Best teach you Neurocutaneous syndromes

1. Neurocutaneous
Syndrome
MOHD HANAFI RAMLEE

2. Neurocutaneous Syndromes
• The neurocutaneous syndromes include a heterogeneous
group of disorders characterized by abnormalities of both the
integument and central nervous system.
• Most disorders are familial, believed to arise from a defect in
differentiation of the primitive ectoderm.

3. Phakomatoses
1. Neurofibromatosis
2. Tuberous sclerosis
3. Ataxia telangiectasia
4. Sturge-Weber syndrome
5. von Hippel-Lindau disease
6. Incontinentia pigmenti
7. Nevoid basal cell carcinoma syndrome

4. 5 years old boy brought to
your office for
• behavioral evaluation
PE reveals
• short stature
• large head
• skin spots

5. 1. NEUROFIBROMATOSIS

6. Neurofibromatosis
• Café au Lait spot
• Discrete, well-circumscribed
uniformly brown lesions with
irregular border
• 2 - 20 mm
• Isolated lesions occur in 10 -
20% of population; 98% of
normal individuals have less
than three lesions

7. Café au Lait spot
• cafe-au-lait spots: are not
necessarily a diagnostic sign of
NF
• Multiple lesions occur in a
variety of syndromes:
N
• Neurofibromatosis
V
• Von Hippel – Lindau disease
A
• Fanconi anemia
• Ataxia Telangiectasia
T
• Tuberous sclerosis
S
• Silver-Russell dwarfism
B
• Bloom syndrome
• Basal cell nevus syndrome
• Gaucher disease
H
• Chédiak-Higashi syndrome
• Hunter syndrome
M
• Marfan's syndrome
• Maffucci syndrome
• McCune-Albright syndrome
• Multiple endocrine neoplasia
type 2
P
• Peutz-Jeghers Syndrome

8. Neurofibromatosis
• NF1 and NF2 are autosomal dominant, with approximately 50%
of cases having no family history
• NF1 is also called von Recklinghausen disease
• NF2 is also called bilateral acoustic neurofibromatosis

9. Neurofibromatosis
• ETIOLOGY
• NF1 is caused by DNA mutations located on the long arm of
chromosome 17 responsible for encoding the protein
neurofibromin.
• NF2 is caused by DNA mutations located in the middle of the long
arm of chromosome 22 responsible for encoding the protein
merlin.

10. Neurofibromatosis
EPIDEMIOLOGY&DEMOGRAPHICS
• NF1 is the most common neurocutaneous syndrome, affecting
approximately 1/3000 persons
• NF2 occurs in about 1/50,000
• Equally affects males and females.

11. Neurofibromatosis
• PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Common features of NF1 include:
• Café-au-lait macules (100% of children by age 2)
• Hyperpigmented skin lesions occurring anywhere on the body except the face, palms,
and soles
• Appear early in life and increase in size and number during puberty
• Focal or diffuse
• Axillary and inguinal freckling (70%)
• Multiple cutaneous and subcutaneous neurofibromas (95%)
• Firm, varying in size from mm to cm
• Vary in number from a few to thousands
• May be sessile, pedunculated, regular or irregular in shape
• Lisch nodule (small hamartoma of the iris) found in >90% of adult cases
• Visual defects possibly related to optic gliomas (2% to 5%)
• Neurodevelopment problems (30% to 40%)
• Common features of NF2 include:
• Hearing loss and tinnitus related to bilateral acoustic neuromas (>90% of adults)
• Cataracts (81%)
• Headache
• Unsteady gait
• Cutaneous neurofibromas but less than NF1
• Café-au-lait macules (1%)

12. Neurofibromatosis
Axillary freckles
• Small (0.5cm) brown, well-
circumscribed macules
• Generally go unnoticed
• High correlation with
neurofibromatosis when six or
more freckles are present in
the axilla

13. Neurofibromatosis
Lisch Nodules
a pigmented hamartomatous
nevus (a type of benign tumor)
affecting the iris

14. Neurofibromatosis
Multiple cutaneous and
subcutaneous neurofibromas

15. Neurofibromatosis
Acoustic Neuroma
In NF2

16. Neurofibromatosis
Spinal
Neurofibroma

17. Neurofibromatosis
• Scoliosis

18. Neurofibromatosis
Intraspin
al
tumors

19. Neurofibromatosis
• DIAGNOSIS
• NF1 is diagnosed if the person has two or more of the following
features:
• Six or more café-au-lait macules >5 mm in prepubertal patients and >15 mm in
postpubertal patients
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Axillary or inguinal freckling
• Optic glioma
• Two or more Lisch nodules (iris hamartomas)
• Sphenoid wing dysplasia or cortical thinning of long bones, with or without
pseudarthrosis
• A first-degree relative (parent, sibling, or child) with NF1 based on the previous
criteria

