Phakomatoses

PHAKOMATOSES

• Coined by van der Hoeve

• Definition :-

• No satisfactory definition has been

• Neuro oculo cutaneous syndrome with autosomal dominant

inheritance.

• Neuro oculo syndrome with one or more characterstic skin

lesions

• Presence or development of multi-organ Hamartomas

Hamartias Hamartomas

• Non tumorous growths

on skin and mucos

membranes arising

from cells normally

found in tissue at

involved site

• Congenital vascular

malformations of

ataxia telangectasia

• Localised tumors

arising from cells,

normally found at site

of growth

• Glial tumors of

Tuberous sclerosis

Common Syndromes

• NF1

• NF2

• Tuberous sclerosis

• Sturge-Weber Syndrome

• Von Hipple Lindau disease

• Wyburn Mayson syndrome

Uncommon

• Klipple trenaunay Weber syndrome

• Louis bar syndrome

• Diffuse congenital hemangiomatosis

• Oculodermal melanocytosis

• Basal cell nevus syndrome

Tuberous sclerosis

• Multi organ tumor syndrome

• Characterised by :-

1. Multifocal retinal astrocytic hamartomas

2. Astrocytic tumors of CNS

3. Cutaneous lesions

4. Mental retardation

5. Seizures

6. Cysts of different organs

Epidemiology and Pathogenesis• Prevalance estimated to be 1 case per 10,000 persons

• 1/3rd cases are familial

• 2/3rd cases are sporadic

• No racial prediliction

• Both sexes affected equally

• Sign and symptoms begin usually at 6 year age

• Genes location :- 9q32-34 ( Most common)

11q

16p13

12q22-24

Ocular TS

• Classical feature is retinal astrocytoma

• 50% patients develop at least one Retinal astrocytoma in

one eye

• Malignant transformation occurs but rarely

• Arise from astrocytes of sensory retina

Astrocytic Hamartoma• Histologically – composed of felt-like network of atypical

astrocytes and small blood vessels located in superficial layers

of retina

• Do not produce loss

Of vision unless

located in papillo-

Macular bundle

Three types of Hamartomas

1. Type1 :-

• Flat, soft and semitransparent lesions

• Usually at posterior pole

• Boundaries are grey or faint yellow

2. Type 2:-

• Elevated,nodular and solid apparing masses

• Usually near disc margin and also at midperiphery

3. Type 3:-

• Border is flat, soft and transparent

• Centrally elevated and nodular

Cutaneous Lesions

• Adenoma sebaceum

• Ash leaf spots

• Shagreen patch

• Confetti lesions

• Periangual fibroma

Adenoma sebaceum• Facial dematological eruptions

• Pin head to pea sized

• Yellowish to reddish-brown

• Butterfly fashion over nose ,cheeks,labial fold

• Histopathologically :- skin lesions are angiofibromas

Ash leaf spots• Hypo-pigmented macule

• Size vary from 1mm to several

centimetres

• Seen prominently under ultraviolet light

Shagreen patch

Confetti lesions

Subungual fibroma

Neurological TS

• Cortical & subcortical tubers

• White matter lesions

• Subependymal nodules

• SGCA

Cortical tubers Sub ependymal nodulesLocation-Frontal,

Parietal,Temporal,Cerebellar.Location-Caudothalamic groove of

lateral ventricle.

White matter lesions SGCALocation-alone lines of neural

migrationLocation-Foramen of monro

ThoracicTS• LAM Cardiac rhabdomyomas

Investigation

• Fundus examination

• Dermatological evaluation

• CT and MRI of the CNS and abdominal viscera

• Examination of family members

Treatment

• Purely symptomatic

• Periodic physical examination

• CT or MRI of CNS and Abdominal thoracic viscera

Neurofibromatosis• Neuroectodermal tumors arising within multiple organs

• Autosomal dominant inheritance

• Two types :-

1.NF1

2.NF2

Neurofibromatosis type 1

• Aka Von Recklinghausen disease

• Most common type of phakomatosis

• Frequency of 1 in 3500-4000 persons in general population

• Men and women affected with same frequency

• No racial prediliction

• Gene location Chromosome 17q11

• 50% autosomal dominant inheritence.

