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RARE PHAKOMATOSIS Mtor & 19/01/21 OTHER RARE European Course on Pediatric Neuroradiology PHAKOMATOSES th 10 Cycle Module 2 Basal Cell Nevus Syndrome Organoid Nevus Syndrome 23-27 January 2021 Cowden-Lhermitte-Duclos (COLD) Epidermal nevus Syndrome Encephalocraniocutaneous Lipomatosis Xeroderma pigmentosum RARE VASCULAR RARE MELANO PHAKOMATOSES PHAKOMATOSES PHACE Sdr Hypomelanosis of Ito THE RARE PHAKOMATOSES Ataxia Telangiectasia Incontinentia Pigmenti Wyburn-Mason Waardenburg Syndrome HHT Neurocutaneous Melanosis MTOR AND BEYOND Blue Rubber Bleb Nevus of Ota Nevus McCune-Albright Meningioangiomatosis Nelson Syndrome Mariasavina Severino, MD MAIN PHAKOMATOSES Neuroradiology Unit Neuro@ibromatosis type I IRCCS Istituto Giannina Gaslini, Genoa, Italy Neuro@ibromatosis type II Tuberous Sclerosis C. Sturge-Weber S. Von Hippel Lindau S. 1 2 OTHER RARE PHAKOMATOSES Basal Cell Nevus Syndrome Organoid Nevus Syndrome Cowden-Lhermitte-Duclos (COLD) Epidermal nevus Syndrome Encephalocraniocutaneous Lipomatosis Xeroderma pigmentosum RARE VASCULAR RARE MELANO PHAKOMATOSES PHAKOMATOSES PHACE Syndrome Hypomelanosis of Ito Ataxia Telangiectasia Incontinentia Pigmenti Wyburn-Mason Waardenburg Syndrome Neurocutaneous Melanosis HHT Nevus of Ota AUTOSOMAL DOMINANT Blue Rubber Bleb Nevus McCune-Albright AUTOSOMAL RECESSIVE Meningioangiomatosis Nelson Syndrome MAIN PHAKOMATOSES X-LINKED NeurofiBromatosis I NeurofiBromatosis II MOSAICISM TuBerous Sclerosis C. MELANO VASCULAR Sturge-WeBer S. PHACE Syndrome Von Hippel Lindau S. PHAKOMATOSES PHAKOMATOSES 3 4 GENETIC mTOR & RAS PATHWAYS MOSAICS KEY CELL SIGNALING PATHWAYS EXTENT AND SEVERITY ü timing of the postzygotic mutation ü amount of involved cells Campbell MI et al 2015 van Steensel, J Pediatr Genet 2015 5 6 1 19/01/21 mTOR & RAS PATHWAYS mTOR & RAS PATHWAYS KEY CELL SIGNALING PATHWAYS KEY CELL SIGNALING PATHWAYS Regulation of eukaryotic cellular functions translation, transcription, protein turnover, cell growth, differentiation, cell survival, metabolism, energy balance, and stress response Developmental disorders Tumors Overgrowth van Steensel, J Pediatr Genet 2015 7 8 ROLE OF G-PROTEINS IN CELL SIGNALING McCUNE-ALBRIGHT SYNDROME ACTIVATING INTRACELLULAR ENZYMES Skin hyperpigmentation (cost of Maine pattern) Macroadenomas Guanine nucleo+de binding proteins G-protein coupled receptor (GPCR) GNAS1 mutations Inactivate state: GDP Fibrous osseous Activate state: GTP dysplasia The α-subunit scoots off and activates the associated enzyme © blobs.org Dumitrescu and Collins, OJRD 2008 9 10 mTOR & RAS PATHWAYS KEY CELL SIGNALING PATHWAYS van Steensel, J Pediatr Genet 2015 11 12 2 19/01/21 5-year-old boy - Seizures, psychomotor delay, scoliosis, sensorimotor deficits, ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS choristoma and nevus psiloliparus • CUTANEOUS LESION: Nevus psiloliparus -> hairless fatty tissue nevus of the scalp (dermatological hallmark!) • OCULAR ANOMALIES: Choristomas, corneal and anterior chamber anomalies, colobomas, microphthalmia, and calcification • CNS INVOLVEMENT: lipomas, HME, low-grade tumors, ventricular dilatation, mental