Nomenclature The Common Phakomatoses • From Greek φακός, phakos – spot, lens Birgit Ertl-Wagner • Named by Jan van der Hoewe in 1920 (Dutch ophtalmologist): “lens- like” changes on fundoscopy in a ECPNR, 10th Cycle, Rome tuberous sclerosis patient • Newer nomenclature: neurocutaneous syndromes neuro-oculo-cutaneous syndromes

https://de.wikipedia.org/wiki/Jan_van_d er_Hoeve

Many more diagnoses encompassed now “The Big Five”

• type 1 • Neurofibromatosis type 2 • Neurofibromatosis type 1 • Tuberous sclerosis • Neurofibromatosis type 2 • Sturge-Weber syndrome • von Hippel-Lindau disease • Ataxia telangiectasia • Tuberous sclerosis • • Nevoid basal cell carcinoma • Sturge-Weber syndrome syndrome • Wyburn-Mason syndrome (Bonnet– • von Hippel-Lindau disease Dechaume–Blanc syndrome) • And many more…

3-year old boy with and developmental delay Tuberous Sclerosis Complex

• aka M. Bourneville-Pringle 9 • Autosomal dominant • 70% sporadic (de novo ) • 2 : TSC1 on chromosome 9q34 16 TSC2 on chromosome 16p13.3 • Incidence: 1:8000 live births • Developmental (tau abnormally expressed)

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

Tuberous Sclerosis Complex - Background Tuberous Sclerosis Complex - Skin

• Original „Vogt triad“: • cognitive impairment • Ash Leaf spots – hypomelanotic lesions • • Adenoma sebaceum - • adenoma sebaceum in the face • 18 to 55% do not suffer from mental retardation • Koenen tumours of the fingernails • Adenoma sebaceum usually only in later childhood / • Dental enamel pits adolescence Umeoka et al., 2008

www.webmd.com; Rayer „Traites des maladies de la peau“ 1835 www.ourdermatology.blogspot.com Tuberous Sclerosis Complex - Extracranial Tuberous Sclerosis Complex - Tubers

• Tuber = swelling; in plants: for • storage of nutrients • Renal • of the – usually • Contain balloon cells spontaneously regress large, eosinophilic postnatally • Can be heterotopic or • Lymphangioleiomyo- transhemispheric matosis (LAM) of the • Number and location of tubers • Cystic bone lesions may play a role in • Giant drusen on neurocognitive outcome

fundoscopy Kassiri et al., 2011

Tuberous Sclerosis Complex - Tubers Cystic Appearing Tubers • Frontal > parietal > occipital > temporal > cerebellum • Tubers may appear - • 50% are calcified by age 10 y like • Signal variable relative to myelin • High signal intensity T2w, maturation low signal intensity T1w • FLAIR hyperintense in older children • More aggressive type of • 3-4% enhance seizures? • Higher ADC values in more epileptogenic tubers • AMT (α-11C-methyl-L-tryptophan) PET may identify epileptogenic

tubers Kassiri et al., 2011 Manoukian et al., 2015

Tuber vs. FCD Type IIb White Matter Radial Migration Lines

• Focal cortical dysplasia type • Heterotopic glia with neurons IIb histologically identical to along migration pathways tuber • Linear to curvilinear • May also have a funnel- shaped migration part • Radial migration abnormalities correlate with • FCD IIb do not calcify outcome • If in doubt: • Cyst-like structures in white • Skin examination with matter possible as well (origin Wood´s light unknown) • Renal • Kassiri et al., 2011 Kassiri et al., 2011

Subependymal Nodules Subependymal Nodules

• Subependymal • 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 Giant Cell - SEGA Subependymal Giant Cell Astrocytoma - SEGA

• WHO grade I • At Foramen Monroi • CT: may have calcification • T2WI / FLAIR: iso- to • In 15-20% of patients with TSC hyperintense, heterogeneous • Round configuration, • T1WI: hypo- to isointense pronounced enhancement • T2* may have low SI from • May lead to ipsilateral dilatation calcifications of lateral • Contrast-enhancement • (Asymmetric) Diagnosis based on size and growth Enlarging, enhancing mass >1.3 cm near foramen Monroi

SEGA - Treatment Tuberous Sclerosis Complex – Imaging Patterns

• Mammalian target of rapamycin (mTOR) inhibitors (e.g., ) • normalize the mTOR pathway also in other TSC manifestations (angiomyolipomas, , epilepsy) • consider treatment effects when evaluating SEGAs Cortical tuber, subependymal nodules, giant cell Jozwiak et al., 2013; Krueger et al., 2013; Lam et al., 2010

