Control # 848 Title: “Polkadots and Moonbeams” Neurocutaneous Syndromes Made Easy eEdE# eEdE-197

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“Polkadots and Moonbeams” Neurocutaneous Syndrome Made Easy Nucharin Supakul, MD 1 Chang Y Ho, MD 2 1 Ramathibodi Hospital, Mahidol University Bangkok, Thailand 2 Riley Hospital for Children, Indiana University School of Medicine Indianapolis, Indiana, USA

Purpose To recognize characteristic imaging findings for the most common neurocutaneous syndromes To develop a search pattern for each disease To understand and be able to suggest a proper imaging technique for further evaluation and follow-up.

Introduction Neurocutaneous syndrome  aka phakomatoses  Group of neuroectodermal disorders Central nervous system disorder associated with lesions in the skin, eye and other visceral organs

Case list Neurofibromatosis type 1Neurofibromatosis type 1 Neurofibromatosis type 2Neurofibromatosis type 2 Tuberous sclerosis Ataxia telangiectasia Sturge -Weber syndromeSturge -Weber syndrome Von Hipple-Lindau syndromeVon Hipple-Lindau syndrome Neurocutaneous melanosisNeurocutaneous melanosis Basal nevous syndromeBasal nevous syndrome

NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 von Recklinghausen disease Most common neurocutaneous disorder 1: 1, ,000 50% autosomal dominant, 50% spontaneous mutation Chromosome 17 (17q11.2) NF1 gene  Neurofibromin protein Multisystemic manifestations (skin, CNS and orthopedic)  Neurofibromas  Café-au-lait spots  Axillary or inguinal freckles  Lisch nodule  Skeletal dysplasia  Malignant nervous system tumor Highly related to learning disability/autism

Neurofibromatosis type 1 Diagnostic Criteria ( ≥ 2 findings for diagnosis)  ≥ 6 café-au-lait spots  > 2 axillary or inguinal freckles  ≥ 2 typical neurofibromatosis or 1 plexiform neurofibroma  Optic nerve glioma  ≥ 2 Lisch nodules (Iris harmartomas)  Sphenoid dysplasia or typical long bone abnormalities  1 st degree relative with NF1 Classic Radiographic Findings  Plexiform neurofibromas (target appearance)  Sphenoid wing dysplasia  Optic nerve gliomas  Deep gray and white matter changes (myelin vacuolization / unidentified bright objects) Moya Moya pattern of vasculopathy Imaging Recommendation  MRI with contrast

Neurofibromatosis type 1 10-year-old boy with café-au-late spots A-B: Axial and coronal T2 images demonstrate extensive, ropy T2 hyperintense lesions with target appearance consistent with plexiform neurofibromas (orange arrows) along the right side of the face extending to the intra- and extraconal space of the right orbit and along the right Meckel cave. Noted is right sphenoid wing dysplasia (blue star). C: Coronal T1 post contrast image demonstrates diffuse heterogeneous enhancement of the plexiform neurofibromas (orange arrows). D: Axial T2 image of a different patient (2 year-old girl with NF1) shows multiple bilateral foci of abnormal signal intensity in the deep cerebellar white matter and dentate nuclei consistent with NF related dysplasia/myelin vacuolization (pink arrows). A B C D BACK to case list

NEUROFIBROMATOSIS TYPE 2

Neurofibromatosis type 2 1: 25,000 – 30, % autosomal dominant, 50% spontaneous mutation Chromosome 22 (22q12) NF2 gene  Merlin protein Manifestations (skin and CNS)  Café-au-lait spots (few or absent)  MISME (Multiple Inherited Schwannomas Meningiomas and Ependymomas) Late presentation and diagnosis  less cutaneous manifestations compared to NF 1 Clinical presentations: Hearing loss/ vertigo

