A PPT on neurocutaneous markers containing short history, and short description of following N C markers Cafe au lait spots Ash leaf patch Litsch nodules Axillary and inguinal freckling. Facial angiofibromas . Cutaneous neurofibromatosis. Multiple unqualified fibromas . Cutaneous neurofibromatosis Adenoma sebacum. Hypo / hyper pigmented Macules hairy tuft at sacrum. Facial angioma /Port wine stain

1. NEUROCUTANEOUS
MARKERS
BY Dr. TEJAS MANDLECHA

2. HISTORY
• The term phacomatoses / neurocutaneous marker is coined by van
der hoeve in 1920
• In Greek phakos meaning ‘mother spot’ ,’mole’ or ‘freckle’ .
• Tendancy to form hamartomas(benign tumor like formation)

3. Neurocutaneous syndromes(Phakomatosis)
• Heterogeneous group of disorders characterized by the abnormalities
of integuments(Cutaneous ) and CNS.
• Mostly familial.
• Defect in differentiation in primitive ectoderm
• These are the multisystem disorder involving nervous system ,eyeball
, retina ,and skin.
• Common ectodermal origin.

4. Neurocutaneous markers
1. Cafe au lait spots
2. Ash leaf patch
3. Litsch nodules
4. Axillary and inguinal freckling.
5. Facial angiofibromas .
6. Cutaneous neurofibromatosis.
7. Multiple unqualified fibromas .
8. Shagreen patch.
9. Adenoma sebacum.
10. Hypo / hyper pigmented Macules
11. hairy tuft at sacrum.
12. Facial angioma /Port wine stain

5. VARIOUS NEUROCUTANEOUS SYNDROMES
• NEUROFIBROMATOSIS 1 AND 2
• TUBEROUS SCLEROSIS
• STRUGE WEBER SYNDROME
• VON HIPPEL LINDAU SYNDROME
• PHACE SYNDROME(posterior fossa malformation,hemangioma,arterial anomaly,coarctation of
aorta,cardiac defect, eye abnormality.)
• LINEAR NEVUS SYNDROME
• INCONTINETIA PIGMENTI
• HYPOMELANOSIS ITO
• ATAXIA TELANGICTESIA
• OSLER WEBER RENDU SYNDROME
• NEUROCUTANEOUS MELANOSIS
• FABRYS DISEASE

6. NEUROCUTANEOUS MARKERS
NEUROCUTANEOUS MARKERS NEUROCUTANEOUS SYNDROME
CAFÉ AU LATE SPOTS, AXILLARY FRECKLING,
NEUROFIBROMA’S, LISCH NODULE ,
NEUROFIBROMATOSIS
ADENOMA SEBACUM, SHAGREEN PATCH, ASH LEAF
MACULES
TUBEROUS SCLEROSIS
HEMANGIOMA STRUGE WEBER SYNDROME
TUFT OF HAIR SPINA BIFIDA
NEVUS LINEAR NEVUS SYNDROME
HYPOMELANOSIS OF ITO INCONTINETIA PIGMENTI
TELENGECTASIA ATAXIA TELENGECTASIA

7. Cafe au lait spots
• These are the Macules , hyperpigmented, birthmarks.
• The name cafe au lait is French for coffee with miles refer to there light brown colour.
• They are also called Giraffe spot.
• It is caused by collection of pigment producing melanocyte in the epidermis of skin, typically
permanant ,may grow or increase in number over time.
• They are harmless.
• Syndrome associated with
• 1.Neurofibromatosis 1
• 2. Tuberous sclerosis
• 3.Fanconi anemia
• 4.Idiopathic
• 5. Ataxia telangiectasia
• 6.Basal cell nevus

8. •It is most frequently occuring neurocutaneous marker.
• It is due to increase melanin content, often with the presence of giant
melanosomes.
• Typically they present at birth.`
•Trunk and extremities.
•A wood lamp may improve the ability to visualise these faint spots..
•Hallmark of neurofibromatosis.
• TREATMENT : Lasers

9. NEUROFIBROMAS
•Benign nerve sheath tumor in peripheral nervous system.
•Typically aries skin, peripheral nerves, blood vessels, viscera like GI tract.
•Appear during adolescence, and pregnacy.( hormonal imbalance)
•Small, rubbery lesion, purplish discoloration.
• normally benign, harmless, vary in size are flesh and have broad or stalk
like bases.
Plexiform neurofibromas evident at birth from diffuse thikening of nerve
trunks frequently in orbital or temporal region.
•Treatments – Excision

10. NEUROFIBROMA

11. LISCH NODULES
• Known as iris hematoma
• Aggregate of dendritic melanocytes on the iris
• Recognised by ophthalmologist karl lisch.
• 74% with NF 1
• Prevalance increase with age.
• Clear yellow brown, oval round shaped papules from iris surface
• Detected by slit lamp examination
• In NF1 pt, present greater than 94% of patient over the age 6 yr.

