This document discusses several neurocutaneous disorders known as phakomatoses that are characterized by abnormalities affecting the skin, eyes, and nervous system. It provides detailed information on type 1 and type 2 neurofibromatosis, tuberous sclerosis complex, Von Hippel-Lindau disease, and several neurocutaneous angiomatoses including Ataxia-Telangiectasia, Sturge-Weber syndrome, Klippel-Trénaunay-Weber syndrome, Rendu-Osler-Weber syndrome, Wyburn-Mason syndrome, and Fabry's disease. For each condition, it describes the genetic basis, characteristic features, diagnostic criteria, clinical manifestations, treatment approaches, and

2. INTRODUCTION
• Phakomatoses – Van der Hoeve (1920)
• Phakos – Birthmark
• Heterogenous group of hereditary disorders
with cutaneous, ocular and neurological
manifestations

3. PHAKOMATOSES
• Neurofibromatosis
• Tuberous sclerosis complex (Bourneville's
disease)
• Von Hippel-Lindau disease (retinocerebellar
angiomatosis)
• Neurocutaneous angiomatoses
– Ataxia-telangiectasia
– Sturge-weber
– Klippel trénaunay-weber
– Rendu-Osler-Weber syndrome
– Wyburn-Mason syndrome
– Fabry's disease

6. TYPE 1 NEUROFIBROMATOSIS
or
von Recklinghausen’s disease
or
Peripheral Neurofibromatosis

7. TYPE 1 NEUROFIBROMATOSIS
• Most common of the neurocutaneous tumor syndromes
• Neurofibromin protein, chromosome 17q11.2
• RAS pathway - Loss of function
• 97% of patients with NF1 meet diagnostic criteria by age 8

8. 1
2 or more
6 or more
2 or more
or

10. • Multidisciplinary care team
• The lesions necessitating neurosurgical care
– Plexiform or other neurofibromas
– Optic pathway gliomas
– Brainstem gliomas
– Cerebellar gliomas

11. NEUROFIBROMAS
• Consist of a mixture of Schwann cells, fibroblasts,
perineural cells, endothelial cells, mast cells,
pericytes, and other intermediate cell types.
• HPE - Schwann cells with decreased axonal
association, along with breakdown of the
perineural layer and disorganization of supporting
cells
• Typically benign and slow growing
• Routine spinal imaging, not indicated
• Surgical resection is reserved for symptomatic
cases

13. PLEXIFORM NEUROFIBROMAS
• Extend across the length of a nerve and
may involve multiple nerve fascicles or
multiple branches of a large nerve
• Can cause nerve root or spinal cord
compression
• Goal of surgery - to arrest or alleviate
symptoms, (rather to perform a gross
total resection)
• Recurrence common, further surgery is
still beneficial

14. MALIGNANT PERIPHERAL NERVE
SHEATH TUMORS (MPNSTs)
• Neurofibromas degenerate to MPNTs
• The lifetime risk with NF1 - 6% to 13%
• Primarily from nodular neurofibromas or
plexiform neurofibromas.
• Pain or rapid enlargement of a known mass is
a classic symptom

15. MPNSTs
• Mostly affects adults
(15% in <17 years)
• Mean length of
survival - 2 to 3 years
• Treatment - radical
surgical excision with
radiotherapy as
adjuvant or
neoadjuvant , and
chemotherapy for
high-grade, systemic
disease.

16. OPTIC PATHWAY GLIOMAS (OPGs)
• 15% of patients with NF1
• Typically affect the anterior optic apparatus
(optic nerve or chiasm)
• Typically low grade (most commonly pilocytic
astrocytomas), but some are higher grade
lesions
• Symptoms - headache, visual changes,
proptosis, endocrine abnormalities, and
symptoms of hydrocephalus

17. • Non-enhancing OPGs typically do not progress
• Surgical intervention for tissue diagnosis for
patients with an atypical tumor appearance on
MRI
• Progression of either symptoms or imaging
findings - Tumor debulking
• Adjuvant therapy - chemotherapy, with
vincristine and carboplatin as first-line agents.
• Radiation therapy - also a consideration

18. BRAINSTEM GLIOMAS
• Indolent course in NF-1
• Intervention is reserved for cases of clinical or
radiographic progression.

