This document discusses several neurocutaneous disorders including neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, xeroderma pigmentosum, ataxia-telangiectasia, Cockayne's syndrome, and Von Hippel-Lindau disease. These disorders are characterized by abnormalities affecting the skin, brain, and other organs that develop due to genetic mutations affecting tissues of ectodermal origin. The document provides details on the clinical features, diagnosis, and treatment of each condition.

1. Neurocutaneous
Disorders
Dr. WALID REDA ASHOUR, MD
Assist. Professor of Neurology
Zagazig University, Egypt

3. DEFINITION: They Previously called
Phakomatoses. In Greek (Phakos = birthmark)
These disorders are “hereditary”, characterised
by multiorgan malformations and tumors with
characteristic nervous system, ocular and
cutaneous lesions of variable severity.
* Skin and brain have a common ectodermal
origin, so there are many genetic and acquired
diseases that affect both tissues.

7. NEUROFIBROMATOSIS (NF)

8. NEUROFIBROMATOSIS (NF)
Neurofibromatosis (NF) is pathologically classified into 8
types: NF1 through NF8. NF1 is the most common.
Type 1 (NF1) (VON RECKLINGHAUSEN’S disease or
‘peripheral’ neurofibromatosis)
Characterised by CAFÉ AU LAIT spots and
neurofibromas.
Incidence: 1:4000
Inheritance: Autosomal Dominant.
Neurofibromin defect at chromosome 17q11.

9. Clinical Features (NF 1)
Skin manifestations: café au lait spots: light brown
patches on the trunk with well demarcated edges.
• Subcutaneous neurofibromata lying along
peripheral nerves and enlarging with age.
• Mollusca fibrosa: cutaneous fibromas large,
pedunculated and pink in colour.
• Plexiform neuroma: diffuse neurofibroma
associated with skin and subcutaneous
overgrowth.

12. Skeletal manifestations: about 50% of patients exhibit scoliosis.
Subperiosteal neurofibromas may give rise to bone hypertrophy or
rarification with pathological fractures.
Ocular: Lisch nodules are melanocytic hamartomas of the iris and
are seen on slit-lamp examination in 90% of patients.
Neoplasia: A high incidence of leukaemia, neuroblastoma,
medullary thyroid carcinoma, and multiple endocrine neoplasia
occurs.
Neurological manifestations: Mental retardation and epilepsy
occur in 10–15% of patients without intracranial neoplasm. As a
rule, the more florid the cutaneous manifestations the less likely
is there nervous system involvement.

13. LISCH NODULES

14. Diagnostic Criteria for NF1
Two or more of the following:
• Six or more CAFÉ-AU-LAIT spots 1.5 cm or larger
in post-pubertal individuals, 0.5 cm or larger in pre-
pubertal individuals.
• Two or more NEUROFIBROMAS of any type or one
or more plexiform neurofibroma.
• FRECKLING in the axilla or groin.
• Optic glioma (tumor of the optic pathway).
• Two or more LISCH NODULES (benign iris
hamartomas).
• A distinctive bony lesion: dysplasia of the
sphenoid bone or dysplasia or thinning of long bone
cortex.
• A first-degree relative with NF1.

15. Neurofibromatosis Type 2 (NF2)
Characterised by tumours (schwannomas) of the
eighth cranial nerve (vestibular division) (‘bilateral
acoustic neuromas’ or ‘central’ neurofibromatosis)
Incidence: 1:50 000
 Inheritance: Autosomal dominant. This syndrome
is caused by mutation of the NF2 gene
 NF2 encodes a protein called neurofibromin 2,
schwannomin or merlin.

16. Clinical features:
• Skeletal manifestations are absent. Café au lait
spots rare. Posterior subcapsular cataracts occur
in 50% of cases.
• An elastic, firm, sharply margined subcutaneous
neurilemmoma is the main cutaneous symptom
• The condition is defined by bilateral vestibular
schwannomas but may present as early unilateral
acoustic neuroma plus a family history of NF2.

