INTRODUCTIONPhakomatoses (or "neurocutaneous syndromes") are multisystem disordersinherited or spontaneous mutationCommon ectodermal originAdvances in molecular biology have been able to localize the genetic abnormality
NEUROFIBROMATOSIS TYPE 1NF1 is the classic von Recklinghausen or "peripheral" disease.AD disorder/Spontaneous mutationMost common, 1 in 2000 to 3000 live birthsInherited predisposition for the development of benign peripheral nerve sheath tumors (neurofibromas) true CNS neoplasms
Diagnostic criteriaTwo or more of the following: Six or more cafe´ au lait spots 0.5 cm or larger in prepubertal individuals 1.5 cm or larger in postpubertal individualsone plexiform neurofibromas or 2/more neurofibromas of any typeTwo or more Lisch nodules (benign hamartomas)Freckling in the axilla or groinOptic gliomasA distinctive bony lesion Dysplasia of the sphenoid bone ,Dysplasia or thinning of long bone cortexFirst degree relative with NF1
Neuroimaging FindingsCNS lesions in 15-20% brain, spinal cord, dural, orbital, vascularHamartomatous and neoplastic lesionsMultifocal T2 hyperintense signal changes in 80% of patientsOptic nerve(5-15%) and non optic glioma(low grade astrocytoma)Plexiform Neurofibromas in the head and neck(1/3rd of patients)-diagnostic
Optic Nerve GliomasAn important and often diagnostic feature of NF1Surveillance is important, because up to 80% of patients with ONGs are asymptomaticB/L ONGs is considered specific for NF1Primary findings of ONG includeabnormal optic nerve thickeningbeading and elongationabnormal enhancement
Plexiform neurofibromacutaneous or subcutaneous neurofibromasintraorbital and facial br of CN III - VI,MC affects CN VDiffuse plexiform neurofibroma of the face and eyelids,Sphenoid dysplasia is one of the "distinctive bone lesions”
SKELETAL MANIFESTATIONS : MOST COMMONLY INVOLVED AREAS-SPINE & SKULL. 1.SPINE:KYPHOSCOLIOSIS OF LOWER THORACIC SPINE(MOST COMMON),CERVICAL SPINE. POSTERIOR VERTEBRAL BODY SCALLOPING; POSTEROCENTRAL DUE TO DURAL ECTASIA. ECCENTRIC UNILATERAL DUE TO DUMBBELL NEUROFIBROMA. ENLARGED INTERVERTEBRAL FORAMEN PARASPINAL SOFT TISSUE. DUMBBELL NEUROFIBROMA INTRATHORACIC meningocele
2.SKULL: -AGENESIS OR HYPOPLASIS OF POSTERIOR WALL OF ORBIT, WINGS OF SPHENOID & ORBITAL PLATE OF FRONTAL. -OPTIC FORAMEN ENLARGEMENT -GEOGRAPHIC BONE LESION AROUND THE LAMDOID SUTURE ALONG WITH MASTOID HYPOPLASIA. MACROCRANIUM. 3. RIB: - TWISTED RIBBON RIB– THIN IRREGULAR, SCALLOPED ATTENUATED APPEARANCE OF RIBS. 4. LONG BONES: - PSEUDOARTHOSIS. -FOCAL GIGANTISM -SUBPERIOSTEAL OR CORTICAL LUCENCIES DUE TO INTRAOSSEOUS NEUROFIBROMA. -CORTICAL PRESSURE RESORPTION DUE TO ADJACENT SOFT TISSUE
CASE 1: Cranio-orbital-temporal Neurofibromatosis(Plexiform neurofibroma of ophthalmic division oftrigeminal nerve) History :- # 15 year old female patient presented with a large painless swelling over right eyelid and face causing cosmetic deformity. Clinical examination :- # A large boggy swelling over right upper lid and temporal regions with a feeling of bag of worms on palpation. No vascular pulsation noted.
