Neurocutaneous syndromes involve abnormalities of both the skin and central nervous system. This document summarizes several key neurocutaneous syndromes including tuberous sclerosis complex, neurofibromatosis type 1, and Sturge-Weber syndrome. Tuberous sclerosis complex is characterized by benign tumors in multiple organ systems and features such as facial angiofibromas and hypomelanotic macules. Neurofibromatosis type 1 causes cafe-au-lait spots and benign nerve tumors known as neurofibromas. Sturge-Weber syndrome is associated with a port-wine stain of the face and leptomeningeal angiomas of the brain.

1. Neurocutaneous syndromes
Dr.Jagadeesh
Gen Med PG
Katuri Medical college

2. Introduction
• Neurocutaneous syndromes are a heterogenous
group of disorders.
• These involve the integument and the CNS.
• These are mostly familial.
• Arise due to a defect in the differentiation of
primitive ectoderm.

3. • TUBEROUS SCLEROSIS
• NEUROFIBROMATOSIS
• STURGE-WEBER SYNDROME
• VON HIPPEL-LINDAU SYNDROME
• HEREDITARY HEMORRHAGIC TELANGIECTASIA
• HYPOMELANOSIS OF ITO
• INCONTINENTIA PIGMENTI

4. • ATAXIA-TELANGIECTASIA
• EPIDERMAL NEVUS SYNDROME
• NEUROCUTANEOUS MELANOSIS
• EHLERS-DANLOS SYNDROME
• CEREBROTENDINOUS XANTHOMATOSIS
• PROGRESSIVE FACIAL HEMIATROPHY
• KINKY HAIR SYNDROME (MENKES DISEASE)

5. TUBEROUS SCLEROSIS

6. Introduction
• Tuberous sclerosis complex (TSC) is a disorder
of cellular differentiation and proliferation
that can affect the brain, skin, kidneys, heart,
and other organs.
• Abnormal neuronal migration plays a major
role in neurological dysfunction.

7. • prevalence of 1 per 6000 to 9000
individuals.
• In infants, cardiac involvement and seizures
are presenting signs.
• whereas dermatological, pulmonary, or
renal involvement may lead to diagnosis in
older individuals.

8. • Autosomal dominant
Two genes are responsible for TSC:
• TSC1, coding for hamartin at chromosome
9q34.3.
• TSC2, coding for tuberin at chromosome
16p13.3

9. Cutaneous lesions
• The cutaneous lesions of TSC include hypomelanotic
macules, the shagreen patch, ungual fibromas, and
facial angiofibromas.
• Hypomelanotic macules (ash leaf spots) occur in up to
90% of affected individuals .
• Other pigmentary abnormalities include confetti
lesions (areas with stippled hypopigmentation,
typically on the extremities) and poliosis (a white patch
or forelock) of the scalp, hair, or eyelids.

10. • Facial angiofibromas (adenoma sebaceum)
consist of vascular and connective tissue
elements.
• Although considered specific for TSC, they are
found in only three-fourths of affected
individuals and often appear several years
after other means have established the
diagnosis.

11. • The shagreen patch most often is found on
the back or flank area; it is an irregularly
shaped, slightly raised, or textured skin lesion.
• Only 20% to 30% of patients with TSC have
one patch, which may not be seen in young
children.
• Usually considered specific for TSC.

12. • Ungual fibromas are nodular or fleshy lesions
that arise adjacent to (periungual) or
underneath (subungual) the nails.
• Ungual fibromas occur in only 15% to 20%
of patients with TSC, more likely in
adolescents or adults.

13. Sub ungual fibromas

14. Shagreen patch

15. Facial angiofibromata

16. Ash leaf spot

17. Neurological features
• The predominant neurological
manifestations of TSC are intellectual
disability, seizures, and behavioral
abnormalities.
• Although milder forms of the disease with
little or no neurological impairment are
common.

18. • Neurological lesions probably result from
impaired cellular interaction resulting in
disrupted neuronal migration along radial glial
fibers and abnormal proliferation of glial
elements.
• Neuropathological lesions of TSC include
subependymal nodules (SENs), cortical and
subcortical hamartomas (tubers), areas of
focal cortical hypoplasia, and heterotopic gray
matter.

