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The PhakomatosesThe PhakomatosesJames G. Smirniotopoulos, M.D. James G. Smirniotopoulos, M.D.
Uniformed Services UniversityUniformed Services University4301 Jones Bridge Road4301 Jones Bridge Road
Bethesda, MD 20814 Bethesda, MD 20814 Voice: 301Voice: 301--295295--31453145
FAX: 301FAX: 301--295295--38933893
Visit us on the WEB:Visit us on the WEB:http://http://rad.usuhs.rad.usuhs.eduedu
Educational ObjectivesEducational Objectives
Describe why NFDescribe why NF--1 is truly 1 is truly ““NeurofibromatosisNeurofibromatosis””Describe three neoplasms caused by the Describe three neoplasms caused by the chromosome 22 mutation in NFchromosome 22 mutation in NF--22Explain why Tuberous Sclerosis is a Explain why Tuberous Sclerosis is a disorder of neuronal migrationdisorder of neuronal migration
DorlandDorland’’s Medical Dictionarys Medical DictionaryBirthmarksBirthmarks
“Bummer of a birthmark,
Hal”
PHAKOMATOSES:PHAKOMATOSES:Why Study Them?Why Study Them?
They are COMMON diseasesThey are COMMON diseasesDIAGNOSED by ImagingDIAGNOSED by ImagingGENETIC ImplicationsGENETIC ImplicationsSCREEN RelativesSCREEN RelativesSURVEILLANCE of AffectedSURVEILLANCE of Affected
Phakomatoses Mnemonic ToolPhakomatoses Mnemonic ToolNFNF--1 (von Reck's)1 (von Reck's)–– TRUE Neurofibromatosis #17TRUE Neurofibromatosis #17
NFNF--2 (Bilateral VS Syndrome)2 (Bilateral VS Syndrome)–– M.I.S.M.E. #22M.I.S.M.E. #22
TUBEROUS SCLEROSISTUBEROUS SCLEROSIS–– Pringle's "HAMARTOMA" DiseasePringle's "HAMARTOMA" Disease
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Tumor Suppressor Gene:Tumor Suppressor Gene:““Two HitTwo Hit”” HypothesisHypothesis
No gene
No protein
One copy of gene,
some protein
1st Mutation ‘Hit’Germ Line
Mutation: Ovary, Testis, or Embryo
Somatic
Mutation
2nd Mutation ‘Hit’
NEUROFIBROMATOSES NEUROFIBROMATOSES -- TYPESTYPES
Neurofibromatosis Type 1 (NFNeurofibromatosis Type 1 (NF--1)1)-- von Recklinghausen Diseasevon Recklinghausen Disease-- "True" Neurofibromatosis"True" Neurofibromatosis-- Prominent Cutaneous SignsProminent Cutaneous Signs-- Chromosome 17qChromosome 17q
Neurofibromatosis Type 2 (NFNeurofibromatosis Type 2 (NF--2)2)-- Bilateral Acoustic SchwannomaBilateral Acoustic Schwannoma-- "Central Neurofibromatosis""Central Neurofibromatosis"-- Minimal Skin ManifestationsMinimal Skin Manifestations-- Chromosome 22qChromosome 22q
Neurofibromatosis Type Neurofibromatosis Type 11
von Recklinghausen von Recklinghausen DiseaseDisease
Chromosome 17Chromosome 17
NIH Diagnostic Criteria: 2 from NIH Diagnostic Criteria: 2 from listlist
CafeCafe--AuAu--Lait spotsLait spots–– 6 or more6 or more–– 5 mm child, 15 mm adult5 mm child, 15 mm adult
Neurofibromas Neurofibromas -- 2 or more2 or morePlexiform Neurofibroma Plexiform Neurofibroma -- 11Axillary (Intertriginous) Freckling Axillary (Intertriginous) Freckling -- 11Optic GliomaOptic GliomaLisch Nodules (Iris) Lisch Nodules (Iris) -- 2 or more2 or more"Distinctive Bone Lesions""Distinctive Bone Lesions"11stst degree Relative with NFdegree Relative with NF--11
NFNF--1: EYE MANIFESTATIONS1: EYE MANIFESTATIONS
LISCH Nodules (Iris Hamartomas)LISCH Nodules (Iris Hamartomas)–– Penetrance > 90%Penetrance > 90%–– Specificity > 90%Specificity > 90%–– Translucent/pigmentedTranslucent/pigmented–– Small ( < 3mm.), SlitSmall ( < 3mm.), Slit--Lamp ExamLamp Exam
OPTIC GLIOMAOPTIC GLIOMA–– Up to 15% of patientsUp to 15% of patients–– Pilocytic AstrocytomasPilocytic Astrocytomas–– Benign ("HamartomaBenign ("Hamartoma--like"), Tx?like"), Tx?–– True Neoplasms, spread along SASTrue Neoplasms, spread along SAS–– up to 1/2 of Childhood ONG w/NFup to 1/2 of Childhood ONG w/NF--11
Lisch NodulesLisch Nodules
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Optic Nerve GliomaOptic Nerve Glioma Optic Nerve GliomaOptic Nerve Glioma
Bilateral Optic Nerve GliomaBilateral Optic Nerve Glioma
Courtesy of Greg Petermann, M.D.
