A pediatric perspective on the diagnosis and management of the various Neurocutaneous Syndromes.

1. NEUROCUTANEOUS
SYNDROMES
A PEDIATRIC PERSPECTIVE
DR NISHANT YADAV
RESIDENT PEDIATRICS

2. INTRODUCTION
• 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.

3. 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,
• Incontinentia pigmenti.

4. Neurofibromatoses
• Neurofibromatoses are autosomal dominant disorders that cause
tumors to grow on nerves (Neurofibromas) and result in other
abnormalities such as skin changes and bone deformities.
• 2 types of neurofibromatosis (type 1 and type 2);
• However, it is recognized that they are clinically and genetically
distinct diseases and should be considered separate entities:
neurofibromatosis 1 (NF-1) and neurofibromatosis 2 (NF-2).

5. Neurofibroma
• A benign nerve sheath tumor in the peripheral nervous system
• Arise from nonmyelinating-type Schwann cells that exhibit
biallelic inactivation of the NF1 gene that codes for the protein
Neurofibromin.
• Neurofibromin is responsible for regulating the RAS-mediated cell
growth signaling pathway.
• In contrast to Schwannomas, many additional types of cells and
structural elements are incorporated in addition to Schwann cells.

6. Types of Neurofibroma
• Dermal(Cutaneous) and Plexiform
1. Dermal or Cutaneous :
• Associated with a single peripheral nerve
• 3 subtypes
• Discrete cutaneous –
• Sessile/pedunculated
• Fleshy
• Nontender
• Discrete subcutaneous
• Bumps on the skin
• Sometimes tender
• Deep nodular
• Involves tissues and organs underneath the dermis
• Otherwise resembling Cutaneous and Subcutaneous types.

7. • Age of onset :
• Teenage years
• Onset of puberty
• Increase in number and size throughout adulthood
• Complications :
• Stinging
• Itching
• Pain
• Disfiguration
• No evidence of malignant transformation

8. 2. Plexiform :
• Can grow from nerves in the skin or from internal nerve bundles
• Can be very large
• Internal plexiform neurofibromas extend through multiple layers of
tissues and are difficult to remove.
• Complications
• Disfigurement
• Neurological and other clinical deficits
• 10% undergo transformation into a Malignant Peripheral Nerve Sheath
Tumor (MPNST).

9. NF - 1
• Most prevalent Neurocutaneous syndrome.
• Incidence 1/3,000
• Autosomal Dominant
• Majority of mutations in NF-1 occur in paternal germ line
• Though , NF-1 is an autosomal dominant disorder, over half the
cases are sporadic, representing de novo mutations.
• The NF1 gene on chromosome region 17q11.2 encodes a protein
also known as neurofibromin. Neurofibromin acts as an inhibitor
of the oncogene ras.

10. Diagnostic Criteria
• 2 out of the following 7 signs :
1. Six or more café-au-lait macules over 5 mm in greatest
diameter in prepubertal individuals and over 15 mm in
greatest diameter in postpubertal individuals.
2. Axillary or inguinal freckling
3. Two or more iris Lisch nodules
4. Two or more neurofibromas or one plexiform
neurofibroma

11. Diagnostic Criteria (continued)
5. A distinctive osseous lesion such as Sphenoid dysplasia(
which may cause pulsating exophthalmos) Or Cortical
thinning of long bones with or without Pseudoarthrosis.
6. Optic gliomas
7. A first-degree relative with NF-1 whose diagnosis was
based on aforementioned criteria.

12. Neurofibromas
• Neurofibromas typically involve the skin, but they may be situated
along peripheral nerves and blood vessels and within viscera
including the gastrointestinal tract.
• These lesions appear characteristically during adolescence or
pregnancy, suggesting a hormonal influence.
• They are usually small, rubbery lesions with a slight purplish
discoloration of the overlying skin.

13. • 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 neurofi broma may be
hyperpigmented to a greater degree than a caf é -au-lait spot.
• Plexiform neurofibromas may produce overgrowth of an
extremity and a deformity of the corresponding bone.