17. Subcutaneous neurilemmoma

19. MRI brain demonstrating bilateral vestibular schwannomas
(acoustic neuromas, arrows) compressing the
pontomedullary region. These extra-axial lesions (arrows)
are hypointense on T1 (A), are hyperintense on T2 (B), and
show gadolinium enhancement (C)

20. Many individuals with neurofibromatosis type 2 also
have non-neoplastic lesions, which include
* Schwannosis (nodular ingrowth of Schwann cells
into the spinal cord).
*Meningioangiomatosis (a proliferation of
meningeal cells and blood vessels that grows into
the brain).
* Glial hamartia (microscopic nodular collections of
glial cells at abnormal locations, often in the
superficial and deep layers of the cerebral cortex).

21. Diagnostic Criteria for Neurofibromatosis Type 2 (NF2)
• Bilateral 8th nerve masses on neuroimaging or
First-degree relative with NF2 and either:
• Unilateral 8th nerve mass or 2 of the following:
• Neurofibroma
• Meningioma
• Glioma
• Schwannoma
• Juvenile posterior subcapsular lenticular opacity

22. TREATMENT
No known medical therapies are beneficial to patients with NF.
NF1
• Tumors: Surgery may remove painful or disfiguring
growths.
• Optic tumors: surgery, radiation, and chemotherapy.
• Café-au-lait spots: laser therapy and dermabrasion;
nevertheless, they tend to recur.
• epileptic seizures: well controlled with medication in
approximately 50–70 % of patients.
• pruritus due to cutaneous neurofibromas:
Diphenhydramine & avoid hot showers.

23. NF 2
• Although surgical resection of symptomatic tumors
represents the most common approach to clinically
significant lesions, in some rare instances, radiation and/or
chemotherapy may be recommended.
• Therapeutic use of ERLOTINIB or BEVACIZUMAB (an
antivascular endothelial growth factor monoclonal
antibody) has shown promise in the treatment of
unresectable, progressive vestibular schwannomas,
resulting not only in a decrease in tumor size but also in
improvement in auditory function.
• NEW: Stereotactic radiosurgery and auditory brainstem
implants.

25. TUBEROUS SCLEROSIS
Bourneville’s Disease

26. Incidence: 1:30000. Autosomal Dominant inheritance
with high sporadic mutation rate (60-70%).
 The genes responsible for tuberous sclerosis are
( Tuberous Sclerosis Complex)
TSC 1 on chromosome 9 (9q34) Hamartin.
TSC 2 on chromosome 16 (16p13) Tuberin.
 Both are thought to play a role in tumor
suppression.

27. Clinical features
1- Skin manifestations
• ADENOMA SEBACEUM (facial angiofibroma): a red raised
papular-like rash over the nose, cheeks and skin, appears
towards the end of the 1st year, though occasionally as late
as the 5th year. They occur in 85% of patients.
• ASH LEAF MACULES: Small oval white patches occur in
80% of those affected. These are important as they may be
the only manifestation at birth.
• SHAGREEN PATCH: patch of shagreen-like rough skin,
often on the lower back are common.

28. ADENOMA SEBACEUM

29. ASH LEAF SPOTS

30. Ash leaf spots. "confetti" macules. Multiple,
discrete, small, confetti-like, hypopigmented
macules of variable size on the leg.

31. SHAGREEN PATCH.

32. PERI-UNGUAL FIBROMAS: occur in 50% of patients.
Develop in adult life as small pink sausage-like lesions
emerging from the nail folds.

33. 2- Neurological manifestations: MENTAL RETARDATION is present
in 60% of patients, though the onset and its recognition may be
delayed.
• SEIZURES occur in almost ALL PATIENTS, often as early as the
1st week of life. Attacks are initially focal motor and eventually
become generalised. The response to anticonvulsants is
variable.
• Intracranial neoplasms – astrocytomas – arise from tubers
usually close to the ventricles and may result in an obstructive
hydrocephalus.
3- Neoplasia: RENAL CARCINOMA occurs in 50% of patients.
Retinal tumours (hamartomas) and muscle tumours
(rhabdomyomas) are common, the latter often involving the
heart.

34. Diagnosis
• The presence of epilepsy and adenoma sebaceum is
diagnostic.
• CT scan may show subependymal areas of calcium
deposition. MRI shows uncalcified subependymal tubers.
• Multiple retinal hamartomas.
• Cardiac rhabdomyoma, single or multiple.
• Lymphangiomyomatosis (lung disease that results in a
proliferation of disorderly smooth muscle growth
(leiomyoma) throughout the lungs and lymphatics,
resulting in the obstruction of small airways) and
lymphatics.
• Renal angiomyolipoma.

