2. INTRODUCTION
 Van der Hoeve (1920) applied the term phakomatoses
(from the Greek phakos, meaning “mother spot,”
“mole,” or ―freckle‖).
 These diseases have many features in common—
 hereditary transmission
 Involvement of organs of ectodermal origin (nervous
system, eyeball, retina, and skin)
 slow evolution of lesions in childhood and adolescence
 Tendency to form hamartomas (benign tumor-like
formations due to maldevelopment), and a disposition
to fatal malignant transformation.

3.  Major syndromes
1. Tuberous sclerosis complex
2. Neurofibromatosis
3. Sturge-Weber syndrome
4. Ataxia-telangiectasia
5. Von Hippel-Lindau

4. Other - 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)
 Fabry disease
 Incontinentia Pigmenti (Bloch-Sulzberger)
No inheritance
 Cobb syndrome (cutaneous meningeal angiomatosis)
 Linear Sebaceous Naevus of Jadassohn

5. TUBEROUS SCLEROSIS
(BOURNEVILLE DISEASE)
 Tuberous sclerosis is a congenital disease of hereditary
type in which a variety of lesions, due to a limited
hyperplasia of ectodermal and mesodermal cells, appear
in the skin, nervous system, heart, kidney, and other
organs.
 It is characterized clinically by the triad of adenoma
sebaceum, epilepsy, and mental retardation.

6. HISTORY
 Virchow recognized scleromas of the cerebrum (1860 )
 Von Recklinghausen reported a similar lesion combined with
multiple myomata of the heart (1862)
 Bourneville’s articles, appearing between 1880 and 1900,
presented the first systematic accounts of the disease, and it was
he who related the cerebral lesions to those of the skin of the
face.
 Vogt (1890) -significance of the neurocutaneous relationship and
formally delineated the triad of facial adenoma sebaceum,
epilepsy, and mental retardation.
 ―Epiloia,‖ a term for the disease introduced by Sherlock in
(1911)

7. EPIDEMIOLOGY
 This disease has been described in all parts of the world and
is equally frequent in all races and both sexes.
 The disease is determined by two autosomal dominant genes.
 The estimated prevalence is 1 in 20,000 to 300,000.
 Tuberous sclerosis accounts for about 0.66 percent of the
mentally retarded in institutions and 0.32 percent of
epileptics.

8. ETIOLOGY
 The disease is inherited in an autosomal dominant
fashion.
 The abnormal gene is localized to one of two sites—the
long arm of chromosome 9, designated as TSC 1
(hamartin), and the short arm of chromosome 16, TSC 2
(tuberin).
 Hamartin and tuberin interact to suppress cell growth
and function as tumor suppressor proteins. This may, in
part, explain the proclivity to develop various growths
and hamartomas.
 The tumor-like growths in different organs may include
cells of more than one type (e.g., fibroblasts, cardiac
myoblasts, angioblasts, glioblasts, and neuroblasts), and
their number is locally excessive.

9. CLINICAL FEATURES
 The disease may be evident at the time of birth but
more often the infant is judged at first to be normal.
 In approximately 75 percent of cases, attention is
drawn to the disease initially by the occurrence of focal
or generalized seizures or by retarded psychomotor
development.
 The facial cutaneous abnormality, adenoma sebaceum,
appears later in childhood, usually between the fourth
and tenth years.

10.  Seizures -In the first year or two they take the form of
massive flexion spasms with hypsarrhythmia.
 As many as 25 percent of patients with these types of
seizures have been found to have tuberous sclerosis.
 Later, the seizures change to more typical generalized
motor and psychomotor attacks or atypical petit mal.

12.  Mental function continues to deteriorate slowly.
 Exceptionally there is a spastic weakness or mild
choreoathetosis of the limbs and in a few cases an
obstructive hydrocephalus.
 In nearly half of the cases, affective and behavioral
derangements, often of hyperkinetic and aggressive
type are present.