Neurofibromatosis type 2 Diagnostic Criteria:  Bilateral vestibular schwannomas or  1st degree relative with NF2 and 1 vestibular schwannoma or  1st degree relative with NF2 and 2 of the following findings  Neurofibroma  Meningioma  Glioma  Schwannoma  Posterior subcapsular lenticular opacity Classic Radiographic Findings: MISME  Multiple Inherited Schwannomas  Meningiomas  Ependymomas Carefully check other cranial nerves in any new diagnosis of schwannoma or meningioma in a child or young adult Imaging Recommendation  MRI with contrast, high resolution T1+C to evaluate cranial nerves

Neurofibromatosis type 2 30-year-old female with history of headache and dizziness. A-B: Axial T1 postconstrast images show bilateral enhancing masses in the internal auditory canals, consistent with vestibular schwannomas (orange arrows). A large extra-axial mass with homogeneous enhancement along the posterior falx cerebri, consistent with a meningioma (blue star). C-D: Axial T1 (C) and sagittal T1 (D) postcontrast images show a mixed enhancing mass in the medulla with a dorsal cyst, consistent with a ependymoma (pink arrows). A homogeneous intensely enhancing mass is noted at the cranial cervical junction, consistent with a cervical meningioma (blue arrow). A B D C BACK to case list

TUBEROUS SCLEROSIS

Tuberous Sclerosis 50% autosomal dominant 50% sporadic mutation 1 : 10,000 Clinical triad  Facial angiofibromas (90%)  Mental retardation (50-80%)  Seizure (80-90%) A: Ash leaf macule B: Adenoma sebaceum C: Periungual fibroma D: Shagreen patch

Tuberous Sclerosis Diagnostic criteria: 2 major or 1 major+2 minor Major:  Facial angiofibroma/forehead plaque  sub-/periungual fibroma  ≥ 3 hypomelanotic macules  shagreen patch  multiple retinal nodular hamartomas  cortical tuber,  Subependymal nodule (SEN)  Subependymal giant cell astrocystoma (SEGA)  Cardiac rhabdomyoma  Lymphangioleiomyomatosis  Renal angiomyolipoma Minor:  Dental enamel pits  Hamartomatous rectal polyps  Bone cysts  Cerebral WM radial migration lines (> 3 = major sign)  Gingival fibromas  Nonrenal hamartoma  Retinal achromic patch  Confetti skin lesions  Multiple renal cysts Classic Radiographic Findings:  Cortical tuber  Subependymal nodule (<1.3 cm)  Subepedymal giant cell astrocytoma (> 1.3 cm) Imaging Recommendations:  MRI brain with contrast  FLAIR is the most sensitive for white matter abnormalities

Tuberous Sclerosis 5-year-old girl with seizure A-B: Axial FLAIR images shows multiple areas of FLAIR hyper intensity involving bifrontoparietal and occipital cortical and juxtacortical white matter, consistent with cortical tuber (orange arrows). C: Axial post contrast T1 image shows an enhancing lesion within the right foramen of Monro, measuring approximately 1.5 cm in size, consistent with subependymal giant cell astrocytoma (blue arrow). D: Axial T2 image shows few T2 hypointense foci along the ependymal lining of the left lateral ventricle, consistent with subependymal nodules (pink arrows). A B C D BACK to case list

ATAXIA TELANGIECTASIA

Ataxia telangiectasia Rare Autosomal recessive 1: 40, ,000 Chromosome 11 (11q33-23) ATM gene mutation Complex multi systemic disorder  Cerebellar ataxia (incoordination and lack of balance)  Mucocutaneous telangiectasia  Immune deficiency  recurrent bronchopulmonary and sinonasal infection  Sensitive to ionizing radiation Increased risk of heart disease and cancer (leukemia/lymphoma in children and solid tumors in adult) Most common cause of death: recurrent sinopulmonary infection