20. Neurofibromatosis
• DIAGNOSIS
• NF2 is diagnosed if the person has either of the following two
criteria:
• Bilateral eighth nerve masses seen by appropriate imaging studies
• OR
• a unilateral eighth nerve mass
• A first-degree relative with NF2 and either
• or two of the following: neurofibroma, meningioma, glioma, schwannoma, or
juvenile posterior subcapsular lenticular opacity

21. Neurofibromatosis
• WORKUP
• LABORATORY TESTS
• Genetic testing is available. Results can only tell if an individual is
affected but cannot predict the severity of the disease.
• In NF2, linkage analysis testing provides a >99% certainty the
individual has NF2.
• IMAGING STUDIES
• MRI with gadolinium is the imaging study of choice in both NF1 and
NF2 patients. MRI increases detection of optic gliomas, tumors of the
spine, acoustic neuromas, and “bright spots” thought to represent
hamartomas.

22. Neurofibromatosis
• TREATMENT
• Primarily supportive
• AEDs for seizures
• Surgery for for accessible tumors
• Orthopedic procedures for bony deformities
• Routine MRI studies to screen for optic gliomas in
nonsymptomatic children

23. • 14 years old girl was
brought to you for facial
rash. You found out that
the girl has been in
special education and
getting treatment for
seizures.

24. 2) TUBEROUS SCLEROSIS

25. Tuberous Sclerosis
• The classic clinical triad is skin lesions in association with
epilepsy and mental retardation.
• Multisystemic disorder affecting primarily tissues derived from
ectoderm but also involving organs of mesodermal and
endodermal origin, particularly the eyes, kidneys, and heart.

26. Tuberous Sclerosis
ETIOLOGY AND EPIDEMIOLOGY
• Autosomal dominant condition with variable expression and an
estimated frequency of 1/6,000 . Mutations have been mapped
to chromosome 9q34 (TSC1) and 16p13.3 (TSC2).
• The TSC2 product is tuberin, which has sequence homology with
a GTPase-activating protein and may have a role in regulating
cellular growth by acting as a growth suppressor gene.
• TSC1 also is postulated to act as a growth suppressor.
• Approximately half of cases are due to new mutations.

27. Tuberous Sclerosis
Clinical Manifestations
ash-leaf macule
• the most reliable early cutaneous sign.
• presents at birth or in early infancy,
often years before other signs of the
disease.
• seen in more than 90% of cases in this
age group.
• also appear in 2–3/1,000 normal
newborns.
• they are sharply demarcated, pale, 0.5–
3cm lesions that often assume the
shape of a mountain ash leaflet.

28. Tuberous Sclerosis
Clinical Manifestations
Shagreen patch
• Is present by 15 years in 50% of
affected children
• Most often occurs on trunk or in
lumbosacral area but can occur
on any glabrous skin
• Discrete, usually flesh-colored,
flat to slightly elevated lesions
with a “pig-skin” or “orange-peel”
appearance
• Highly variable in size
• Are plaques of subepidermal
fibrosis

29. Tuberous Sclerosis
Clinical Manifestations
Café-au-lait spots
• occur with increased
frequency but are not as
numerous as in
neurofibromatosis

30. Tuberous Sclerosis
Clinical Manifestations
Adenoma sebaceum
• Present in approximately 50%of
patients who are > four years old;
unusual before 4 years of age
• Earliest manifestations are erythema
that slowly progresses to flesh-
colored to pink lesions at nasolabial
folds, malar region, chin, forehead
and, sometimes, the scalp
• Often confused with acne
• Are actually angiofibromas

31. Tuberous Sclerosis
Clinical Manifestations
Subungual fibromas
• arise from the stratum lucidum of
the finger and toe in many
patients with TS during
adolescence.

