General
- AKA: Bourneville’s disease,
- Development disorder of cell proliferation, migration, and differentiation.
- A group of autosomal dominant neurocutaneous disorder characterized by multi-organ hamartomas (noncancerous tumor made of an abnormal mixture of normal tissues and cells from the area in which it grows) and benign neoplastic lesions of many organs including the skin, brain, eyes, and kidneys.
- Brain hamartomas:
- Cortical tubers, glial nodules located subependymally or in deep white matter,
- Subependymal giant cell astrocytomas (SEGA).
- Not all these lesions are necessarily present in each patient.
- Associated brain findings include pachygyria or microgyria.
Numbers
- Incidence: 1/6,000–10,000 live births.
- Prevalence: 1/20,000
- Most have manifestation before 10 yrs old
Genetic
- Majority are spontaneous mutations
- Autosomal dominant inheritance
- Two distinct tumour suppressor genes producing similar phenotypes but only one needed to be affect to get disease:
- TSC1 gene (chr 9q34) codes for TSC1 (AKA hamartin)
- TSC2 gene (chr 16p13.3) codes for TSC2 (tuberin).
- Both together form a tuberin-hamartin complex → which normally sequesters Rheb → preventing Rheb from activating mTOR.
- In TSC: the tuberin-hamartin complex cannot form → Rheb not sequestered → constant activation of mTOR → inc. proliferation and cell growth
- Genetic counselling for unaffected parents with one affected child: 1–2% chance of recurrence.
- Genetic testing for TSC1 and TSC2 is not routinely done as the gene is large and complex with a variety of mutations available (point mutations to deletions)
Clinical features
- Classic clinical triad (Vogt triad):
- Seizures
- Mental retardation
- Sebaceous adenomas
- (full triad seen in 1/3 of patients)
Diagnostic criteria of tuberous sclerosis
- Source: Adapted from Northup et al 2013.
Criteria
- Definitive diagnosis:
- 2 major criteria OR
- 1 major + 2 minor
- Possible diagnosis
- 1 major only OR
- 2 minor
Major Features | Minor Features |
Hypomelanotic macules | "Confetti" skin lesions |
Angiofibromas or fibrous cephalic plaque | Dental enamel pits |
Ungual fibromas | Intraoral fibromas |
Shagreen patch | Retinal achromic patch |
Multiple retinal hamartomas | Multiple renal cysts |
Cortical dysplasias | Nonrenal hamartomas |
Subependymal nodules | ㅤ |
Subependymal giant cell astrocytoma | ㅤ |
Cardiac rhabdomyoma | ㅤ |
Lymphangiomyomatosis | ㅤ |
Angiomyolipomas | ㅤ |
Major criteria
- ≥3 hypomelanotic macules≥ 5mm diameter (Ash-leaf hypopigmented macules)
- ≥3 angiofibromas or fibrous cephalic plaque
- Facial rash that appears as a spread of small pink or red spots across the cheeks and nose in a butterfly distribution
- Usually appear between 3-10 years of age and increase in size and number until adolescence
- Also found around the nails, scalp and forehead
- Previously incorrectly called adenoma sebaceum
- ≥2 ungual fibroma
- Smooth, firm, flesh-coloured lumps that emerge from the nail folds
- Periungual sites (around the nail) are more common than subungual sites (under the nail)
- More common on feet than hands
- A longitudinal groove in the nail may occur without visible fibroma
- Short red streaks (splinter haemorrhage) or white streaks (leukonychia) on affected nails
- ≥2 angiomyolipomas
- Shagreen patch
- Flesh coloured orange-peel connective tissue naevi of varying sizes, usually on the lower back
- Multiple retinal hamartomas
- Retinal hamartomas occur in ≈ 50% (central calcified hamartoma near the optic disc or a more subtle peripheral flat salmon-colored lesion).
- Cortical dysplasias: Consist of
- Tubers
- Collection of abnormal neurons and glia
- Located in the cortex
- Pathognomonic for TSC
- Stable throughout life
- Associated with seizure and autistic spectrum disorder
- Present in 80 to 100% patients with TSC
- Infratentorial in 25% cases
- Cerebral white matter radial migration lines
- Subependymal nodules (“tubers”)
- Benign hamartomas that are almost always calcified
- Protrude into the ventricles.