NEUROFIBROMATOSIS NEUROFIBROMATOSIS -- 11
Cutaneous ManifestationsCutaneous Manifestations–– CafeCafe--auau--Lait spotsLait spots–– Intertriginous FrecklingIntertriginous Freckling–– Neurofibromas (Skin and SubQ)Neurofibromas (Skin and SubQ)–– Fibroma Molluscum (TNTC NFB)Fibroma Molluscum (TNTC NFB)–– Elephantiasis Neuromatosa Elephantiasis Neuromatosa
diffuse skin thickening/plexiform NFBdiffuse skin thickening/plexiform NFB--oror-- focal gigantismfocal gigantism
CafCaféé--auau--lait spotlait spot Axillary FreckleAxillary Freckle
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NEUROFIBROMATOSIS NEUROFIBROMATOSIS -- 11Bone Dysplasia and RemodelingBone Dysplasia and Remodeling
MacrocephalyMacrocephalyCraniofacial dysplasiaCraniofacial dysplasia–– especially sphenoidespecially sphenoid
VertebraeVertebrae (scalloping, scoliosis)(scalloping, scoliosis)PseudoarthrosisPseudoarthrosis–– especially congenitalespecially congenital
Genu Valgum/VarumGenu Valgum/VarumTwisted "Ribbon Ribs"Twisted "Ribbon Ribs"
Sphenoid DysplasiaSphenoid Dysplasia
Courtesy of Greg Petermann, M.D.
Sphenoid DysplasiaSphenoid Dysplasia
Courtesy of Greg Petermann, M.D.
Progressive Progressive PseudoarthrosisPseudoarthrosis
Bowing Deformity 8 mo. Later
PseudoPseudo--arthrosisarthrosis
Hyperemic
demineralization
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Focal GigantismFocal Gigantism NERVE SHEATH TUMORSNERVE SHEATH TUMORSSchwannoma (Sporadic >> NFSchwannoma (Sporadic >> NF--2 > NF2 > NF--1)1)–– focal massfocal mass–– usually sensory root, cranial and spinal nervesusually sensory root, cranial and spinal nerves
NeurofibromaNeurofibroma–– usually NFusually NF--1, esp. if spinal or paraspinal1, esp. if spinal or paraspinal–– spindle or dumbspindle or dumb--bell lesionbell lesion
Plexiform Neurofibroma (usually NFPlexiform Neurofibroma (usually NF--1)1)–– diffuse or fusiform enlargementdiffuse or fusiform enlargement
Malignant Peripheral Nerve Sheath TumorMalignant Peripheral Nerve Sheath Tumor–– NFNF--1 or Sporadic1 or Sporadic
Neurofibroma vs. SchwannomaNeurofibroma vs. Schwannoma
NeurofibromaNeurofibroma–– Schwann cellsSchwann cells–– FibroblastsFibroblasts–– Acellular materialAcellular material–– InfiltratingInfiltrating–– Resect Parent NerveResect Parent Nerve
SchwannomaSchwannoma–– Schwann Cell Schwann Cell
NeoplasmNeoplasm–– Secondary vascular Secondary vascular
changeschanges–– Mostly cellularMostly cellular–– EncapsulatedEncapsulated–– Nerve Sparing SurgeryNerve Sparing Surgery
SchwannomaSchwannoma
NeurofibromaNeurofibroma Distribution of Nerve Sheath Distribution of Nerve Sheath TumorsTumors
IntraIntra--Cranial => SchwannomaCranial => Schwannoma–– Sporadic >> NFSporadic >> NF--22Spinal => Both Types (S >> N)Spinal => Both Types (S >> N)Dumbbell => Both (N >> S)Dumbbell => Both (N >> S)PNS => BothPNS => BothCutaneous => NeurofibromaCutaneous => Neurofibroma–– Usually N in NFUsually N in NF--11