32. Tuberous Sclerosis
Clinical Manifestations
Periungual Fibroma
• Also called Koenen tumors
• Generally do not manifest until
puberty
• May involve and eventually
destroy the entire nail

33. Tuberous Sclerosis
Clinical Manifestations
• Mental deficiency occurs in
60–70%; nearly all have
epilepsy.
• Epilepsy is also present in
approximately 70% of those
patients without mental
retardation.
• Epilepsy begins in infancy (IS)
or early childhood and is
often progressively more
severe.
Clinical Manifestations
• Retinal tumors
• Rhabdomyoma of the heart
• Renal tumors
• Cysts of the kidney,bones
and lungs

34. Tuberous Sclerosis
• two astrocytic
hamartomas. One is
calcified.

35. Tuberous Sclerosis
• Renal Angiomyolipomas

36. Tuberous Sclerosis
Diagnosis
• Diagnosis of TS relies on a high index of suspicion when assessing a child
with infantile spasms.
• A careful search for the typical skin and retinal lesions should be
completed in all patients with a seizure disorder.
• Head CT scan or MRI confirms the diagnosis in most cases.
• The CT scan typically shows calcified tubers in the periventricular area,
but these may not be apparent until 3–4 yr of age.

37. Tuberous Sclerosis
• CT of the brain revealed
ventriculomegaly and
multiple calcified
subependymal nodules in
the lateral ventricles

38. Tuberous Sclerosis
• periventricular tubers

39. Tuberous Sclerosis
Diagnosis
• Molecular genetic testing of the TSC1 and TSC2
genes is complicated by the large size of the two
genes, the large number of disease-causing
mutations, and a 10% to 25% rate of somatic
mosaicism
• However, the molecular testing for both genes is
available

40. Tuberous Sclerosis
Management consists of :
• seizure control
• baseline studies, including
• brain CT/MRI
• renal ultrasonography
• echocardiogram
• chest X-ray
• In Europe and Canada, infantile spasms associated with TS are
often treated with vigabatrin (rather than ACTH), with good
results. Vigabatrin is not available in the United States.

41. Tuberous Sclerosis
Prognosis:
• 75% of patients with tuberous sclerosis die before the age
of 25 yr, most commonly as a complication of:
• Epilepsy
• intercurrent infection
• cardiac failure
• pulmonary fibrosis

42. 5 years old mentally retarded girl with recurrent
sinopulmonary infections and gait disturbance.

43. 3) ATAXIA TELANGIECTASIA

44. Ataxia Telangiectasia
(Louis-Bar syndrome)
INCIDENCE: 1/40,000 live births (the most common
degenerative ataxias)
PREDOMINANT SEX: Males = Females

45. Ataxia Telangiectasia
• GENETICS:
• Autosomal recessive
• chromosome 11q22-23
• More than 100 mutations have been discovered
• The gene product is involved in cell-cycle progression and
the checkpoint response to DNA damage.

46. Ataxia Telangiectasia
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Children show normal early development until they start to walk,
when gait and truncal ataxia become apparent.
• Choreoathetosis
• Occulomotor apraxia 90%
• Intellectual development normal at first but often lags with time.1/3
ultimately mildly MR.
• Telengiectasia usually develops after age of 2 years:
• bulbar conjunctivae
• upper half of the ears
• on the flexor aspects of the limbs
• in a butterfly distribution on the face
• Dull or expressionless face

49. Ataxia Telangiectasia
COMPLICATIONS:
• Recurrent sinopulmonary infections occur secondary to
impaired humoral and cellular immunity
• Increased frequency of cancers is noted, particularly T-
cell leukemia and lymphoma.

50. Ataxia Telangiectasia
DEFERENTIAL DIAGNOSIS
• Friedreich’s ataxia
• Abetalipoproteinemia (Bassen-Kornzweig Syndrome)
• Acquired Vitamin E deficiency
• Early onset cerebellar ataxia with retained reflexes (EOCA)
• Ataxia associated with biochemical abnormalities: associated with
• ceroid lipofuscinosis
• xeroderma pigmentosa
• Cockayne’s syndrome
• adrenoleukodystrophy
• metachromatic leukodystrophy
• mitochondrial disease
• sialidosis,
• Niemann Pick

51. Ataxia Telangiectasia
WORKUP
• IgA is absent in 70-80%
• IgE is diminished or absent in 80-90%
• IgM may be elevated
• AFP elevated in 90%
• Karyotype: high incidence of chromosomal breaks,
especially on chromosome 14
• Fibroblasts can be screened in vitro for x-ray sensitivity and
radioresistant DNA synthesis
• Pathology shows cerebellar degeneration, loss of
pigmented neurons, and posterior column degeneration in
the spinal cord

