This document discusses several phakomatoses or neurocutaneous syndromes characterized by hamartomas of the skin, eye, central nervous system and other organs. It provides details on the clinical features, genetics, systemic and ophthalmic manifestations as well as management of specific conditions like Neurofibromatosis types 1 and 2, Von Hippel-Lindau disease, Tuberous sclerosis, Sturge-Weber syndrome, and Ataxia telangiectasia. Key aspects like characteristic tumors, genetic mutations, diagnostic criteria and treatment approaches are highlighted for each discussed syndrome.

1. Presented by Dr Rohit Rao

2. • Phakomatoses derived from Greek word
phakomata or birth mark
• Syndromes characterized by hamartomas of
the skin, eye, central nervous system (CNS),
and other viscera are collectively called
Phacomatosis

4. • Neurofibromatosis type 1 (NF1), the most
common type,von Recklinghausen's
neurofibromatosis or peripheral
neurofibromatosis.
• Neurofibromatosis type 2 (NF2) or central or
bilateral acoustic neurofibromatosis.

5. Neurofibromatosis Type 1
• Most common phacomatosis
• autosomal-dominant disorders.
• The gene involved in NF1 is on chromosome
17 (17q11.2).
• It encodes for neurofibromin, a tumour
suppressor

7. Clinical Features
• Cutaneous Findings
• Café-au-lait spots and other hyperpigmented
skin lesions seen in 99% of adults with NF1.
РCaf̩-au-lait spots are pigmented, flat (macular)
skin lesions typically with smooth edges.
– Present at birth, they increase in size and number.

8. • Other pigmented lesions include freckles
(lentigines)
• These areas of hyperpigmentation are present
in axilla or groin.

9. • Neurofibromas are benign nerve sheath tumors
consisting of Schwann cells, fibroblastic
elements, and embedded axons.
– Solitary neurofibromas
• Located on skin, especially on trunk, & face.
• Arise in deep peripheral nerves, spinal nerve roots, and
autonomic nerves of blood vessels.
– Multiple neurofibromas are pathognomonic of NF1.
– Plexiform neurofibroma, diffuse mass with extensive
interdigitations with surrounding tissue.

10. Multiple neurofibromas
Plexiform neurofibroma

11. Ocular Findings

13. •Congenital glaucoma associated with upper eyelid
neurofibroma.
–Gonioscopy shows iris insertion anterior to scleral
spur.
–Angle appears to be covered by a membrane.
•Optic nerve gliomas are pilocytic hamartomas of anterior
visual pathways.
–Bilateral optic nerve gliomas are pathognomonic of
NF1.
•Pulsatile exophthalmos due to sphenoid dysplasia .
•Prominent corneal nerves.
•Conjunctival and scleral neurofibroma are rare.

17. MANAGEMENT
• Patients need detailed counseling regarding the
prognosis, genetic, and psychological aspects of
disease.
• First-degree relatives should be evaluated.
• Malignant tumors : excision, chemotherapy,
and/or radiotherapy may be indicated.

18. • Management of optic nerve glioma remains
controversial.
–Therapeutic indication and outcomes with
various forms of treatment include
observation, chemotherapy, excision, and
radiotherapy.
• Long-term follow- up shows a good prognosis.
• Chemotherapy may stabilize vision or induce
tumor regression in more than 50% of cases.

19. NEUROFIBROMATOSIS TYPE 2

20. • Central NF
• Unlike NF1,cutaneous findings are not
predominant .
• Schwannomas are the characteristic tumors of
NF2.

21. • Autosomal dominant
• About 50% of cases represent new mutations.
• Chromosome 22q12.
– It encodes a protein known as schwannomin

24. SYSTEMIC FINDINGS
• Bilateral vestibular schwannomas (VS) are
diagnostic of NF 2.
• The mean age at onset of VS is less than 25 years
• Symptoms of NF2 are due to VS rather than to
ocular involvement.
– Deafness with or without tinnitus is most common.
Seizures, vertigo, and numbness are less common.
– Blindness occurs as presenting symptom in only 1% of
cases.

25. • Spinal schwannomas are present in more than
75% of the cases with NF2.
• Additionally, intracranial or optic nerve
meningiomas and spinal ependymomas are
also observed.

27. OPHTHALMIC FINDINGS
• Posterior subcapsular cataract or wedge
cortical cataracts.
• Retinal hamartoma and combined
hamartomas of the retina and retinal pigment
epithelium (RPE).
• Rarely Lisch nodules

28. Wedge cortical cataracts

29. Combined hamartomas of
RPE and retina

30. MANAGEMENT
• Patients should be screened by neurologic,
ophthalmic, and neuro-otologic testing.
• MRI (contrast-enhanced, multi planar T1- weighted)
is a cost-effective first-line investigation in
detection of VS.
• Majority (90%) of patientspresent with bilateral VS.
• Management of VS include observation,
stereotactic radiotherapy, and surgical resection.

