visit www.dnbpediatrics.com for MD DNB Pediatrics study material

1. NEUROCUTANEOUS
SYNDROME
DR. PANKAJ BAJAJ
1ST YEAR DNB PEDIATRIC
J.L.N.Hospital & Research Centre, Bhilai Steel Plant
5/30/2012 JLNH & RC 1

2. TOPICS TO BE
COVERED……….
 DEFINITION
 CLASSIFICATION
 DETAILS OF EACH NEURO
CUTANEOUS SYNDROME
5/30/2012 JLNH & RC 2

3. DEFINITION
The neurocutaneous syndromes include a
Heterogeneous group of disorders
Characterized by abnormalities of both the
Integument and central nervous system
(CNS).
Most disorders are familial and believed to
Arise from a defect in differentiation of the
Primitive ectoderm.
5/30/2012 JLNH & RC 3

4. CLASSIFICATION
 Disorders classified as neurocutaneous syndromes
Include
 Neurofibromatosis
 Tuberous Sclerosis
 Sturge-Weber Syndrome
 Von Hippel–Lindau Disease
 PHACE Syndrome
 Ataxia Telangiectasia
 linear Nevus Syndrome
 Hypomelanosis of Ito NST
LP
 Incontinentia Pigmenti HINT
5/30/2012 JLNH & RC 4

5. NEUROFIBROMATOSIS
 Neurofibromatosis are autosomal dominant
Disorders that cause tumors to grow on
Nerves and result in other abnormalities
such As skin changes and bone deformities
 Neurofibromatosis 1 (NF-1)
 Neurofibromatosis 2 (NF-2)
5/30/2012 JLNH & RC 5

6. NEUROFIBROMATOSIS 1
(NF-1)
 Most prevalent type
 Incidence of 1/3,000
 Autosomal dominant disorder
 Over half the cases are sporadic,representing
De novo mutations.
 Chromosome region 17q11.2
 Encodes a protein also known as
Neurofibromin.
5/30/2012 JLNH & RC 6

7.  It is diagnosed when any 2 of the following 7 features Are
present:
(1) Six or more Cafe-au-lait macules
(2) Axillary or inguinal freckling .
(3) Two or more iris Lisch nodules
(4) Two or more neurofibromas
or 1 plexiform neurofibroma.
(5) A distinctive osseous lesion such as
Sphenoid dysplasia.
(6) Optic gliomas low-grade astrocytomas.
(7) A first-degree relative with NF-1.
5/30/2012 JLNH & RC 7

8. Cafe-au-lait macules
• Over 5 mm in greatest diameter in prepubertal individuals.
• Over 15 mm in greatest diameter in postpubertal individuals.
• Hallmark of neurofibromatosis almost 100% of patients.
• Present at birth but increase in size, number, and pigmentation, especially during
The first few yrs of life.
5/30/2012 JLNH & RC 8
• Predilection for the trunk and extremities but sparing the face.

9. Axillary or inguinal freckling
• Multiple hyperpigmented areas 2-3 mm in diameter.
• Skinfold freckling usually appears between 3 and 5 yr of age.
• Frequency greater than 80% by 6 yr of age.
5/30/2012 JLNH & RC 9

10. Two or more iris Lisch nodules
• Hamartomas.
• located within the iris .
• Best identified by a slit-lamp examination.
• They are present in >74% of patients with NF-1 but are not a component of NF-2.
• The prevalence increases with age.
• Only 5% of children <3 yr of age.
• 42% among children 3-4 yr of age. JLNH & RC
5/30/2012 10
• 100% of adults ≥21 yr of age.

