NEUROCUTANEOUS SYNDROMEDR. SUMIT KAMBLEDM SENIOR RESIDENTGMC, KOTA

INTRODUCTION Heterogeneous group of disorders characterised by the

abnormalities of integument and CNS.

Mostly familial.

Defect in differentiation in primitive ectoderm (nervous system, eyeball, retina, and skin) .

Various syndromes include-

• Neurofibromatosis• Tuberous Sclerosis• Sturge Weber Syndrome• Von Hippel Lindau Syndrome• Ataxia-telangiectasia• Hereditary Haemorrhagic Telangiectesia • Epidermal nevus Syndrome

OTHERS AD• Hemorrhagic telangiectasia (Osler-Rendu-Weber)• Incontinentia Pigmenti Achromians (Hypomelanosis of Ito) AR• Chediak-Higashi• Divry-Van Boegart• Meckel-Gruber• Xeroderma pigmentosa X-linked• Albright syndrome (polyostotic fibrous dysplasia)• Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)• Incontinentia Pigmenti (Bloch-Sulzberger) No inheritance• Cobb syndrome (cutaneous meningeal angiomatosis)• Linear Sebaceous Naevus of Jadassohn

NEUROCUTANEOUS DISORDERS INCIDENCE

• Neurofibromatosis Type 1 1/1,000 -1/7,800 • Tuberous Sclerosis 10.6/100,000• Ataxia Telangiectasia 1.7/100,000• Xeroderma Pigmentosum 1/100,000 - 1/250,000 • Neurofibromatosis type 2 1/200,000

NEUROFIBROMATOSIS

• NF comprises two distinct disorders, genes for which are located on different chromosomes.

• NF1 and NF2 are autosomal dominant.• 50% of cases having no family history.• NF1 is also called Von Recklinghausen disease.• NF2 is also called bilateral acoustic neurofibromatosis

• Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci.

NEUROFIBROMATOSIS TYPE 1 (CLASSICAL OR PERIPHERAL NF)

• 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.

DIAGNOSTIC CRITERIA OF NF TYPE 1

Diagnosed when any 2 or more of the following 7 features are present:• (1) Six or more Cafe-au-lait macules (macules >5 mm in prepubertal

patients and >15 mm in postpubertal patients )• (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 , thinning long

bone cortex + pseudarthrosis. • (6) Optic gliomas low-grade astrocytomas. • (7) A first-degree relative with NF- 1

Cafe-au-lait macules• Hallmark of neurofibromatosis

almost 100% of patients.• Present at birth but increase in

size, number, and pigmentation, especially during first few years of life.  

• Predilection for the trunk and extremities but sparing the face.

Axillary or inguinal freckling• Multiple hyperpigmented areas

2-3 mm in diameter.• Skinfold freckling usually

appears between 3 and 5 years of age.

• Frequency greater than 80% by 6 year of age.

• High correlation with neurofibromatosis when six or more freckles are present in the axilla.( Crowe sign)

Two or more iris Lisch nodules• Pigmented hamartomatous nevus

(type of benign tumor) affecting iris.

• Best identified by a slit-lamp examination.

• Present in >74%• Prevalence increases with age.Only 5% of children <3 yr of age.42% among children 3-4 yr of age. 100% of adults ≥21 yr of age.

Two or more neurofibromas or 1 plexiform neurofibroma

• Neurofibroma- benign tumors arising from Peripheral nerve.

• Small, rubbery lesions with a slight purplish discoloration of 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.

