This document discusses several neurocutaneous syndromes including their definitions, genetics, classifications, and key details. It provides in-depth information on Neurofibromatosis types 1 and 2, Tuberous Sclerosis, Sturge-Weber Syndrome, and Von Hippel-Lindau disease. For each condition, it outlines diagnostic criteria, clinical manifestations, management approaches, and important follow-up considerations.

1. NEUROCUTANEOUS
SYNDROME
Dr. C. Kannan
Post graduate
Pediatrics
MGMCRI

2. DISCUSSION
• Definition
• Genetics
• Classification
• Details of each Neurocutaneous syndrome

3. DEFINITION
• Heterogeneous group of disorders
• Abnormalities of both the Integument and CNS
• Most disorders are familial
• Arise from a defect in differentiation of the Primitive ectoderm

4. NCS # CHROMOSOMES # GENES

5. NCS # GENETIC PRINCIPLES

8. CLASSIFICATION
• Neurofibromatosis
• Tuberous Sclerosis
• Sturge-Weber Syndrome
• Von Hippel – Lindau Disease
• PHACE Syndrome
• Ataxia Telangiectasia
• linear Nevus Syndrome
• Hypomelanosis of Ito
• Incontinentia Pigmenti

9. NEUROFIBROMATOSIS

10. NEUROFIBROMATOSIS
• NF are autosomal dominant Disorders
• Causes tumors to grow on Nerves
• Results in other abnormalities such as
• Skin changes and bone deformities
• Classified into
• Neurofibromatosis 1
• Neurofibromatosis 2

11. 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 - Neurofibromin

12. DIAGNOSTIC CRITERIA
2 of the following 7 features are diagnostic
1. Six or more Cafe-au-lait macules
2. Axillary or inguinal freckling
3. Two or more iris Lisch nodules
4. Two or more Neurofibroma 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

13. CAFE-AU-LAIT MACULES
• Six or more
• > 5 mm in prepubertal individuals
• > 15 mm in post pubertal individuals
• Hallmark of almost 100% of patients
• Present at birth but increase in
• Size
• Number
• Pigmentation (esp. during the 1st few years )
• Involves trunk/extremities but sparing the face

14. AXILLARY OR INGUINAL FRECKLING
• Multiple hyperpigmented areas 2-3 mm in diameter
• Skinfold freckling usually appears between 3 and 5 yrs
• Frequency > 80% by 6 yrs of age.

15. 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
• 5% of children <3 yrs of age
• 42% of children 3-4 yrs of age
• 100% of adults ≥21 yrs of age.

16. NEUROFIBROMA
• 2 or more neurofibromas or 1 plexiform neurofibroma is significant
• Sites involve the
• Skin, peripheral nerves, blood vessels and viscera
• Hormonal influence
• Small, rubbery lesions with a slight purplish discolouration
• Plexiform neurofibromas are usually evident at birth
• Diffuse thickening of nerve trunks
• Orbital or temporal region of the face

17. • The skin overlying a plexiform neurofibroma may be
• Hyperpigmented then Cafe-au-lait spot
• Plexiform neurofibromas may produce
• Overgrowth and deformity of corresponding bone

18. Distinctive Osseous lesion - Sphenoid Dysplasia

19. OPTIC GLIOMA
• Optic Gliomas are mostly low-grade astrocytomas
• Children age 10 yrs or younger with NF-1 undergo
• Annual ophthalmologic examinations
• When they enlarge
• Compresses optic nerves and chiasm
• Impairs visual acuity and visual fields
• Extension into the hypothalamus leads to
• Endocrine deficiencies or failure to thrive

20. COMPLICATIONS
• Seizures
• Hydrocephalus
• Learning disabilities
• ADHD/Speech disorder
• Macrocephaly
• Moya-moya Disease
• Precocious puberty
• Hypertension
• Fibromuscular dysplasia
• Pheochromocytoma
• Malignancy
• Neurofibrosarcoma
• Malignant Schwanoma

21. 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
• Posterior subcapsular lens opacities are identified in
• 50% of patients with NF

22. DIAGNOSTIC CRITERIA
1 of the following 4 features is diagnostic
1. Bilateral vestibular schwannomas
2. A parent, sibling, or child with NF-2 plus
• Either unilateral vestibular schwannoma or
• Any 2 of meningioma, Schwannoma, glioma, neurofibroma, or Posterior
subcapsular lenticular opacities
3. Unilateral vestibular schwannoma plus any 2 of following
• Meningioma, schwannoma, Glioma, neurofibroma & posterior Subcapsular
lenticular opacities
4. Multiple meningiomas (2 or more) plus
• Unilateral vestibular schwannoma or any 2 of the following schwannoma,
glioma & neurofibroma