11. Two or more neurofibromas or 1 plexiform
neurofibroma
• SITES involve the skin, peripheral nerves and blood vessels, viscera .
• Hormonal influence.
• They are usually small, rubbery lesions with a slight purplish discoloration of the
overlying skin.
• Plexiform neurofibromas are usually evident at birth and result from diffuse
thickening of nerve trunks that are frequently located in the orbital or temporal region
of the face.
• The skin overlying a plexiform neurofibroma may be hyperpigmented to a greater
degree than a Cafe-au-lait spot.
• Plexiform neurofibromas may produce overgrowth of an extremity and a deformity of
the 5/30/2012
corresponding bone. JLNH & RC 11

12. Distinctive Osseous lesion
Sphenoid Dysplasia
5/30/2012 JLNH & RC 12

13. • Scoliosis is Most Common Orthopedic manifestation- Not specific for
diagnostic criterion
• Cortical thining of long bones with or without pseudoarthrosis.
5/30/2012 JLNH & RC 13

14. Optic Gliomas
represent mostly low-grade Astrocytomas
• it is recommended that all children age 10 yr or younger with NF-1 undergo annual
ophthalmologic examinations.
•When they enlarge and put pressure on the optic nerves and chiasm resulting in
impaired visual acuity and visual fields.
• Extension into the hypothalamus can lead to endocrine deficiencies or failure to thrive.
5/30/2012 JLNH & RC 14

15. •The MRI findings of an optic glioma include diffuse thickening, localized enlargement, or a
distinct focal mass originating from the optic nerve or chiasm
5/30/2012 JLNH & RC 15

16. •A first-degree relative with NF-1 whose diagnosis was based on the aforementioned
criteria.
5/30/2012 JLNH & RC 16

17. Complications
 Seizures
 Hydrocephalus
 learning
disabilities, ADHD, Speech
disorder
 Macrocephaly
 Moya-moya Disease
 Precocious puberty
 Hypertension.
 Fibromuscular dysplasia
 Pheochromocytoma
 Malignancy
› Neurofibrosarcoma
› Malignant Schwanoma
5/30/2012 JLNH & RC
17

18. NEUROFIBROMATOSIS 2
(NF-2)
 Rarer condition
 Incidence of 1/25,000
 The NF2 gene (also known as merlin or
Schwannomin)
 located on chromosome 22q1.11
 Cafe-au-lait spots and skin neurofibromas are
less common in NF-2
 Posterior subcapsular lens opacities are
identified In about 50% of patients with NF-2
5/30/2012 JLNH & RC 18

19.  May be diagnosed when 1 of the following
4 Features is present:
 (1) bilateral vestibular schwannomas
 (2) a parent, sibling, or child with NF-2 and
Either unilateral vestibular schwannoma or
Any 2 of the following:
meningioma, Schwannoma, glioma, neurofi
broma, or Posterior subcapsular lenticular
opacities.
5/30/2012 JLNH & RC 19

20.  (3) unilateral vestibular schwannoma and
any 2 of the following:
meningioma, schwannoma, Glioma, neurofi
broma, or posterior Subcapsular lenticular
opacities.
 (4) multiple meningiomas (2 or more) and
Unilateral vestibular schwannoma or any 2
of The following:
schwannoma, glioma, Neurofibroma or
5/30/2012 JLNH & RC 20

21. Bilateral Acoustic Neuromas
•Hearing loss
•Unsteadiness
•Headache
•Facial weakness
•More commonly in 2nd and 3rd decade.
Subcapsular opacity- 50% of the cases of NF-
II
5/30/2012 JLNH & RC 21

22. • Ependymomas –most
(80%)in spinal cord.
• Spinal Schwannomas
(70%) intradural
extramedullary.
5/30/2012 JLNH & RC 22

23. Treatment and Management of
NF-I and NF-II
• Genetic counseling • Tests should be
• Half result from ordered if positive
fresh Mutation physical findings are
• Prenatal diagnosis in present
familial cases. • Annual evaluation
– By pediatrician
– By pediatric
ophthalmologist
5/30/2012 JLNH & RC
23

24. Tuberous Sclerosis
 TSC is an extremely heterogeneous disease
With a wide clinical spectrum varying from
Severe mental retardation and
incapacitating Seizures to normal
intelligence and a lack of Seizures, often
within the same family. The Disease affects
many organ systems other Than the skin
and brain, including the
heart, Kidney, eyes, lungs, and bone.
5/30/2012 JLNH & RC 24