19. • SENs commonly arise from germinal matrix
progenitors in the caudothalamic groove near
the foramen of Monro.
• These lesions can grow over time, but usually
only into adolescence, after which time they
calcify.
• These remain asymptomatic unless they enlarge
and transform into subependymal giant-cell
astrocytomas (SEGAs).

20. • Similar to normal brain, tubers develop
between 14 and 16 weeks gestation, such
that the tuber load is establishedbefore
birth, though they may not be visible on
imaging until later childhood, given
myelination status.

21. • Seizures of various types occur in 80% to 90%
of patients. Most develop during the first
year postpartum, which is an indicator for
autism and poor cognitive development.
• TSC is the most common cause of infantile
spasms, and one-third of children with TSC
develop them.

22. • Children with infantile spasms have more
cortical lesions demonstrated by magnetic
resonance imaging (MRI) and are more likely
to exhibit long-term cognitive impairment.
• For many, vigabatrin has been a more
effective treatment option than
adrenocorticotropin hormone (ACTH).

23. • Corpus callosotomy is an option in young
children.
• Resective epilepsy surgery is a consideration
in individuals with seizures localizing to a
single tuber, resulting in seizure freedom
or at least significant seizure reduction.

24. • Most TSC patients with intellectual disability have
epilepsy, but many have seizures and normal
intelligence
• The number of subependymal lesions does not
correlate with the clinical severity of TSC, but
patients with MRI evidence of numerous cortical
lesions tend to have more cognitive impairment
and more difficulty with seizure control.

25. • The most abnormal regions seen on MRI tend
to coincide with focal abnormalities of the
electroencephalogram (EEG).
• Many children with TSC have serious behavioral
disorders. Autistic behavior, hyperkinesis,
aggressiveness, and frank psychosis sometimes
occur, either as isolated problems or in
combination with epilepsy or intellectual deficit.

26. • The prevalence of autistic spectrum disorders is 25% to
50% and equal between boys and girls.
• Subependymal giant-cell astrocytomas (SEGAs) develop in
6% to 14% of patients with TSC.
• Unlike the more common cortical tubers and SENs, giant-
cell astrocytomas can enlarge and cause symptoms of
increased intracranial pressure.
• Giant-cell tumors are usually benign but locally invasive,
and early surgery can be curative.

27. • Computed tomography (CT) best
demonstrates the calcified subependymal
nodules that characterize TSC
• CT sometimes shows superficial cerebral
lesions, but they are far more obvious
with T2-weighted MRI

28. Retinal Features
• Frequency of retinal hamartomas in TSC varies
from negligible to 87% of patients.
• Findings vary from classic mulberry lesions
adjacent to the optic disc to plaque-like
hamartoma or depigmented retinal lesions.
• Occasionally, patients have a pigmentary defect
of the iris.

29. Systemic features
Cardiac
• Approximately two-thirds of patients with TSC have a
cardiac rhabdomyoma
Renal
• Renal angiomyolipomas occur in up to three-fourths
of patients with TSC
• Most of these lesions are histologically benign tumors
with varying amounts of vascular tissue, fat, and
smooth muscle
• Single or multiple renal cysts are also a feature of TSC

30. Pulmonary
• Pulmonary disease presents after puberty in the form
of LAM and is five times more common in females
than in males.
• Pulmonary lesions, symptomatic or asymptomatic,
can be demonstrated in almost half of women with
TSC who undergo chest CT.
• Spontaneous and recurrent pneumothorax,
dyspnea, cough, and hemoptysis are typical
symptoms of pulmonary TSC.

31. Diagnostic criteria

33. Neurofibromatosis

34. Neurofibromatosis
• Neurofibromatosis (NF) is actually two
separate diseases, each caused by a different
gene.
• NF type 1 (NF1), or von Reckling-hausen
disease, is the most common of the
neurocutaneous syndromes, occurring in
approximately 1 in 3000 people.

35. • Inheritance is an autosomal dominant pattern,
but approximately half of NF1 cases result
from a spontaneous mutation.
• A mutation of the 60-exon NF1 gene on
chromosome 17q11.2 causes NF1. The NF1 gene
product, neurofibromin, is a tumor-suppression
GTPase-activating protein functioning to inhibit
Ras-mediated cell proliferation.