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Neurofibromatosis : SpineNeurofibromatosis : Spine
Scoliosis (NFScoliosis (NF--1, only?)1, only?)–– Simple ("idiopathic")Simple ("idiopathic")–– Acute Cervical KyphosisAcute Cervical Kyphosis
Dural Ectasia (NFDural Ectasia (NF--1, only?)1, only?)–– Vertebral ScallopingVertebral Scalloping–– Arachnoid "cysts"Arachnoid "cysts"–– Lateral Thoracic meningoceleLateral Thoracic meningocele
Acute Cervical KyphoscoliosisAcute Cervical Kyphoscoliosis
Neurofibromatosis : SpineNeurofibromatosis : Spine
Neurofibroma (NFNeurofibroma (NF--1)1)Osteoporosis (NFOsteoporosis (NF--1, only?)1, only?)–– IdiopathicIdiopathic–– Parathyroid AdenomaParathyroid Adenoma
Schwannoma (NFSchwannoma (NF--2)2)Meningioma (NFMeningioma (NF--22Ependymoma (NFEpendymoma (NF--2)2)
NF-2
Neurofibromatosis:Neurofibromatosis:Enlarged Neural ForamenEnlarged Neural Foramen
Nerve Sheath TumorNerve Sheath Tumor–– NeurofibromaNeurofibroma
NFNF--1 >> sporadic1 >> sporadic"dumbbell"dumbbell““ shapeshape
–– SchwannomaSchwannomasporadic >> NFsporadic >> NF--22
Mesodermal DefectMesodermal Defect–– NFNF--1 only?1 only?–– Dural weaknessDural weakness–– Bone weaknessBone weakness
Multiple Dumbbell LesionsMultiple Dumbbell Lesions NeurofibromaNeurofibroma vs.vs. SchwannomaSchwannoma
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Rib NotchingRib Notching•Aortic Coarctation
–Older than 5-6 years–3-9 possible–Ribs 5-8 most often–1-2 arise from subclavian artery–Usually Bilateral–Unilateral on the Right
–if Coarctation involves Left Subclavian origin
•A-V Fistulae•Nerve Sheath tumors
Plexiform NFPlexiform NF
Multiple NeurofibromasMultiple Neurofibromas Tumors of the Nerve SheathsTumors of the Nerve Sheaths
Courtesy of Greg Petermann, M.D.
NEUROFIBROMATOSIS NEUROFIBROMATOSIS -- 1:1:DBODBO’’ss MR Signal AbnormalitiesMR Signal Abnormalities
T1W Bright FociT1W Bright Foci–– globus pallidusglobus pallidus
T2W Bright FociT2W Bright Foci–– w/o mass, don't enhancew/o mass, don't enhance–– Cerebellar peduncles, Pons, midbrainCerebellar peduncles, Pons, midbrain–– globus pallidus, thalamus, optic radiationsglobus pallidus, thalamus, optic radiationsWhat in the heck are they??What in the heck are they??–– Ectopic Schwann cells, Ectopic Schwann cells, MelanocytesMelanocytes ????–– IntramyelinIntramyelin VacuolesVacuoles–– DysmyelinationDysmyelination ????–– Intracellular proteinaceous fluid ?Intracellular proteinaceous fluid ?
May become Neoplasms (uncommon)May become Neoplasms (uncommon)
High signal in Brain on T2 High signal in Brain on T2 Resolve over age 10Resolve over age 10
Courtesy of Greg Petermann, M.D.
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DBODBO’’ss of NFof NF--1: Cerebellar peduncle1: Cerebellar peduncle
Early ----- Later
Neurofibromatosis Type 1Neurofibromatosis Type 1
Neurofibromatosis Type 2Neurofibromatosis Type 2
vs.
James Brown or James S.?James Brown or James S.?