13. CUTANEOUS
MANIFESTATIONS
 In approximately 90 percent of patients with tuberous
sclerosis, congenital hypomelanotic macules—―ash-leaf‖
lesions appear before any of the other skin lesions.
 The hypomelanotic areas are arranged in linear fashion over
the trunk or limbs and range in size from a few millimeters
to several centimeters.
 Their configuration is oval, in the shape of an ash leaf.
 Electron microscopic examination of the hypomelanotic
lesions shows a normal or reduced number of melanocytes,
but their dopa reaction is reduced and melanosomes are
small.

15.  The well-developed facial lesions (adenomas of
Pringle), pathognomonic of tuberous sclerosis, are
present in 90 percent of patients over 4 years of age.
 Typically they are red to pink nodules with a smooth,
glistening surface, and they tend to be limited to the
nasolabial folds, cheeks, and chin.

17.  The ―shagreen patch‖ (a plaque of subepidermal
fibrosis) found most often in the lumbosacral region.
 It appears as a flat, slightly elevated, flesh colored area
of skin 1 to 10 cm in diameter, with a ―pigskin,‖
―elephant hide,‖ or ―orange peel‖ appearance).
 Subungual fibromas usually appear at puberty and
continue to develop with age.

19. PATHOLOGY
 Tubers: Broadening, unnatural whiteness, and firmness of parts of
some of the cerebral convolutions.
 On the surface of the brain, they range in width from 5 mm to 2 or
3 cm. Their cut surface reveals a lack of demarcation from cortex
and white matter and the presence of white flecks of calcium.
 Under the microscope ,the tubers are seen to be composed of
interlacing rows of plump, fibrous astrocytes.
 In the cerebral cortex and ganglionic structures, derangements of
architecture result from the presence of abnormal-appearing cells:
greatly enlarged―balloon‖ neurons and glial cells
 Neoplastic transformation of abnormal glial cells usually takes the
form of a large-cell astrocytoma, less often of a glioblastoma or
meningioma

20. Tuberose Sclerosis Complex Clinical
Diagnostic Criteria
1 primary OR 2 secondary OR 1 secondary + 2
tertiary
Primary features
 1. Facial angiofibromas (adenoma sebaceum) 1-4 yrs.
75%
 2. Multiple ungual fibromas. >20 y. 20%
 3. Cortical tuber
 4. Multiple calcified subependymal nodules
 5. Multiple retinal astrocytomas
 6. Subependymal nodule or giant cell astrocytoma (on
path)

21. Secondary Features
 1. First degree relative
 2.Cardiac rhabdomyoma
 3. Retinal hamartoma
 4. Cerebral tubers
 5. Noncalcified subependymal nodules
 6. Shagreen patch
 7. Forehead plaque
 8. Pulmonary lymphangiomyomatosis (histology) -
females
 9. Renal angiomyolipoma
 10. Renal cysts (histology)

22.  Tertiary features
1. Hypomelanotic macules (polygonal, ash leaf) 90%.
2. ―Confetti‖ skin lesions
3. Renal cysts (x-ray)
4. Enamel pits
5. Rectal polyp hamartomas (histology)
6. Bone cysts (x-ray)
7. Pulmonary lymphangiomatosis (x-ray)
8. Cerebral white matter ―migration
tracts‖/heterotopias (x-ray)

23.  Lab -The calcific lesions tend to be periventricular and
are particularly well shown on the CT scan.
 MRI is more sensitive in detecting hamartomatous
subcortical lesions.

