Tumors Optic Pathway Gliomas (OPGs) • 15% of NF1 patients • Peak age 4-5 yrs • Asymptomatic or reduced visual

acuity • Mostly pilocytic astrocytomas (WHO

grade I), but highly malignant subtypes

• Enhancing lesion • Optic nerve, uni (50%)- or bilateral

(20%) and / or chiasma • Can be extensive • May regress spontaneously

Ferraz-Filho et al., 2013; Barbier et al., 2011; Chabernaud et al., 2009

OPGs – Are GBCAs Necessary in Surveillance?

• GBCAs may not be needed for follow-up

• GBCA enhancement does not necessarily correlate with biological behavior

Maloney et al., 2018

NF-1 – Gliomas (Outside Optic Pathway)

• Incidence of gliomas increased

• Any WHO grade possible

• 5x higher risk of high grade gliomas

• Mortality higher in symptomatic and adult patients

Rasmussen et al, 2001 Guillamo et al., 2003 Rodriguez et al, 2008

NF-1 – Brainstem Gliomas

• May be diffuse or focal

• 68% medullary, 52% pontine,44% midbrain

• 56% multiple locations

• Diffuse brainstem gliomasgenerally slower progression in NF-1

• Beware of hydrocephalus Rasmussen et al, 2001 Guillamo et al., 2003 Rodriguez et al, 2008

NF-1 – Spine

• Kyphoscoliosis common

• Dural ectasia – dysplasia of meninges, vulnerable to CSF pulsation, vertebral scalloping

• Lateral meningoceles

NF-1 – Neurofibromas

• Tumors of the nerve sheaths • Degree of connective tissue • Intraspinal, paraspinal,

peripheral • Variable signal intensity on

T2w• Enhancement with GBCA

17-year old girl with lower back pain

NF-1 – Malignant Peripheral Nerve Sheath Tumors

• Malignant peripheral nerve sheath tumors (MPNST) in 5-13% of NF-1 patients

• FDG-PET may predict malignant transformation

Tsai et al., 2013

NF-1 – Plexiform Neurofibromas

• Characteristic for NF-1 • Locally aggressive • Transspatial lesion • No metastases • Diffuse growth along a nerve • Can be disfiguring • May transform to MPNST

(10%)

Tsai et al., 2013

NF-1 – Vascular Abnormalities

• Moyamoya pattern • Arterial ectasias • Aneurysms• Renal artery stenosis • Aortic stenosis

NF-1 – Imaging Patterns

FASIs, gliomas – optic nerve / chiasma, neurofibromas

14-year old boy with bilateral hearing loss Neurofibromatosis Type 2

• „Neurofibromatosis with bilateral acoustic schwannomas“

• autosomal dominant • NF2 gene (neurofibromin 2 –

merlin): long arm of chromosome 22 (22q12.2)

• Est. incidence: 1:60.000 • About 50% de novo

mutations

Evans, 2009

Neurofibromatosis Type 2

• Often becomes symptomatic in early adulthood

• Café au lait spots and cutaneous neurofibromas less common than in NF-1

• May lead to cataracts (subcapsular, posterior)

Bosch et al, Eye (2005) 19, 705–706

NF-2 – Vestibular Schwannomas

• Uni- or bilateral • Mostly superior branch of

vestibular nerve • Faster growth rate than

spontaneous forms • Clinical trials for medical

treatments (lapatinib,bevacizumab)

Karajannis et al., 2012; Plotkin et al., 2012

NF-2 – Diagnostic Criteria Bilateral vestibular schwannomas (disease-defining) ORRelative with NF-1 PLUS Unilateral vestibular schwannoma < 30y/oAny 2 of the following: Meningioma, ependymoma,

schwannoma, glioma, cataract

In a child / adolescent even unilateral vestibular schwannoma or solitary meningioma suspicious for NF-2

Beware: 25% of pts. > 50 years and 50% of pts > 70 years with bilateral vestibular schwanomas do NOT have NF2 mutations

Evans et al., 2015

NF-2 - Schwannomas May also affect other cranial

nerves, e.g. • Trigeminal nerve • Oculomotor nerve • Facial nerve NF2-related schwannomas

have higher proliferative activity than sporadic schwannomas

Look into the corners…

NF-2 - Meningeomas

• Multiple meningeomas possible

• Intraventricular location possible

Goutagny et al., 2012

Meningeoma(s) at a young age – consider NF-2

NF-2 – Ependymomas

Incidence of brain stem andspinal ependymomas increased

6% of NF-2 patients develop ependymomas

Goutagny et al., 2012

Beware of intraaxial brain stem and spinal cord

ependymomas in patients with NF2

NF-2 – Spinal Tumors

Look at the entire neuro-axis! Intra- or paraspinal Spinal schwannomas Meningiomas Ependymomas Beware of: myelopathy,

syringohydromyelia Spinal tumours associated with

higher number of intracranial meningiomas,schwannomas, frameshiftmutations

Goutagny et al., 2012

NF-2 – Imaging Patterns

Vestibular schwannomas, other cranial nerve and / orspinal schwannomas, meningeomas, ependymomas

