PHAKOMATOSES

By : Dr.Nikhil Mehta

Moderator : Dr.H.R.Nagrale

• The term is derived from the Greek root phako, which refers to the lens; phakomatosis thus means a tumor-like condition of the eye (lens)

Definition

Definition Exception

Phakos, oma, osis.Van der Hoeve in 1921

Sturge Weber syndrome (no neoplastic component)

Neuro-cutaneoussyndromes.Yakovlev and Guthrie in 1931

Von Hippel Lindau disease (no cutaneous manifestation)

COMMON

1. NF1

2. NF2

3. Tuberous sclerosis

4. Sturge-Weber Syndrome

5. Von Hipple Lindau disease

UNCOMMON

1. Li-fraumeni syndrome

2. Cowden syndrome

3. Basal cell naevus syndrome

4. Proteus syndrome

5. Klipple trenaunay

6. Ataxia telangiectasia

7. Meningio-angiomatosis

Neurofibromatosis

Autosomal dominant

• NF1- mutation of the NF1 gene on chromosome Ch 17,

• NF 2 -mutation of the NF2 gene on chromosomeCh 22

NF 1 presents in children & NF2 at a later

age.

• Neurofibromatosis type 1 (NF1) also known as von Recklinghausen disease.

• When extreme, NF1 can be highly disfiguring and is sometimes dubbed "elephantiasis neuromatosa" or "elephant man disease."

Cutaneous NF

Café au laitspots

Lisch

nodules

Plexiformneurofibromas

Axillaryfreckling

Molloscumfibrosum

Café au lait spots

Lisch nodules

• Melanocytic hamartoma of the iris.

Plexiform neurofibroma

Axillary freckling

Molluscum fibrosum

NF1: IMAGING

• Scalp/Skull, Meninges, and Orbit– Cutaneous scalp, plexiform NFs

• Solitary/multifocal scalp nodules• PNFs infiltrate and may extend into cavernous sinus

– Sphenoid wing dysplasia• Hypoplasia → enlarged orbital fissure• Enlarged middle fossa • Temporal lobe may protrude into orbit

– Dural ectasia• Tortuous optic nerve sheath• Patulous Meckel caves• Enlarged IACs

Cutaneous Neurofibromas

PFN: "Target" sign (bright with central collagen dot) o PFN, NF and ONG have variable T2 signal which may inc or dec with time

Neurofibromas

Localized

Fusiform

Plexiform

Rope likeBag of

worm like

Diffuse

Plaque like

Sphenoid wing dysplasia

• Brain– Hyperintense T2/FLAIR WM foci

• Wax in first decade, then wane• Rare in adults

– Astrocytomas• Most common: Pilocytic• Optic pathway > hypothalamus > brainstem• Malignant astrocytoma (anaplastic astrocytoma, glioblastoma

multiforme) less common

• Arteries– Progressive ICA stenosis → moyamoya– Fusiform ectasias, AVFs

• Vertebral > carotid

These foci of abnormal signal (FASIs) are seen in 70% of children with NF1.

Optic glioma

Arterial

Moya moya

Thoracic NF

Mediastinal masses

Neurofibroma

Lateral thoracic meningocele

Extra-adrenal pheochromocytoma

Lung parenchymaldisease

Intersitial fibrosis

Bullae

Skeletal NF

Skull

Sphenoid wing dysplasia

Enlarged neural foramina

Lambdoid suture defects

Spine

Posterior vertebral scalloping

Scoliosis

Rib

Rib notching

Ribbon ribs

Long bones

Pseudoarthrosis

NF1: DIAGNOSTIC CLINICAL FEATURES (AT LEAST TWO REQUIRED)

• Cutaneous Lesions– ≥ 6 café au lait spots (earliest manifestation)

• Prepubertal: ≥ 0.5 cm• Postpubertal: ≥ 1.5 cm

– Freckling of armpits or groin– ≥ 2 neurofibromas (any type)– 1 plexiform neurofibroma

• Eye Abnormalities– ≥ 2 Lisch nodules (pigmented iris hamartomas)– Optic pathway pilocytic astrocytoma

• DistinctiveBone Lesion– Sphenoid dysplasia/absence– Long bone cortex dysplasia/thinning

• Family History– First-degree relative with NF1

NF2

• NF2 is also known as neurofibromatosis with bilateral vestibular ("acoustic") schwannomas. Historically, NF2 was termed central neurofibromatosis (to distinguish it from so-called peripheral neurofibromatosis, i.e., NF1)

Pathology

• The most common NF2-related schwannomas are vestibular schwannomas (VSs) .