36. Diagnostic criteria of NF 1

37. Clinical features of NF1
Cutaneous features
• Cutaneous lesions of NF1 include café-au-lait
spots, subcutaneous neurofibromas, plexiform
neurofibro mas, and axillary freckling.
• Café-au-lait spots are flat, light to medium brown
areas that vary in shape and size. They typically
are present at birth but increase in size and
number during the first few years of life

38. • Later in childhood, skin freckling, 1 to 3 mm
in diameter, often occurs symmetrically in
the axillae (Crowe sign) and other
intertriginous regions

39. • Neurofibromas are benign tumors arising
from peripheral nerves. These tumors are
composed predominantly of Schwann cells
and fibroblasts but contain endothelial,
pericytes, and mast cell components.
• Neurofibromas can develop at any time but
their size and number often increase after
puberty.

40. • Plexiform neurofibromas often occur on the face and
can cause substantial deformity. Patients with plexiform
tumors of the head, face, or neck and those who
presented before 10 years of age are more likely to do
poorly .
• Plexiform neurofibromas have a 5% to 13% lifetime risk of
malignant degeneration into malignant peripheral nerve
sheath tumors. Malignant peripheral nerve sheath
tumors (MPNST) carry poor 5-year survival rates despite
treatment . PNFs and MPNST are difficult to distinguish
radiographically and sometimes even pathologically.

41. café-au-lait spots and axillary
freckling

42. Plexiform neurofibroma

43. Systemic Features of
Neurofibromatosis Type 1
• Lisch nodules are pigmented iris hamartomas
.They are pathognomonic for NF1.
• Dysplasia of the renal or carotid arteries occurs in
a small percentage of patients with NF1
• The most common skeletal manifestations in NF1
consist of short stature and macrocephaly

44. • Other skeletal abnormalities include long-
bone dysplasia (resulting in pathological
fractures and subsequent pseudoarthrosis),
scoliosis, and bony erosion secondary to
adjacent tumor.
• Dysplasia of the sphenoid wing is common.

45. Lisch nodules of the iris

46. Neurological Features in NF
Type 1
• NF1 affects the nervous system in several ways.
• Tumors occur in the brain, spinal cord, and
peripheral nerves.
• Optic nerve glioma is the most common CNS
tumor caused by NF1. Approximately 15% of
patients with NF1 have unilateral or bilateral
optic glioma.

47. Bilateral optic nerve gliomas

48. • The growth rate of these tumors varies, but
they tend to behave less aggressively in
patients with NF1 than those without NF1.
• When symptomatic, the presenting features are
optic atrophy, progressive vision loss, pain, or
proptosis.
• Precocious puberty is a common presenting
feature of chiasmatic optic nerve tumors in
children with NF1.

49. • Ependymomas, meningiomas, and
astrocytomas of the CNS occur in patients
with NF1 less often than in patients with NF2.
• Neurofibromas and schwannomas are common
but not always symptomatic; they develop on
either cranial nerves or spinal nerve roots. The
symptoms from these tumors (discomfort, pain,
numbness, weakness, and bowel/bladder
dysfunction) reflect their size, location, and rate
of growth.

50. • Macrocephaly is seen in half of NF1
patients, typically attributable to
megalencephaly related to increases in white
matter volume.
• Approximately 60% to 78% of patients with
NF1 have increased signal lesions within
the basal ganglia, thalamus, brainstem, and
cerebellum on T2-weighted MRIs

51. • The origin and significance of these
radiographic lesions are unclear, and they are
referred to at times as unidentified bright
objects (UBOs)
• Whether these MRI lesions correlate with the
likelihood of cognitive impairment still is
debatable; radiographic findings do not
correlate with neurological deficits.

52. • Patients with NF1 tend to have intelligence
quotient (IQ) scores within the low-normal range
and to exhibit behavioral problems.
• These symptoms may be related to vascular
changes in myelin sheath.
• Deep gray-matter radiological findings tend to
decrease with time, while cortical and subcortical
findings do not decrease or increase.