Hugh Curtin of the
Mass Eye and Ear
Little man behind the
Curtin
Neurofibromatosis Type Neurofibromatosis Type 22oror
WishartWishart DiseaseDiseaseChromosome 22Chromosome 22
NEUROFIBROMATOSES NEUROFIBROMATOSES -- TYPESTYPES
Neurofibromatosis Type 1 (NFNeurofibromatosis Type 1 (NF--1)1)-- von Recklinghausen Diseasevon Recklinghausen Disease-- "True" Neurofibromatosis"True" Neurofibromatosis-- Prominent Cutaneous SignsProminent Cutaneous Signs-- Chromosome 17qChromosome 17q
Neurofibromatosis Type 2 (NFNeurofibromatosis Type 2 (NF--2)2)-- Bilateral Acoustic SchwannomaBilateral Acoustic Schwannoma-- "Central Neurofibromatosis""Central Neurofibromatosis"-- Minimal Skin ManifestationsMinimal Skin Manifestations-- Chromosome 22qChromosome 22q
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NEUROFIBROMATOSIS NEUROFIBROMATOSIS -- Type Type 22
Incidence: 1/50,000Incidence: 1/50,000Inheritance: Autosomal DominantInheritance: Autosomal DominantAge at Presentation: Birth to 40's (peak in 20Age at Presentation: Birth to 40's (peak in 20’’s)s)Sx at Presentation: Hearing loss from VSSx at Presentation: Hearing loss from VSDiagnostic Criteria: VIII massesDiagnostic Criteria: VIII massesChromosome Abnl.: 22Chromosome Abnl.: 22Cutaneous Findings: minimal (skin tags)Cutaneous Findings: minimal (skin tags)CNS Findings: Schwannoma, Meningioma, CNS Findings: Schwannoma, Meningioma, Ependymoma (intramedullary spinal cord)Ependymoma (intramedullary spinal cord)
CNS Neoplasms CNS Neoplasms -- Chromosome Loss Chromosome Loss of Heterozygosityof Heterozygosity
Schwannoma Schwannoma -- 22q22qMeningioma Meningioma -- 22q (long arm)22q (long arm)Ependymoma Ependymoma -- 2222
NF-2
NOT Neurofibroma
NOT Astrocytoma
NOT Optic GliomaNF-1
NFNF--2 ("CENTRAL"), 1 OR MORE2 ("CENTRAL"), 1 OR MORE
Bilateral VIIIth MassesBilateral VIIIth MassesRelative with NFRelative with NF--2 and either:2 and either:–– Unilateral VIIIth MassUnilateral VIIIth Mass
–– Any Two:Any Two:"Neurofibroma", Meningioma, Glioma, "Neurofibroma", Meningioma, Glioma, Schwannoma, (Congenital) Lens OpacitySchwannoma, (Congenital) Lens Opacity
Intracanalicular SchwannomaIntracanalicular Schwannoma
Bilateral Vestibular Bilateral Vestibular SchwannomaSchwannoma
T1W axial
From Laszlo Mechtler, DNI
SCHWANNOMASCHWANNOMA
55--10% of All CNS Tumors10% of All CNS TumorsBenign, Slowly growingBenign, Slowly growingF > M (Intracranial), M > F (Spinal)F > M (Intracranial), M > F (Spinal)30's 30's -- 60's, w/NF60's, w/NF--2 10's 2 10's -- 30's30'sSensory Nerves (usually):Sensory Nerves (usually):–– CNN VIII (Sup.Vestibular), V, XCNN VIII (Sup.Vestibular), V, X–– Spine: Dorsal RootsSpine: Dorsal Roots
Majority (>90%) are SporadicMajority (>90%) are SporadicMultiple in NFMultiple in NF--2, Bilat.VIII Pathognomonic2, Bilat.VIII Pathognomonic
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Bilateral Vestibular SchwannomaBilateral Vestibular Schwannoma Bilateral Vestibular SchwannomaBilateral Vestibular Schwannoma
Bilateral vestibular and one Trigeminal Schwannoma
T1-contrast axialFrom Laszlo Mechtler, DNI
8th
8th
5th
Multiple MeningiomasMultiple Meningiomas
Multiple Schwannomas and Multiple Schwannomas and MeningiomasMeningiomas
8th 8th
Multiple Schwannomas, Multiple Schwannomas, Meningiomas, and EpendymomasMeningiomas, and Ependymomas