• Plexiform neurofibromas may produce overgrowth of an extremity and a deformity of the corresponding bone

• 5-13% risk of malignant transformation

Distinctive Osseous lesion• Sphenoid Dysplasia• Scoliosis is Most Common• Cortical thining of long bones

with or without pseudoarthrosis

SYSTEMIC FEATURES OF NF1

• Dysplasia of renal and carotid arteries• Systemic hypertension – Renal artery stenosis and

pheochromocytoma• Cerebral artery dysplasia- Moyamoya syndrome• Arterial aneurysms• Short stature and Macrocephaly with normal-sized ventricles• Precocious puberty may become evident in the presence or

absence of lesions of the optic chiasm and hypothalamus • Pheochromocytoma, Rhabdomyosarcoma, Leukemia, and

Wilms tumor

NEUROLOGICAL FEATURES OF NF1

Optic nerve Glioma• Most common CNS tumor• Seen 15% - Unilateral or

bilateral• Progressive vision loss, optic

atrophy, pain or proptosis• Precocious puberty- chiasmatic

optic nerve tumor• Children age >10 years with

NF-1 undergo annual ophthalmologic examinations

NEUROLOGICAL FEATURES OF NF 1

• Ependymomas, Meningiomas and Astrocytomas• Neurofibromas, Schwannomas

• Other MRI Abnormalities • Areas of increased T2 signal intensity (UBOs)• – 43 - 79 % of NF1 in pediatric age group in BG, Thalamus, brainstem and

cerebellum• – Most- multiple, no mass effect.• – Path- atypical glial infiltrate, and areas of microcalcificaiton, and areas of

dysmyelination and spongy changes in WM around lesion

NEUROFIBROMATOSIS 2 (NF-2)• Rarer condition• Incidence of 1/25,000• NF2 gene (also known as merlin or Schwannomin), located on

chromosome 22q1.11• Posterior subcapsular lens opacities are identified In about 50%

of patients with NF-2• Bilateral acoustic neuromas - most distinctive feature (In

contrast with NF-1 – optic gliomas).

DIAGNOSTIC CRITERIA OF NF TYPE 2

May be diagnosed when 1 of the following 3 Features is present:1. Bilateral vestibular schwannomas2. First degree relative with NF-2 and unilateral vestibular

schwannoma 3. First degree relative with NF-2 and any 2 of the following:

Meningioma, Schwannoma, Glioma, Neurofibroma, or Posterior subcapsular lenticular opacities

Bilateral Acoustic Neuromas• Hearing loss • Unsteadiness • Headache • Facial weakness • More commonly in 2nd and

3rd decade.

Subcapsular opacity- 50% of cases of NF-2 

LABORATORY TESTS

• Genetic testing is available. Results can only tell if an individual is affected but cannot predict the severity of the disease.

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”

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 non

symptomatic children

 TUBEROUS SCLEROSIS (Bourneville’s disease)

• 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.

• Disease affects many organ systems other than skin and brain, including heart, Kidney, eyes, lungs, and bone.

• 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

• 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.

• Loss Of either tuberin or hamartin results in the Formation of numerous benign tumors (Hamartomas)

DIAGNOSTIC CRITERIA

A. GENETIC DIAGNOSTIC CRITERIA• Identification of Mutation in either TSC1 or TSC2• 10% to 25% of TSC patients have no mutation ( normal result

does not exclude TSC)

B. CLINICAL DIAGNOSTIC CRITERIA• Definite diagnosis: Two major features or one major feature with

≥2 minor features• Possible diagnosis: Either one major feature or ≥2 minor features

•  

Major features1. Hypomelanotic macules (≥3, at least 5-mm diameter)2. Angiofibromas (≥3) or fibrous cephalic plaque3. Ungual fibromas (≥2)4. Shagreen patch5. Multiple retinal hamartomas6. Cortical dysplasias7. Subependymal nodules8. Subependymal giant cell astrocytoma9. Cardiac rhabdomyoma10. Lymphangioleiomyomatosis (LAM)11. Angiomyolipomas (≥2)

Minor features1. “Confetti” skin lesions2. Dental enamel pits (>3)3. Intraoral fibromas (≥2)4. Retinal achromic patch5. Multiple renal cysts6. Nonrenal hamartomas

DERMATOLOGIC AND DENTAL FEATURES

Hypomelanotic macules (Ash leaf spots)• Observed in about 90% of

individuals• Typically appear at birth or infancy

Facial Angiofibromas (adenoma sebaceum)• About 75% of TSC patients• Between ages 2 and 5 years• Also seen in Birt-Hogg-Dubé