40. TREATMENT
Dermabrasion, excision, cryotherapy and laser
therapy are conducted on the cutaneous lesions
for cosmetic reasons, which nevertheless tend to
recur.
* ANTICONVULSANTS for convulsive seizure.
* There is no treatment for the progressive mental
retardation.
** The prognosis depends on the severity of cerebral
tumourous lesions and renal lesions.

41. STURGE-WEBER
SYNDROME

42. This disorder is characterised by a FACIAL
ANGIOMA associated with a LEPTOMENINGEAL
VENOUS ANGIOMA. There is no clear pattern of
inheritance as it’s caused by a spontaneous
genetic mutation. Practically all cases are
SPORADIC.
 What prompts the mutation is unknown and so far
no genetic factors have been found.
 It is a nonhereditary condition.
 It occurs in about 1 in 100,000 people.

43. CLINICALLY:
• CAPILLARY NAEVUS “PORT WINE STAIN” usually
involving forehead and eyelid conforming to the 1st or 1st
and 2nd divisions of the trigeminal nerve.
• Thickened leptomeninges, commonly ipsilateral to the
facial naevus and full of abnormal vessels, overlie an
ATROPHIC HEMISPHERE with degenerative changes and
vascular calcification usually most marked in the parieto-
occipital vessels.
• EYE DISORDERS: are common: buphthalmos (congenital
glaucoma) & choroidal angioma.

44. EPILEPSY occurs in 75% usually presenting in infancy and
can worsen with age.
HEMIPARESIS, HOMONYMOUS HEMIANOPIA occur in 30%.
BEHAVIOURAL DISORDER AND MENTAL RETARDATION
occur in 50%.
Skull X-rays show parallel linear calcification (TRAM-LINE
SIGN) and CT scan, in addition, shows the associated
atrophic change. Angiography demonstrates dilated deep
cerebral veins with decreased cortical drainage.
Arteriovenous and dural venous sinus malformations are
present in 30%.

47. Treatment
• Children as young as 1 month old can undergo LASER
treatment to reduce or remove port-wine stains.
• SURGERY can control glaucoma and vision problems.
• ANTICONVULSANT medication may be used to control
seizures.
** Intractable epilepsy may require LOBECTOMY, or even
HEMISPHERECTOMY. Some recommend early excision of
the surface lesion, but the rarity of the condition prevents
thorough treatment evaluation.

48. XERODERMA PIGMENTOSUM

51. • Autosomal Recessive disorder.
• There is inability to repair DNA damage (DNA repair
defect) caused by UV light and some chemicals
leading to a high incidence of skin cancers.
• The skin is normal at birth.
• Multiple freckles, roughness and keratoses on
exposed skin appear between the ages of 6 months
and 2years.
• Photosensitivity increases thereafter.
• The atrophic facial skin shows telangiectases and
small angiomas.

52. Many tumours develop on light damaged skin: basal cell
carcinomas, squamous cell carcinomas,
Keratoacanthomas & malignant melanoma.
Many patients die before the age of 20 years.
Eye problems are common and include: photophobia,
conjunctivitis and ectropion.
Diagnosis becomes evident on clinical grounds, although
variants with minor signs may cause difficulty.
The DNA repair defect can be detected in a few laboratories
after the ultraviolet irradiation of cultured fibroblasts or
lymphocytes from the patient.

54. ATAXIA-TELANGIECTASIA

55.  ATAXIA TELANGIECTASIA (AT) is a multisystem
disorder characterised by progressive cerebellar
ATAXIA, ocular and cutaneous TELANGIECTASIA and
IMMUNODEFICIENCY.
• It is an Autosomal Recessive disease caused by
mutation of the ATM (ataxia telangiectasia mutation)
gene which results in spontaneous breakage of
chromosomes (DNA repair defect).
 Neurodegeneration (spinocerebellar and movement
disorder)
 Sinopulmonary infections and lymphoproliferative
neoplasms.

56. • It is usually noticed in the second year of life as a
child develops problems with balance and slurred
speech caused by ataxia.
• A progressive ataxia develops in infancy.
Telangiectasia develops later, becoming more
obvious after exposure to the sun.
• About 70% of children with A-T also have immune
system problems that make them more
susceptible to chronic RTI, lung infections, and
certain cancers, such as leukaemia and
lymphoma.