53. Neurofibramatosis 2.

54. • NF type 2 (NF2) is characterized by bilateral
vestibular schwannomas and often is
associated with other brain or spinal cord
tumors. NF2 occurs in only 1 in 35,000 to
50,000 people.
• Autosomal dominant

55. • A mutation of the NF2 gene on
chromosome 22 causes NF2. The NF2
protein product is schwannomin or merlin,
Moesin-Ezrin-Radixin-Like Protein.
• The NF2 gene suppresses tumor function.
Dysfunction of the NF2 gene accounts for the
occurrence of multiple central nervous system
(CNS) tumors in patients with NF2.

56. Clinical Features of NF Type 2
• Few cutaneous lesions
• Instead, patients often have multiple types of CNS
tumors (thus, the designation of central NF).
• Café-au-lait spots and subcutaneous neurofibromas
are less common.
• Lisch nodules are uncommon, although some patients
show presenile posterior subcapsular cataracts.

57. • Symptoms of NF2 typically develop in
adolescence or early adulthood but can begin
in childhood.
• Most patients who meet established diagnostic
criteria for NF2 eventually develop bilateral
vestibular schwannomas
• Common complaints with large acoustic tumors
include hearing loss, tinnitus, vertigo, facial
weakness, poor balance, and headache.

58. Diagnostic criteria NF 2

59. bilateral vestibular
tumors

60. STURGE WEBER SYNDROME

61. STURGE-WEBER
SYNDROME(SWS)
• The characteristic features are a facial cutaneous
angioma(port-wine nevus)and associated ipsilateral
leptomeningeal and brain angioma.
• Additional features include intellectual
disability,seizures,contralateral hemiparesis and
hemiatrophy and homonymous hemianopia.
• Syndrome occurs sporadically.
• Somatic mutations in GNAQ recently was identified in
patients with port-wine stains and SWS.

62. Etiology
• Anomalous development of primordial
vascular bed in early stages of cerebral
vascularization.
• Overlying meninges are richly vascularised and
cortex atrophied and calcified

63. Cutaneous Features
• Nevus typically involves forehead and upper eyelid,but
can involve both sides of face and can extend on to trunk
and limbs.
• Facial angioma is obvious at birth,it may thicken over
time and develop a nodular texture.Reactive hypertrophy
of adjacent bone and connective tissue may occur.
• 10% to 20% of children with port-wine nevus have
leptomeningeal angioma.

64. • Leptomeningeal angioma is typically ipsilateral to a
unilateral facial nevus, amblyopia and buphthalmos
are present in some new borns.
• Glaucoma is also seen,if untreated causes
progressive blindness.Periodic measurement of
intraocular pressure is mandatory.
• Some may develop choroid angiomas or
heterochromasia of iris .

66. Neurological Features
• Epileptic seizures,intellectual disability and focal neurological
deficits are principal abnormalities
• Seizure onset before age 2 years increases likelihood of
intellectual disability and refractory epilepsy
• Seizures usually start in conjunction with hemiparesis
• Focal motor seizures or generalized tonic-clonic seizures are
most typical
• Older children and adults are more likely to have complex
partial or focal motor seizures,

67. • Neurological impairment caused by SWS depends in part
on the site of intracranial region
• Occipital region involvement– visual field defects
• Hemiparesis develops acutely in conjunction with initial
flurry of seizures,it may be permenant
• Some children develop sudden weakness without
seizures,either as repeated episodes of weakness or as a
single stroke episode with persistent neurological deficit.

68. CT showing occipital gyriform
calcification

69. Diagnostic Studies
• Neuroimaging studies help distinguish children with SWS from
those with isolated cutaneous lesions
• CT shows intracranial calcification much earlier than skull
radiographs
• MRI readily shows even subtle atrophy
• MRI with gadolinium contrast effectively demonstrates the
abnormal intracranial vessels in patients with SWS.
• Functional imaging and PET demonstrates reduced
metabolism of brain adjacent to leptomeningial lesion

70. Gadolinium reveals leptomeningeal
and intraparenchymalangioma.

71. • Single-photon emission computed tomograh(SPECT)
shows reduced perfusion of affected brain.
• Cerebral arteriography is no longer routine in
evaluation but is sometimes useful in atypical
patients or prior to surgery for epilepsy.
• Microscopic haemorrhages are noticeable in
pathology specimens