• 50% new mutation

Ocular Manifestations1. Lignes grises- hyperplastic intrastromal nerves

2. Lisch Nodules

3. Subcutaneous pedunculated and plexiform neurofibromas of

the eyelids

4. Optic nerve Gliomas

5. Multifocal choroidal Nevi

6. Occasional retinal tumors

Lignes grises

Lisch Nodules• Melanocytic hamartomas of iris stroma

• Rare at birth

• Develop in 2nd to 3rd decade of life in 90-95% cases

• Histopathologically :-

• Closely packed dendritic or spindle shaped melanocytes in

anterior layers of Iris stroma

Eye Lids

• Nodular or plexiform neurofibromas

• Develop early in life

• Enlarge progressively

• NODULAR PLEXIFORM

Optic nerve gliomas• 10-15% cases

• Can be unilateral or bilateral

• Frequently involve Optic chiasma

• In the orbit it causes proptosis and optic atrophy

• Frequently result in unilateral or bilateral blindness

Choroidal nevi

• Some cases develop bilateral

choroidal nevi

• Increased risk of developing

• Uveal Melanoma

Retinal tumors

• Some patients may

present with astrocytic

hamartomas

Glaucoma in NF

• Possible mechanism suggested

1. Infiltration of angle structures and obstruction to outflow by

neurofibroma

2. Closure of angle by forward displacement of anterior uvea

( as a result of infiltration of neoplastic tissue )

3. Secondary fibrovascular proliferation and closure of filration

mechanism by synechiae

Cutaneous NF

• Café au lait spots

• Lisch nodules

• Plexiform neurofibromas

• Axillary freckling

• Molloscum fibrosum

Café au lait spots

• Multiple

• Size of 0.5 cm in diameter in childhood

• May enlarge to 1.5 cm by post pubertal

age

• Six or more Café au lait spots larger

than 1.5 cm in post pubertal age

generally considered diagnostic

Plexiform neurofibroma• Appear during childhood

• Large and ill-defined

Axillary or inguinal freckling

• Seen in 90-95% of cases

Molluscum fibrosum• Appear at puberty

• Pedunculated, flabby nodules consisting of neurofibromas or

schwannomas

• Increase in number throughout life

Neurological NF1• Hamartomas.

• Gliomas:

• Optic glioma.

• Pilocytic astrocytoma.

• Diffuse brain stem glioma.

• Spinal astrocytoma

• Dural calcification at vertex

• Dural ectasia

• Buphthalmos.

Chest• Mediastinal masses:

• Neurofibroma.

• Lateral thoracic meningocele :

• typically on convex side of scoliosis (through widened neural

formina)

• extra adrenal pheochromcytoma.

• Lung parenchymal disease : ~ 20%

• Diffuse interstitial fibrosis: lower zone

• Bullae formation : upper zone

Skeletal disorders NF1

• Sphenoid wing dysplasia

• Lambdoid suture defects.

• Enlarged neural foramina.

• Kyphoscoliosis.

• Posterior vertebral scalloping.

• Rib notching.

• Tibial or ulnar pseudoarthrosis

Sphenoid wing Lambdoid

dysplasia suture

defect

Vertebral Tibial

scalloping pseudoarthrosis

Diagnostic criteria for NF1• Six or more café-au-lait spots

- each 1.5 cm or larger in postpubertal individuals

- each 0.5 cm or larger in prepubertal individuals

• Two or more neurofibromas of any type or one or more

plexiform neurofibroma

• Freckling in the axilla or groin

• Optic nerve glioma

• Two or more Lisch nodules of the iris

• A distinctive bony abnormality

- dysplasia of sphenoid bone

- dysplasia or thinning of long bone cortex

• A first degree relative with NF1

Neurofibromatosis 2 / Central NF• Affect 1 in 40,000-50,000 persons

• Gene Location Chromosome 22q12

• Characterised by Bilateral vestibular schwannomas ( acoustic

neuromas )

• Neurofibromas

• Meningiomas

• Gliomas

• Schwannomas

• Most frequent extra ophthalmic problem is sensorineural

deafness

Diagnostic criteria for NF 2• Bilateral acoustic neuromas

Or

• A first degree relative with NF2

Plus

• Unilateral, acoustic neuromas appearing before 30 year

Or

• Any two of following

1. Meningioma

2. Glioma

3. Schwannoma

4. Juvenile posterior subcapsular lens opacity and combined

hamartoma of retina

NF2

• Pre senile cataract Retinal Hamartomas

NF2• Intracranial Schwannomas.