19. CEREBELLAR GLIOMAS
• Small percentage of NF1 patients
• Most commonly low grade (pilocytic
astrocytoma)
• Tend to be at subependymal white matter of
the fourth ventricle
• More malignant
• Should be managed aggressively with surgical
resection - curative

20. TYPE 2 NEUROFIBROMATOSIS
or
Central Neurofibromatosis

21. TYPE 2 NEUROFIBROMATOSIS
• Autosomal dominant
• Penetrance nearly 100%.
• >50% - de novo mutations
• Present in late adolescence or early adulthood
• Mutations of the NF2 ,chromosome 22(protein-
merlin), regulates contact-mediated growth
inhibition
• Bilateral acoustic schwannomas, intracranial and
spinal meningiomas, and other spinal cord
tumors.

22. DIAGNOSIS

23. NIH CRITERIA
• Bilateral acoustic schwannomas
• First-degree family relative with NF2 and unilateral
acoustic schwannoma or any one of the following:
meningioma, schwannoma, glioma, neurofibroma,
juvenile posterior subcapsular lens opacity(MSGNJ)
MANCHESTER CRITERIA
• Bilateral acoustic schwannomas
• First-degree family relative with NF2 and unilateral
acoustic schwannoma or any two of the following:
MSGNJ
• Unilateral acoustic schwannoma and any two of the
following: MSGNJ
• Multiple meningiomas and unilateral acoustic
schwannoma or any two of the following: SGNJ

24. Baser criteria -
Sensitivity up to 79%
and specificity of 100%

25. SCREENING
Screening for NF2 should occur in at-risk
individuals even before satisfaction of diagnostic
criteria
Accepted criteria for NF2 screening
• First-degree relative with NF2
• Acoustic schwannomas before the age of 30
• Spinal tumor or meningioma before the age of 20
• Cutaneous schwannomas
• Multiple spinal tumors

26. SCREENING
• Detailed personal and family histories, cutaneous and
ocular examinations, and MRI of the neuraxis.
• Interval screening - For those with a confirmed NF2
– Annual hearing evaluation with BERA
– Annual ophthalmologic examinations
– Annual dermatologic examinations
– MRI of the neuraxis beginning at age 10, repeated every 2 years up to
age 20, then repeated every 3 to 5 years afterward

27. CLINICAL FEATURES
• 70% of affected individuals may have skin
tumors such as schwannomas, neurofibromas,
or mixed tumors
• bilateral acoustic schwannomas, other cranial
nerve schwannomas, intracranial and spinal
meningiomas, and other spinal tumors.

28. ACOUSTIC SCHWANNOMAS
• Benign tumors, when bilateral, are
pathognomonic for NF2 (upto 95%)
• Hearing preservation rates are highest when
tumors are small, but it is difficult to predict
which tumors will grow.
• Tumors are often multifocal and may grow to
involve facial nerve fibers.

29. • Microsurgical resection - significant tumor
recurrence
• Stereotactic radiosurgery - successful in unilateral
• Development of secondary malignancies in NF2
Intracranial meningiomas (50% of NF2 patients)
• Earlier onset and higher grade than sporadic
Spinal tumors (90% of NF2 patients)
• MC - meningiomas or schwannomas,
Intramedullary tumors such as ependymomas are
also common
• Surgical resection - radiographic progression or
neurological decline.

30. TUBEROUS SCLEROSIS COMPLEX

31. TUBEROUS SCLEROSIS COMPLEX
• Autosomal dominant
• Affects the CNS, heart,
kidneys, liver, skin, and
lungs.
• De novo mutations -
80%
• Major cause of
epilepsy, autism, and
neurocognitive deficits
• Mutations - 9q34
(TSC1) hamartin or
16p13 (TSC2) tuberin