22-year old woman with progressive back pain (and known visual problems)

Von Hippel-Lindau Syndrome • Retino-cerebellar

angiomatosis • Autosomal dominant • Short arm of chromosome 3

(3p26-p25); VHL tumour suppressor gene

• Rate of spontaneous mutations about 50%

• Incidence:1:35,000 live births • Often becomes symptomatic

in adolescence with visual symptoms Bader et al., 2012

Kim et al., 2010

VHL – Diagnostic Criteria / Subtypes Two or more CNS hemangioblastomas OROne CNS hemangioblastoma plus visceral lesion or retinal

hemorrhage

Subtypes of VHL•Type 1: Low risk of pheochromocytoma •Type 2: High risk of pheochromocytoma

•Type 2A: low risk of renal cell carcinoma •Type 2B: high risk of renal cell carcinoma •Type 2C: familial pheochromocytoma without renal cell cancer or hemangioblastoma

Binderup et al., 2015

VHL – Extracranial Manifestations

• Retinal haemangioblastomas

• Clear cell renal carcinomas – most common cause ofpremature death in VHL

• Pheochromocytomas • Papillary cystadenoma of

the epididymis andmesosalpinx

• Polycythemia National Eye Institute http://www.nei.nih.gov/photo/eyedis/index.asp Kim et al., 2010

VHL – NIH Screening Recommendations

• Contrast-enhanced MRI of the brain and spinal cord every 2 years from age 11 years

• Yearly ultrasonography of the abdomen from age 11 years

• Abdominal CT from age 20 years, yearly to every other year

• MRI of the temporal bone if hearing loss or tinnitus or vertigo

Bamps et al., 2013

VHL – Cerebellar Hemangioblastomas

• 60% of haemangioblastomas are cerebellar

• Commonly lead to hydrocephalus

• Can produce erythropoietin • Often cyst with enhancing

mural nodule • However: 1/3 solid

Maher et al., 2012

VHL – Spinal Hemangioblastomas

• Look at the entire neuro-axis • 30% of hemangioblastomas

are spinal • Give GBCA to increase

sensitivity • Syringohydromyelia may be

indirect sign – 95% have syrinx

Beitner et al., 2011

VHL – Endolymphatic Sac Tumors (ELST)

• Posteromedial surface of the temporal bone

• May invade the labyrinth • About 4% prevalence in

VHL • Symptoms: vertigo, tinnitus,

sensorineural hearing loss • Ca be large • May recur after resection

Kim et al., 2013 Bastier et al., 2013 Bausch et al., 2015

VHL – Imaging Patterns

Cerebellar and spinal hemangioblastomas– cyst with mural nodule or solid; endolymphatic sac tumours

17-year old girl with seizures

Sturge-Weber Syndrome • Encephalotrigeminal

angiomatosis • Somatic mutation of GNAQ • Incidence < 1:50.000 • Facial naevus flammeus

(trigeminal area(s)) • Can be bilateral (20%) • Persistent fetal vasculature,

deep venous stasis • Glaucoma

Lo et al., 2012 Shirley et al., 2013

www.apotheken-umschau.de

Sturge-Weber Syndrome – X-Ray (historical) 1922: description of tram-

track calcifications in radiographs of the skull

Often hyperpneumatisation of the frontal sinus

Toronto

Sturge-Weber Syndrome

• Absence of normal cortical venous drainage

• Venous stasis • Flow redirection to the

deep vessels • Enlarged medullary and

basal veins • Contrast-enhanced

FLAIR sequence most sensitive

Alkonyi et al., 2012

Sturge-Weber Syndrome

• Early swelling and „accelerated“ myelination

• Venous stasis • Regional perfusion and

cortical metabolic alterations • Ensuing focal atrophy in the

affected area • Calcifications • Hypertrophy of the choroid

plexus • Increased leptomeningeal

enhancement

Sturge-Weber Syndrome – Imaging Patterns

Calcifications, atrophy, leptomeningeal enhancement, hypertrophy ofthe choroid plexus (early: accelerated myelination, swelling)

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