DEFINITION:
A neurocutaneous syndrome characterized by cutaneous and neurologic manifestations (mental retardation and seizures), and tumors.
EPIDEMIOLOGY:
- incidence: 1/30,000
- age of onset:
- 1st decade
- risk factors:
- familial - autosomal dominant with variable penetrance
- chrom.#: 9q33-34 (Type 1)
- ?11q23 (Type 2)
- ?12q23.3 (Type 3)
- 16p13 (Type 4)
- 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:
1. Tubers
- 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
1. Cutaneous Manifestations
1. Adenoma Sebaceum (80%)
- 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
1. Seizures (90%)
- 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>
- 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
1. Retinal (50-80%)
1. Mulberry Tumor
- 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%)
1. Angiomyolipomas
- multiple yellow-white nodules or cystic tumors embedded within the parenchyma
- usually benign but may cause hematuria, pain, and renal failure
3. Heart (50%)
1. Cardiac Rhabdomyomas
- 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%)
1. Koenen's Tumors
- subungual or periungual fibromas
- usually first appear in adolescence
- toes > fingers
5. Intracranial (15%)
1. Astrocytomas
- 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
1. Respiratory
- 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:
1. Imaging Studies
1. CT
· 1. Intracranial Calcifications (60%)
- most reliable finding in TS is calcified subependymal tubers
- also occur in the region of the foramina of Monro and periventricular regions
- multiple scattered calcium deposits may vary in size up to several cm
- occur as early as 5 months and become more prominent with time (typically around 3-4 years of age)
· 2. Others
- only 5% of patients with the clinical features of TS have normal CT's
- may also identify cerebral atrophy, subependymal tumors, ventriculomegaly, and areas of diffuse demyelination
2. MRI
- 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
1. Infantile Spasms
- 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:
1. Supportive
- 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
1. Infantile Spasms
- 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
1. Surgical Resection
- 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
1. Genetic Couselling
- 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