57. * The disorder is characterized by spinocerebellar
degeneration (cerebellar ataxia, sensory
neuropathy, and posterior column involvement)
and chorea or dystonia.
* Oculomotor apraxia with head thrust is commonly
observed.
* Oculocutaneous telangiectasia develops with the
onset of ataxia at about 2-3 years of age.

58. • As the disease advances:
• MRI shows cerebellar atrophy.
• α-Fetoprotein level is elevated after age 2 years in
over 80% of affected individuals.
• Levels of immunoglobulins (IgA, IgE, IgG) are
usually low.

59. Treatment
 Currently, there is NO CURE for A-T and no way to stop its
progression.
 Physical therapy and occupational therapy may help
maintain flexibility.
 Speech therapy can help address slurring and other speech
problems.
• Treatment is palliative and related primarily to the
movement disorder.
• The disorder is associated with early mortality, due to
either general decline in neurologic function or neoplasia.

60. COCKAYNE'S SYNDROME
• Autosomal Recessive condition that is associated with
impaired DNA repair.
• Skin manifestations: photosensitivity.
• Neurological problems are related to learning
difficulties, progeroid appearance, ataxia, short
stature, and neuropathy. There is frequently slowing
of conduction on nerve conduction studies and
brainstem auditory evoked potentials are abnormal,
reflecting a disorder of peripheral and central
dysmyelination.

62. VON HIPPEL-LINDAU

63. • A genetic AD disorder involving the abnormal growth of blood
vessels (hemangioblastoma). * 1 in 40 000. * Caused by mutation
of VHL tumor-suppressor gene on chromosome 3.
• Mutation associated with an increase in vascular endothelial
growth factor (VEGF), which in turn stimulates new blood vessel
formation (angiogenesis).
• VHL is one of the most common Autosomal Dominant inherited
genetic diseases that cause familial cancers.
• Characterized by certain types of central nervous system
tumours (cerebellar and spinal haemangioblastomas) and retinal
angiomas, in conjunction with bilateral renal carcinomas and
phaechromocytoma.

64. * Symptoms usually appear between 5 and 30 years.
* Diagnostic criteria for VHL are:
1- Evidence of more than one haemangioblastoma in the
central nervous system or retina;
2- Two types of tumours commonly found in VHL in the same
patient (e.g. cerebellar haemangioblastoma and renal
carcinoma); or
3- A typical tumour related to VHL and a family history of
VHL.

66. • VHL treatment will depend on the size and location of the
angiomas.
• Complete resection of the haemangioblastoma can be
curative; however, recurrences or new tumours are
common.
• Tumours of the brainstem and spinal cord carry a high
postoperative morbidity from haemorrhage.
• Haemangiomas of the cerebellum are more easily
accessible, and sometimes preoperative embolization can
reduce the risk of haemorrhage.
TREATMENT

67. HYPOMELANOSIS OF ITO
* Rare, sporadic, multisystem disorder, but is the third most
common neurocutaneous syndrome after
neurofibromatosis type 1 and tuberous sclerosis. About
50% of patients show chromosomal abnormalities.
* Hypopigmented or depigmented streaks or whorls in the
skin. These changes are present within the first year of life
in 70%of cases.
• The neurological problems are due to cerebral and
cerebellar developmental abnormalities, arteriovenous
malformations, or tumours.

68. The most frequent neurological abnormalities are mental
retardation and seizures.

69. • Management is symptomatic: Anticonvulsants for seizures,
physiotherapy for motor difficulties, educational support
for those with learning difficulties, and specialist opinion
for ocular, dental, and skeletal problems.

70. PROTEUS SYNDROME
(Multiple Hamartomas)
* Partial, usually asymmetrical, enlargement of the
hands or feet, hemiatrophy on one side of the face
body or limbs, pigmented naevi, tumours skull
abnormalities (e.g. cranial exostosis, exostosis of
the external auditory meatus and nasal bridge,
macrocephaly or asymmetry of the skull), and
plantar hyperplasia (overgrowth of the
subcutaneous tissues of the soles of the feet.
There may be macrodactyly or syndactyly.

72. • Neurological manifestations may include spinal
cord compression from tumour infiltration,
cerebral malformations, or spinal stenosis as a
result of kyphoscoliosis.