31. VON HIPPEL–LINDAU DISEASE

32. • Eugen von Hippel, a German ophthalmologist,
coined the term angiomatosis retinae in 1904.
• Arvid Lindau, a Swedish pathologist,
established a relationship between cerebellar
and retinal hemangioblastomas

33. • Autosomal dominant
• VHL gene on chromosome 3p25-26

35. SYSTEMIC FINDINGS
• VHL disease is a multisystem disorder with a
predilection for the retina and CNS.
• Retinal capillary hemangiomas (RCH) occur in ‹
75% of cases, CNS hemangiomas in more than
50%, renal carcinomas in ‹ 50% , and
pheochromocytomas in ‹ 25%.
• Probability of developing any components of
disease increases with age.

36. • Central nervous system hemangioma commonly
involve cerebellum (75%) and spinal cord (15%).
• Tend to be multiple and occur at a younger age as
compared to sporadic cases.
• Headache is initial symptom of cerebellar
hemangiomas and pain is common symptom of
spinal cord hemangiomas.

38. • Renal cell carcinoma is leading cause of
mortality.
– Bilateral in 93% of cases; multiple, renal cysts, and
occur at younger age compared to sporadic cases.
• Pheochromocytomas, rare benign tumors of
adrenal medulla, tend to be multiple and
bilateral.
– Elevated serum levels of catecholamines
(norepinephrine and epinephrine) that lead to
symptoms such as palpitations, headaches, and
sweating.

40. OPHTHALMOLOGIC FINDINGS
• Retinal capillary hemangioma (RCH) is one of the
most common manifestations
• Circumscribed, round retinal lesion with an
orange-red color with prominent feeder vessels.
• Presence of multiple RCH (two or more), other
manifestations of VHL disease, or a positive
family history are diagnostic of underlying VHL
disease.

42. MANAGEMENT
• Treatment of RCH determined by size,
location, and associated subretinal fluid,
retinal traction, and visual potential of eye.
• Retinal angiomas can be effectively treated
with cryotherapy or laser photocoagulation

43. • Early diagnosis increases the likelihood of
successful treatment yet the ocular lesions are
asymptomatic prior to RD.
• Should undergo periodic ophthalmologic
evaluation beginning at about age 5 years.
• Life expectancy may be improved by early
detection and treatment of various tumors.

44. TUBEROUS SCLEROSIS

45. • Coined by Desire Magloire Bourneville
(1840–1909), a French physician.
• He described a patient with seizures, hemiplegia,
mental subnormality, and renal tumors.
• He based the terminology tuberous sclerosis, on
multiple potato-like (tubers) lesions in the brain

46. GENETICS
• Tuberous sclerosis complex (TSC) includes two
genetic diseases (TSC1 and TSC2) with autosomal
dominant inheritance or sporadic.
• The genes responsible for TSC, TSC1
(chromosome 9q34)71 and TSC2,72 have now
been identified.
• TSC1 and TSC2 genes, encode the proteins
hamartin and tuberin, respectively.

48. SYSTEMIC FINDINGS
• Characterized by hamartomas of various
organs.
• Hamartomas in the brain (astrocytoma and
ependymoma) lead to childhood seizures and
mental retardation.

49. • Clinical manifestations of TSC1 and TSC2 are
similar except that the TSC1 is milder with a
reduced risk of mental retardation as
compared to TSC2.
• Other findings of TSC1 such as seizures, renal
involvement, facial angiofibroma, and retinal
hamartomas are also less frequent or less
severe compared to TSC2.

50. • Cutaneous manifestations of TSC are mainly
of diagnostic significance.
– Hypomelanotic macules are the most frequent
and the earliest finding, best visualized with
Wood’s lamp (UV light).
– Fibrous plaques appear as reddish-orange
patches on the forehead.
– Facial angiofibromas are not present at birth
and appear usually by age 5 years.

51. Shagreen patches
Subungual
fibromas
Hypomelanotic macules

53. • Visceral manifestations include pulmonary
lymphangiomyomatosis, renal
angiomyolipoma, and cardiac rhabdomyoma
• Imaging studies such as MRI of brain and CT -
abdomen are important to detect CNS and
visceral involvement.

54. • OPHTHALMOLOGIC FINDINGS
• Retinal or Optic nerve hamartomas
• Three morphologic types of retinal astrocytic
hamartomas are opthlamoscopically recognized:
1. More common subtle, flat, round, semitranslucent
lesion;
2. Large, elevated, nodular, and calcified mulberry
lesion;
3. Mixed type of lesion, being calcified in the central
portion and semitranslucent in the periphery.