6-year old boy with developmental delay Neurofibromatosis Type 1

• Autosomal dominant • Long arm of chromosome 17 (17q11.2) • NF-1 (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 NF-1 – Diagnostic Criteria: 2 or more

• Café-au-lait spots • First degree relative with NF-1 (>5, >25mm, + symptoms) • Six or more Cafe-au-lait spots • Axillary or inguinal freckling • Axillary freckling • Two or more Lisch nodules (iris hamartomas) • Lisch-nodules (hamartomas of • Two or more or one or more plexiform the iris) • Optic pathway • Cutaneous / subcutaneous • Distinctive bone lesion (e.g. dysplasia of the sphenoid) neurofibromas

Gutmann et al., 2012 Gutmann et al., 2012 Pictures: www.de.wikipedia.org NF-1 – FASI (Focal Areas of Signal Intensity) NF-1 – FASI (Focal Areas of Signal Intensity)

• Also called “UBOs” (unidentified bright objects) • Hyperintense on T2WI, • Transient intramyelin edema isointense on T1WI • Start in childhood, tend to • No edema, no swelling disappear in adulthood • DTI decreased FA • 80-90% in pre-teen children with • MRS decreased NAA/Cr & NF-1 NAA/Cho (thalamic) • 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; Ferraz-Filho et al., 2013; Barbier et al., 2011; Chabernaud et al., 2009 Chabernaud et al., 2009

NF-1NF 1 – LocationLocation of TumorsTumors Optic Pathway (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? NF-1 – Gliomas (Outside Optic Pathway)

• GBCAs may not be needed • Incidence of gliomas increased for follow-up • Any WHO grade possible • GBCA enhancement does not necessarily correlate • 5x higher risk of high grade with biological behavior gliomas • Mortality higher in symptomatic and adult patients

Rasmussen et al, 2001 Guillamo et al., 2003 Maloney et al., 2018 Rodriguez et al, 2008

NF-1 – Brainstem Gliomas NF-1 – Spine

• May be diffuse or focal • Kyphoscoliosis common • 68% medullary, 52% pontine, 44% midbrain • Dural ectasia – dysplasia of meninges, vulnerable to CSF • 56% multiple locations pulsation, vertebral • Diffuse brainstem gliomas scalloping generally slower progression in NF-1 • Lateral meningoceles • Beware of hydrocephalus

Rasmussen et al, 2001 Guillamo et al., 2003 Rodriguez et al, 2008 NF-1 – Neurofibromas 17-year old girl with lower back pain

• Tumors of the nerve sheaths • Degree of • Intraspinal, paraspinal, peripheral • Variable signal intensity on T2w • Enhancement with GBCA

NF-1 – Malignant Peripheral Nerve Sheath Tumors NF-1 – Plexiform Neurofibromas

• Malignant peripheral nerve • Characteristic for NF-1 sheath tumors (MPNST) in 5- 13% of NF-1 patients • Locally aggressive • Transspatial lesion • FDG-PET may predict • No metastases malignant transformation • Diffuse growth along a nerve • Can be disfiguring • May transform to MPNST (10%)

Tsai et al., 2013 Tsai et al., 2013

NF-1 – Vascular Abnormalities NF-1 – Imaging Patterns

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

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 – ): long arm of chromosome 22 (22q12.2) • Est. incidence: 1:60.000 • About 50% de novo mutations

Evans, 2009 Neurofibromatosis Type 2 NF-2 – Vestibular Schwannomas

• Often becomes symptomatic • Uni- or bilateral in early adulthood • Mostly superior branch of • Café au lait spots and vestibular nerve cutaneous neurofibromas • Faster growth rate than less common than in NF-1 spontaneous forms • May lead to cataracts • Clinical trials for medical (subcapsular, posterior) treatments (lapatinib, bevacizumab)

Bosch et al, Eye (2005) 19, 705–706 Karajannis et al., 2012; Plotkin et al., 2012