25.  Autosomal dominant trait with variable
Expression.
 Prevalence of 1/6,000 newborns.
 Spontaneous genetic mutations occur in 2/3 of the
Cases.
 Molecular genetic studies have identified 2 foci
For TSC
GENE LOCATION ENCODES
TSC1 gene Chromosome9q34 Protein called
hamartin
TSC2 gene Chromosome16p13 the protein tuberin
5/30/2012 JLNH & RC 25

26.  The TSC1 and TSC2 genes are tumor
suppressor Genes.
 Both are involved in a key pathway in the cell
that Regulates protein synthesis and cell size.
The loss Of either tuberin or hamartin results
in the Formation of numerous benign tumors
(Hamartomas)
 Definite TSC is diagnosed when at least 2
major Or 1 major plus 2 minor features are
present
5/30/2012 JLNH & RC 26

27.  MAJOR FEATURES OF TUBEROUS SCLEROSIS
COMPLEX
 Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Facial angiofibroma or forehead plaque
Ungual or periungual fibroma (nontraumatic)
Hypomelanotic macules (>3)
Shagreen patch
Multiple retinal hamartomas
Cardiac rhabdomyoma
Renal angiomyolipoma
Pulmonary lymphangioleiomyomatosis
5/30/2012 JLNH & RC 27

28.  MINOR FEATURES OF TUBEROUS
SCLEROSIS COMPLEX
 Cerebral white matter migration lines
Multiple dental pits
Gingival fibromas
Bone cysts
Retinal achromatic patch
Confetti skin lesions
Nonrenal hamartomas
Multiple renal cysts
Hamartomatous rectal polyps
5/30/2012 JLNH & RC 28

29. Ash leaf skin lesions
 at least 3 hypomelanotic macules must be
present
• Hypopigmented in 90% of patients
• Enhanced by wood’s lamp examination
• At least 3 hypomelanotic macules must
5/30/2012 JLNH & RC
be present 29

30. Retinal lesions
• Mulberry Tumors
• Retina Nerve fiber
and undifferentiated
glial tissue
• 1/3 to ½ patients
• Can also be found in
Neurofibromatosis
and Normal persons.
5/30/2012 JLNH & RC
30

31. Tuberous Sclerosis
Sebaceous adenomas –Facial Angiofibroma– 8-10 .
by adolescence fully developed Forehead Plaque.
5/30/2012 JLNH & RC
31

32. Shagreen patch
• Roughened, raised lesion with an
Orange-peel consistency located
Primarily in the lumbosacral region
5/30/2012 JLNH & RC
http://www.massgeneral.org/livingwithtsc/affects/skin.htm 32

33. Ungual or periungual fibroma
5/30/2012 JLNH & RC 33

34. Confetti skin lesions
5/30/2012 JLNH & RC
34

35. Characteristic Tubers
• -Candle Dripping appearance.
• -subependymal/decreased neurons/proliferation of astrocytes.
• 5/30/2012
-calcification/obstruction------emedicine
JLNH & RC
35

36. Cardiac Rhabdomyoma.
5/30/2012 JLNH & RC
36

37. Infantile Spasm
Hypsarrhythmias
5/30/2012 JLNH & RC
37

38. Treatment
• Renal Ultrasound • Seizure control-
• Echo ACTH for infantile
• CT/MRI brain spasm
• Symptomatic tumor
treatment.
• Cosmetic treatments
• For treatment of
SEGAs- everolimus
5/30/2012 JLNH & RC
subependymal giant
cell astrocytomas
38

39. kidneys angiomyolipomas
 The current recommendation is to follow
Them by yearly imaging, and when the
lesion Becomes larger than 4 cm, to use
Transcatheter Tumor embolization for
treatment
5/30/2012 JLNH & RC 39

40. ROUTINE FOLLOW-UP
 Physical examination:
 Brain MRI every 1-3 yr,
 Renal imaging (ultrasound, CT, or MRI)
every 1-3 yr
 Neurodevelopmental testing at the time of
Beginning 1st grade.
5/30/2012 JLNH & RC 40