• Intracranial & spinal meningiomas.

• Spinal intramedullary ependymomas.

Sturge-Weber syndrome/

encephalotrigeminal angiomatosis• Dermato-oculo-neural syndrome

• Characterstic lesions:-

1.Cutaneous facial nevus flammeus ( in distribution of branches of

trigeminal nerve )

2.Ipsilateral diffuse cavernous hemangioma choroid

3.Ipsilateral meningeal hemangiomatosis

• These lesions are always present at birth in affected patients

Epidemiology and Pathogenesis• Majority cases have sporadic nonfamilial disease

• Both sexes affected equally

• No racial predilection

• Results from an early embryologic malformation of vascular

development

• Normally ,a vascular plexus develops around the cephalic

portion of the neural tube, under the area of ectoderm which is

destined to become facial skin.

• Residual vascular tissue in SWS forms the angiomata of the

leptomeninges, face, and ipsilateral eye

Ocular Manifestations• Classical feature is diffuse choroidal hemangioma

• Telangiectasia of conjunctiva and episclera

• Ipsilateral congenital, infantile, or juvenile glaucoma

Congenital glaucoma

• cong

Cutaneous manifestation

• Facial nevus flammeus/port wine stain

- zone of dilated telangiectatic cutaneous capillaries

- usually unilateral

- frequently involves the regions of face innervated by first

branch of trigeminal nerve

CNS manifestation• Ipsilateral leptomeningeal hemangiomatosis

• Atrophy of cortical parenchyma

• Seizures

• Mental retardation

• Lesions present at birth, detected by MRI or CT

• Progressive throughout life

• Meninges become irregularly calcified, detected by Skull

radiographs

Investigations

• Patient with SWS and seizures or mental retardation need

periodic neurological evaluation

• Intermittent evaluation by MRI or CT

• Screening for treatable ocular complication i.e glaucoma

and exudative RD

Treatment

• Usually symptomatic directed towards complications

caused by vascular lesions of brain and eyes

• Seizures treated medically

• Intractable seizures and progressive MR may need

subtotal hemispherectomy

• Facial nevus flammeus can be treated by laser

Von Hippel Lindau disease

• Multi organ disorder

• Autosomal dominant inheritence

• Solid and cystic visceral hamartomas

• Malignant neoplasms – RCC ,pheochromocytoma

• Early death due to-

Intracranial haemangiomatous lesions

RCC

Epidemiology and Pathogenesis• Rare

• Precise incidence not determined

• Median age of presenting first clinical feature is 20-25 yrs

• Earliest detected manifestation – capillary haemangioma of

retina.

• Probability of developing retinal capillary haemangioma and

CNS haemangioblastoma is 80%

• 60% probability for developing RCC

• Both sexes affected equally

• VHLS gene location – chromosome 3p25-26

Ocular changes1. Early stage of angioma formation

- development of feeder and draining vessels

2. Stage of exudation, hemorrahgic and retinal detachment

3. Final stage of destruction of eye with secondary

glaucoma and phthisis bulbi

• Ocular symptoms:-

1. Blurring of vision( exudative detachment)

2. Ocular pain( secondary glaucoma)

Ocular lesions VHLS

• Classical lesion retinal capillary hemangioma

• 50-60% patients of VHLS develop retinal capillary

hemangiomatosis

• 50% of these have multiple lesions in both eyes

Fundus in VHL

• Fullnes of retinal veins which become dilated and tortouos

• Dilated vessels feeds the angioma present mostly in

periphery

• In 33% cases lesions are multifocal

• Tumor usually grow towards the vitreous

• can invade choroid or grow agressively to invade lens

,cornea or perforate the globe

• The angiomatous tumor forms lipid

• Exudation of serum and lipid occurs in area away from

tumor ( particularly macular area )