Ataxia telangiectasia Classic Radiographic Findings:  Progressive cerebellar volume loss  Compensatory enlargement of the 4 th ventricle  Cerebral white matter dysmyelination/demyelination  Microhemorrhages/ telangiectasis  Decreased/ absent lymphoid tissue: adenoid gland, thymus, mediastinal lymphoid tissue Imaging Recommendation:  MRI due to no ionizing radiation and high tissue contrast 7-year-old boy with history of autism and developmental delay A and B: Sagittal T1 (A) and coronal T2 (B) images demonstrate severe atrophy of the cerebellar hemisphere with widening of the cerebellar folia and CSF space (orange arrows). Note the hypoplastic adenoid tissue for this age (blue arrow). A B BACK to case list

STURGE-WEBER SYNDROME

Sturge-Weber Syndrome Synonym: encephalotrigeminal angiomatosis Rare Sporadic 1: 20, ,000 Clinical presentation Port wine stain (CN V1 98%) Seizure (75-90%) Hemiparesis (30-66%) Pathophysiology: failure to develop of fetal cortical vein plus persistent primordial vessels  venous stasis  hypoperfused cortex

Sturge-Weber Syndrome Classic Radiographic Findings:  Ipsilateral to port wine stain  Gyral/subcortical white matter calcifications (tram- track calcification)  hemispheric brain atrophy  Serpentine leptomeningeal enhancement  Engorged/enlarged enhancing choroid plexi Location:  Occipital > parietal > fronto/temporal > midbrain > cerebellum 90% of infants with facial port wine stains do not have intracranial lesions and are expected to develop normally. Imaging Recommendation:  MRI with contrast  leptomeningeal angiomatosis  GRE/SWI sequence  gyral/subcortical calcification

Sturge-Weber Syndrome 3-year-old girl with history of facial hemangioma and seizure A: Non contrast CT image of the brain shows severe atrophy of the right cerebral hemisphere with extensive cortical/subcortical calcifications (orange arrows) in the right cerebral hemisphere and left parieto-occipital lobe. B: GRE image shows hypointensity without blooming involving the right cerebral hemisphere and left occipital cortical/subcortical white matter, consistent with calcifications (orange arrows) seen on the prior CT. C: Axial FLAIR image shows severe atrophy of the right cerebral hemisphere. Bilateral choroidal cysts are noted (blue arrows). D: Post contrast T1 image demonstrates extensive leptomeningeal enhancement involving right cerebral cortical sulci and left parieto-occipital sulci (pink arrows) as well as avid enhancement of the choroid plexi bilaterally (yellow arrows). Relative lack of cortical veins of the atrophied right cerebral hemisphere compared to the contralateral normal brain parenchyma and increased pial enhancement of the left parietal occipital lobe. A B CD BACK to case list

VON HIPPLE-LINDAU SYNDROME

Von Hipple-Lindau Syndrome 80% Autosomal dominant (Variable expression and high penetrance; 97% by age of 65) 20% sporadic mutation Chromosome 3 (3p25-26) VHL gene  VHL protein 1 : 36,000 Multi Systemic manifestations:  Less than 5% with skin manifestration (Capillary malformation)  Hemangioblastomas (Cerebellar 40-70%, retinal 40-60% and spinal cord 10-60%)  Pancreatic lesion (cyst 50-90%, neuroendocrine tumor/ serous cystadenoma 5-15%)  Renal lesion (cyst 60%, renal cell carcinoma 20-45%)  Pheochromocytoma (0-60%)  15% of VHL patients develop endolymphatic sac tumor; 30% bilateral Clinical presentation:  Hemangioblastoma symptoms  headache, dizziness, double vision, weakness  Pheochromocytoma symptoms  high blood pressure, sweating, rapid/irregular heart rate, tremor, weight loss

Von Hipple-Lindau Syndrome Diagnostic Criteria  ≥ 1 hemangioblastomas in the CNS (brain and spinal cord) or retina or  A hemangioblastoma in the CNS or retina plus a visceral manifestation or  Positive family history plus any of above manifestations Classic Radiographic Findings:  Mixed cystic lesion with peripheral nodular enhancement  Near pial surface Imaging Recommendation: MRI brain and spine with contrast NIH recommendation for screening:  MRI brain and spine with contrast from age of 11 then every 2 years  US abdomen from age of 11, then every year  CT abdomen from age of 20, then every year  MRI temporal bone if hearing loss/ tinnitus/ vertigo