52. Ataxia Telangiectasia
• Cerebellar atrophy

53. Ataxia Telangiectasia
TREATMENT
• Supportive, no effective treatment to date
• Surveillance for infections and neoplasms
• Infections should be treated vigorously
• IVIG
• Minimize radiation as may induce further chromosomal
damage and lead to neoplasms
PROGNOSIS
• 67% of children die by age 20, typically from infection or
neoplasm

55. 4) STURGE-WEBER SYNDROME

56. Sturge-Weber disease
Port-wine stain

57. Sturge-Weber Syndrome
• It occurs sporadically, with a frequency of approximately
1/50,000 and consists of:
• Facial nevus (port-wine stain)
• Seizures
• Hemiparesis
• Intracranial calcifications
• Mental retardation

58. Sturge-Weber Syndrome
Clinical Manifestations
• The facial nevus is present at birth and tends to be unilateral and always
involves the upper face and eyelid. The nevus may also be evident over the
lower face, trunk, and in the mucosa of the mouth and pharynx.
• Unilateral in 70% and ipsilateral to the venous angioma of the pia
• Even when the facial nevus is bilateral,the pial angioma is usually unilateral.
• The size of the cutaneous angioma does not predict the size of the intracranial
angioma.
• Not all children with facial nevi have Sturge-Weber disease.
• Buphthalmos and glaucoma of the ipsilateral eye are a common complication.

59. Sturge-Weber Syndrome
Clinical Manifestations
• Seizures develop in most patients during the 1st year of life
• typically focal tonic-clonic and contralateral to the side of the facial
nevus
• seizures tend to become refractory to AEDs and are associated with a
slowly progressive hemiparesis in many cases.

60. Sturge-Weber Syndrome
Clinical Manifestations
• Although neurodevelopment appears to be normal during the 1st year
of life, mental retardation or severe learning disabilities are present in
at least 50% during later childhood.

61. Sturge-Weber Syndrome
Diagnosis.
• The CT scan highlights the extent of the calcification that is usually
associated with unilateral cortical atrophy and ipsilateral dilatation of
the lateral ventricle.

62. Sturge-Weber disease
• Axial CT without and with
contrast in a one-year-old boy
with seizures.
• In (a) no calcifications have yet
formed; cortical atrophy is
seen on the left.
• In (b) marked cortical
enhancement following
contrast injection.

63. Sturge-Weber Syndrome
Treatment
• Treat seizure
• hemispherectomy or lobectomy may be needed
• Because of the risk of glaucoma, regular measurements of intraocular
pressure with a tenonometer is indicated.
• Flashlamp-pulsed laser therapy holds considerable promise for
clearing of the port-wine stain.
• because of the high frequency of developmental disabilities, special
educational facilities are frequently required.

64. 5) VON-HIPPLE LINDAU DISEASE

65. Von Hippel-Lindau Disease
• von Hippel-Lindau disease affects many organs, including the
cerebellum, spinal cord, medulla, retina, kidney, pancreas, and
epididymis.
• von Hippel-Lindau disease is inherited as an autosomal dominant trait
with variable penetrance and delayed expression.
• The gene for von Hippel-Lindau disease has been mapped to
chromosome 3p25.

66. Von Hippel-Lindau Disease
• The major neurologic features of the condition
include
• cerebellar hemangioblastomas
• retinal angiomas
• Patients with cerebellar hemangioblastoma present
in early adult life or beyond with symptoms and
signs of increased intracranial pressure.

67. Von Hippel-Lindau Disease

68. Von Hippel-Lindau Disease
• Approximately 25% of patients with cerebellar hemangioblastoma have retinal
angiomas.
• Retinal angiomas are usually located in the peripheral retina so that vision is
unaffected. However, exudation in the region of the angiomas may lead to retinal
detachment and visual loss.
• Retinal angiomas are treated with photocoagulation and cryocoagulation, with
good results.

69. Von Hippel-Lindau Disease
• Retinal angiomas before
and after
cryocoagulation.

70. Von Hippel-Lindau Disease
• Cystic lesions of the kidneys, pancreas, liver, and epididymis as well as
pheochromocytoma are frequently associated with von Hippel-Lindau
disease.

71. Von Hippel-Lindau Disease

72. Von Hippel-Lindau Disease
• Renal carcinoma is the most common cause of death.
Regular follow-up and appropriate imaging studies are
necessary to identify lesions that may be treated at an early
stage.

73. Von Hippel-Lindau Disease

75. • 2 days old newborn with streaks of vesicular lesions and
erythema along the body lines.