(BHD) syndrome, and (MEN1)

Ungual fibromas• About 20% overall • Adults

Shagreen patch• Large plaques on the lower

back that have a bumpy or orange-peel surface

• Seen in 50% of individuals• Onset in the first decade

“ Confetti” skin lesions• Numerous 1- to 3-mm

hypopigmented macules scattered over arms and legs

• 3% in children to about 58% overall

Dental enamel pits• Multiple, randomly

distributed pits in dental enamel

• 100% of adult TSC patients

Intraoral fibromas• Occur in about 20–50% of individuals • Gingival fibromas• May also be observed on the buccal or labial mucosa and even the

tongue

OPHTHALMOLOGIC FEATURESMultiple retinal hamartomas• 30–50% of TSC• Do not cause problems with

vision 

Retinal achromic patch• Areas of hypopigmentation

on the retina• 39% of TSC patients

NEUROLOGICAL FEATURES• Intellectual disability, behavioral abnormalities• Seizures - various types occur in 80% to 90% of patients.• Most common cause of infantile spasms

• Neuropathological lesions of TSC include subependymal nodules (SENs), cortical and subcortical hamartomas (tubers), areas of focal cortical hypoplasia, and heterotopic gray matter.

Cortical tubersLocation- Frontal, Parietal, Temporal,Cerebellar

Sub ependymal nodules• Location-Caudothalamic

groove of lateral ventricle.

White matter lesions• Location-alone lines of

neural migration

SEGA• 6-14%

CARDIOVASCULAR FEATURES

Cardiac rhabdomyoma• Major feature• Benign tumors of heart that

are rarely observed in non-TSC–affected individuals

• Most frequently located in the ventricles

• Observed in TSC-affected individuals during fetal life

• Prenatal presence of a cardiac rhabdomyoma is associated with a 75–80% risk of TSC

Pulmonary features• Lymphangioleiomyomatosis• Interstitial expansion of the

lung with benign-appearing smooth muscle cells that infiltrate all lung structures

• 30–40% of female TSC patients

• Multifocal micronodular pneumocyte hyperplasia (MMPH)

• Clear cell tumor of the lung

Renal features• Angiomyolipomas•  Benign tumors composed of

vascular, smooth muscle, and adipose tissue

•  80% of TSC patients

• Multiple renal cysts

Endocrine features•  Hamartoma • Adrenal angiomyolipoma • Thyroid papillary adenoma• Angiomyolipoma or

fibroadenoma in the pituitary gland, pancreas, or gonads

Gastrointestinal features• Liver angiomyolipomas• Hamartomatous rectal polyps

STURGE WEBER SYNDROME• Characteristic features are facial cutaneous angioma (port-wine

nevus) and an associated ipsilateral leptomeningeal and brain angioma.

• Occurs sporadically, with a frequency of approximately 1/50,000

• Somatic mutation in GNAQ recently identified

CUTANEOUS FEATURES

Nevus (port-wine)• Involves the forehead and

upper eyelid • Usually obvious at birth; • Reactive hypertrophy of

adjacent bone and connective tissue

• Only 10% to 20% of children with a port-wine nevus of the forehead have leptomeningeal angioma.

• Leptomeningeal angioma is typically ipsilateral to a unilateral facial nevus

OCULAR FEATURES

Glaucoma • Risk has two age peaks, first in infancy and second in late

childhood. • Periodic measurement of the intraocular pressure is mandatory,

particularly when the nevus is near the eye.

• Amblyopia and buphthalmos (enlarged globe) • Choroid angiomas or heterochromasia of the iris ipsilateral to

the nevus.

NEUROLOGICAL FEATURES

• Epileptic seizures- develop in 72% to 80% of patients with unilateral lesions and in 93% of patients with bihemispheric involvement.

• Focal motor seizures or generalized tonic-clonic seizures, infantile spasms, myoclonic seizures, and atonic seizures

• Intellectual disability - Only 8% of the patients with bilateral brain involvement are intellectually normal

• Focal neurological deficits- Transient stroke-like episodes or visual defects

DIAGNOSTIC STUDIES

• Skull radiograph –Intracranial calcification in occipitoparietal region.