26. TREATMENT
 Genetic counseling
 AEDs
 ACTH-used to suppress infantile spasms
 Dermabrasion of facial lesions
 Surgery –single epileptogenic cortical tuber

27. NEUROFIBROMATOSIS
 Epidemiology -Neurofibromatosis (NF) is a common
hereditary disease in which the skin, nervous system,
bones, endocrine glands, and sometimes other organs
are the sites of a variety of congenital abnormalities.
 Prevalence of the disease -30 to 40 per 100,000
 Incidence - one case in every 2500 to 3300 births

28. CAUSE AND PATHOGENESIS
 NF comprises two distinct disorders, the genes for
which are located on different chromosomes.
 Both are inherited in an autosomal dominant pattern
with a high degree of penetrance
 50% of the cases are due to new mutations.
 NF1 is caused by a mutation located near the
centromere on chromosome 17 in a gene called
neurofibromin.
 The second type, in which the main feature is bilateral
acoustic nerve neuromas, is caused by a gene termed
merlin
 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, and the

29. Neurofibromatosis Type 1
(Classical or Peripheral NF)
 Spots of hyperpigmentation and cutaneous and
subcutaneous neurofibromatous tumors are the basis of
clinical diagnosis.
 Pigmentary changes in the skin are nearly always
present at birth, but neurofibromas are infrequent at that
age.
 Approximately one-third were found to have only the
cutaneous manifestations

30.  The cardinal features of neurofibromatosis are café au
lait spots, axillary freckling, cutaneous neurofibromas,
and iris hamartomas (Lisch nodules).
Café-au-lait spot
 This is a flat, oval eruption of the color of coffee with
cream or darker brown. It varies in size and appears on
the trunk and extremities.
 A café-au-lait spot on the axillary fossae, called axillary
freckling, is thought to be a specific symptom of NF1.
 Café-au-lait spots are present in 70% of all newborns.
After infancy, the number of spots does not increase.

33.  Neurofibroma- A neurofibroma is a soft tumor of normal
skin color or light brownish-pink of various sizes.
 It may be produced on any site of skin. It may be elevated
and dome-shaped or papillary, or flat and palpable.
 neurofibroma first appears between childhood and puberty,
after which it gradually enlarges and increases in number.
 It may increase rapidly during pregnancy and after delivery.
 Nodular plexiform neurofibroma, neurofibroma in the
peripheral nerves, is a slightly palpable, spindle-shaped
tumor that appears on the skin over the subcutaneous nerves

36.  Lisch nodule- This is a small whitish spot (actually a
hamartoma) in the iris that was present in 94 percent of
Riccardi’s type 1 cases.

37.  Other features-
 Complex partial and generalized tonic-clonic seizures are a frequent
complication
 Hydrocephalus secondary to aqueductal stenosis – rare
 Macrocephaly with normal-sized ventricles is a common finding
 Cerebral vessels may develop aneurysms, or stenosis resulting in
moyamoya disease
 Precocious puberty may become evident in the presence or absence
of lesions of the optic chiasm and hypothalamus
 Hypertension, which may result from renal vascular stenosis or a
pheochromocytoma
 The incidence of pheochromocytoma, rhabdomyosarcoma,
leukemia, and Wilms tumor is higher than in the general population
 Tumors that occur in NF1 are optic nerve gliomas, astrocytomas of
brain and spinal cord, and malignant peripheral nerve tumors

38.  Neurofibromatosis Type 2 (Acoustic or Central NF)-
 Bilateral acoustic neuromas - most distinctive feature (In contrast
with NF-1 – optic gliomas).
 Symptoms of hearing loss, facial weakness, headache, or
unsteadiness may appear during childhood, although signs of a
cerebellopontine angle mass are more commonly present in the
2nd and 3rd decades of life.
 Café au-lait spots and skin neurofibromas - less common in NF-2
 Posterior subcapsular lens opacities -50% of patients with NF-2.
 CNS tumors - including Schwann cell and glial tumors, and
meningiomas are common in patients with NF-2.
 Gene for NF-2 is located near the center of the long arm of
chromosome 22q1.11

39. PATHOLOGY
 Neurofibroma is formed by Schwann cells and
intraneural fibroblasts, with thin undulating collagen
fibers in the middle.
 Verocay bodies, which are characteristic to
neurilemmoma, are found in NF2.
 The pigmented (cafe au lait) lesions contain only the
normal numbers of melanocytes. The dark color of the
skin is due to an excess of melanosomes in the
melanocytes.