56. MANAGEMENT
• Depends upon location & extent of organ
involvement.
• Retinal astrocytic hamartomas usually need
only periodic evaluation by ophthalmoscopy
and fundus photography.
• Patients with TSC-related mental retardation
require supervision for daily living.

57. • Common causes of mortality are renal
disease, brain tumors and status epilepticus.
• Patients need lifelong follow-up for early
detection of potentially life threatening
complications.

59. • Sturge (1879) reported the case of a child with
facial “port-wine stain,” epilepsy,
buphthalmos, and a dark choroid.
• Schirmer had noted the association with
glaucoma in 1860.
• Weber (1922) reported brain X-ray findings of
“railtrack” sign

60. SYSTEMIC FINDINGS
• Predominant manifestation is a diffuse
hemangioma in leptomeninges, choroid, and
facial skin.
• Sturge–Weber syndrome with its neural
involvement leads to intractable seizures,
developmental delay, and behavioral
problems.

61. • Cutaneous manifestations of nevus flammeus,
although most evident, are mainly of
diagnostic significance,
• Glaucoma and diffuse choroidal hemangioma
may be associated with some visual loss.

62. • Leptomeningeal hemangiomatosis is ipsilateral to
cutaneous involvement.
–This can lead to a seizure disorder due to
effects on underlying cerebral cortex.
–Contrast-enhanced MRI for detecting cerebral
atrophy and leptomeningeal angiomatous
malformations.
–If MRI is normal, CT scan to detect intracranial
calcifications.

64. • Cutaneous hemangioma is also called nevus flammeus
or port wine stain.
– Only 10% are associated with SWS.
– SWS only occurs in patients with, involvement of V1
or V2 distribution of trigeminal nerve.
– Bilateral port wine stains have higher associatpon.
• Leptomeningeal and ocular involvement in SWS are
always associated with port wine stain involving eyelids.

66. OPHTHALMOLOGIC FINDINGS
• Glaucoma is the most frequent manifestation
of SWS and occurs in 70% of all cases.
• Angle maldevelopment or raised episcleral
venous pressure can lead to glaucoma.

67. • Incidence of glaucoma is higher if the eyelids
are involved with nevus flammeus.
• Choroidal hemangioma is usually unilateral
and ipsilateral to the nevus flammeus.
– Appears as an orange-colored, diffuse choroidal
thickening associated with exudative RD.

69. MANAGEMENT
• Medical therapy of glaucoma is effective in some
cases, but eventually require multiple
trabeculectomies combined trabeculotomy with
trabeculectomy, or even drainage implants.
• Choroidal hemangioma can be treated with low-
dose standard radiotherapy or with proton beam
radiotherapy.
• Seizures are generally controlled with medications
but intractable cases require surgical resection of
leptomeningeal angiomatosis with underlying
cerebral cortex.

71. • Madame Louis-Bar in 1941 described a young
boy with progressive cerebellar ataxia and
oculocutaneous telangiectasia.
• Term ‘ataxia telangiectasia’ was proposed by
Boder and Sedgwick in 1958
• Autosomal recessive.
• Causative gene in AT is called ATM (ataxia -
telangiectasia mutated gene) and is found on
chromosome llq22.3.

72. SYSTEMIC FINDINGS
• Childhood neurodegenerative disorder with
neural, ocular, and cutaneous manifestations
associated with immune dysfunction.
• Progressive cerebellar ataxia in early childhood is
hallmark of AT
• Show increased sensitivity to the tissue-damaging
side effects of therapeutic radiation and
chemotherapeutic agents.

73. • Defective T-cell function associated with
hypoplasia of the thymus and decreased levels of
circulating immunoglobulin.
• Recurrent respiratory tract infections are a
serious problem,
• Increased susceptibility to various malignancies,
particularly lymphomas and leukemias,
contributes to early mortality.

74. Ocular findings
• Telangiectasia of conjunctiva has later onset than
ataxia and appears at age 3-7 years.
• First noted in the interpalpebral bulbar
conjunctiva away from limbus.
• Later ocular telangiectasia becomes generalized
and simulates a conjunctivitis.

75. • Ocular abnormalities include oculomotor
apraxia, deficient accommodation, impaired
smooth pursuit, hypometric saccades,nystagmus,
absence of optokinetic nystagmus, frequent
blinking.
• Combination of oculomotor apraxia and failure
to suppress the vestibulo-ocular reflex is
characteristic.

76. • Patients will develop impairment of pursuits
by school age.
• Increased saccadic latency, saccadic
hypometria, and saccadic intrusions are also
seen.
• Visual acuity, pupillary response, and
funduscopic examination are usually normal.

77. MANAGEMENT
• AT patients suffer from recurrent sino-
pulmonary infections because of immune
dysfunction.
• AT-associated malignancies such as lymphoma
and leukemia require modified chemotherapy
and radiotherapy dosages because of
hypersensitivity to radiation and
chemotherapy-induced DNA damage.