24. MANAGEMENTOF NF-I/NF-II
• Genetic counselling (Half result from fresh Mutation)
• Tests should be ordered if +ve findings
• Prenatal evaluation in familial cases
• Annual evaluation
• Pediatrician/pediatric ophthalmologist

25. TUBEROUSSCLEROSIS

26. TUBEROUS SCLEROSIS (TSC)
• Extremely heterogeneous disease
• Has wide clinical spectrum
• From severe MR/Incapacitating Seizures to
• Normal intelligence and a lack of Seizures
• Affects often within the same family.
• The Disease affects
• Heart/Kidney/Eyes/lungs/Bone
• Skin/brain – Not involved

27. Contd.,
• Autosomal dominant trait with variable Expression
• Prevalence of 1/6,000
• Spontaneous genetic mutations occur in 2/3 of the Cases
• TSC1 gene/Chromosome 9q34/Protein - hamartin
• TSC2 gene/Chromosome 16p13/Protein - tuberin

28. Contd.,
• The TSC1 and TSC2 genes are tumor suppressor Genes
• Regulates protein synthesis and cell size
• The loss of tuberin/hamartin results in
• Formation of numerous benign tumors (Hamartomas)
• Definite TSC is diagnosed
• when 2 major Or 1 major plus 2 minor features are present

29. MAJOR FEATURES
• 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 angiomyolipomas
• Pulmonary lymphangioleiomyomatosis

30. MINOR FEATURES
• 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

31. ASH LEAF SKIN LESIONS
• At least 3 hypomelanotic macules must be present
• Hypopigmented in 90% of patients
• Enhanced by wood’s lamp examination

32. 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

33. SEBACEOUSADENOMAS/FACIALANGIOFIBROMA

34. SHAGREEN PATCH
• Roughened/Raised lesion
• Orange-peel consistency
• Located Primarily in the lumbosacral region

35. UNGUAL/PERIUNGUAL FIBROMA

36. CONFETTI LESIONS
An area with stippled hypopigmentation typically on the extremities

37. SUBEPENDYMAL TUBERS
• Candle Dripping appearance
• Abnormal neuronal migration
• Subependymal proliferation of astrocytes
• Calcification/obstruction of CSF path

38. TREATMENT
• Renal Ultrasound/CT/MRI brain spasm/ Echo
• Seizure control - ACTH for infantile
• Symptomatic tumor treatment
• Cosmetic treatments
• For treatment of SEGAs- Everolimus
• (Subependymal giant cell astrocytomas)

39. FOLLOW-UP
• Kidneys angiomyolipomas
• To follow by yearly imaging
• When the lesion Becomes larger than 4 cm
• Transcatheter Tumor embolization
• Routine physical examination
• Brain MRI every 1-3 yrs
• Renal imaging (ultrasound, CT, or MRI) every 1-3 yrs
• Neurodevelopmental testing

40. STURGE-WEBERSYNDROME

41. STURGE-WEBER SYNDROME
• Sporadic Vascular disorder
• With constellation of symptoms and signs
• A facial capillary malformation (port-wine Stain)
• Abnormal blood vessels of the brain (leptomeningeal angioma)
• Abnormal Blood vessels of the eye leading to glaucoma
• 1 per 50,000 LB / Etiology remains unclear
• Anomalous development of the embryonic vascular bed
• In early stages of facial and cerebral development

42. CLINICAL MANIFESTATIONS
• The facial port-wine stain
• Capillary malformation
• Overall incidence be 8-33%
• Buphthalmos and glaucoma
• Transient stroke like episodes/visual defects
• Result From thrombosis of cortical veins
• MR or severe learning disabilities 50% in later childhood.

43. PORT WINE STAIN
• Unilateral
• Always involves the upper face/eyelid
• Distribution consistent with
• Ophthalmic division of the trigeminal nerve

44. PORTWINESTAIN # CORTICALATROPHY

45. BUPHTHALMOS

46. EPILEPSY
• 75-90% in 1st year of life
• Focal tonic-clonic
• Contralateral to the side Of the facial capillary Malformation.
• Refractory to anticonvulsants
• Associated with a slowly progressive hemiparesis

47. DIAGNOSIS
• Based on the involvement of the brain/face
• 3 types according to the Roach Scale
• Type I
• Both facial and leptomeningeal angioma
• May have glaucoma
• Type II
• Facial angioma alone (no CNS Involvement)
• May have glaucoma
• Type III
• Isolated leptomeningeal angioma
• Usually no glaucoma