41. Sturge-Weber Syndrome
 Sturge-Weber syndrome (SWS) is a
sporadic Vascular disorder and consists of a
Constellation of symptoms and signs
including A facial capillary malformation
(port-wine Stain), abnormal blood vessels
of the brain (leptomeningeal angioma), and
abnormal Blood vessels of the eye leading
to glaucoma.
5/30/2012 JLNH & RC 41

42.  1 per 50,000 live births have SWS.
 Etiology remains unclear.
 ??Anomalous development of the
embryonic vascular bed in the early stages
of facial and cerebral development.
5/30/2012 JLNH & RC 42

43. Clinical Manifestations
 The facial port-wine stain.
Overall incidence be 8-33%
 The capillary malformation.
 Buphthalmos and glaucoma
 Transient strokelike episodes or visual
defects Result From thrombosis of cortical
veins.
 Mental retardation or severe learning
5/30/2012 JLNH & RC 43
Disabilities 50% In later childhood.

44. Unilateral, and always involves the upper face
And eyelid, in a distribution consistent with the
Ophthalmic division of the trigeminal nerve.
Port Wine Stain
5/30/2012
facial nevus
JLNH & RC 44

45. Buphthalmos
5/30/2012 JLNH & RC
45

46.  Epilepsy
75-90%,1st yr of life.
Focal tonic-clonic and Contralateral to the
side Of the facial capillary Malformation.
Refractory to anticonvulsants associated
With A slowly progressive hemiparesis .
5/30/2012 JLNH & RC 46

47. Diagnosis
 Based on the involvement of the brain and the
Face, there are 3 types according to the Roach
Scale:
 1 Type I: Both facial and leptomeningeal
Angiomas; may have glaucoma
2 Type II: Facial angioma alone (no CNS
Involvement); may have glaucoma
3 Type III: Isolated leptomeningeal
angiomas; Usually no glaucoma
5/30/2012 JLNH & RC 47

48. Rail-Road Track Calcification
• Gyriform Pattern of the Cortical
5/30/2012 JLNH & RC
Calcification. 48

49. Unilateral cortical atrophy
5/30/2012 JLNH & RC
49

50. Treatment
 Symptomatic and multidisciplinary.
 It is aimed at
 Controlling seizures
 Treating headaches
 Preventing strokelike episodes
 Monitoring for Glaucoma
5/30/2012 JLNH & RC 50

51.  laser therapy for the cutaneous capillary
Malformations.
 If the seizures are refractory to
anticonvulsant therapy Than consider
hemispherectomy.
 Regular measurement of intraocular
pressure.
 Pulsed dye laser therapy for port-wine
stain, ParticularlyJLNH & RC is located on the
5/30/2012 if it 51

52. Von Hippel–Lindau Disease
 Von Hippel–Lindau (VHL) disease affects
many Organs, including the
cerebellum, spinal
cord, Retina, kidney, pancreas, and
epididymis.
 Incidence is around 1 : 36,000.
 Autosomal dominant mutation affecting a
Tumor suppressor gene, VHL.
 Chromosome 3q25. & RC
5/30/2012 JLNH 52

53.  Include cerebellar hemangioblastomas and
Retinal angiomas.
 Cystic lesions of the
kidneys, pancreas, liver, And epididymis as
well as pheochromocytoma Are frequently
associated.
 Renal carcinoma is the most common cause
of Death.
5/30/2012 JLNH & RC 53

54. Cerebellar Hemangioblastoma
 Raised Intra Cranial
Pressure
 Cystic cerebellar lesion
with a vascular mural
nodule- erythropoietin
like protein.
 Spinal Cord-
abnormalities of
proprioception, disturba
nces of bladder control
and gait impairement.
http://www.cc.nih.gov/ccc/papers/vonhip/cnshemangioblastomas.html
5/30/2012 JLNH & RC
54

55. Retinal Angioma
 Peripheral-Initially vision is
unaffected
 Grow, bleed, leave serous
fluid-retinal detachment
 Small-Laser photocoagulation
 Large-Freezing probe from
outside the globe.
 25% of retinal angioma
patients will have extraocular
manifestation
 60% with nonocular
manifestations will have
Retinal Angioma.
http://www.kellogg.umich.edu/theeyeshaveit/congenital/retinal-
angioma.html
5/30/2012 JLNH & RC