Fig 2b T2WI Fig 2c T2WI Fig 2d T1WI-GDFig 2a T1WI MRI (T1WI) & 3D Volume rendered CT images reveal – # Enlargement of the right middle cranial fossa with herniation of the right temporal lobe into the posterior aspect of the right orbit with a preceding anterior sleeve of CSF (fig 2a) # Hypoplasia of the greater wing of the sphenoid bone and superiorly displaced Fig 2e Fig 2f lesser wing, together giving the typical ‘Bare orbit sign’ (fig 2e)
CASE2: Cutaneous Neurofibroma with Extracranial Arterio-venous malformation and Atlanto-axial dislocation # 25 year old male patient presented with vertigo, tinnitus in left ear and a gradually progressing quadriparesis for 25 days. # Clinical examination revealed: 1. Multiple subcutaneous nodules with plexiform neurofibroma 2. Decreased power of all the limbs with intact sensations and bilateral extensor plantar jerks 3. Otoscopic examination, audiometry and Laboratory parameters were unremarkable.
Fig 3a T2FS sagittal Fig 3b T2FS sagittal Fig 3c T2 Coronal Sagittal and coronal MR images shows :- # Atlanto-axial dislocation with retropulsion of odontoid tip leading to secondary foramen magnum stenosis (fig 3a). # Dilated, Tortuous V3 segment of left vertebral artery with formation of multiple blood filled channels. (fig 3c,d). # Distended venous sac in anterior epidural space displacing the spinal cord posteriorly and to the right, causing compressive cord myelopathic changes (Fig 3b,c )Fig 3d T2 coronal
Fig 3d Fig 3a Fig 3b Fig 3cMR TOF Angiography images reveal:- Fig 3e# Arterio-venous malformation in posterolateral aspect of left side of neck .Feeders --- V3 segment of vertebral artery (fig 3a,b) & an anomalous artery arising from 1st part of left subclavian artery (fig 3c).Draining --- left sigmoid sinus (fig 3e) with a hugely distended venous sac in cervical canal. Fig 3f
Case 3 : Neurofibromas of the vagus nerve of the neck 32-years old female patient . Gradual onset of swelling , increasing on size on the right side of the neck for about few months. Clinical examination :An ill-defined, palpable lobulated lesion was observed on the left side of the neck. Café au lit spots were not detected on the skin.
Carotid an-giography done at Apollo hospital Delhi Biopsy.excluded a tumor of carotid wall Histological examination showed that the typical features of neu-rofibromatic tumour -spiral cells and highly collagenised stroma. Neurofibromas of the vagus nerve on the neck are extremely rare .
NF-1 : MR Signal Abnormalities - Globus pallidus T2W bright foci w/o mass, don’t enhance - Cerebellar peduncles, pons, midbrain - Globus pallidus , thalamus , optic radiations What in the heck are they?? - intracellular proteinous fluid? -Dysmyelination ?? T1W bright foci
Neurofibromatosis 2 NF2 also has an AD pattern,1 in 50000 Multiple cranial nerve schwannomas are the hallmark MC in vestibulocochlear nerve
DIAGNOSTIC CRITERIA FORNEUROFIBROMATOSIS 2 (NF2)Bilateral CP angle masses (histologic proof not required)A first-degree relative with NF2 and either-A unilateral CPA mass or-Any two of the following:schwannoma, meningioma, glioma, neurofibroma, or juvenile posterior subcapsular cataract
CNS lesions -100%Brain - CN VII schwannomas, multiple schwannomas of other cranial nerves,Meningiomas,Spinal cord/roots - Cord ependymomas, multilevel bulky schwannoma, MeningiomaSpine-Secondary changesCutaneous manifestations rare
DIAGNOSTIC CRITERIA FOR STURGE-WEBERSYNDROMESeizuresMental handicapPort-wine stain (neveus flammeus)Leptomeningeal capillary/venous malformation (ipsilateral to no. 1)Cerebral hemiatrophy (ipsilateral to no. 1)Facial hemihypertrophy (ipsilateral to no. 1)Somatic hemiatrophy (contralateral to no. 1)
CT and MR can reveal the secondarychanges, cerebral cortical atrophy, gyriform cerebral calcification (tram-track), compensatory ventricular enlargement, "angiomatous“ enlargement of the ipsilateral choroid plexus, and calvarial hemihypertrophy MR- direct visualization of the persistent embryologic plexus in subarachnoid space Ocular lesions - Buphthalmos, Scleral/choroidal angiomata
Dyke-Davidoff-Masson syndrome (DDMS) was initially described as changes in the skull seen on skull X-ray in patients with cerebral hemiatrophy, but is now applied more broadly to cross-sectional imaging also. It is characterised by :•thickening of the skull vault (compensatory)•enlargement of the frontal sinus (also ethmoidal and mastoid air-cells)•elevation of the petrous ridge•ipsilateral falcine displacementIn some sources it is equated to hemispheric infarction, whereas in other sources any cause ofcerebral hemiatrophy are included. EtymologyInitially described by C.G Dyke , L.M Davidoff and C.B Masson in 1933 5Differential diagnosisGeneral considerations includehemimegalencephaly :Sturge-Weber syndrome : can also be an associationRasmussen encephalitis : tends not to have calvarial changes
Tuberous sclerosisAD; 50% from new spontaneous mutations1 in 20,000 to 1 in 50,000nearly 40% of patients die by the age of35 yearsprominent cutaneous, visceral, and CNS manifestationsMost lesions are hamartomas
DIAGNOSTIC CRITERIA FOR TSCDefinite TSCTwo major features, orone major plus two minor features.Probable TSCOne major plus one minor feature.Possible TSCone major feature, ortwo or more minor features.