77. INCONTINENTIA PIGMENTI

78. Incontinentia pigmenti

79. Incontinentia pigmenti
(Bloch-Sulzberger syndrome)
• Rare, X-linked, dominantly inherited disorder of skin
pigmentation that often is associated with CNS,
ocular, and dental abnormalities.
• Female carriers may have only subtle findings with
stage IV skin and teeth abnormalities.
• Lethal in the majority of affected males in utero.

80. Incontinentia pigmenti
Skin:
• Stage 1:
• at birth
• vesicular stage, with linear vesicles, pustules, and bullae with erythema along
the lines of Blaschko.
• Stage 2:
• between ages 2 and 8 weeks
• the verrucous stage, with warty, keratotic papules and plaques.
• Stage 3:
• between ages 12 and 40 weeks.
• the hyperpigmented stage, with macular hyperpigmentation in a swirled
pattern along the lines of Blaschko. These changes often involve the nipples,
axilla, and groin.
• Stage 4
• from infancy through adulthood.
• the hypopigmented stage, with hypopigmented streaks and/or patches and
cutaneous atrophy.

81. Incontinentia pigmenti

82. Incontinentia pigmenti

83. Incontinentia pigmenti

85. Incontinentia pigmenti
• Ocular changes are seen in about 1/3 of patients. The changes can include the following:
• Retinal pigmentary changes with mottled diffuse hypopigmentation, which is nearly
pathognomonic
• Abnormal peripheral retinal vessels with areas of nonperfusion, which is also nearly
pathognomonic
• Microphthalmia
• Retrolental mass formation
• Cataracts or leukocoria
• Strabismus
• Optic atrophy or foveal hypoplasia
• Exudative retinal detachment (occurs only in a minority of patients)
• Teeth and jaw changes occur in approximately 65-90% of patients. These changes can include delayed
eruption of teeth; hypodontia; microdontia; abnormally shaped teeth—round, conical, or peg;
micrognathia; and prognathia.
• The CNS is involved in 10-40% of patients. The manifestations can include the following:
• Microcephaly
• Mental retardation
• Spasticity
• Seizures
• Strokes

86. Incontinentia pigmenti
• Onychodystrophy (nail dysplasia) occurs in 40-60% of patients. Other nail changes can include
subungual keratotic tumors.

87. Incontinentia pigmenti
• The hair is thin and sparse; alopecia is seen in 35-70% of patients. The hair changes can include a wooly
hair nevus, which is a coarse, lusterless, and wiry patch of hair.
• Skeletal and structural anomalies can occur in approximately 14% of patients but usually are associated
with severe neurological deficits. The anomalies can include the following:
• Somatic asymmetry
• Hemivertebrae
• Scoliosis
• Spina bifida
• Syndactyly
• Ear anomalies
• Extra ribs
• Skull deformities
• Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary.

88. Incontinentia pigmenti
Work Up
• Complete blood count (CBC) frequently shows eosinophilia.
• CT scan or MRI of brain may show abnormalities.
• Skin biopsy.
• MOLECULAR GENETICS: NEMO gene.

89. Incontinentia pigmenti
Medical Care:
• No specific treatment is available for incontinentia pigment.
• The stage 1 lesions should be left intact and kept clean.
• Meticulous dental care is very important.
Consultations:
• Ophthalmology
• Dentistry
• Neurology, only if neurological abnormalities are present

90. Incontinentia pigmenti
Patient Education:
• As incontinentia pigmenti is an X-linked dominant disease, genetic
counseling regarding the risk of affected offspring is very important.

91. Nevus Sebaceous of Jadassohn
• Predilection for scalp but may be
present in any anatomic site including
mucous membranes
• Usually solitary
• Yellow to yellowish brown waxy-
appearing lesion during the neonatal
period; becomes verrucoid as child ages
• May increase in size and become more
verrucoid during puberty
• Has potential to undergo malignant
degeneration
• Rx: Excision

93. Neurofibromatosis
• NF1
• 1:4000 patients
• Often inherited but 30-50%
occur as mutations
• 5 or more café au lait spots
(some may be present at
birth)
• 2 or more neurofibromas
• Most lead healthy normal
lives, occasionally surgery
may be required e.g. painful
disfiguring lesions
• NF 2
• 1:40,000 patients
• Bilateral 8th nerve tumours
• Presents in early teens with
hearing loss and symptoms of
pressure on adjacent cranial
nerves and structures e.g.
headache, facial numbness,
poor balance, tinnitus