TUBEROUS SCLEROSIS
DEFINITION:
A neurocutaneous syndrome characterized by cutaneous and
neurologic manifestations (mental retardation and seizures), and
tumors.
EPIDEMIOLOGY:
- incidence: 1/30,000
- age of onset:
- risk factors:
- familial - autosomal dominant with variable penetrance
- chrom.#: 9q33-34 (Type 1)
- if 2 or more siblings with Tuberous Sclerosis (TS) then one
parent always has at least one skin manifestation of TS
- sporadic rate varies from 58-77%
- if both parents are normal the TS in a child is probably a
new mutation
HISTORY:
1880-1900 - Bourneville and Brissaud
- first pathologic description of TS
- first to call the disease tuberous sclerosis
- first to relate cerebral sclerosis to the renal tumors
1908 - Vogt
- emphasized association of adenoma sebaceum & cerebral
sclerosis
- emphasized cardiac and renal tumors are constituents of TS
- triad: mental retardation (MR), seizures, adenoma sebaceum
PATHOLOGY:
- basic cause is unknown but considered a disorder of early
embryogenesis
- greater the # of tubers the greater the neurologic
impairment
- found anywhere within the cerebral hemispheres:
- typically present in the subependymal region (located in
the walls of the lateral ventricles and on the surface of the
basal ganglia) and may extend into the ventricles
- in the region of the foramen of Monro where they may cause
obstruction -> hydrocephalus
- also cortical gyri, sulcus terminalis
2. Sclerosis
- areas of:
- decreased numbers of neurons
- areas of increased numbers of oddly-shaped, multinucleated
"monster" giant neurons
- proliferation (overgrowth) of fibrillary astrocytes which
occasionally differentiate into malignant astrocytomas
- demyelination
- calcium deposition in gliotic areas
- blood vessels with hyaline degeneration of their walls
CLINICAL FEATURES:
- clinical presentation is extremely variable depending on the
age of the patient, which organs are involved, and the severity of
involvement
- clinical variability even within the same family
- rarely present at birth
- usually presents between 4-6 years of age:
- are present in 12% at 1 year
- are present in 33% at 2 years
- are present in 40% at 3 years
- are angiofibromas:
- usually pink or red papules appearing in patches or in a
butterfly-shaped distribution on or about the nose, cheeks,
and chin
- with time may enlarge, coalesce, and assume a fleshy
appearance
2. Ash-leaf Spots (90%)
- hypopigmented oval or leaf-shaped spots
- vary in size from mm -> cm
- vary in number from several to 75 or more
- found on the trunk and limbs in a linear orientation
- apparent at birth and seen prior to 2 years in 50% of
patients
- visualized using a Wood's light (melanin absorbs
wavelengths at 360 nm)
- represent depigmented macules inwhich the melanocytes are
normal but the melanosomes are reduced in number and contain
less melanin
3. Shagreen Patches (35%)
- isolated "leathery" raised and thickened plaques
- have an orange-peel consistency
- may be grayish-green or light brown in colour
- found over the lumbosacral or gluteal region
- develop in late infancy or early childhood but may also be
present at birth
- may be preceded by patches of grey or white hair (these
hairy patches may be the first manifestation of TS)
4. Others
- cafe-au-lait spots (7-16%)
- fibromas:
- flattened and can appear on the trunk, gingivae,
periungual region, and along the hairline or eyebrows
- angiomas
2. Neurologic Manifestations
- most common symptom of TS
- initally present as infantile spasms:
- 25-50% of patients with infantile spasms later develop
signs of TS
- can appear as early as 1 week of age
- later develop other types of generalized seizures:
- tonic, clonic, myoclonic, akinetic, Lennox-Gastaut
Syndrome
- epileptogenic focus may occur independently of tubers
2. Mental Retardation (60-70%)
- highly variable but when present is irreversible
- may be initally normal but then deteriorate intellectually
during the latter part of the 1st decade (secondary to seizure
or increased intracranial pressure)
- earlier the onset of seizures the greater the likelihood