40. DIAGNOSTIC CRITERIA OF
NEUROFIBROMATOSIS
TYPE 1 AND TYPE 2
 NF 1: > 2 criteria
1. > 6 café-au-lait macules >5 mm prepubertal
> 15 mm postpubertal
2. > 2 neurofibromas or 1 plexiform neurofibroma
3. Freckling axillary/inguinal
4. > 2 Lisch nodules (iris hamartomas)
5. Optic pathway glioma
6. Bone lesion (sphenoid dysplasia, thinning long
bone cortex + pseudarthrosis)
7. First degree relative

41.  NF 2
1. Bilateral VIIIth nerve tumours
2. First degree relative - unilat VIIIth nerve tumour or 2 of
-neurofibroma
- meningioma
- glioma
- schwannoma
- juvenile posterior subcapsular lenticular opacity

43. Treatment –
 The skin tumors should excised if they are cosmetically
objectionable or show an increase in size, suggesting malignant
change.
 Plexiform neuromas about the face pose especially difficult
problems.
 Cranial and spinal neurofibromas are amenable to excision, and the
gliomas and meningiomas usually demand surgical measures as
well.
 Bilateral optic nerve gliomas are usually treated with
radiation,unilateral ones are excised.
 Genetic counseling.

44. STURGE WEBER
SYNDROME
 Sporadic in occurrence
 Frequency : 1/50,000 live births
 Consists of a constellation of symptoms and signs
Facial nevus (port-wine stain)
Seizures
Hemiparesis
Stroke like episodes
Intracranial calcifications
In many cases, mental retardation

45. Etiology –
 Result from anomalous development of the primordial
vascular bed in the early stages of cerebral vascularization.
 The blood supply to the brain, meninges, and face is
undergoing reorganization, while the primitive ectoderm in
the region differentiates into the skin of the upper face and the
occipital lobe of the cerebrum.
 In patients with Sturge-Weber syndrome, the overlying
leptomeninges are richly vascularized and the brain beneath
becomes atrophic and calcified, particularly in the molecular
layer of the cortex

46. Clinical manifestations-
 Facial nevus is present at birth, tends to be unilateral, and
always involves the upper face and eyelid.
 The nevus may also be evident over the lower face, trunk, and
in the mucosa of the mouth and pharynx.
 Buphthalmos and glaucoma of the ipsilateral eye are common
complications.
 Seizures develop in most patients in the 1st year of life.
 Typically focal tonic-clonic and contralateral to the side of the
facial nevus .

48.  Seizures may become refractory to anticonvulsants and are
associated with a slowly progressive hemiparesis in many
cases.
 Transient stroke-like episodes or visual defects persisting for
several days and unrelated to seizure activity is due to
thrombosis of cortical veins in the affected region.
 Neurodevelopment appears to be normal in the 1st year of life
 Mental retardation or severe learning disabilities are present in
at least 50% in later childhood
 Probably the result of prolonged generalized seizures and
increasing cerebral atrophy secondary to local hypoxia and
use of numerous anticonvulsants

49. Diagnosis :
 Skull radiograph -Intracranial calcification (white lesions) in
the occipitoparietal region.
 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

52. Treatment
 Seizure control.
 Identification and management of behavioral or learning
problems.
 Because of the risk of glaucoma - regular measurements of
intraocular pressure with a tenonometer is indicated .
 Facial nevus - Flashlamp-pulsed laser therapy often provides
excellent clearing of the port-wine stain, particularly if it is
located on the forehead

53. ATAXIA TELENGIECTASIA
 Ataxia-telangiectasia has been attributed to defective
repair of DNA.
 The inheritance pattern is autosomal recessive.
 The onset of the disease coincides more or less with the
acquisition of walking, which is awkward and unsteady.
 By the age of 4 to 5 years, the limbs become ataxic,
and choreoathetosis,grimacing, and dysarthric speech
are added.