retardation and/or seizures * * * Parazzini AJNR 1999 Moog Am J Med Genet A 2007 13 14 @ 10.5 years … Multifocal DNET T2 T1 Gd+ FLAIR Gd+ 15 16 mTOR & RAS PATHWAYS KEY CELL SIGNALING PATHWAYS MOSAIC SOMATIC MUTATION PIK3CA- RELATED OVERGROWTH SPECTRUM MIC-CM, M-CM, CILF CLOVES and KTS 17 18 3 19/01/21 MACROCEPHALY-CAPILLARY MALFORMATION MACROCEPHALY-CAPILLARY MALFORMATION Formerly known as Macrocephaly–cutis marmorata telangiectatica congenita Formerly known as Macrocephaly–cutis marmorata telangiectatica congenita • Macrocephaly Hemimegalencephaly 53%, Megalencephaly, Hydrocephalus, • Patchy, reticular CM PMG, Chiari I, Enlarged dural sinuses, Vascular abnormalities (philtrum, upper lip and nose, limbs and trunk) * * • Overgrowth and asymmetry • Syndactyly/polydactyly and connective tissue defects Martinez-Gletz et al. AJMG Part A 2010 Conway et Al. Am J Med Genet Part A 2007 19 20 5-year-old boy with capillary malformation of the philtrum, developmental delay and left body overgrowth mTOR & RAS PATHWAYS KEY CELL SIGNALING PATHWAYS MOSAIC SOMATIC MUTATION 21 22 PROTEUS SYNDROME CNS: macrocephaly, HME, callosal dysgenesis, neuronal migration disorders and calciUications SKIN: Cerebriform connective tissue nevi and epidermal nevi OVERGROWTH: Distorting, progressive overgrowth, adipose dysregulation (lipomatous overgrowth/lipoatrophy), tumors LUNG: bullous pulmonary degeneration - predisposition to deep vein thrombosis and pulmonary embolism VASCULAR: CM, VM and LM 15 year-old girl with macrocephaly, scoliosis, cerebriform connective tissue nevi, previous thyroid cancer and ovary germ cell tumor Rodenbeck et al 2016 23 24 4 19/01/21 16-day-old girl with facial epidermal nevus and epilepsy PNS tumor Lipomas Odontogenic adamantinous tumor 1 year later… Ovaric and Renal Tumors 3 years later… * * * 25 26 mTOR & RAS PATHWAYS PTEN HAMARTOMA TUMOR SYNDROME AD cancer-predisposition syndrome KEY CELL SIGNALING PATHWAYS • COWDEN SYNDROME : multiple hamartoma syndrome, benign and malignant tumors of the thyroid, breast, and endometrium • BANNAYAN-RILEY-RUVALCABA SYNDROME: macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis • PTEN-RELATED PROTEUS SYNDROME and PROTEUS-LIKE SYNDROME AUTOSOMAL DOMINANT MUTATION DYSPLASTIC GANGLIOCYTOMA OF THE CEREBELLUM LHERMITTE–DUCLOS DISEASE Bosemani et Al Neuroimag Clin N Am 2016 27 28 7 year-old boy with macrocephaly, penis freckling, cognitive impairment and autistic features mTOR & RAS PATHWAYS KEY CELL SIGNALING PATHWAYS MOSAIC SOMATIC MUTATION 29 30 5 19/01/21 EPIDERMAL NEVUS SYNDROMES EPIDERMAL NEVUS SYNDROMES SPECTRUM OF CONDITIONS WITH OVERLAPPING FEATURES CNS manifestations: HME, ventricular enlargement, neuronal EPIDERMAL AND ADNEXAL HAMARTOMAS nevus sebaceous, inflammatory migration abnormalities, vascular malformations, enlarged linear verrucous epidermal nevus, nevus comedonicus, keratinocytic nevi perivascular spaces EXTRACUTANEOUS ABNORMALITIES predominantly affecting the eye, heart, and the musculoskeletal and nervous systems newborn Follow-up after 4 years Amato et al, AJNR 2010 Amato et al, AJNR 2010 31 32 mTOR & RAS PATHWAYS NEUROCUTANEOUS MELANOSIS KEY CELL SIGNALING PATHWAYS