• Meningiomas occur in approximately half of all patients with NF2 and can be found anywhere in the skull and spine. The most frequent sites are along the falx and cerebral convexities.

NF2: DIAGNOSTIC CLINICAL FEATURES

• Definite NF2– Bilateral vestibular schwannomas (VSs)– First-degree relative with NF2 and unilateral VS younger than 30 years of age– Or first-degree relative with NF2 and 2 of the following

• Meningioma• Glioma• Schwannoma• Juvenile posterior subcapsular lenticular opacities or cataracts

• Probable NF2– Unilateral VS younger than 30 years of age and 1 of the following

• Meningioma• Glioma• Schwannoma• Juvenile posterior subcapsular lenticular opacities or cataracts

– ≥ 2 meningiomas and 1 of the following• 1 VS younger than 30 years of age• 1 meningioma, glioma, schwannoma, or lens opacity

Vestibular Schwannoma

Meningiomas

Scwanommas

Ependymomas

NF1 NF2

• Common (90% of all NF cases)• Chromosome 17 mutations• Almost always diagnosed by age 10

• Cutaneous lesions common (> 95%)Café au lait spotsLisch nodulesCutaneous NFs (often multiple)Plexiform NFs (pathognomonic)

• CNS lesions less common (15-20%)T2/FLAIR hyperintensities (myelin vacuolization; lesions wax, then wane)Astrocytomas (optic pathway gliomas—usually pilocytic—other gliomas)Sphenoid wing, dural dysplasiasMoyamoyaNeurofibromas of spinal nerve roots

• Much less common (10% of all NF cases)• Chromosome 22 mutations• Usually diagnosed in second to fourth

decades

• Cutaneous, eye lesions less prominentMild/few café au lait spotsJuvenile subcapsular opacities

• CNS lesions in 100%Bilateral vestibular schwannomas(almost all)Nonvestibular schwannomas (50%)Meningiomas (50%)Cord ependymomas (often multiple)Schwannomas of spinal nerve roots

Tuberous sclerosis

• The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called "tubers" in the brains of postmortem patients.

• These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville's disease.

• Tuberous sclerosis complex is a neurocutaneous syndrome characterized by the formation of nonmalignant hamartomasand neoplastic lesions in the brain, heart, skin, kidney, lung, and other organs.

Tuberous sclerosis

Etiology:

• 50 % autosomal dominant inheritence.

• 50 % spontaneous mutation.

Genetics

• Defects in TSC1 gene on chromosome

9(hamartin) & TSC 2 gene on chromosome

16(tuberin).

Tuberous sclerosis

Tuberous sclerosis Complex

Seizures Adenomasebaceum

Mental retardation

Fits

ZitsNitwits

CutaneousTS

Adenoma sebaceum

Ash leaf spots

Shagreenpatch

Confetti lesions

Periangualfibroma

Adenoma sebaceum

Facial angiofibromas

• Small erythematous papules

Ash leaf spots

• Hypo-pigmentd macule

الدردار

Shagreen patch

Confetti lesions

Periangual fibroma

Neurological TS

Cortical & subcortical

tubers

White matter lesions

Subependymalnodules

SGCA

CORTICAL TUBERS

• Cortical tubers are firm, whitish, pyramid-shaped, elevated areas of smooth gyral thickening, with or without central depressions, that grossly resemble potatoes ("tubers").

SUBEPENDYMAL NODULES

• Subependymal nodules (SENs) are located immediately beneath the ependymal lining of the lateral ventricles, along the course of the caudate nucleus.

• SENs appear as elevated, rounded, hamartomatous lesions that grossly resemble candle guttering or drippings. They often calcify with increasing age.

WHITE MATTER LESIONS

• White matter (WM) lesions are almost universal in patients with TSC. They appear as foci of bizarre dysmorphic neurons and balloon cells in the subcortical WM and/or fine radial lines extending outward from the lateral ventricles.