• Gyral calcifications- characteristically assumes a serpentine or

railroad-track appearance.

• CT scan highlights the extent of the calcification that is usually associated with unilateral cortical atrophy and ipsilateral dilatation of the lateral ventricle.

• MRI is a useful adjunct to CT for delineation of the size and location of the vascular malformation and the presence of white matter lesions

Functional imaging• PET- reduced metabolism of the brain adjacent to the

leptomeningeal lesion • SPEC- reduced perfusion of the affected brain. • Both PET and SPECT often reveal vascular changes extending

well beyond the area of abnormality depicted by CT

Cerebral arteriography – • Useful in atypical patients or prior to surgery for epilepsy. • Veins are more abnormal than the arteries, with enlarged,

tortuous, subependymal, and medullary veins and sparse superficial cortical veins.

.• Occipital gyriform

calcification pattern

• leptomeningeal and brain angioma

TREATMENT

• Treat seizure

• Resection of a localized brain vascular lesion or hemispherectomy

• 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.

VON-HIPPLE LINDAU DISEASE• Autosomal dominant trait with variable penetrance and delayed

expression

• Incidence of 1/36,000 people

• Caused by germ line mutations in the VHL tumor suppressor gene located on 3p25–26

• Affects many organs, including the cerebellum, spinal cord, medulla, retina, kidney, pancreas, and epididymis

• Median age of presenting first clinical feature is 20-25 years.• Earliest detected manifestation – capillary haemangioma of

retina.• Probability of developing retinal capillary haemangioma and

CNS haemangioblastoma is 80%• 60% probability for developing RCC• Both sexes affected equally

NEUROLOGICAL FEATURES

Hemangioblastomas - cerebellum in approximately half of patients , followed by spinal and medullary sites. • Begin in the second decade of life.• Symptoms of cerebellar and brainstem hemangioblastomas-

headache, ataxia, nausea and vomiting, and nystagmus • Spinal hemangioblastomas - conus medullaris and the

cervicomedullary junction are most common sites.

Endolymphatic sac tumors - 10% to 15• Sometimes they are bilateral. • Symptoms - abrupt change in hearing accompanying

hemorrhage or vertigo and tinnitus

• Magnetic resonance imaging showing multiple cerebellar hemangioblastomas

OCULAR FEATURES

Retinal hemangioblastomas• Seen in 50-60% • 50% multiple• Usually asymptomatic

• Hemorrhage leading to retinal injury and detachment,

• Glaucoma, uveitis, macular edema, and sympathetic ophthalmitis.

SYSTEMIC FEATURES

• Renal Cysts - present in more than half of individuals • RCC- develops in more than 70% of patients and is the leading

cause of death. • Pheochromocytoma - occur in 7% to 19% , may be bilateral

and occur outside the adrenal glands. • Cyst adenomas of pancreas and epididymis

SCREENING PROTOCOL

HEREDITARY HEMORRHAGIC TELANGIECTASIA

• Also known as Rendu-Osler-Weber syndrome or Osler-Weber-Rendu syndrome

• Highly penetrant autosomal dominant disorder • Characterized by telangiectasias of the skin, mucous

membranes, and various internal organs. • Prevalence is 1 in 10,000. • Absence of elastic fibers and smooth muscles leads to

telangiectasia in the arteriovenous anastomotic region.

Two genes• Chromosome 9q33-34 (HHT1) encodes for endoglin, a TGF-β

binding protein.• Chromosome 12q13 (HHT2), encodes for activin A receptor

type II-like 1 kinase, or ACVRL1.

• 30% of cases arise from spontaneous mutations.