Large/multiple congenital melanocitic nevi associated with meningeal and parenchymal melanosis or intracranial melanomas • Posterior axial location of giant CMN NCM criteria (i) size: > 20 cm in an adult, > 9 cm on the • Hydrocephalus, focal neurological signs, infant scalp, or > 6 cm on the infant body (ii) number: greater than or equal to 3 MOSAIC SOMATIC epilepsy (48%) (iii) no evidence of cutaneous malignant MUTATION melanoma except when examined • MELANOSIS: benign accumulation of meningeal lesions are histologically benign (iv) no evidence of malignant CNS melanoma, melanotic cells in areas where such cells except where examined areas of the are normally present cutaneous lesions are histologically benign 33 34 Hemimegalencephaly and PhaKomatoses MC-M Tuberous Sclerosis Hypomelanosis of Ito Capillary Adenoma Hypomelanosis along malformation Sebaceum Blaschko lines Klippel-Trenaunay Epidermal nevus Proteus Encephalocraniocutaneous syndrome case8c.jpg 457syndrome×691 pixels Syndrome 17/01/11lipomatosis 17:01 Port-wine stains and limb Nevus sebaceus of Cerebroid-gyriform Facial lipoma and The Rare Phakomatoses. Edelstein S et al, in Pediatric Neuroradiology, Tortori-Donati hypertrophy Jadassohn hypertrophy of the skin Nevus psiloliparus 35 36 6 http://dermatology.cdlib.org/DOJvol7num1/NYUcases/nevus/case8c.jpg Pagina 1 di 1 19/01/21 Hemimegalencephaly and Phakomatoses GENETIC MOSAICS The extent and the severity of the condition will depend on the timing of the postzygotic mutation and the amount oF cells involved. PROGRESSIVE ATROPHY OF ENLARGED HEMISPHERE Destructive-apoptotic process MEG/HME/FCD is a single neurobiological spectrum disorder! Abnormal gyral pattern Calci@ications Accelerated myelination Enlarged ventricles Griffiths Ajnr 1998, Sakuma Brain Dev 2005 37 38 GENETIC ACTUAL PERSPECTIVES MOSAICS TARGETED THERAPY FOR RARE PHAKOMATOSES EXTENT AND SEVERITY ü timing of the postzygotic mutation BRAF ü amount of inhibitors involved cells RAPAMYCIN Ef@icacy in various TSC manifestations (renal angiomyolipomas, SEGA) 39 40 9-month old girl, GH de@iciency, dev delay, CM 2011 2010 PIK3CA- RELATED OVERGROWTH SPECTRUM CILF Congenital inUiltrating lipomatosis of the face © Dr C. Doneda 41 42 7 19/01/21 Sirolimus (Rapamycin) Feb 2016 – May 2017 Sep 2018 ? BYL719 inhibitor of PIK3CA 43 44 CONCLUSIONS CONCLUSIONS v The mosaic and germline disorders of the mTOR and RAS v These clinical presentations should be genetically signaling pathways share a common molecular axis confirmed because each condition has unique implications controlling: for disease management v Cell proliferation v Malformations v Cell differentiation v Overgrowth v Understanding how mutations in these genes intersect with v Cell death v Tumors one signaling pathway provides rationale for practical therapeutic approaches v Distinct mutations in these pathways are associated with highly variable clinical presentations v Recognizing how mosaic involvement leads to variations in patterning explains the patchy and often asymmetric distribution of cutaneous and systemic involvement 45 46 Thank you! [email protected] 47 8.
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