14. Plexiform Neurofibromas on
face

15. Café-au-lait spots
• Café-au-lait spots are the hallmark of neurofibromatosis
• Present in almost 100% of patients.
• Present at birth but increase in size, number and pigmentation,
especially during the 1st few years of life.
• Predilection for trunk and extremities.
• Facial sparing

17. Other conditions with Café-au-lait
macules
• Neurofibromatosis type 2
• Macune albright Syndrome
• Ataxia telangiectasia
• Bloom’s syndrome
• Watsons’s syndrome
• Familial Café-au-lait macules

18. Other findings in NF-1
• Learning disabilities
• Attention deficit disorders
• Behavioral and psychosocial problems
• Abnormalities of speech
• Seizures – Complex partial and GTCS

19. Other findings (continued)
• Hydrocephalus secondary to aqueductal stenosis
• Macrocephaly with normal-sized ventricles
• Cerebral vessel aneurysms, or stenosis resulting in Moyamoya
disease > Transient Ischemic Attacks
• Precocious puberty
• Risk of hypertension due to Renal Vascular Stenosis or a
Pheochromocytoma

20. Other findings (continued)
• Higher incidence of Pheochromocytoma ,
rhabdomyosarcoma,Leukemia and Wilm’s tumor
• Unusual associations involving Myleoid leukemia, Juvenile
xanthogranuloma, and NF-1
• Malignant Peripheral Nerve Sheath Tumor (MPNST)
• Malignant neoplasms
• Neurofibrosarcoma
• Malignant schwannomas

21. Other findings (continued)
• Tumors of the CNS account for significant morbidity and mortality
• Optic gliomas
• Meningiomas of the brain and spinal cord
• Neurofibromas
• Astrocytomas
• Neurilemmoma

22. NF-2
• Rarer condition
• Incidence – 1/25,000
• The NF2 gene (also known as merlin or schwannomin) is located
on chromosome 22q1.11.

23. Diagnostic criteria for NF-2 :
• 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, neurofibroma, or posterior subcapsular
lenticular opacities
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 cataract.

24. • Symptoms
• Tinnitus
• Hearing loss
• Facial weakness
• Headache
• Unsteadiness
• Café-au-lait spots
• Skin neurofibromas

25. Lesions associated with NF-2

26. Management in a case of
Neurofibromatosis

27. • Close multidisciplinary follow-up is necessary
• Regular clinical assessments at least yearly, focusing the history
and examination on the potential problems for which they are at
increased risk.
• Yearly ophthalmologic examination,
• Neurologic assessment,
• Blood pressure monitoring,
• Scoliosis evaluation

28. • Neuropsychologic and educational testing should be considered
as needed.
• All symptomatic cases (i.e., those with visual disturbance,
proptosis , or increased intracranial pressure) must be studied
without delay.
• Cosmetic interventions

29. Genetic Counseling
• Molecular testing for the NF1 gene is available and can be useful
in a number of cases.
• Scenarios in which genetic testing is helpful include
• patients who have only 1 of the criteria for clinical diagnosis,
• those with unusually severe disease, and
• those seeking prenatal/pre-implantation diagnosis.

30. Tuberous Sclerosis
• Autosomal dominant
• Widespread hamartomas – Brain, eyes, skin, kidneys, liver, heart
and lungs.
• Clinical triad
• Described by Vogt
• Epi-loi-a
• Epilepsy
• Low intelligence
• Adenoma sebaceum
• Only in 1/3rd patients

32. • Clinical features
• May present as Infantile spasms and a hypsarrythmic EEG pattern
• Later may develop into myoclonic epilepsy
• Skin lesions
• Ash leaf macules
• Sebaceous adenomas
• Shagreen patch
• Subungual or Periungual fibromas

34. • Periungual fibroma

35. • Retinal lesions
• Mulberry tumors
• Hamartomas
• Depigmented areas
• Brain lesion
• Cortical tuber – apparent by 3-4 years of age
• Identified by T2 weighted MRI
• Undergo calcification and project into ventricular cavity – Candle-dripping
appearance
• Obstructive hydrocephalus
• Number of tubers is directly related to degree of neurological impairment.
• Occasionaly differentiates into a malignant Subependymal giant cell
astrocytoma

36. CT scan
with subependymal calcifi cations characteristic
of tuberous sclerosis.
MRI demonstrates
multiple subependymal nodules in the same
patient
(arrow).

37. • Other features
• Rhabdomyomas of the heart
• In 50 % cases
• At the apex of the left ventricle
• Can cause Congestive Heart Failure and Arrythmias
• Slowly resolve spontaneously
• Angiomyolipomas of kidney
• In 75-80 % of >10 year old patients
• Benign
• Single or multiple renal cysts
• Lymphangiomyomatosis
• Classical pulmonary lesion
• Most common in female patients

38. • Management
• Seizure control
• Renal imaging every 1-3 year
• Echocardiogram
• Chest roentgenogram
• Brain MRI every 1-3 year
• Neurodevelopmental testing at the time of beginning 1st grade.