CURAÇAO’S DIAGNOSTIC CRITERIA FOR HEREDITARY HEMORRHAGIC TELANGIECTASIA

Diagnosis of HHT • Definite: 3 criteria are present • Possible or suspected: 2 criteria are present• Unlikely: < 2criteria are present

• 1. Epistaxis: spontaneous, recurrent nose bleeds • 2. Telangiectases: multiple, at characteristic sites (lips, oral

cavity, fingers, nose) • 3. Visceral lesions such as gastrointestinal telangiectasia (with

or without bleeding), pulmonary arteriovenous malformation (AVM), hepatic AVM, cerebral AVMs, spinal AVM

• 4. Family history: a first degree relative with HHT according to these criteria

CUTANEOUS FEATURES

Cutaneous telangiectasias • Occur on the face, lips, and

hands • Telangiectasias of the nasal

mucosa often cause epistaxis • One-third of patients have

conjunctival telangiectasias, and 10% have retinal vascular malformations

SYSTEMIC FEATURES

• Widespread vascular dysplasia - lungs, gastrointestinal tract, or genitourinary system,

• Hemoptysis, hematemesis, melena, or hematuria.

• Pulmonary arteriovenous malformations (AVMs) occur in 15% to 20% of patients.

NEUROLOGICAL FEATURES

• Headache, dizziness, and seizures.

• Paradoxical embolism with stroke, intraparenchymal or subarachnoid hemorrhage.

• Meningitis or brain abscess - 1% develops cerebral abscess or meningitis, probably because septic microemboli bypass the normal filtration of the pulmonary circulation via a pulmonary AVF.

• AVMs, high-flow pial fistulae, and telangiectasias , cavernous malformations, venous angiomas, and vein of Galen malformations

• Screening should begin with MRI and MR angiography (MRA) of the brain - every 5 years

HYPOMELANOSIS OF ITO• Incontinentia pigmenti achromians

• Heterogeneous and complex neurocutaneous disorder affecting skin, brain, eye, skeleton, and other organs.

• Third most frequent neurocutaneous disease after NF1 and tuberous sclerosis complex.

• HI is usually a sporadic disorder

CUTANEOUS FEATURES

Hypopigmented whorls, streaks, and patches• Present at birth and tend to

follow Blaschko lines,• Usually multiple, involve

several body segments• Unilateral or bilateral. • Café-au-lait spots, cutis

marmorata, aplasia cutis, nevus of Ota, trichorrhexis, focal hypertrichosis, and nail dystrophy.

NEUROLOGICAL FEATURES

• Neurological abnormalities - 50% to 80% • Seizures - Approximately half of patients with HI have seizures,

usually with onset in the first year of life. Focal seizures are most common.

• Intellectual disability • Macrocephaly

IMAGING

• Generalized cerebral or cerebellar hypoplasia• Neuronal migration anomalies, hemimegalencephaly, and

lissencephaly. • Extensive periventricular white-matter lesions , Small

periventricular cysts and gray-matter heterotopias • About a third of patients with HI have normal cranial MRI

studies.

SYSTEMIC FEATURES

• Seen in 50% to 70% of patients 1. Ocular - microphthalmia, heterochromia iridis,

dacryostenosis, pannus, corneal opacities, cataract, optic atrophy, retinal detachment, and pigmentation anomalies of the retina.

2. Musculoskeletal anomaly – hemihypertrophy, short stature, pectus carinatum and excavatum, cleft palate, butterfly vertebrae, scoliosis, and clinodactyly and polysyndactyly.

3. Dental anomalies- conical or hypoplastic teeth, hypoplastic dental enamel, and cleft lip and palate.

4. Cardiac defects - tetralogy of Fallot, pulmonary stenosis, and septal defects.

INCONTINENTIA PIGMENTI (Bloch-Sulzberger syndrome)

• Rare X-linked dominant condition affecting the skin, eyes, and CNS.

• Female >>male

CUTANEOUS FEATURES

• Characteristic pigmentation occurs on the skin.

• Clinically classified into 4 stages.1. Inflammatory stage (blister)- neonatal period 2. Verrucous stage - infancy 3. Pigmented stage - childhood and adulthood 4. Regression stage (atrophic and hypopigmented)

• Blisterlike and verrucous stage

• Hyperpigmented stage

OCULAR FEATURES

• Develop in about one third cases.