12. LISCH NODULES

13. Axillary and Inguinal Freckling
•Multiple hyperpigmented areas of 2-3mm in diameter.
•Frequency is >80% in 6yr age.
• Freckles any of the small brownish spot on the skin that turn darker or
increase in number upon exposure to the sun
•It is the flat tan coloured spot in the armpit area.
• Axillary freckle are sometime referred to as crowes sign.
• Can be associated with a disease 20-30% of NF2.

14. AXILLARY AND INGUANAL FRECKLING

15. ASH LEAF SPOTS
Woods lamp examination

16. Ash leaf spot
•These are the hypopigmented Macules are range in size from 1 to 12 cm in diameter
and are rounded at one end and tapper at the other end resemble like leaf of ash
tree most common site is trunk.
• best detected with woods light (uv light 365 nm wavelength ).
• It is first cutaneous sign of tuberous sclerosis.
•It is early indicator of tuberous sclerosis.
WOODS LAMP EXAMINATION- areas with reduced or absent Melanin tissue which
absorb the light and appear lighter than normal skin

17. DIFFERENTIALS OF ASH LAEF SPOTS
VITILIGO ASH LAEF SPOTS
NEVUS ANEMICUS

18. Facial Angiofibromas
•It is form for a group of lesion with different clinical presentation but with the same
histopathology.
•generally an angiofinromas present as 1 to 5 mm skin coloured to erythematous shaped
papule.
• facial rash that apperas as spread of small pink or red spots across the cheeks and nose in
butterfly distribution. Also found around the nails scalp and forehead.
• Appear between 3-10 yrs of age and increase in, size and numbers until adolescence.
•Also knwon as fibrous papule.
• Seen in 1.tuberous sclerosis
2.multiple endocrine neoplasia 1
•

19. FACIAL ANGIOFIBROMAS

20. SHAGREEN PATCH
•THE SHAGRREN PATCH ARE OVOID FLESH COLORED ORANGE PEEL CONNECTIVE
TISSUE NAEVI OF VARING SIZES, USUALLY ON THE LOWER BACK.
•Present at birth or infancy
•1st described by Hallopeau and Leredde in 1895
• it is connective tissue firm to rubbery irregular
• hyperpigmented rough 1 to 10 cm.
HISTOPATHOLOGY: papillomatosis and dense collagen bundle in dermis
Seen in : Tuberous Sclerosis
.

21. SHAGREEN PATCH

22. UNGUAL FIBROMAS
• Thes are the smooth , firm ,flesh coloured lumps that emerge from the
nail folds.
• Periungaual site is more common than subungual sites .
• most common on feet than hand. Longitudinal groove in the nail may
occure without visible fibroma.
• short red ( splinter haemorrages) or white sreaks (leukonychia) may be
seen in affcted nail.
•Seen in : Tuberous Sclerosis
•TREATMENT : Surgical excision , Topical rapamycine

23. UNGUAL FIBROMAS
PERIUNGUAL FIBROMA

24. ADENOMA SEBACUM
• consisting angiofibromas that begin in childhood i.e. 2-5 yrs of age
and appear clinically as red papules on the face on nasolabial folds,
cheek and chin.
• gradually the papules become more prominent with the time and
persist throughout life.
• Associated with tuberous sclerosis.
• These are the multiple wartlike yellowish red , waxy papules on the
face thTa are not sebaceous. The lesion are composed of fibrovasular
tissue and are usually benign.
Treatment: argon or pulse dye laser or scalpel .

25. ADENOMA SEABACUM

26. SACRAL DIMPLE
• Indentetion present at birth
• Lower back, jst above crease of
buttocks
• Harmless, doesn’t require
treatment
• Sacral dimples accompanied by a
tuft of hair, skin tag or skin
discoloration associated with spinal
cord anomaly like spina bifiada.