NF-2 – Diagnostic Criteria NF-2 - Schwannomas

Bilateral vestibular schwannomas (disease-defining) May also affect other cranial OR nerves, e.g. Relative with NF-1 • Trigeminal nerve PLUS • Oculomotor nerve Unilateral vestibular schwannoma < 30y/o • Facial nerve Any 2 of the following: Meningioma, ependymoma, schwannoma, glioma, cataract NF2-related schwannomas have higher proliferative In a child / adolescent even unilateral vestibular schwannoma or solitary meningioma suspicious for NF-2 activity than sporadic schwannomas Beware: 25% of pts. > 50 years and 50% of pts > 70 years with bilateral vestibular schwanomas do NOT have NF2 mutations Look into the corners…

Evans et al., 2015

NF-2 - Meningeomas NF-2 – Ependymomas

• Multiple meningeomas Incidence of brain stem and possible spinal ependymomas increased • Intraventricular location 6% of NF-2 patients develop possible ependymomas

Beware of intraaxial brain Meningeoma(s) at a young stem and spinal cord age – consider NF-2 ependymomas in patients with NF2

Goutagny et al., 2012 Goutagny et al., 2012

NF-2 – Spinal Tumors NF-2 – Imaging Patterns

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, frameshift Vestibular schwannomas, other cranial nerve and / or mutations spinal schwannomas, meningeomas, ependymomas Goutagny et al., 2012 22-year old woman with progressive back pain Von Hippel-Lindau Syndrome (and known visual problems) • Retino-cerebellar • 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 VHL – Extracranial Manifestations

Two or more CNS hemangioblastomas OR • Retinal One CNS hemangioblastoma plus visceral lesion or retinal haemangioblastomas hemorrhage • Clear cell renal carcinomas – most common cause of Subtypes of VHL premature death in VHL •Type 1: Low risk of pheochromocytoma • Pheochromocytomas •Type 2: High risk of pheochromocytoma • Papillary cystadenoma of •Type 2A: low risk of the epididymis and •Type 2B: high risk of renal cell carcinoma mesosalpinx •Type 2C: familial pheochromocytoma without renal cell • Polycythemia National Eye Institute Kim et al., 2010 cancer or hemangioblastoma http://www.nei.nih.gov/photo/eyedis/index.asp Binderup et al., 2015

VHL – NIH Screening Recommendations VHL – Cerebellar Hemangioblastomas

• Contrast-enhanced MRI of the brain and spinal cord • 60% of every 2 years from age 11 years haemangioblastomas are • Yearly ultrasonography of the abdomen from age 11 cerebellar years • Commonly lead to hydrocephalus • Abdominal CT from age 20 years, yearly to every other year • Can produce erythropoietin • MRI of the temporal bone if hearing loss or tinnitus or • Often cyst with enhancing vertigo mural • However: 1/3 solid

Maher et al., 2012

Bamps et al., 2013

VHL – Spinal Hemangioblastomas VHL – Endolymphatic Sac Tumors (ELST)

• Look at the entire neuro-axis • Posteromedial surface of the temporal bone • 30% of hemangioblastomas are spinal • May invade the labyrinth • Give GBCA to increase • About 4% prevalence in sensitivity VHL • Syringohydromyelia may be • Symptoms: vertigo, tinnitus, indirect sign – 95% have sensorineural hearing loss syrinx • Ca be large • May recur after resection Kim et al., 2013 Beitner et al., 2011 Bastier et al., 2013 Bausch et al., 2015 VHL – Imaging Patterns 17-year old girl with seizures

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

Sturge-Weber Syndrome Sturge-Weber Syndrome – X-Ray (historical) • Encephalotrigeminal 1922: description of tram- angiomatosis track calcifications in • Somatic of GNAQ radiographs of the skull • Incidence < 1:50.000 Often hyperpneumatisation www.apotheken-umschau.de • Facial naevus flammeus of the frontal sinus (trigeminal area(s)) • Can be bilateral (20%) Toronto • Persistent fetal vasculature, deep venous stasis • Glaucoma

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

Sturge-Weber Syndrome Sturge-Weber Syndrome

• Absence of normal • Early swelling and cortical venous drainage „accelerated“ myelination • Venous stasis • Venous stasis • Flow redirection to the • Regional perfusion and deep vessels cortical metabolic alterations • Enlarged medullary and • Ensuing focal atrophy in the basal veins affected area • Contrast-enhanced • Calcifications FLAIR sequence most • Hypertrophy of the choroid sensitive plexus

Alkonyi et al., 2012 • Increased leptomeningeal enhancement

Sturge-Weber Syndrome – Imaging Patterns THANK YOU FOR YOUR

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