Von Hipple-Lindau Syndrome 20-year-old male with history of headache and back pain A: Non contrast CT image shows a cystic lesion (orange asterisk) in the left cerebellar hemisphere with surrounding vasogenic edema. Mass effect on the 4th ventricle (red arrow), causes obstructive hydrocephalus (blue arrows). B: Axial T1 post contrast image shows cystic lesions with mural nodular enhancement (pink arrows) in the left cerebellum and right-sided pons. Also noted are few nodular enhancing foci in the right cerebellar hemisphere (pink arrows). C: Sagittal T1 post contrast image of the thoracic spine demonstrates several enhancing lesions in the spinal cord (yellow arrows). D: Coronal contrasted CT image of the abdomen shows multiple heterogeneous enhancing lesions scattered through both kidneys (green arrows), pathologically proven renal cell carcinoma. A B C D BACK to case list

NEUROCUTANEOUS MELANOSIS

Neurocutaneous melanosis Rare genetic disorder 100+ case reports Mutation of NRAS gene Clinical presentation: melanocytic deposition within  Skin  Giant or multiple melanocytic nevi  CNS Diagnostic Criteria:  Melanocytic deposition within the CNS and skin lesions  Important to establish that cutaneous lesions are benign or malignant to rule out metastasis of cutaneous melanoma 5-15% lifetime risk of malignant transformation Can have poor prognosis with median survival of 6.5 months after symptom onset Classic Radiographic Findings:  T1 shortening with susceptibility artifact on GRE or SWI  No contrast enhancement  Locations: amygdala, cerebellum, brainstem, inferior frontal lobes and thalami Imaging Recommendation:  MRI with contrast of the brain and spine  GRE/ SWI sequences

Neurocutaneous melanosis 13-day-old term infant with multiple congenital nevi A-B: Axial T1 noncontrast images demonstrate a wedge-shaped T1 hyperintensity in the right caudal thalamic groove and foci of T1 hyperintensity in the right medial temporal lobe/ amygdala (orange arrows). C-D: Post contrast T1 image demonstrates no contrast enhancement within these lesions. A B C D BACK to case list

BASAL CELL NEVUS SYNDROME

Basal cell nevus syndrome Synonym: Gorlin syndrome 2/3 Autosomal dominant with complete penetrance and variable expressivity 1/3 sporadic mutation 1 : 31,000 Chromosome 9 (9q22.1-q31) PICH1 gene  patched-1 protein

Basal cell nevus syndrome Diagnostic criteria (2 majors, or 1 major + 2 minor) Major criteria  Early development of multiple basal cell carcinomas  Greater than 10 basal cell nevi  Odontogenic keratocysts, commonly in the mandible  Palmar and plantar pitting  Ectopic intracranial calcification, most often along falx cerebri  Family history Minor criteria  Craniofacial anomalies (macrocephaly, frontal bossing, hypertelorism)  Bifid ribs  Early onset desmoplastic medulloblastoma  Cardiac or ovarian fibroma, often bilateral  Lymphomesenteric cysts  Congenital malformation (cleft lip/palate, polydactyly, eye abnormalties- colobomas, cataract, glaucoma Classic Radiographic Findings:  Multiple odontogenic keratocysts  Early dural calcifications  Basal cell nevi and carcinomas Odontogenic keratocyst (keratocytic odontogenic tumor: KOT) in Gorlin syndrome usually develop earlier than non-syndromic KOT Most patients with basal cell nevus syndrome have KOT; however, only 5% of patients with KOT have basal cell nevus syndrome. Associated with desmoplastic medulloblastoma Imaging Recommendation:  MRI to screen for medulloblastoma, cystic jaw lesion  CT of face for oral surgery planning