DIAGNOSTIC CRITERIA FOR TSCMAJOR FEATURESHypomelanotic macules (three or more), Shagreen patchFacial angiofibromas (adenoma sebaceum) or ungual or periungual fibromasMultiple retinal nodular hamartomas,Cortical tubers, Subependymal nodule, Subependymal giant cell astrocytomaCardiac rhabdomyoma - single or multipleLymphangiomyomatosis.Renal angiomyolipoma
DIAGNOSTIC CRITERIA FOR TSC MINOR FEATURES Multiple pits in dental enamel Gingival fibromas Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Retinal achromic patch Multiple renal cysts Nonrenal hamartoma "Confetti" skin lesions
Cortical tubers:considered to be closely related to neurologic manifestations of TS - epilepsy, cognitive disability, and neurolobehavioral abnormalities50% seen in frontal lobeHypointense on T1-WIHyperintense on T2-WI, FLAIROnly 10 % enhance
Subependymal Nodulesrepresent hamartomatous change.seen in 98%calcification detected in CT (88%)hyperintense on T1WIIso- to hyp0intense on T2WI
SGCAsproliferative astrocytes and giant cells.1.7%–26% prevalenceTypically in foramen of MonroDiffer from other cerebral astrocytomas in having a benign biologic and pathologic features (slow growth, minimal or no attendant brain edema, and minimal invasiveness)tend to be larger tumors (>1 cm) with incomplete calcifn & more intense enhancementMRS shows high Cho/Cr and low NAA/Cr r
White Matter AbnormalitiesSuperficial white matter abnormalities associated with cortical tubers, Radial white matter bands (15%–27%)Cystlike white matter lesions(15%–44%)
PULMONARY AND THORACICINVOLVEMENTlymphangioleiomyomatosis (LAM)multifocal micronodular pneumocyte hyperplasia (MMPH).approx 1%–2.3% of TS patients. complications of LAM Pneumothorax and chylous pleural effusion ascites.
round, thin-walled cysts of variable size and contour At thin-section CT, multiple tiny nodules (1–8 mm in diameter) are diffusely scattered throughout the lung in a random distribution
RENAL AND RETROPERITONEALINVOLVEMENTRenal angiomyolipoma (AML),renal cysts, andRCCRenal AML in 55%–75% patients with TSRetroperitoneal LAM in up to 20% of patients with pulmonary LAM.
AMLsMC benign tumors of the kidney.characterized by variable amounts of abnormal vessels, immature smooth-muscle and fat cellsCompared with sporadic lesions, AMLs seen in patients with TS tend to manifest at a younger agemultiple, larger, and bilateral andTend to grow.noncalcified cortical tumors containing fat of less than −20 HU
Retroperitoneal LAMthick- or thin-walled cystic lesions.may reflect dilatation of lymph vessels due to obstruction
SKELETAL INVOLVEMENTCyst like lesions,hyperostosis of the inner table of the calvaria ,osteoblastic changes,periosteal new bone formation, andscoliosis.