27. FACIAL ANGIOMA
• Port wine stain ( nevus flammeus) called firemark
• Birthmark, developed between 4 and 6 yrs of age
• Capillary malformation
• Persist throughout life
• Most commonly on face, can occur anywhere particular on neck and
upper trunk
• Prognosis: hypertrophy, disfiguration
• Treatment: freezing, surgery, radiation, tattoing

28. FACIAL ANGIOMA

29. Neurocutaneous disorders with chromosomal
defect
DISORDER CHROMOSOME
NF1 17q11.2
NF2 22q12.3
TUBEROUS SCLEROSIS 16p13.3,12q14,
INCONTNENTIA PIGMENTI Xq28 Xlinked dominant
ATAXIA TELENGECTASIA 11q22.3
HYPOMELANOSIS ITO 9q33-qter
VON HIPPLE LINDAU 11q13

30. NEUROCUTANEOUS MARKERS
NEUROCUTANEOUS MARKERS NEUROCUTANEOUS SYNDROME
CAFÉ AU LATE SPOTS, AXILLARY FRECKLING NEUROFIBROMATOSIS
TELENGECTASIA ATAXIA TELENGECTASIA
ADENOMA SEBACUM, SHAGREEN PATCH, ASH LEAF
MACULES
TUBEROUS SCLEROSIS
HEMANGIOMA STRUGE WEBER SYNDROME
TUFT OF HAIR SPINA BIFIDA
NEVUS LINEAR NEVUS SYNDROME
HYPOMELANOSIS OF ITO INCONTINETIA PIGMENTI

31. NEUROCUTANEOUS DISEASES
• NEUROFIBROMATOSIS
• TUBROUS SCLEROSIS
• VON HIPPEL LINDAU
SYNDROME
• HYPOMELANOSIS ITO
AUTOSOMAL DOMINANT
• ATAXIA TELENGECTASIA
• XERODERMA PIGMENTOSA
• WERNER SYNDROME
AUTOSOMAL RECESSIVE
X LINKED
• INCONTINENTIA PIGMENTI
SPORADIC
• NEUROCUTANEOUS MELANOSIS
• LINEAR SEBACEOUS NEVUS
• STRUGE WEBER

32. NEUROFIBROMATOSIS 1
• NF1 , Von recklinghausen disease
• Childhood
• Prevalance – 1/3000
• autosomal dominant
• Gene on chromosome 17q11.2
• Protein is neurofibromin.
• Half of the NF1 cases are new
mutatations.
NEUROFIBROMATOSIS 2
• NF2 ,Vestibular Schwannomas
• 3rd decade
• Prevalance -1/25000
• autosomal dominant
• Gene on chromosome 22q11.2
• Protein Merlin (schwannomin)

33. CLINICAL FEATURES

34. NEUROFIBROMATOSIS 1
ASH LEAF MACULES
PLEXIFORM
NEUROFIBROMA
NEUROFIBROMA AXILLARY
FRECKLING
CUTANEOUS

35. NEUROFIBROMATOSIS 1
OCULAR
LISTCH NODULES
OPTIC GLIOMA
SKELETAL
scoliosis
pseudoarthrosis
sphenoid dysplasia
HTN
Renovascular stenosis
Hemiparesis
NEUROFIBROMATOSIS 2
NEURONAL CUTANEOUS
acoustic neuromas Cafe au lait spots
spinal tumors Intracutaneous tumors
Meningiomas subcutaneous nodules
mononeuropathy skin plaque
OCULAR
posterior subcapsular lens Opacities
Retinal hamartoma
OTHER
Absolute macrocephaly in 43-45% of patient with NF1.
13% NF1 patient short staure.
MRI – Ventricular enlargement
Learning affected, visuospatial function affected with
correlated with right hemisphere gray matter volume
OTHER