72. Treatment
• The more extensive the intracranial lesion,the more difficult
to control seizures with medication
• Resection of a localized brain vascular lesion or
hemispherectomy can improve seizure control and may
promote better intellectual development
• Often the patient selected for surgery is one with refractory
seizures, failure to respond an adequate trial of
anticonvulsants
• Corpus calosotomy is useful for patients with refractory tonic
or atonic seizures

73. VHL

74. VON HIPPEL-LINDAU SYNDROME(VHL)
• Autosomal dominant inherited disorder characterized by
hemangioblastomas arising in retina and CNS,as well as
visceral cysts and tumors.
• 1 in 40,000
• Occur sporadically, usually multiple, more likely to occur
in young persons.
• Hemangioblastomas are benign slow growing vascular
tumors.
• Histologically, composed of endothelium lined vascular
channels sorrounded by stromal cells and pericytes.

75. Molecular Genetics
• VHL gene is a tumor suppressor gene located on
chromosome 3p25-26
• A mutation in the VHL gene also appears in many
sporadic renal cell carcinomas
• It demonstrates role in function of hypoxia-induced
factor,HIF 2 alpha.
• Missense mutations are associated with
pheochromocytoma
• Non sense,frameshift, deletions predominate in
families without pheochromocytoma

76. Neurological Features
• Initial symptoms of VHL usually arise from effects of
vascular anomalies in the CNS
• Most common site of hemangioblastomas is
cerebellum,followed by spinal and medullary sites
• Early symptoms of cerebellar and brainstem
hemangiomblastoma are headache, followed by
ataxia,nausea,vomiting and nystagmus
• Spinal hemangioblastoma present with focal back or
neck pain and sensory loss or weakness

77. • They frequently lead to syringomyelia
• Conus medullaris and cervicomedullary junction are
most common sites
• Brainstem hemangioblastomas tend to arise in area
postrema in medulla and may be associated with
syringobulbia
• The incidence of cerebellar hemangioblastomas
increases with age
• These are best visualized using contrast enhanced
MRI

78. MRI with multiple cerebellar
hemangioblastomas

79. Ocular Features
• Childhood onset of symptoms is unusual, but retinal
hemangiobalstomas may occur in children
• Retinal hemangioblastomas may be symptomatic,
especially if they occur in periphery of retina
• Vision loss occurs when lesions are large and
centrally located, even in absence of heamorrhage
• Heamorrhage may lead to retinal injury and
detachment, glaucoma,uveitis,macular edema and
sympathetic ophthalmitis

80. Systemic Features
• Renal cysts are present in more than half of
individuals with VHL, rarely lead to renal failure.
• Renal cell carcinoma develops in more than 70% of
patients and is leading cause of death.
• These tumors in kidneys are usually multiple and
tend to occur at a younger age than sporadic renal
cell carcinoma.
• Pheochromocytoma (7% to 19%) sometimes is the
only clinical manifestation of VHL, even in carefully
screened individuals.

81. • Symptoms of pheochromocytoma include episodic
or sustained hypertension, severe headache, and
flushing with profuse sweatingOr even hypertensive
crisis, stroke, MI,and heart failure
• Cysts and tumors of pancreas and epididymis are
also features of VHL

82. Treatment
Cambridge Screening Protocol
AFFECTED PATIENT
• Annual physical examination and urine testing Annual
direct and indirect ophthalmoscopy with fluorescein
angioscopy or angiography
• Cranial magnetic resonance imaging (MRI) or computed
tomography (CT) every 3 years to age 50 and every 5
years thereafter
• Annual renal ultrasound, with abdominal CT scan every 3
years (more frequently if multiple renal cysts are
discovered)
• Annual 24-hour urine collection for vanillylmandelic acid
• acid

83. AT-RISK RELATIVE
• Annual physical examination and urine testing
• Annual direct and indirect ophthalmoscopy from age 5
years
• Annual fluorescein angioscopy or angiography from age
10 years until age 60
• Cranial MRI or CT every 3 years from age 15 to 40 and
every 5 years until age 60
• Annual renal ultrasound, with abdominal CT scan every 3
years from age 20 to 65 years
• Annual 24-hour urine collection for vanillylmandelic

84. -------------------THANQ------------------