SUBEPENDYMAL GIANT CELL ASTROCYTOMA

• Subependymal giant cell astrocytoma (SEGA)—also known as subependymalgiant cell tumor—is seen almost exclusively in the setting of TSC. Grossly, SEGAs appear as well-circumscribed solid intraventricular masses located near the foramen of Monro

Tuberous Sclerosis Complex

Cortical Tubers

• In infants, tubers appear as thickened hyperintense cortex compared to the underlying unmyelinated WM on T1WI and become moderately hypointense on T2WI.

• Signal intensity changes after myelin maturation.

• Tubers gradually become more isointense relative to cortex on T1WI.

• In older children on T2/FLAIR the periphery of the expanded gyrus is isointense with cortex while the deeper component is strikingly hyperintense.

White matter lesions

Location:

• Along lines of neuronal migration

SGCA

large enhancing nodule at the foramen of Monro.

• TSC: DIAGNOSTIC CLINICAL FEATURES• Diagnosis

– Definite TSC• 2 major features or 1 major + 2 minor

– Probable TSC• 1 major + 1 minor feature

– Possible TSC• 1 major or ≥ 2 minor features

• Major Features– Identified clinically

• ≥ 3 hypomelanotic ("ash leaf") macules (97%)• Facial angiofibromas (75%) or forehead

plaque (15-20%)• Shagreen patch (45-50%)• Ungual/periungual fibroma (15%)• Multiple retinal hamartomas (15%)

– Identified on imaging• Subependymal nodules (98%)• Cortical tubers (95%)• Cardiac rhabdomyoma (50%)• Renal angiomyolipoma (50%)• Subependymal giant cell astrocytoma (15%)• Lymphangioleiomyomatosis (1-3%)

Minor FeaturesIdentified clinically

Gingival fibromas (70%)Affected first-degree relative (50%)Pitting of dental enamel (30%)Retinal achromic patch (35%)Confetti-like skin macules (2-3%)

Identified on imagingWM hamartomas, radial migration lines (100%)Hamartomatous rectal polyps (70-80%)Nonrenal hamartomas (40-50%)Bone cysts (40%)Renal cysts (10-20%)

DD of tuberous sclerosis

DD of subependymalnodules

Non clacified Subependymal heterotopia

Calcified TORCH

DD of cortical tubers Focal cortical dysplasia

DD of SGCA Foramen of Monro masses

Subependymal nodules Subependymal hetertopia

Rounded or oval with their

long axis perpendicular the

ventricular wall.

Oval with their long axis

parallel to the ventricular

wall.

Variable. Iso-intense to grey matter

on all pulse sequences

May be calcified. Never calcified.

May be enhancing. No enhancement

DD of subpendymal nodules

Subependymal

nodules

Subependymal heterotopia

CMV TS

Abdominal TS

Renal

AML

Cysts

RCC

Oncocytoma

Retroperitoneal LAM

GIT polyps

ThoracicTS

Lymphangioleiomyomatosis Cardiac rhabdomyomas

Skeletal TS

Sclerotic bone lesions

Hyperostosis of inner table of the calvarium

Scolosis Bone cysts

AML

Cardiac rhabdomyomas

• Multiple hyperechoic masses

Sturge-Weber syndrome

• also known as encephalo-trigeminal angiomatosis. Its hallmarks are variable combinations of

• (1) a capillary malformation of the skin in the distribution of the trigeminal nerve,

• (2) retinal choroidal angioma (either with or without glaucoma)

• (3) a cerebral capillary-venous leptomeningeal angioma

• Sturge-Weber is an embryonal developmental anomaly resulting from errors in mesodermal and ectodermal development.

• Unlike other neurocutaneous disorders (phakomatoses), Sturge-Weber occurs sporadically

STURGE-WEBER SYNDROME

Etiology• At four or five weeks of gestation, the visual cortex is

juxtaposed to the optic vesicle and the upper part of the embryonic face.

• During this period, a primordial venous plexus surrounds the neural tube and invades the adjacent fetal brain, skin, and eye.

• Somatic mutation results in persistence of primitive veins, lack of definitive cortical veins.

• Pathology

– Pial ("leptomeningeal") angioma

– Cortical venous ischemia, atrophy

– Parietooccipital > frontal

• Clinical findings

– Unilateral facial nevus flammeus ("port-wine stain")

– Usual cutaneous distribution = CN V1₁, V₂ > V₃

Port wine stain (Portuguese wine)

Pial angiomatosis

Imaging

– CT: Atrophic cortex

• Cortical Ca++ (not in angioma!) ↑ with age

• thick Ipsilateral calvaria, sinuses enlarged

– MR: Cortical/subcortical hypointensity on T2

• Ca++ "blooms" on T2*GRE

• Pial angioma enhances

• Ipsilateral choroid plexus enlarged

Von Hippel Lindau disease

• von Hippel-Lindau disease (VHL) is also known as von Hippel-Lindau syndrome and familial cerebello-retinal angiomatosis.