36. DIAGNOSIS CRITERIA
• DIAGNOSIS= ANY 2 OF FOLLOWING 7
• Six or more café au lait macules ( >5mm=
prepubertal individual, >15= postpubertal
individual)
• Two or more iris lisch nodules.
• Two or neurofibromas or any type or plexiform
neurofibroma.
• Freckling in the axillary or inguinal region.
• Optic glioma.
• A distinctive osseous lesion such as sphenoid
dysplasia, thinning of the long bone cortex with
or without psudoarthrosis.
• A first degree relative with NF1 by the above
criteria.
• DIAGNOSIS 1 of 4
• Bilateral vestibular schawannoma
• Unilatral vestibular schawannoma and any of the
following meningioma, schwanomma, glioma,
neurofibroma, posterior subcapsular lenticular
opacities
• Multiple meningiomas( 2 or more) and unilateral
vestibular schwannoma or or any two of the
following : shwannoma, glioma, neurofibroma
cataract.
• A parent, child or sibling with NF2, or unilateral
vestibular schwannoma with any 2 of
meningioma, schwannoma, glioma,
neurofibroma.
NEUROFIBROMATOSIS 1 NEUROFIBROMATOSIS 2

37. TUBEROUS SCLEROSIS

38. TUBEROUS SCLEROSIS
• Incidenc 1/ 6000-9000
• Dominant inheritance with spontaneous mutation
• Variable expression within families.
• TSC1 – 9q- HAMARTIN
• TSC2- 16p- TUBERIN
• Regulate protein synthesis and cell size.
• DIAGNOSIS= 2 major or 1 major+2 minor

39. MAJOR FEATURE TSC MINOR FERATURE TSC
• Facial angiofibroma
• Multiple retinal hamrtoma
• Multiple periungual fibroma
• Cortical tubers
• Subependymal nodules
• Giant cell astrocytoma
• 3 or more hypomelanotic macules
• Shagreen patch
• Renal angiolipoma
• Cardiac rhabdomyoma
• AFFECTED FIRST DEGREE RELATIVE
• DENTAL ENAMEL PIT CYSTS
• BONE CYSTS
• FOREHEAD PLAQUE
• RENAL ANGIOLYPOMA
• GINGIVAL FIBROMAS
• CEREBRAL WHITE MATTER MIGRATION
LINES
• MULTIPLE RENAL CYST.
• HAMRTOMAOUS RECTAL POLYPS

40. TSC- CUTANEOUS MANIFESTATION
• HYPOMELANOTIC MACULES- 90%
• SHAGREEN PATCH 20-30%
• UNGUAL FIBROMAS 15-20% FACIAL ANGIOMA( ADENOMA SEBACUM)
75%
• FOREHEAD PLAQUE
• CINFETTI HYPOPIGMENTED SKIN LESION
• GINGIVAL FIBROMAS
• POLIOSIS

41. NEUROLOGIC FEATURE -TSC
• MC is epilepsy, cognitive impairment, autism spectrum disorder.
• In infancy= infantile spasm
• Seizure difficult to control > convert to myoclonic epilepsy
• Brain tumour- giant cell astrocytoma
• CARDIOVASCULAR- Arrythemia, rhabdomyomata, thromboembolism
• RENAL- angiolippoma, cyst
• PULMONARY- pulmonary lymphangiomomatosis. Symptoms are
pneumothorax, dyspnea,pulmonary failure.
• All asymptomatic patient = MRI BRAIN monitor for new occurrence
subependymal giant cell astrocytoma(SEGA)

42. STRUGE WEBER SYNDROME
PORT WINE STAIN
Atrophy of cerebral
hemisphere

43. STURGE – WEBER SYNDROME
• Sporadic vascular disorder; 1: 50,000 incidence
• Unilateral or bilateral facial capillary malformations (Port-wine stain) in the
distribution of the first branch of the trigeminal nerve
• Ipsilateral intracranial vascular anomalies of the capillaries and venules of
the leptomeninges (leptomeningeal angiomas)
• Abnormal blood vessals of eye leading to Glaucoma
• Presentation of patient can be with
a. hemiparesis
b. seizure
c. developemental delay
d. headache

44. STURGE WEBER SYNDROME
• It is thought it results from anomalous devlopment of embryonic
vascular earLy stage of facial and cerebral development.
• HYPOTHESES- 1. aberrant sympathetic innervation
2.increase vascular growth factor
3. defect in extracellular matrix
• Complications- 1.glaucoma , buphthalmous of ipsilateral eye
2.epilepsy 75-90% mc in 1 yr of life , tonic clonic, contralaeral to side
of capillary malformation.
3. learning disabilities, progressive hemiparesis