of mental retardation (if seizures begin <1 year of age a 92%
chance of MR)
- all who have mental retardation (MR) have had seizures
- 33% of TS have normal intelligence
3. Others
- hydrocephalus:
- if tubers obstruct the foramina of Monro or the
- Sylvian aqueduct
- developmental delay
- may develop autistic features
3. Tumors
- a nodular astrocytoma of the retina on or about the
optic nerve head
- refractile, yellowish, multinodular cystic lesions
2. Hamartomas
- round or oval grey-yellow glial flat patches found
centrally or peripherally
- complications do not include papilledema or impaired
vision
2. Renal (50-80%)
- multiple yellow-white nodules or cystic tumors embedded
within the parenchyma
- usually benign but may cause hematuria, pain, and renal
failure
3. Heart (50%)
- solitary or multiple; infiltrative and/or diffuse
- solitary lesions usually found at the apex of the left
ventricle
- may cause congestive heart failure or arrhythmias but
tend to slowly resolve spontaneously
- may cause death before skin manifestations evident
4. Cutaneous (20%)
- subungual or periungual fibromas
- usually first appear in adolescence
- toes > fingers
5. Intracranial (15%)
- fibrillary astrocytomas may differentiate into giant
cell astrocytomas
- occur around the walls of the lateral ventricle or the
anterior portion of the 3rd ventricle
- may present as:
- elevated intracranial pressure (papilledema, headache,
nausea, vomiting)
- diminished vision
- lateralizing signs (hemiparesis)
6. Oral
- oral fibromas or papillomas
- usually found on the anterior aspect of the gingiva
4. Other Manifestations
- lesions in lungs are either cystic or fibrous
- angiomyolipomas may produce these generalized multicystic
or fibrous pulmonary changes
- may present with SOBE, and/or spontaneous pneumothorax
- females more affected than males
2. Musculoskeletal
- cystic changes and periosteal thickening of bones in hands
and feet
INVESTIGATIONS:
- preferable for the visualization of cortical tubers, areas
of heteropias, and hamartomas
- tubers which project into the lateral and 3rd ventricles
may appear as "candle drippings"
- important to identify heteropias as these may act as
seizure foci
3. Skeletal X-Rays
- cystic rarefaction of phalanges and metacarpals (67%)
appear around puberty
- sclerotic areas of long bones
- areas of variable skull bone density with thickened
calvaria
4. Chest X-Rays
- fine reticular infiltrates and/or multicystic changes
2. EEG
- hypsarrhythmias, can persist up to 8 years of age
2. Generalized Seizures
- generalized slow wave-and-spike activity or independent
multifocal spike discharges
3. Cerebral Spinal Fluid
- elevated protein with elevated intracranial pressure (ICP)
MANAGEMENT:
- a multidisciplinary approach involving:
- Paediatrics, Neurology, Ophthalmology, Nephrology,
Cardiology, Dermatology, Neurosurgery, Orthopedics, PT, OT,
Respirology
- ensure regular follow-up for tumor surveillence
- supplemental education
2. Cutaneous Manifestations
- surgical resection if lesions are continually irritated or
subjected to trauma
3. Neurologic Manifestations
- hormonal therapy: ACTH, prednisone
- anticonvulsants: clonazepam, VPA, nitrazepam, clobazam
- ? pertussis immunization -> triggers infantile spasm
- recommend not giving pertussis immunization to infants
with TS
2. Generalized Seizures
- anticonvulsant therapy and may be difficult to control
3. Developmental delay
- physiotherapy, early intervention
4. Tumors
- of intracranial tumors if complications:
- elevated ICP -> hydrocephalus
- malignant transformation
- of other tumors if complications:
- cardiac -> congestive heart failure or arrhythmias
- renal -> renal failure
5. Others
- 25% of parents without personal or family history of TS
may be shown by careful history, physical (Wood's light,
fundoscopic exam), & investigations (CT, renal ultrasound) to
be affected
- incompletely affected parents (those with isolated
findings such as adenoma sebaceum, retinal hamartomas, viseral
tumors) can have children with complete TS
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