32. DIAGNOSIS
• Vogt’s Triad - epilepsy, low intelligence and
adenoma sebaceum, “Epiloia” (less than half
of cases)

33. RENAL ANGIOMYOLIPOMAS
CARDIAC RHABDOMYOMAS
PULMONARY
LYMPHANGIOMYOMATOSIS
RENAL CELL CARCINOMA OR CYSTS

34. FACIAL ANGIOFIBROMAS
ADENOMA SEBACEUM LEAF SPOTS
SUBUNGUAL FIBROMAS SHAGREEN PATCHES GINGIVAL FIBROMAS

35. CORTICAL TUBERS SUBEPENDYMAL NODULES
SUBEPENDYMAL GIANT CELL ASTROCYTOMAS
(SEGAS)

36. DIAGNOSTIC CRITERIA
FOR
TUBEROUS SCLEROSIS COMPLEX

37. PRIMARY (PATHOGNOMONIC) FEATURES
FACIAL
ANGIOFIBROMAS
MULTIPLE UNGUAL FIBROMAS
CORTICAL
TUBERS ON HPE
CALCIFIED
SUBEPENDYMAL NODULES
M/L RETINAL
ASTROCYTOMAS
SEGA

38. SECONDARY (PRESUMPTIVE) FEATURES
FIRST DEGREE
AFFECTED CARDIAC RHABDO
RETINAL
HAMARTOMA ACHROMIC PATCH
RENAL AML
SHAGREEN PATCH FOREHEAD PLAQUE
CORTICAL TUBERS ON
RADIOLOGY
RENAL CYSTS
NON-CALCIFIED
SUBEPENDYMAL NODULES PULMONARY LAM

39. TERITIARY (SUSPICIOUS) FEATURES
CONFETTI LESIONS
ASH LEAF MACULES
ENAMEL PITS & GINGIVAL
FIBROMAS
RENAL CYSTS PULMONARY LAM
HAMARTOMATOUS
RECTAL POLYPS
BONE CYSTS
INFANTILE SPASMS
HAMARTOMAS IN
OTHER ORGANS
MIGRATION
TRACTS

42. CNS MANIFESTATIONS

44. • Smooth, firm, pale gliotic plaques typically distributed
along GW matter jn
• Hamartomas of abnormal neurons and glia
• Can act as seizure foci
CORTICAL TUBERS

45. • other intracranial abnormalities, such as
cortical dysplasia and white matter linear
migration lines, are visible on imaging.

46. SUBEPENDYMAL NODULES
• Small, usually asymptomatic calcifications projecting
from the ependymal surface of the lateral ventricles.
• Pathologically similar to SEGAs but do not show
enhancement with contrast material

47. SEGAs
• Manifest during the first two decades
• Benign tumors of neuroglial origin (5% to
20% of TSC)
• Slow-growing tumors, typically found at
the caudothalamic groove adjacent to
the foramen of Monro

48. CURRENT SCREENING GUIDELINES
Contrast-enhanced MRI every 1 to 3 years until age 25
• If no additional SEGA is identified during this period,
then some practitioners cease obtaining imaging.
• Some advice to receive serial imaging after this age,
but the interval may be significantly prolonged.
• Any patient who develops new symptoms or
demonstrates a history of serial growth of a SEGA
should promptly undergo imaging, regardless of age.

49. Management of SEGAs
• Watchful waiting, surgical resection, and
pharmacotherapy with mTOR inhibitors.
• The choice is case dependent
• Incidental SEGAs without hydrocephalus and who
do not demonstrate tumor growth on repeat
imaging - monitoring
• Surgery – If, intratumoral hemorrhage or
symptomatic hydrocephalus
• Gross total resection or radical subtotal resection
may be curative

50. VON HIPPEL-LINDAU DISEASE

51. VON HIPPEL-LINDAU DISEASE
• Autosomal dominant
• 1 per 36,000 people
• Familial - 80% of cases, with penetrance 90%
• Mutation - 3p25 - tumor suppressor protein
pVHL (coordinates multiple aspects of the cell
cycle and facilitates angiogenesis via hypoxia-
inducible factor 1-alpha and 2-alpha)
• “Two-hit” hypothesis

55. HEMANGIOBLASTOMAS
• Most frequently observed in
VHL
• Sporadic hemangioblastomas
vs VHL disease–associated
• Mean age at presentation is 29
years

56. • Unpredictable growth pattern - “stuttering”
• Surgery for symptomatic or rapidly growing
lesions
• Preoperative embolization may help to facilitate
surgery by decreasing tumor vascularity
• Hemangioblastomas of the brainstem and spinal
cord can be resected safely
• Preoperative neurological function - best
predictor of postoperative neurological outcome