54.  The eye movements become jerky, with slow and long-
latency saccades, and there is also apraxia for voluntary
gaze.
 The characteristic telangiectatic lesions, appear at 3 to 5
years of age or later and are most apparent in the outer
parts of the bulbar conjunctivae, over the ears, on
exposed parts of the neck, on the bridge of the nose and
cheeks in a butterfly pattern, and in the flexor creases of
the forearms.

56.  The disease is progressive, and death usually occurs in the
second decade from intercurrent bronchopulmonary infection
or neoplasia—usually lymphoma, less often glioma.
 There is an absence or decrease in several immunoglobulins -
IgA, IgE and isotypes, IgG2, IgG4.
 This immunodeficient state accounts for the striking
susceptibility of these patients to recurrent pulmonary
infections and bronchiectasis.
 The defective gene (designated ATM) is a kinase that
mediates DNA repair by halting the cell cycle after DNA
damage.

57. THE von HIPPEL – LINDAU SYNDROME
 An 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
 25% of patients with cerebellar hemangioblastoma have
retinal angiomas

58.  Major neurologic features: cerebellar hemangioblastomas and
retinal angiomata.
 Patients with cerebellar hemangioblastoma present with
symptoms and signs of increased intracranial pressure.
 Spinal cord - abnormalities of proprioception and disturbances
of gait and bladder dysfunction.
 CT scan and MRI typically show a cystic cerebellar lesion
with a vascular mural nodule .

59.  Retinal angiomas are characterized by small masses of thin-
walled capillaries that are fed by large and tortuous arterioles
and venules.
 Cystic lesions of the kidneys, pancreas, liver, and epididymis
as well as pheochromocytoma are frequently associated with
von Hippel-Lindau disease.
 Renal carcinoma is the most common cause of death.
 Regular follow-up and appropriate imaging studies are
necessary to identify lesions that may be treated at an early
stage.

62. LINEAR NEVUS SYNDROME
 Sporadic condition characterized by a facial nevus and
neurodevelopmental abnormalites .
 The nevus is located on the forehead and nose and tends to be
midline in its distribution.
 May be quite faint during infancy but later becomes
hyperkeratotic, with a yellow brown appearance.
 More than half of patients have a seizure disorder and are
mentally retarded.
 The seizure may be generalized, myoclonic, or focal motor.
 A wide variety of cerebral lesions—unilateral cerebral
atrophy, porencephalic cyst, leptomeningeal hemangioma,
arteriovenous malformation, and atresia of cerebral arteries
and veins.

63. RENDU –OSLER-WEBER SYNDROME
(HERIDITARY HEMMORHAGIC
TELENGIECTASIA)
 This vascular anomaly is transmitted as an autosomal
dominant trait.
 It affects the skin, mucous membranes, gastrointestinal
and genitourinary tracts, lungs, and occasionally the
nervous system.
 Absence of elastic fibers and smooth muscles leads to
telangiectasia in the arteriovenous anastomotic region.
 The significance of the lesions lies in their hemorrhagic
tendency.

66.  They may give rise to severe and repeated epistaxis or
gastric, intestinal, or urinary tract bleeding.
 Pulmonary fistulas constitute another important feature
of the generalized vascular dysplasia.
 An unexplained gastrointestinal, genitourinary,
intracranial, or intraspinal hemorrhage warrants a
search for small cutaneous lesions, which are easily
overlooked

67. NEUROCUTANEOUS
MELANOSIS
Clinical features:
 Neurocutaneous melanosis is 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 leptomeninx.