73. HEMIATROPHY
• Facial hemiatrophy is a hereditary condition that usually
starts in the teens and produces progressive atrophy of the
skin and connective tissues of one side of the face, or
occasionally one side of the body. There may be
associated atrophy of the eye and bone and hemicortical
atrophy in the ipsilateral cerebral hemisphere.
• The cause is unknown.
• Seizures, hemianaesthesia, hemianopia, aphasia, migraine,
and syringomyelia have also been described. The
condition may halt spontaneously and the degree of

74. • There is no treatment that halts the disease, but
symptomatic relief of seizures and pain may be helpful.
HEMIHYPERTROPHY
(Klippel–Trenaunay–Weber syndrome)
* Rare condition which is the result of hypertrophy of the
connective tissues and long bones, cutaneous
haemangiomas, and varicose veins. The cause is unknown.
Neurological manifestations include seizures.

76. * A unilateral porencephalic cysts with cortical
atrophy.
* Intracranial lipomas, often located in the
cerebellopontine angle.
* Ipsilateral connective tissue usually lipomatous
hamartomas of the scalp, eyelid, and outer globe of
the eye
* Cranial asymmetry.
* “Marked” developmental delay and mental
retardation.
* Seizures.
* Spasticity of the contralateral limbs.

77. Large nonscarring
hairless patch
involving the left
fronto-parietal scalp
and part of the right
side with 3 localized
atrophic skin areas.

78. A, Multiple skin colored papules on the left
eyelid and yellowish limbal dermoid
(choristoma) on the bulbar conjunctiva,
encroaching the cornea. B, Hypertrophied and
congested bulbar conjunctiva in the left eye.

79. • CT brain shows
*Intracranial calcifications
*Porencephalic cyst,
*Atrophy of the left
cerebral hemisphere.

80. • MENKE'S SYNDROME (trichopoliodystrophy,
kinky-hair disease)
• An X-linked recessive focal neurodegenerative condition
that affects 1 in 35 000 live births and probably results from
problems with copper metabolism.
• Levels of serum copper and caeruloplasmin are reduced,
the copper content of the liver is low, but copper content of
the fibroblasts is increased. There is a problem with dietary
copper absorption; however, patients can utilize copper
given intravenously, although this does not prevent or treat
the clinical and neurological manifestations.

81. • The appearance of the infant usually points to the
diagnosis. Clinically, the hair is colourless, friable, and
kinked, curly.
• There is focal grey matter damage in the brain and tortuous
arteries with damage to the intima. Neurological symptoms
appear in the neonatal period, with failure to thrive and
hypothermia. Seizures are common and progressive
neurological deterioration occurs.
• DIAGNOSIS: confirmed by copper studies. Increased
copper content in the fibroblasts allows intrauterine
diagnosis in those with previously affected family
members.

83. • Gorlin syndrome (naevoid basal cell carcinoma syndrome)
Rare AD disorder characterized by multiple naevoid basal cell
carcinomas, odontogenic keratocysts of the mandible,
anomalies of the eye, skeleton, and reproductive system, and
medulloblastomas and other neoplasms.
• characteristic skin lesions and seizures in childhood. The
diagnostic criteria are the presence of two major, or one major
and one minor, criteria from the following:
• major criteria: more than two basal cell carcinomas in someone
under the age of 30 years, odontogenic keratocyst, palmar pits,
falx calcification, positive family history;
• minor criteria: rib or vertebral abnormalities, macrocrania,
fibroma, medulloblastoma, lymphomesenteric cysts.

84. * A unilateral porencephalic cysts with cortical
atrophy.
* Intracranial lipomas, often located in the
cerebellopontine angle.
* Ipsilateral connective tissue usually lipomatous
hamartomas of the scalp, eyelid, and outer globe of
the eye
* Cranial asymmetry.
* “Marked” developmental delay and mental
retardation.
* Seizures.
* Spasticity of the contralateral limbs.

85. Large nonscarring
hairless patch
involving the left
fronto-parietal scalp
and part of the right
side with 3 localized
atrophic skin areas.

86. A, Multiple skin colored papules on the left
eyelid and yellowish limbal dermoid
(choristoma) on the bulbar conjunctiva,
encroaching the cornea. B, Hypertrophied and
congested bulbar conjunctiva in the left eye.

87. • CT brain shows
*Intracranial calcifications
*Porencephalic cyst,
*Atrophy of the left
cerebral hemisphere.

89. THANK
YOU