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M I S M E SyndromeM I S M E Syndrome
M M ultipleultipleI I nheritednheritedS S chwannomachwannomaM M eningiomaeningiomaE ependymomaE ependymoma
Tuberous SclerosisTuberous Sclerosisor or
Bourneville DiseaseBourneville DiseaseChromosomes 9 and 16Chromosomes 9 and 16
TUBEROUS SCLEROSISTUBEROUS SCLEROSIS
Original Original ““VOGT TRIADVOGT TRIAD””FACIAL NEVUS (ADENOMA SEBACEUM)FACIAL NEVUS (ADENOMA SEBACEUM)SEIZURESSEIZURESMENTAL DEFICIENCYMENTAL DEFICIENCY
TUBEROUS SCLEROSISTUBEROUS SCLEROSIS
AUTOSOMAL DOMINANTAUTOSOMAL DOMINANTNo Racial/SexualNo Racial/SexualHigh Spontaneous MutationHigh Spontaneous MutationHigh PenetranceHigh Penetrance–– "SPORADIC" over"SPORADIC" over--reportedreported
Multiple GenesMultiple Genes–– TSC1 TSC1 -- 9q9q–– TSC2 TSC2 -- 16p16p
Tuberous Sclerosis, NIH Consensus Tuberous Sclerosis, NIH Consensus ConferenceConference
Major Features: Major Features: Facial angiofibroma or forehead Facial angiofibroma or forehead plaque plaque Ungual or Periungual fibroma Ungual or Periungual fibroma >3 >3 HypomelanoticHypomelanotic macules macules ShagreenShagreen patch patch Multiple retinal nodular Multiple retinal nodular hamartomas hamartomas Cortical Tuber Cortical Tuber Subependymal Nodule Subependymal Nodule Subependymal Giant Cell Subependymal Giant Cell Astrocytoma Astrocytoma Cardiac rhabdomyoma Cardiac rhabdomyoma Lymphangiomyomatosis Lymphangiomyomatosis Renal angiomyolipoma Renal angiomyolipoma
Minor Features: Minor Features: Multiple dental Multiple dental enamalenamal pits pits Hamartomatous rectal polyps Hamartomatous rectal polyps Bone cysts Bone cysts White matter migration lines White matter migration lines Gingival fibromas Gingival fibromas NonNon--renal hamartoma renal hamartoma Retinal achromic patch Retinal achromic patch "Confetti" skin lesions "Confetti" skin lesions Multiple renal cysts Multiple renal cysts
Hyman MH, Whittemore VH:"National Institutes of Health Consensus Conference:tuberous sclerosis Complex" Arch Neurol 2000; 57: 662-665.
Definite TS - (2 Major) or (1 Major + 2 Minor)
Probable TS - 1 Major + 1 Minor
Possible TS - (1 Major) or (2 Minor)
Adenoma Sebaceum Adenoma Sebaceum
AKA PRINGLE'S DISEASEAKA PRINGLE'S DISEASENOT present at birthNOT present at birthdevelop before pubertydevelop before pubertynasolabial fold nasolabial fold -->bi>bi--malarmalarpapules of angiofibromapapules of angiofibroma
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PringlePringle’’s Diseases Disease PringlePringle’’s Diseases Disease
PringlePringle’’s Diseases Disease
PringlePringle’’s Names Name–– Entire DiseaseEntire Disease–– Facial lesion onlyFacial lesion only
Mild Mental Mild Mental RetardationRetardationSeizuresSeizuresHard PotatoesHard PotatoesTubular Can Tubular Can ––‘‘TuberousTuberous’’
Subungual/Periungual FibromaSubungual/Periungual Fibroma
Confetti HypopigmentationConfetti Hypopigmentation Depigmentation:Depigmentation:
AshAsh--Leaf SpotsLeaf Spots–– (Lance(Lance-- Ovate Shape)Ovate Shape)
ConfettiConfetti-- Like HypopigmentationLike Hypopigmentation–– (Inverse Freckle)(Inverse Freckle)
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Ash Leaf MaculeAsh Leaf Macule
Lance Ovate Shape
Astrocytic HamartomaAstrocytic Hamartoma
Astrocytic HamartomaAstrocytic Hamartoma Tuberous Sclerosis Tuberous Sclerosis -- Brain:Brain:
HETEROTOPIAS AND HAMARTOMASHETEROTOPIAS AND HAMARTOMAS–– in white and gray matterin white and gray matter
CORTICAL TUBERSCORTICAL TUBERS–– "HAMARTOMAS""HAMARTOMAS"–– but with abnormal "N" cellsbut with abnormal "N" cells–– neither Astrocyte nor Neuronneither Astrocyte nor Neuron–– Decreased MyelinationDecreased Myelination–– No laminar architectureNo laminar architecture
Tuberous Sclerosis Tuberous Sclerosis -- Brain:Brain:
SUBEPENDYMAL NODULES (almost 100%)SUBEPENDYMAL NODULES (almost 100%)–– "hamartomas" vs. neoplasia"hamartomas" vs. neoplasia–– Caudothalamic grooveCaudothalamic groove–– Polypoid "Candle Gutterings"Polypoid "Candle Gutterings"
DILATED VENTRICLESDILATED VENTRICLES–– variablevariable–– obstructive, atrophic vs. "idiopathic"obstructive, atrophic vs. "idiopathic"
TUMORS 15%TUMORS 15%SubSub--ependymal Giant Cell Astrocytomaependymal Giant Cell Astrocytoma–– True neoplasm, Benign WHO Grade ITrue neoplasm, Benign WHO Grade I
Cortical TubersCortical Tubers
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Cortical TubersCortical Tubers Periventricular Ca++Periventricular Ca++
Subependymal NodulesSubependymal Nodules Subependymal NodulesSubependymal Nodules
TS in newbornTS in newborn
Courtesy Mauricio Castillo, M.D. UNC
Subependymal NodulesSubependymal Nodules
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Germinal MatrixGerminal Matrix
Hypervascular
Neuroblast Factory
Post-mitotic neuroblasts migrate out along radial glia
Subependymal nodule Cortical
tuber
medpix20791.jpg Subependymal Giant Cell Subependymal Giant Cell AstrocytomaAstrocytoma
Tubers, Nodules, and TumorsTubers, Nodules, and Tumors AngioAngiomyomyolipomalipoma
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AngioAngiomyomyolipomalipoma ANGIOMYOLIPOMA:ANGIOMYOLIPOMA:
10% w/enough FAT for plain film10% w/enough FAT for plain film1/6 of Solitary AML Pts. Have TS1/6 of Solitary AML Pts. Have TS1/31/3--1/2 of solitary AML Pts. Have other 1/2 of solitary AML Pts. Have other stigmata of TSstigmata of TS5050--80% of Pts. W/TS will have AML80% of Pts. W/TS will have AML3/4 Multiple3/4 Multiple1/3 1/3 -- 1/2 Bilateral (probably more)1/2 Bilateral (probably more)variable amts. of variable amts. of FATFAT, Smooth mm., and , Smooth mm., and vesselsvessels
Renal CystsRenal Cysts Cardiac RhabdomyomaCardiac Rhabdomyoma
SummarySummary
Phakomatoses Mnemonic ToolPhakomatoses Mnemonic ToolNFNF--1 (von Reck's)1 (von Reck's)–– TRUE Neurofibromatosis #17TRUE Neurofibromatosis #17
NFNF--2 (2 (BilBil. VIII Syndrome) . VIII Syndrome) –– M.I.S.M.E. #22M.I.S.M.E. #22
TUBEROUS SCLEROSISTUBEROUS SCLEROSIS–– Pringle's "HAMARTOMA" Disease Pringle's "HAMARTOMA" Disease
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NeurfibromatosisNeurfibromatosis Type 1:Type 1:Skin, Nerves, Optic Skin, Nerves, Optic
Astrocytoma, Brain Astrocytoma, Brain DBODBO’’ss, , Spine and BoneSpine and Bone
Courtesy of Greg Petermann, M.D.
Neurofibromatosis Type 2Neurofibromatosis Type 2No specific skin findingsNo specific skin findings
M.I.S.M.E.M.I.S.M.E.
Courtesy of Greg Petermann, M.D.
Tuberous SclerosisTuberous SclerosisHamartomas and PringlesHamartomas and Pringles Thank You!Thank You!
EUXAPIEUXAPIΣΣTTΩΩ !!
Mahalo !Mahalo !Gracias! Gracias! ObregadoObregado
Merci BeaucoupMerci BeaucoupDanke Danke ShoenShoen
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