70.  Neurocutaneous melanosis is caused by proliferation of
melanoblasts that originate from neural crests in the skin and
central nervous system (e.g., leptomeninx).
 In the brain, perivascular proliferation of melanocytes impairs
reabsorption of cerebrospinal fluid, leading to hydrocephalus
 MRI Brain, lumbar puncture and ventriculography are
necessary for diagnosis.
 Increased levels of proteins and reduced sugar levels are often
found in the cerebral fluid. Melanin-containing cells may be
present.
 Symptomatic therapy such as shunting for hydrocephalus and
anti-epilepsy drugs are useful for central nervous symptoms.
 Patients rarely live beyond the age of 20 years.

71. Incontinentia pigmenti
(Bloch-Sulzberger syndrome)
 It is X-chromosome dominantly inherited; female
patients greatly outnumber male patients.
 Characteristic pigmentation occurs on the skin.
 The symptoms are clinically classified into 4 stages.
1. Inflammatory stage
2. Verrucous stage
3. Pigmented stage
4. Regression stage

75.  Ocular symptoms: Ocular symptoms develop in about
one third of incontinentia pigmenti cases.
 Strabismus is most common followed in frequency by
cataract, glioma and microphthalmos.
 Central symptoms: Epilepsy and intelligence
impairment may be caused in half of the cases.
 Abnormality may occur in teeth (e.g.deficiency,
developmental retardation) and bones (e.g., dwarfism,
hyperdactylia).

76. INCONTINENTIA PIGMENTI
ACHROMIANS (HYPOMELANOSIS
OF ITO)
 It is inherited as autosomal dominant trait.
 Typical skin changes occur as hypopigmented lesions
on head, trunk or limbs.
 Females are affected more
 Approximately 75% of patients have anamolies
affecting the CNS, eyes, hair, teeth, skin and nails.
 CNS abnormalities include mental retardation, seizures
and motor system dysfunction.
 Electron microscopy reveals few melanosomes, sparely
dendritic melanocytes and a reduction in the number of
melanosomes in keratinocytes.

78. PARRY-ROMBERG
SYNDROME
 It is usually apparent in early childhood and rarely
shortly after birth.
 It is charecterised by progressive loss of facial soft
tissue, cartilage and bone.
 This 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.

80. Klippel-Trenaunay-Weber syndrome
Clinical features and Pathogenesis
 There is fragility of mesodermal tissue in the vascular
walls.
 Cutaneous hemangioma simplex is present at birth in
many cases.
 Lymphangioma, congenital venectasia, angiokeratoma
and congenital arteriovenous fistula may also occur and
become distinct with age
 Klippel-Trenaunay- Weber syndrome is also
characterized by enlargement and overgrowth of the
bone and soft tissue

81.  The bone abnormality usually occurs in the leg on the
same side of the body as the skin lesion, or rarely, on
the opposing side.
 Angioma in internal organs, syndactylism or other
dysplasia of fingers and toes, and heart failure (if the
arteriovenous fistula is severe) may occur.
 The different length of the legs results in claudication
and compensatory scoliosis.

82. Diagnosis and treatment
 Diagnosis can be confirmed by bone radiography and
systemic CT scan.
 Laser therapy is conducted when the hemangioma
simplex raises cosmetic concerns.
 Ligation or excision is performed on arteriovenous
fistulae, because they may cause heart failure.

84. MAFFUCCI SYNDROME
 Rare disease of unknown etiology characterised by
multiple enchondromas with secondary hemangiomas
and malformations of bone.
 Enchondromas affect the small bones of hands and feet
or any bone preformed in cartilage.
 During childhood they increase in size.
 Neurological complications are secondary to either
cerebral encroachment by cranial enchondromas or a
primary brain tumor.

86. WYBURN-MASON
SYNDROME
 Cutaneous vascular nevi
 Retinal and optic nerve vascular malfomations
 Ipsilateral cerebral avm involving visual pathways and
mid-brain
 Typically unilateral

89. THANK YOU