56. PHACE/S Syndrome
Posterior fossa malformations
Hemangiomas
Arterial anomalies
Coaractation of the aorta
Eye abnormalities
+
Sternal clefting and/or a supraumbilical raphe
5/30/2012 JLNH & RC 56

57. Ataxia Telangiectasia
 Ataxia telangiectasia (A-T) is a Progressive
Degenerative disease involving many major
body Systems.
 It is an autosomal recessive disease.
 A-T is usually noticed in the second year of
life as a Child develops problems with balance
and Slurred Speech caused by ataxia (lack of
muscle control).
 The ataxia occurs because the cerebellum, the
part of The brain that controls muscle
movement, is Degenerating.
5/30/2012 JLNH & RC 57

58. Characterised by telangiectasia of
Conjunctiva, nose, ears and skin
creases.
About 70% of children with A-T also
have Immune system problems that
make Them more susceptible to
chronic URTI, lung infections, and
certain cancers, such As leukaemia
5/30/2012 JLNH & RC 58

59.  Currently, there is no cure for A-T and no
way To stop its progression. But treatment
can help Kids manage symptoms.
 Physical therapy and occupational therapy
may Help maintain flexibility.
 Speech therapy can help address slurring
and Other speech problems.
5/30/2012 JLNH & RC 59

60. linear Nevus Syndrome
 This sporadic condition is characterized by
a Facial nevus and neurodevelopmental
Abnormalities.
 The nevus is located on the forehead and
nose And tends to be midline in its
distribution.
5/30/2012 JLNH & RC 60

61.  84%-Face
 50%-Scalp, Neck and face
 Scalp lesions devoid of hair
 Seizures in 75%
› Infantile spasm
› Generalized Tonic
› Tonic Clonic
 Neurological Deficits
› Cranial Nerve palsies
VI, VII
› Cortical Blindness
› Hemiparesis
(hemimegalencephaly)
 Mental Retardation-in
young children upto70%
5/30/2012 JLNH & RC 61

62. Hypomelanosis of Ito.
5/30/2012 JLNH & RC
62

63.  Mosaicism-Family history is rare
 Neurological Association
› Mental retardation (70%)
› Seizures (40%)
› Microcephaly(25%)
› Developmental delay
› Deafness
› Visual problems
› Headache
› Tooth or mouth problems
5/30/2012 JLNH & RC 63

64. Incontinentia Pigmenti
 This heritable, multisystem ectodermal
disorder features dermatologic, dental, and
ocular abnormalities
 Functional mosaicism
 Random X-inactivation of an X-linked
dominant Gene (IKK-gamma/NEMO gene)
 Lethal in Males
 Xq28
 Increased Frequency of spontaneous abortions.
5/30/2012 JLNH & RC 64

65. Stage I
• Erythematous linear
streaks and plaques
of vescicles
• DD-Herpes, bullous
impetigo, mastocytos
is
• eosinophilic
spogiosis
5/30/2012
• Resolve by 4 mo
JLNH & RC
65

66. Stage II
• Verrucous plaques
• Dry and
hyperkeratotic
• Involute in 6 months
5/30/2012 JLNH & RC
66

67. Stage III
 Hyperpigmentation
 Hallmark
 Macular whorls, linear
streaks
 Lines of Blaschko.
 Sites are not necessorily
same.
 Invariably affects axilla
and groin
 Fade by Early
adoleacence.
5/30/2012 JLNH & RC
67

68. Stage IV
• Hypopigmented
• Hairless
• Anhydrotic
• Usually lower legs.
5/30/2012 JLNH & RC
68

69. Other Manifestations
CNS (33%)  Dental(80%)
› Late dentition
› Motor and cognitive › Hypodontia
developmental › Conical teeth
retardation › Impaction
› Seizures  Ocular(30%)
› Neovascularization
› Microcephaly › Microphthalmos
› Spasticity › Strabismus
› Optic Nerve atrophy
› paralysis › Cataracts
› Retrolenticular masses.
5/30/2012 JLNH & RC
69

70. THANK YOU
5/30/2012 JLNH & RC 70