• A macular star figure or circinate figure can be seen

Extra ocular manifestations

• Hemangioblastomas of brain and spinal cord

• RCC

• Pheochromocytoma

• Cyst adenomas of pancreas and epididymis

CNS :-

• Classical lesion is Solid and cerebellar hemangioblastomas

• Seen in 40% cases by the age of 30 years and 70% of cases by

60 years of age

RCC• Occurs in 5% of cases by the age of 30 years and 40% cases by

60 years

• Bilateral in 75% cases

• No dermatological lesions seen in VHLS

Screening protocolAffected patients

• Annual physical examination

• Annual comprehensive fundus examination

• MRI of brain and spinal cord every 3 years to age of 50 yr and

every 5 yr thereafter

• Annual renal ultrasound scan , with CT scan every 3 yr

• Annual 24 hr urine collection of VMA

At-Risk relatives

• Annual physical examination

• Annual comprehensive fundus examination from age of 5 year

• MRI of brain and spinal cord every 3 year from age of 15 year to

50 year and every 5 year until age of 60 year

• Annual renal ultrasound scan , with CT scan every 3 year from

age 20 year through 65 year

• Annual 24 hr urine collection of VMA

Treatment• Retinal capillary hemangioma treatment options :-

• Photocoagulation

• Cryotherapy

• Corticosteroids

• Diathermy

• Radiation therapy

• Micro surgical resection

• Enucleation ( painful blind eyes )

Course and outcome

• Ocular complications :-

• Intraretinal and intraretinal bleeding

• Exudation

• Gliosis

• Retinal detachment

• Median age of death 45-50 years of age

Wyburn-Mason syndrome• Characterised by arteriovenous malformations (AVM) of retina

and ipsilateral CNS

• Lesions are not distinct tumors

• Not a true phakomatosis

• Most patients have unilateral lesions

• Patient may present with

• - headache

• - seizures

Epidemiology and pathogenesis• Retinal and intracranial AVMs are congenital

• Usually incomplete at birth, progress with age

• Often undetected until 2nd to 4th decade of life

• Both sexes equally affected

• No racial predilection

• No hereditary pattern identified

Ocular manifestation• Classic abnormality is AVM of Retina

Extraophthalmic manifestations• Complex AVMs occur in

- orbit – may cause pulsatile exophthalmos

- periorbital soft tissue

- bones

- Mid brain ipsilateral to the retinal AVM

Investigations• MRI

• Magnetic resonance angiography of ipsilateral orbit and brain

( not indicated in patients with small limited retinal AVM unless

they have neurological symptoms)

Treatment

• No effective treatment currently available for retinal AVM

• Intracranial AVM can be treated by :-

1. Intracranial resection

2. Arterial ligation

3. Arterial embolisation

4. Stereostatic radiosurgery

5. Charged particle beam irradiation

Course and Outcome

• Early death can occur due to spontaneous intracranial

bleeding

• Patient can get blind due to spontaneous or post

therapeutic occlusion of retinal AVM

Other syndromes

• Diffuse congenital hemangiomatosis

• Multiple small cutaneous hemangiomas.

• Ocular findings

• Hemangiomas of :-

1. Iris

2. Conjunctiva

3. lid

• Abnormal chorioretinal vasculature

• Microphthalmos

• Galucoma

• Central system hemangiomas may lead to cortical blindness.

Oculodermal Melanocytosis• Aka Nevus of Ota

• Deep dermal pigmentation in distribution of first and second

divisions of Trigeminal nerv

• Ocular findings :-

1. Hyper pigmentation of sclera,conjunctiva,cornea and iris

2. Increased incidence of uveal and orbital melanomas

3. Glaucoma is also reported

Klippel – trenaunay-weber syndrome

• Triad of:

• Cutaneous hemangiomas extending over the limbs.

• Varicosities in the affected limb

• Hypertrophy of bone and soft tissue.

• Ocular findings:

• Enophthalmos

• Conjunctival telangiectasia.

• Heterochromia iridis

• Iris coloboma

• Retinal varicosities

• Choroidal angiomas

Louis Bar Syndrome/Ataxia Telangiectasia

• Recessive inherited multisystem disease

• Ocular lesions – bulbar conjunctival telangiectasia

• CNS – progressive ataxia in childhood

• Immune deficiency – Thymic hypoplasia

- frequent pulmonary infections

Cutaneous lesions not pathognomic

Basal cell nevus syndrome• Multiple skin tumors

• Autosomal dominant inheritance

• Most lesions are benign

• Ocular findings:-

- congenital cataract

- coloboma of choroid and optic disc

- corneal leucomata

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