Daniela LONGO Bologna, October 6, 2010

[fak′ōm ə tō′sis] pl. phakomatoses Etymology: Gk, phako, lens, oma, tumor, osis, condition (in ophthalmology); any of several hereditary syndromes characterized by benign tumorlike nodules of the eye, skin, and brain. Congenital malformations affecting mainly structures of ectodermal origin, that is, the nervous system, the skin, and the eyes; visceral organs are also involved, but more rarely. Some phakomatoses are associated with a higher risk of developing tumors. What are phakomatoses?

Neurofibromatosis type 1 (NF1) Neurofibromatosis type 1 (NF1) Tuberous sclerosis complex (TSC) Tuberous sclerosis complex (TSC) Sturge-Weber syndrome (SWS) Sturge-Weber syndrome (SWS) Neurofibromatosis type 2 (NF2) Neurofibromatosis type 2 (NF2) Von Hippel-Lindau disease Von Hippel-Lindau disease Ataxia-Telangectasia (Rendu-Osler-Weber syndrome) Neurocutaneous Melanosis Incontinentia Pigmenti Epidermal Nevus Syndrome Hypomelanosis of Ito Basal Cell Nevus Syndrome Cutaneous Hemangioma – Vascular Complex Syndrome Chédiak-Higashi syndrome Cowden Syndrome Parry-Romberg syndrome Encephalocraniocutaneous lipomatosis What are ? What are phakomatoses?

Neurofibromatosis type 1 (NF1) Von Recklinghausen disease Café au lait spots Axillary and inguinal freckling Cutaneous or plexiform neurofibromas Optic nerve and other CNS gliomas Iris Lisch nodules Bone lesions (tibial dysplasia and sphenoid dysplasia) Vasculopathy Multisystemic neurocutaneous disorder Autosomal dominant, gene NF1 (17q11.2) Incidence 1/3.000

Neuroradiological Manifestations UBOs (Unidentified bright objects) Optic nerve gliomas Brainstem and hemispheric tumors Neurofibromas and plexiform neurofibromas Sphenoid dysplasia

Unidentified Bright Objects (UBOs) abnormal high signal intensity lesions on T2-WI globus pallidus, thalamus, hypocampus, pons, midbrain, cerebellar white matter do not enhance after contrast administration, no mass effect, do not cause edema generally absent in the first 2 years of life, they increase in number and size up to the age of 10 – 12 years, then they decrease in number and size T2 FLAIR T2

Optic Nerve Gliomas The most common primary brain abnormality in NF1 (15%) Single or both optic nerves, the chiasm, the optic tracts and radiations Low histologic grade May spontaneously involute Bilateral optic nerve gliomas. Axial postcontrast T1W image shows enhancement of both optic nerve tumors. Enlargement of the optic chiasm and hydrocephalus.

Astrocytomas and Glioblastomas 2 yars-old, seizures Low-grade astrocytoma (WHO I) HE 4XHE 20X Areas of necrosis Astrocytes gemistociti 7-year-old left eyelid ptosis, strabismus Glioblastoma (WHO IV)

Plexiform Neurofibromas and Sphenoid Dysplasia Sphenoid wing dysplasia is often associated with plexiform neurofibromas in the orbit. Histologically : Schwann cells, neurons, collagen and intercellular matrix.. Axial CT shows partial absence of the greater wing of the left sphenoid bone. On MR the soft tissue mass in the left orbit is a plexiform neurofibroma. The postcontrast axial T1W image with fat saturation shows mass enhancement.

DIFFERENTIAL DIAGNOSIS Demyelinating diseases (ADEM, multiple sclerosis) Viral encephalitis (Epstein-Barr, CMV) Mitochondrial diseases (PKAN, Leigh, Kearns-Sayre syndrome) Glutaric-aciduria Halleworden-Spatz Krabbe disease Tuberous sclerosis complex

Tuberous Sclerosis Complex (TSC) (Bourneville-Pringle’s disease) facial angiofibromas or forehead plaque ungual or periungual fibromas hypomelanotic macules (three or more) Shagreen patch (connective tissue nevus) multiple retinal nodular hamartomas cardiac rhabdomyoma lymphangiomyomatosis renal angiomyolipoma multiple pits in dental enamel hamartomatous rectal polyps bone cysts gingival fibromas nonrenal hamartoma retinal achromic patch "Confetti" skin lesions multiple renal cysts Multisystemic disorder (skin, CNS, bones, respiratory system, kidneys, heart and skeletal muscle) Autosomal dominant; genes TSC1 (9q) and TSC2 (16p) Incidence 1/6.000 Clinical triad : mental retardation, epilepsy, facial angiofibromas

Neuroradiological Manifestations Subependymal nodules (90%) Cortical tubers (70%) Giant cell astrocytomas (6%-14%) White matter radial migration lines

Subependymal Nodules and Cortical Tubers

DIFFERENTIAL DIAGNOSIS Subependymal heterotopia Cytomegalovirus Cortical dysplasia

Angiomatosis of the face, the coroid and leptomeninges Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis) Congenital disorder characterized by Seizures, hemiparesis, hemianopsia, and mental retardation Incidence: 1:50.000

Neuroradiological Manifestations Leptomeningeal angioma Hemispheric atrophy Loss of the white matter Hypointensity of the white matter below the affected cortex Gyral calcification Prominent choroid plexus Dilated subependymal veins

DIFFERENTIAL DIAGNOSIS Bilateral empyema Arteriovenous malformations Neurocutaneous syndromes (PHACES, meningioangiomatosis, “blue rubber bleb nevus”syndrome, Wyburn-Mason syndrome)

Daniela Longo Ospedale Pediatrico Bambino Gesù - Roma

Von Hippel-Lindau Disease Autosomal dominant, gene VHL (3p25-p26) Incidence 1: Retinal angiomas (70%) Hemangioblastomas of the brain (50%) and spinal cord Renal cell carcinoma (40%) Pheochromocytoma Endolymphatic sac tumors (10%) Cysts of the pancreas, kidney, liver and epididymis.

DIFFERENTIAL DIAGNOSIS Solitary hemangioblastoma Pilocytic astrocytoma Hemispheric medulloblastoma Multiple AVMs in Osler-Weber- Rendu and Wyburn-Mason