Basal cell nevus syndrome 15-year-old girl with abnormal panoramic radiograph A-B: Coronal and axial CT images through the mandible shows an expansile lucent lesion (orange arrow) in the right angle of the mandible associated with an unerupted molar without cortical breakthrough. C: Axial CT image of the skull near the vertex of the head demonstrates prominent dural calcification along a reflection of the superior sagittal sinus (blue arrows). A B C BACK to case list

Summary Cutaneous manifestations CNS manifestations Other organ manifestations Key images NF1 Neurofibroma Café-au-lait spots Axillary or inguinal freckles Plexiform neurofibroma Optic nerve glioma myelin vacuolization Sphenoid wing dysplasia Lisch nodule Skeletal dysplasia MRI with contrast T2  target lesion  plexiform neurofibroma NF2 Few café-au-lait spotMISME-MRI brain and spine with contrast High resolution cranial nerve Tuberous sclerosis Ash leaf macule Adenoma sebaceum Periungual fibroma Shagreen patch Cortical tuber Subependymal nodules SEGA Cardiac rhabdomyoma Lymphangiomyomatosis Renal AML MRI brain with contrast FLAIR to detect cortical tuber Ataxia telangiectasia Mucocutaneous telangiectasia Progressive cerebellar volume loss Atrophy of lymphoid tissue, thymus, adenoid gland MRI brain to avoid ionizing radiation Sturge-Weber Syndrome Port wine stain along trigeminal nerve Gyral/ subcortical calcification Hemispheric atrophy Sepentine leptomeningeal enhancement Engored/ enlarged choroid plexus -MRI brain with contrast  leptomeningeal angiomatosis SWI/GRE for gyral calcification

Summary Cutaneous manifestations CNS manifestations Other organ manifestations Key images Von Hipple- Lindau Syndrome Capillary malformation (less than 5% of patients) Hemangioblatoma (retina, cerebellum, spine) Pancreas (cyst, neuroendocrine tumor, serous cystadenoma) Renal (cyst, RCC) phreochromocytoma Endolymphatic sac tumor MRI brain and spine with contrast screening -US and CT abdomen -MRI temporal bone Neurocutaneous melanosis Giant or multiple melanocytic nevi Melanocytic deposition within the CNS with no contrast enhancement -MRI brain and spine with contrast GRE/SWI sequence Basal nervous syndrome Basal cell neviEarly dural calficification Odontogenic keratosis Desmoplastic medulloblastoma Bifid ribs Cardiac or ovarian firbromas Lymphomesenteric cyst Cleft lip/palate Polydactyly Eye abnormalities (colobomas, cataract, glaucoma) MRI /CT to demonstrate odontogenic cyst and dural calcification

Conclusion Neurocutaneous syndromes are a heterogeneous group of disorders that primarily affect the central nervous system with cutaneous manifestations. Cross-sectional imaging, especially MRI, can be tailored to help the diagnosis and guide further evaluation and treatment. Radiologists should be familiar with the characteristic imaging findings of specific neurocutaneous syndromes and develop a search pattern for potential associated lesions once a diagnosis is favored.

References Elster AD Radiologic screening in the neurocutaneous syndromes: strategies and controversies. AJNR Am J Neuroradiol Jul-Aug;13(4): Tortori-Donati, Paolo, et al. "Phakomatoses." Pediatric Neuroradiology. Springer Berlin Heidelberg, Pont MS, and Elster AD. Lesions of skin and brain: modern imaging of the neurocutaneous syndromes. American Journal of Roentgenology :6, Coats, David K., Evelyn A. Paysse, and Moise L. Levy. "PHACE: a neurocutaneous syndrome with important ophthalmologic implications: case report and literature review." Ophthalmology (1999): Roach, E. S. "Neurocutaneous syndromes." Pediatric Clinics of North America 39.4 (1992):