45. STURGE WEBER SYNDROME
• TYPES OF STURGE WEBER SYNDROME
• Type 1: facial + leptomeningeal angioma may have glaucoma
• Type 2: facial angioma may have glaucoma
• Type3:leptomeningial angioma no glaucoma
• TREATMENT: pulsed dye laser therapy

46. INCONTINENTIA PIGMENTI

47. INCONTINENTIA PIGMENTI
• X linked, lethal in homozygous males
• Vesicular rash in newborn period
• At birth 1st stage -Erythematous bullous lesion, plaques of vesicles on
limbs , trunk( DD are herpes simplex , bullous impetigo)
• Resolves 4 month of age
• 2nd stage- crusting of lesion on distal limbs. resolves within 6 months
hyperkeratosis,
• 3rd stage- hallmark of IP. Begins in wks of life. whorls , zebra stripes,
speckles. Persist throughout childhood. Disappear by age 16 yrs.
• 4th stage- hairless, hypopigmented patch

48. INCONTENTIA PIGMENTI
• DENTAL ABNORMALITY- Delayed eruption, impacted dentition
• OPHTHALMIC ABNORMALITY- stabismus, cataract, optic atrophy,
microphthalmia
• CNS SYMPTOMS- Seizures, ataxia, microcephaly, hemiplegia,
hemiparesis, spasticity

49. ATAXIA TELENGECTASIA
• Incidence 1/40,000 births
• Carrier frequency 1%
• Chromosome 11q22.3
• Telengectic lesions of
conjunctivae, malar eminences,
ear lobes and upper neck.
• Ataxia, choreoathetosis and
nystagmus.
• Immunologic defiencies

50. ATAXIA TELENGECTASIA
• Progrssive gait and truncal ataxia with onset from 1 to 3 years of age,
progrssively slurred speech,
• chorioathetosis, seizures,
• oculomotor apraxia
• oculocutaneous telangiectasia , usually by 6 yrs of age.

51. XERODERMA PIGMENTOSA
• Rare AR disorder of DNA repair
• NEUROLOGIC MANIFESTATION
a. Microcephaly
b. Low intelligence
c. Abnormal motor activity
d. Hyporeflexia or areflexia
e. Primary neuronal degenaration.
• OPTHALMOLOGIC ABNORMILITY
a. lacrimation
b. Photophobia
c. conjunctivities.

52. XERODERMA PIGMENTOSA
• SKIN ABNORMAITIES
a. Freckles
b. Erythema and atrophy
c. Bullae
d. Xerosis and scaling
e. Benign lesion- actinic keratoses,
fibromas
f. Malignant lesion- basal cell
carcinoma, squamous cell
carcinoma, melanoma.
XERODERMA PIGMENTOSA

53. HYPOMELANOSIS OF ITO
• Small 0.5 – cm hypopigmented or white macules
colaesce to form reticulaed patches along the
lines blaschko
• On both side of body
• Not symmetric patch
• DYSMORPHISM-
Cleft palate
Nail abnormality.
Hemihypertrophy
Face or skull abnormality
Hypopigmentation in whorls
Seizures
Mental retardation
Ophthalmologic anomolies
HYPOMELANOSIS OF ITO

54. LINEAR NEVUS SYNDROME
• Facial nevus and neurodevlopental
anomalies
• nevus – forehead nose, midline
• Faint.> yellow brown hyperkeratotic
• CNS- cortical dysplasia, glial hamartomas,
cerebral and cranial anomalies,
hemimeningoencephaly, enlargment of
lateral ventrical
• Feature= epilepsy, intectual disabilty,
hemiparesis
LINEAR NEVUS SYNDROME

55. PHACE SYNDROME
• Posterior fossa malformation,
hemangiomas, arterial anomalies,
coarctation of aorta, cardiac defect
and eye anomalies
• Facial hemangioma= ipsilatral to
aortic arch
• Dandy walker malformation mc
devp abnormality of brain

56. VON HIPPEL LINDAU SYNDROME
• INCIDENCE1 IN 36000
• Autosomal dominat
• Cerebellar hemangioblastoma and retinal angiomas
• renal carcinoma mc cause of death

57. REFERENCES
• NELSON TEXTBOOK OF PAEDIATRICS.
• Google image engine (for images)
• Harrison’s textbook of medicine