39. Sturge-Weber Syndrome
• Sporadic disorder
• Results from anomalous development of the primordial vascular
bed in the early stages of cerebral vascularisation
• As a result, brain becomes atrophic and calcified, particularly in
the molecular layer of the cortex.
• Clinical manifestations
• Facial capillary malformation – Port-wine stain
• Unilateral facial nevus
• Present at birth
• Always involves the upper face and eyelid

40. • Buphthalmos and glaucoma of the ipsilateral eye
• Seizures in the 1st year of life in most patients.
• Typically focal tonic-clonic and contralateral to the side of nevus.
• Transient stroke like episodes and persisting visual defects
• Neurodevelopment appears to be normal in the 1st year of life
• Mental retardation or severe learning disabilities in at least 50% in
later childhood

41. DIAGNOSIS
• MRI with contrast is the imaging modality of choice for
demonstrating leptomeningeal angioma
• Skull radiograph
• Intracranial calcification in the occipitoparietal region
• Serpentine or Railroad-track appearance
• CT scan
• Calcification
• Unilateral cortical atrophy
• Ipsilateral dilatation of the lateral ventricle
• MRI
• Vascular malformation
• White matter lesion

42. Gadolinium-enhanced
axial T1 FLAIR image of a
15 mo old with
Sturge-Weber syndrome
shows leptomeningeal
enhancement in the left
hemisphere.

43. VonHippel-LindauDisease
• Autosomal dominant trait
• VHL tumor suppressor gene located on 3p25-26
• Clinical Features
• Cerebellar hemangioblastoma –
• Present with signs of raised Intracranial Tension
• Total surgical removal is curative
• Retinal angiomata
• In peripheral retina – so unaffected vision
• Retinal detachment -> Visual loss

44. • Hemangioblastoma of the spinal cord –
• Abnormalities of proprioception and gait
• Bladder sysfunction
• Cystic lesions of the kidneys, pancreas,liver, and epididymis
• Pheochromocytoma
• Most common cause of death – Renal carcinoma
• Management
• Regular follow-up
• Appropriate imaging studies to identify lesions at an early stage

45. PHACE Syndrome
• Female predominance
• Consists of
• Posterior fossa malformation
• Hemangiomas ipsilateral to the aortic arch
• Arterial anomalies
• Coarctation of the aorta,apalsia or hypoplastia of carotid
arteries,aneurysmal carotid dilatation, aberrant left subclavian
artery
• Eye abnormalities- glaucoma, cataracts, microphthalmia, optic
nerve hypoplasia.

46. • Large facial hemangiomas may be associated with Dandy- Walker
malformation
• Interferon- alpha is of value in management of the hemangiomas.

47. Ataxia Telangiectasia
• Autosomal recessive
• Chromosome 11
• Ataxia begins between 12-15 months of age
• Telangiectasia appears by 2-7 years on bulbar conjunctiva and skin
• Abnormal movements
• Vitilago
• Abnormal Glucose Tolerance Test

48. • Decreased serum IgA
• Alpha-fetoprotein elevated
• Sino pulmonary infections
• Lymphoreticular malignancies
• Immune deficiency
• Neuroimaging – Cerebellar atrophy

49. Incontinentia Pigmenti
• Uncommon genodermatosis of the developing neuroectoderm
• Vesicular, verrucous and pigmented lesions are associated with
developmental defects of eyes, skeletal system and central
nervous system.
• X-linked dominant disorder
• Mutisystem disorder
• Skin - Alopecia
• Neurological – motor and cognitive developmental retardation,
seizures, microcephaly,spasticity and paralysis
• Skeletal
• Ocular- neovascularization, microphthalmos, strabismus,optic nerve
atrophy, cataracts, and retrolenticular masses,
• Dental – Late dentition, impaction, hypodontia.

50. • Manifest at birth or during first few weeks of life
• 4 stages in the skin –
• 1. Linear whorled vesicular eruptions along Blaschko’s lines. Acral
locations. Peripheral leucocytosis and eosinophilia
• 2. After 2-6 weeks, vesicular eruptions replaced by verrucous or
lichenoid lesions in 30% of the patients.
• 3.Between 12th and 20th week and characterised by
hyperpigmented lesions.
• 4.Fading of lesions leaving behind hypopigmented macules along
the Blaschko’s lines.

51. • Whorled vesicular phase

52. • Management
• Skin lesions are benign
• Non cutaneous manifestations need to be managed
• Genetic counseling

53. REFERENCES
• NELSON TEXTBOOK OF PEDIATRICS, 20TH EDITION
• ESSENTIAL PEDIATRICS BY DR O P GHAI, 8TH EDITION
• WIKIPEDIA

54. Thank You!!