• The German ophthalmologist Eugen von Hippel first described angiomas in the eye in 1904. Arvid Lindau described the angiomas of the cerebellum and spine in 1927

VHL: GENETICS

• Autosomal dominant inheritence 80%.

• Defect in VHL gene on chromosome 3.

• Type 1 VHL– Truncating/axon deletion mutations of VHL– Low risk of pheochromocytoma

• Type 2 VHL– Missense VHL mutations– High risk of pheochromocytoma– Subtypes

• Type 2A (low risk of renal cell carcinoma)• Type 2B (high risk of renal cell carcinoma)• Type 2C (familial pheochromocytoma, no hemangioblastoma, no renal

cell carcinoma)

Von Hipple Lindau disease

CNS

Hemangioblastoma

Cerebellar

Spinal

Retinal

Choroid plexus papilloma

Endolymphatic sac tumor

VHL: IMAGING

• Multiple Hemangioblastomas– 2/3 cystic, 1/3 solid– Nodule abuts pia– 50% in cord (dorsal > ventral surface)

• Retinal Angiomas– Hemorrhagic retinal detachment– tiny HGBLs appearing as enhancing "dots”

• Uni- or Bilateral Endolymphatic Sac Tumors– Infiltrative, lytic, intratumoral bone spicules– T1 iso/hyper; T2 hyper; strong enhancement– Location: Dorsal Temporal bone between IAC, sigmoid

sinus

Infratentorial Hemangioblastomas

Pilocytic astrocytoma Hemangioblastoma

Age: childrenAge: young adults

Tumor nodule: lack

vascular flow voids

Tumor nodule: show

vascular flow voids

Tumor nodule often

doesn’t abut pial or

ependymal surface.

Tumor nodule abuts

the pial or ependymal

surface

SUPRATENTORIAL HEMANGIOBLASTOMA

EndoLymphtaic Sac Tumor

EndoLymphtaic Sac Tumor

Von Hipple Lindau disease

Abdomen

Pancreas

Cysts

Microcystic adneoma

Islet cell tumor

Adenocarcinoma

Renal

Cysts

AML

RCC

Adrenal

Pheochromocytoma

Liver

Cysts

Epididymis

Papillary cystadenoma

• ~ 45% of those with vHL develop

haemangioblastomas

• ~ 20% of those with haemangioblastoma

have vHL

• Li-Fraumeni syndrome (LFS) is also known as the sarcoma family syndrome of Li and Fraumeni. LFS is an autosomal dominant familial tumor syndrome characterized by a spectrum of malignant neoplasms.

LI-FRAUMENI SYNDROME (LFS)

Histologically, LFS-associated neoplasms are indistinguishable from their sporadic

CNS tumors

common

Astrocytoma

gliosarcomaChoroid plexus

tumors

medulloblastoma

PNET

Rare

Ependymoma

oligodendroglioma

meningioma

• Cowden syndrome (CS) is also known as multiple hamartoma-neoplasia syndrome.

• CS involves hamartomatous overgrowth of tissues of all three embryonic origins.

• The classic brain hamartoma is dysplastic gangliocytoma of the cerebellum, also known as Lhermitte-Duclos disease (LDD). If CS and LDD occur together, the disorder is known as COLD (Cowden-Lhermitte-Duclos syndrome).

• COLD is considered a new phakomatosis.

COWDEN SYNDROME: DIAGNOSTIC CLINICAL FEATURES

• Pathognomonic Criteria

– Dysplastic cerebellar gangliocytoma(LD) and

– Characteristic mucocutaneous lesions• Papillomatous lesions

• Facial trichilemmomas

• Acral keratoses

• Major Criteria

– Breast cancer

– Thyroid cancer (* follicular)

– Endometrial cancer

– Macrocephaly

• Minor CriteriaMental retardationGI polypsFibrocystic breast diseaseLipomasFibromasGU tumors (especially renal cell carcinoma)Genitourinary structural malformationsUterine fibroids