VON HIPPEL-LINDAU DISEASEAD disorder linked to defect on the short arm of chromosome 3p.Prevalence is approximately 1 in 40,000 to 1 in 50,000 peopleCauses of death - cerebellar hemangioblastoma and RCCScreening is important because the lesions in VHL disease are treatable
Manifestations of VHL Disease according toPrevalence Cerebellar hemangioblastoma 44–72% Medullary hemangioblastoma 5% Spinal cord hemangioblastoma 13–59% Retinal hemangioblastoma 45–59% Renal cell carcinoma 24–45% Pheochromocytoma 0–60% Neuroendocrine tumor of the pancreas 5–17% Serous cystadenoma of the pancreas 12% Pancreatic cysts 50–91% Renal cysts 59–63% Papillary cystadenoma of epididymis 10–60 %.
NATIONAL INSTITUTES OF HEALTH CLASSIFICATION Type I VHL without pheochromocytoma most common type Renal and pancreatic cysts, RCC Type II VHL with pheochromocytoma IIa - Islet cell tumors (no cysts) Iib - Renal/pancreatic disease (least common)
DIAGNOSTIC CRITERIAMore than one CNS hemangioblastoma,One CNS hemangioblastoma + visceral manifestations of VHL disease,Any manifestation and a known family history of VHL disease.
HemangioblastomaHallmark of VHLSeen in 2/3 of patients20-50 yrs of ageTypically multipleMC in cerebellumOther::::medulla > pons, spinal cord, and supratentorially in optic N and cerebrum
Retinal angiomasare actually hemangioblastomas (40-50%)asymptomatic or cause a blind spot.may hemorrhage and can cause retinal detachmentHigher signal intensity than normal vitreous on non- enhanced T1WI
Renal lesionsRenal cysts in 59%–63%RCC in 24%–45% either multicentric and bilateral solid hypervascular masses or complex cystic massesComplex or solid lesions enhance on postcontrast T1- WIA hypointense pseudocapsule on T2-WI
Pancreatic involvementsimple pancreatic cysts (50%–91%)serous microcystic adenomasPancreatic neuroendocrine tumors (5%–17%)Pancreatic lesions may be the only abdominal manifestation and may precede any other manifestation by several years
Annual screening examinations of the abdomen, by ultrasound or CT, have been recommended for some patients with VHL
Ataxia-telangiectasiaAR disorder1 in 20,000-100,000Telangiectasias in skin (face) and eyes,cerebellar ataxiaimmunodeficiency syndromes, and recurrent infections and susceptibility to certain neoplastic processes
MR FINDINGSTelangiectasia of pia mater and white matterHypointense WM foci on T1- and T2-WIDiffuse symmetric increased T2 white matter signalSevere cerebellar atrophy
THE PHACE SYNDROMEPosterior fossa malformationsHemangiomasArterial anomaliesCoarctation of the aorta , cardiac defectsEye abnormalities Sometimes, an S is added making it PHACES, with the S standing for Sternal defects and/or Supraumbilical raphe.
Large facial hemangiomas may be associated with a Dandy- Walker malformation, vascular anomalies (coarctation of aorta, aplasia or hypoplastic carotid arteries, aneurysmal carotid dilation, aberrant left subclavian artery), glaucoma, cataracts, microphthalmia, optic nerve hypoplasia, and ventral defects (sternal clefts)Facial hemangioma is typically ipsilateral to the aortic archFemale predominancePatients with large facial cutaneous (S1-S4) hemangiomas were especially at risk of CNS structural and cerebrovascular anomalies; S1 with ocular anomalies; and S3 with airway, ventral, and cardiac anomalies.
Gorlin syndrome Diagnostic criteria A clinical diagnosis can be made using major and minor criteria. To make the diagnosis, either two major or, one major and two minor criteria must be met. Major criteria( Classical triad ) basal cell cancers : > 2 or 1 under the age 20 odontogenic keratocysts (see case 1) palmar pits : 3 or more bilamellar calcification of the falx cerebri rib anomalies : bifid rib fused, splayed first degree relative with Gorlin syndrome Minor criteria macrocephaly frontal bossing, cleft lip or hypertelorism Sprengel deformity, pectus excavatum or pectus carinatum, syndactyly bridging of the sella turcica, hemivertebrae, flame shaped radiolucencies ovarian fibroma, medulloblastoma
ConclusionPhakomatoses are a diverse group of disordersMost common phakomatoses (excluding SWS) are AD; therefore, a correct diagnosis has genetic implicationsA screening evaluation of all first-degree relatives to see if they are also affected is mandatoryA routine follow-up surveillance program should be established. This typically includes annual CNS imaging studies and, where appropriate, abdominal ultrasound, CT, or MR.