59. • Retinal capillary hemangioblastomas and
endolymphatic sac tumors, do not typically
necessitate neurosurgical care

60. NEUROCUTANEOUS ANGIOMATOSIS

61. Ataxia-Telangiectasia
(Louis-Bar Disease)
• Progressive ataxia with degeneration of Purkinje
cells
• Multiple cutaneous telangiectasias
• Immunologic abnormalities
• Hypersensitivity to irradiation and radiomimetic
drugs
• Predisposition to various cancers
• Loss of myelinated fibers in the peripheral nerves,
posterior columns and cerebellospinal tracts
• No treatment is known

64. • Neonatal period - may be asymptomatic
• Toddler stage - walking is clumsy and unsteady
• By 3 years of age and later - cutaneous
telangiectasias appear
• By school age - ataxia, choreoathetosis and
dysarthria may be noted
• By age 10 or so - intellectual impairment and a
mild polyneuropathy may appear
• Death usually occurs in the second decade
from infection or neoplasia

65. Sturge-Weber Syndrome
(Encephalotrigeminal Angiomatosis)
• Sturge-Weber syndrome - skin and the nervous system
involved
• Most cases, however, seem to be caused by a somatic
mutation
– Unilateral facial angioma (port-wine stain)
– Ipsilateral parieto-occipital leptomeningeal venous angiomatosis
– Underlying cortical atrophy
– Calcifications in cortical layers
– Cystic and enlarged choroid plexus.
– Angiomas occasionally in the eye
– Increased scleral venous pressure reduces outflow of aqueous
humor and may produce glaucoma or buphthalmos

67. • Neurological abnormalities
– Seizures
– Spastic hemiparesis
– Hemianopia contralateral to the angiomatosis
– Subarachnoid hemorrhage (uncommon)
TREATMENT
• Skin lesion - Argon laser
• Neurosurgical intervention in patients with
medically intractable seizures
– Hemispherectomy
– Occipital lobectomy
– Local excision of the pial angioma, calcified cortex, or
corpus callosotomy

68. Klippel-Trénaunay-Weber Syndrome
(Spinal Cutaneous Angiomatosis)
• Spinal variant of Sturge-Weber syndrome
– Extensive skin hemangiomas in dermatomal
pattern
– Hemangiomas of the spinal cord in the same
dermatomal distribution
– Osseous or muscular hypertrophy of the involved
area
• Both SW and KTW could be caused by a
similar sporadic mutation affecting different
dermatomes during development

70. Rendu-Osler-Weber Syndrome
(Hereditary Hemorrhagic Telangiectasia)
• Uncommon disorder of systemic fibrovascular
dysplasia
– Telangiectasias
– Arteriovenous malformations
– Aneurysms of the skin, mucous membranes, viscera, and
CNS
• In childhood, diagnosed from the development of
multiple small red or purple angiomas
• Later enlarge and may cause recurrent epistaxis or GI
or GU hemorrhages
• Scattered angiomas in the brain or spinal cord
– Hemorrhage
– Seizures
– Localized cerebral or spinal dysfunction

71. • Subarachnoid hemorrhage (SAH) in
association with multiple arterio-venous
malformations, cutaneous telangiectasias,
repeated epistaxis or a family history of SAH
• Septic emboli to brain because of these
vascular defects in the lung

73. Wyburn-Mason Syndrome
(Bulbar-Facial Angiomatosis)
• Rare disorder
• Hereditary aspects - uncertain

75. Fabry's Disease
(Angiokeratoma Corporis Diffusum)
• Results from - X-linked recessive inborn error of
metabolism
• Deficit in the lysosomal enzyme, a-galactosidase.
• Leads to accumulation of ceramide trihexoside in
the endothelium and media of blood vessels.
• Symptoms - mostly in males, occasionally females
• Prenatal diagnosis - chorionic villi sampling

77. • Vascular involvement is usually more diffuse
and can lead to impaired renal function,
hypertension, myocardial infarction, and
cerebrovascular insufficiency.
• Painful polyneuropathy due to ceramide
trihexoside deposition

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