• Strabismus is most common followed in frequency by cataract, glioma and microphthalmos.

• Increased risk of retinal detachment -most likely to occur in early childhood.

NEUROLOGICAL FEATURES

• Seizures. • Most affected females have normal intelligence. • Affected males are more likely to have developmental delay. • Neurological abnormalities are more likely to occur in

individuals with ocular abnormalities. • Some demonstrate cerebral or cerebellar atrophy.

ATAXIA-TELANGIECTASIA• Autosomal recessive disorder,• Gene associated with AT (ATM) is a large gene located at

chromosome 11q22-23, • Prevalence - 1 in 40,000 to 1 in 100,000.• Begins in early childhood as a slowly progressive ataxia. • Telangiectasias (dilated small blood vessels),

immunodeficiency, and cellular sensitivity to ionizing radiation develop later.

CUTANEOUS FEATURES

• Telangiectasias - develop at age of 3 to 6 years, well after the onset of ataxia.

• Hypertrichosis and occasional gray hairs.• Progeric changes such as poikiloderma, loss of subcutaneous

fat, and sclerosis• Abnormal radiosensitivity- basal cell carcinomas in young • Cutaneous granulomas

NEUROLOGICAL FEATURES

• Ataxia - first manifestation of AT, appears in the second year of life.

• Truncal ataxia predominates, require a wheelchair by the age of 12 years.

• Limb ataxia, intention tremor, and segmental myoclonus• Choreoathetosis , Progressive dystonia of the fingers may

appear in second and third decades of life. • Abnormal eye movements - impaired voluntary ocular motility;

nystagmus and apraxias of voluntary gaze such as disorders of smooth pursuit and limitation of upgaze

• Progressive distal muscular atrophy and fasciculations, • Loss of vibration and position sense

IMMUNODEFICIENCY AND CANCER RISK

• 10% to 15% of patients with AT develop a lymphoid malignancy by early adulthood.

• T-cell malignancies are more common than B-cell tumors• Dysgerminoma, gastric carcinoma, liver carcinoma,

retinoblastoma, and pancreatic carcinoma.• Nonlymphoid tumors, primarily carcinomas, represent

approximately 20% of all malignancies. • Cerebellar astrocytoma, medulloblastoma, and glioma

• Frequent sinopulmonary infection- Recurrent or chronic sinusitis, bronchitis, pneumonia, and chronic progressive bronchiectasis

LABORATORY DIAGNOSIS• α-fetoprotein level - elevated in all patients with AT screening

diagnostic test.

• Approximately 80% have decreased serum immunoglobulin—IgA, IgE, or IgG, especially the IgG2 subclass

• Karyotype: high incidence of chromosomal breaks, especially on chromosome 14

• Fibroblasts can be screened in vitro for x-ray sensitivity and radioresistant DNA synthesis

• Brain imaging - cerebellar atrophy.

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

PARRY-ROMBERG SYNDROME• Early childhood and rarely shortly after birth.• Characterized by progressive loss of facial soft tissue, cartilage

and bone.• Atrophic process ceases by the end of second decade of life.

• Neurological deficits include - recurrent headaches, ipsilateral horner’s syndrome, contralateral partial seizures and hemiparesis.

• Cranial CT can be normal or documents cerebral atrophy.

NEUROCUTANEOUS MELANOSIS• Nonfamilial and occurs in both men and women.• Large congenital melanocytic nevus, in most cases a giant hairy

pigmented nevus, is present on nearly half the trunk or multiple congenital small melanocytic nevi disperse over the whole body.

• CNS symptoms such as increased intracranial pressure and secondary hydrocephalus occur. These are accompanied by headache, vomiting, epileptic seizure and intelligence impairment.

• Malignant melanoma often develops on the site of the body with giant hairy nevus and leptomeninges.

THANK YOU

REFERENCES

• Bradleys Neurology in clinical Practice 7th edition• Uptodate. Com• Medscape. com