This document discusses various phakomatoses, which are defined as neurocutaneous syndromes with autosomal dominant inheritance and multi-organ hamartomas or tumors. It describes several specific phakomatoses including neurofibromatosis types 1 and 2, tuberous sclerosis, Sturge-Weber syndrome, Von Hippel-Lindau disease, and Wyburn-Mason syndrome. For each, it covers epidemiology, pathogenesis, characteristic ocular and systemic findings, diagnostic criteria, investigations, and treatment.

1. 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

2. 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

3. Common Syndromes
• NF1
• NF2
• Tuberous sclerosis
• Sturge-Weber Syndrome
• Von Hipple Lindau disease
• Wyburn Mayson syndrome

4. Uncommon
• Klipple trenaunay Weber syndrome
• Louis bar syndrome
• Diffuse congenital hemangiomatosis
• Oculodermal melanocytosis
• Basal cell nevus syndrome

5. 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

6. 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

7. 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

8. 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

9. 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

10. Cutaneous Lesions
• Adenoma sebaceum
• Ash leaf spots
• Shagreen patch
• Confetti lesions
• Periangual fibroma

11. 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

12. Ash leaf spots
• Hypo-pigmented macule
• Size vary from 1mm to several
centimetres
• Seen prominently under ultraviolet light

13. Shagreen patch

14. Confetti lesions

15. Subungual fibroma

16. Neurological TS
• Cortical & subcortical tubers
• White matter lesions
• Subependymal nodules
• SGCA

17. Cortical tubers Sub ependymal nodules
Location-Frontal,
Parietal,Temporal,Cerebellar.
Location-Caudothalamic groove of
lateral ventricle.

18. White matter lesions SGCA
Location-alone lines of neural
migration
Location-Foramen of monro

19. ThoracicTS
• LAM Cardiac rhabdomyomas

20. Investigation
• Fundus examination
• Dermatological evaluation
• CT and MRI of the CNS and abdominal viscera
• Examination of family members

21. Treatment
• Purely symptomatic
• Periodic physical examination
• CT or MRI of CNS and Abdominal thoracic viscera

22. Neurofibromatosis
• Neuroectodermal tumors arising within multiple organs
• Autosomal dominant inheritance
• Two types :-
1.NF1
2.NF2

23. 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

24. Ocular Manifestations
1. 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

25. Lignes grises

26. 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

27. Eye Lids
• Nodular or plexiform neurofibromas
• Develop early in life
• Enlarge progressively
• NODULAR PLEXIFORM

28. 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

29. Choroidal nevi
• Some cases develop bilateral
choroidal nevi
• Increased risk of developing
• Uveal Melanoma

30. Retinal tumors
• Some patients may
present with astrocytic
hamartomas

31. 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

32. Cutaneous NF
• Café au lait spots
• Lisch nodules
• Plexiform neurofibromas
• Axillary freckling
• Molloscum fibrosum

33. 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

34. Plexiform neurofibroma
• Appear during childhood
• Large and ill-defined

35. Axillary or inguinal freckling
• Seen in 90-95% of cases

36. Molluscum fibrosum
• Appear at puberty
• Pedunculated, flabby nodules consisting of neurofibromas or
schwannomas
• Increase in number throughout life

37. Neurological NF1
• Hamartomas.
• Gliomas:
• Optic glioma.
• Pilocytic astrocytoma.
• Diffuse brain stem glioma.
• Spinal astrocytoma
• Dural calcification at vertex
• Dural ectasia
• Buphthalmos.

38. 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

39. Skeletal disorders NF1
• Sphenoid wing dysplasia
• Lambdoid suture defects.
• Enlarged neural foramina.
• Kyphoscoliosis.
• Posterior vertebral scalloping.
• Rib notching.
• Tibial or ulnar pseudoarthrosis

40. Sphenoid wing Lambdoid
dysplasia suture
defect

41. Vertebral Tibial
scalloping pseudoarthrosis

42. 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

43. 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

44. 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

45. NF2
• Pre senile cataract Retinal Hamartomas

46. NF2
• Intracranial Schwannomas.
• Intracranial & spinal meningiomas.
• Spinal intramedullary ependymomas.

47. 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

48. 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

49. Ocular Manifestations
• Classical feature is diffuse choroidal hemangioma
• Telangiectasia of conjunctiva and episclera
• Ipsilateral congenital, infantile, or juvenile glaucoma

50. Congenital glaucoma
• cong

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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

57. Ocular changes
1. 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)

58. 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

59. 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

60. 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

61. 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

62. Screening protocol
Affected 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

63. 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

64. Treatment
• Retinal capillary hemangioma treatment options :-
• Photocoagulation
• Cryotherapy
• Corticosteroids
• Diathermy
• Radiation therapy
• Micro surgical resection
• Enucleation ( painful blind eyes )

65. Course and outcome
• Ocular complications :-
• Intraretinal and intraretinal bleeding
• Exudation
• Gliosis
• Retinal detachment
• Median age of death 45-50 years of age

66. 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

67. 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

68. Ocular manifestation
• Classic abnormality is AVM of Retina

69. Extraophthalmic manifestations
• Complex AVMs occur in
- orbit – may cause pulsatile exophthalmos
- periorbital soft tissue
- bones
- Mid brain ipsilateral to the retinal AVM

70. Investigations
• MRI
• Magnetic resonance angiography of ipsilateral orbit and brain
( not indicated in patients with small limited retinal AVM unless
they have neurological symptoms)

71. 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

72. 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

73. 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.

74. 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

75. 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

76. 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

77. 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

78. THANK YOU