48. RAIL-ROAD TRACK CALCIFICATION
Gyriform Pattern of the Cortical Calcification

49. UNILATERAL CORTICAL ATROPHY

50. TREATMENT
• Symptomatic and multidisciplinary aimed at
• Controlling seizures
• Treating headaches
• Preventing stroke like episodes
• Monitoring for Glaucoma
• Laser therapy for the cutaneous capillary Malformations
• If the seizures are refractory to AEDs consider hemispherectomy
• Regular measurement of intraocular pressure
• Pulsed dye laser therapy for port-wine stain

51. VONHIPPEL–LINDAUDISEASE

52. VON HIPPEL–LINDAU DISEASE
• VHL disease affects
• Cerebellum/spinal cord/retina/kidney/pancreas/epididymis
• Incidence is around 1 : 36,000
• AD mutation affecting a Tumor suppressor gene in Chr 3q25
• Include cerebellar hemangioblastomas and Retinal angiomas
• Cystic lesions of the kidneys/pancreas/liver/epididymis
• Frequently A/W Pheochromocytoma
• Renal carcinoma is the most common cause of Death

53. CEREBELLAR HEMANGIOBLASTOMA
• Raised Intra Cranial Pressure
• Cystic cerebellar lesion with a vascular mural nodule
• Secretes Erythropoietin like protein
• Spinal Cord
• Abnormalities of proprioception
• Disturbances of bladder control and gait impairment

54. RETINAL GLIOMA
• 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 extra ocular manifestation
• 60% with non-ocular manifestations will have Retinal Angioma

55. PHACE/S SYNDROME
• Posterior fossa malformations
• Haemangioma
• Arterial anomalies
• Coaractation of the aorta
• Eye abnormalities + Sternal clefting and/or
• Supraumbilical raphe

56. ATAXIA TELANGIECTASIA
• AR / Progressive Degenerative disease / Major systems
• AT is usually noticed in 2nd yr of life as
• Child develops problems with balance/Slurred Speech
• lack of muscle control caused by ataxia
• The ataxia - degeneration of cerebellum
• Affects conjunctiva/nose/ears/skin creases
• About 70% with AT are Immunodeficient - Recurrent infection

57. TREATMENT OF AT
• Currently - no cure for A-T - no way to stop its progression
• But treatment can help Kids manage symptoms
• Physical therapy and occupational therapy
• Speech therapy can helps slurring and Other speech problems

58. LINEAR NEVUS SYNDROME
• Sporadic condition - Facial nevus - Neurodevelopmental defects
• The nevus – forehead / nose / midline in its distribution
• 84%-Face / 50%-Scalp(devoid of hair), Neck and face
• Seizures in 75% - Infantile spasm / Gen Tonic / Tonic Clonic
• CN palsies VI, VII / Cortical Blindness / Hemiparesis
• Mental Retardation-in young children upto70%

59. HYPOMELANOSIS OF ITO
• Mosaicism - Family history is rare
• Neurological Association
• Mental retardation (70%)
• Seizures (40%)
• Microcephaly(25%)
• Developmental delay
• Deafness
• Visual problems
• Headache
• Tooth or mouth problems

60. INCONTINENTIAPIGMENTI

61. INCONTINENTIA PIGMENTI
• Heritable / multisystem ectodermal disorder
• Dermatologic/dental/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

62. STAGE 1
• Erythematous linear streaks and plaques of vescicles
• DD – Herpes / bullous impetigo / mastocytosis / Eosinophilic spogiosis
• Resolve by 4 months

63. STAGE 2
• Verrucous plaques
• Dry and hyperkeratotic
• Involute in 6 months

64. STAGE 3
• Hyperpigmentation
• Macular whorls / linear streaks
• Lines of Blaschko.
• Sites are not necessarily same
• Invariably affects axilla and groin
• Fade by Early adolescence

65. STAGE 4
• Hypopigmented
• Hairless
• Anhydrotic
• Usually lower legs

66. CLINICAL MANIFESTATIONS
CNS (33%)
• Motor and cognitive developmental retardation
• Microcephaly / Spasticity / Seizures / paralysis
Dental(80%)
• Late dentition / Hypodontia / Conical teeth / Impaction
Ocular(30%)
• Neovascularization / Strabismus / Optic Nerve atrophy /Cataracts /
Retro lenticular masses / Microphthalmos

67. REFERENCE
• Nelson text book of pediatrics
• OP Ghai text book of pediatrics
• Google images

68. THANK YOU