- Intraventricular calcified protrusions (lateral ventricles)
- Small
- Asymptomatic
- Seen in > 90% of patients with TSC
- Subependymal giant cell astrocytoma (SEGA)
- A WHO grade I benign neoplasm
- Almost always located at the foramen of Monro.
- Occurs in 2-26% of patients with TSC.
- Glioneural origin
- Major cause of TSC-related morbidity and mortality
- HCP
- Size >10 mm
- Foramen or Monro, sometimes bilateral
- Cardiac rhabdomyoma
- Hamartomatous lesion consisting of cardiac muscle tissue (derived from embryonal myoblasts).
- Lymphangioleiomyomatosis
- Abnormal growth of smooth muscle cells in the lung vasculature, lymphatics, and alveoli that leads to the formation of multiple cysts in the lungs bilaterally and respiratory symptoms, such as dyspnea on exertion.
Minor criteria
- Hypomelanotic lesions that cluster and appear reticulated.
- Multiple renal cysts
- TSC2 gene is contiguous with PKD1 gene causing Polycystic kidney disease
- Nonrenal hamartomas
- Has large Variability of phenotype and age of onset
- Infant
- The earliest finding is of “ash leaf” macules (hypomelanotic, leaf shaped) that are best seen with a Wood’s lamp.
- 3 or more white spots at birth suggests the diagnosis of tuberous sclerosis
- Infantile myoclonus may also occur.
- Older children or adults
- Myoclonus is often replaced by generalised tonic-clonic or partial complex seizures, which occur in 70–80%.
- Facial adenomas
- Not present at birth, but appear in >90% by age 4 yrs
- These are not really adenomas of the sebaceous glands, but are small hamartomas of cutaneous nerve elements that are yellowish-brown and glistening and tend to arise in a butterfly malar distribution, usually sparing the upper lip)
- A distinctive depigmented iris lesion may also occur.
- CNS symptoms
- Intractable epilepsy including infantile spasms (80-90%)
- Cognitive impairment (50%)
- Autism spectrum disorder (40%)
- Neurobehavioural disorders ( > 60%)
Evaluation
Plain skull X-rays
- May show calcified cerebral nodules.
CT scan
- Intracerebral calcifications
- Most common (97%)
- Characteristic finding
- Localization
- Subependymally along the lateral walls of the lateral ventricles
- Near the foramina of Monro.
- Low density lesions that do not enhance
- Seen in 61%.
- Represent heterotopic tissue or defective myelination.
- Most common in occipital lobe.
- Hydrocephalus (HCP)
- May occur even without obstruction
- In the absence of tumor, HCP is usually mild.
- Moderate HCP usually occurs only in the presence of tumor.
- Subependymal nodules
- Usually calcified
- Protrude into the ventricle (“candle guttering” described the appearance on pneumoencephalography).
- Paraventricular tumors (SEGAs) are essentially the only enhancing lesions in TSC.
- 1st image showing calcified subependymal nodules and images 2nd and 3rd show cortical tubers that are calcified
Feature | SEGAs | Tubers |
Location | Near the foramen of Munro | Cortical or subcortical |
Growth | Progressive growth over time | Do not typically grow after early childhood |
Imaging | Enhance intensely with contrast on MRI; usually larger than 1 cm | Do not enhance with contrast; high T2 and low T1 signal on MRI |
Clinical Presentation | Symptoms related to increased intracranial pressure (e.g., headaches, nausea, vomiting) | Seizures, developmental delays |
MRI
Cortical/Subependymal tubers are high on T2 and low on T1 and only ≈ 10% enhance.
- Low signal in subependymal lesions may represent calcification.
- Fq calcifies after 2 yrs (forming subependymal nodules
- Subependymal nodule
- Seen to be calcified on CT is visible (red arrow) on FLAIR and T2 as a region of low signal.
- Best seen on FLAIR are radial glial bands (yellow arrows) and cortical / subcortical tubers (green arrows).
T2
Flair
SEGA
- Enhance intensely (enhancing subependymal lesions are almost always SEGAs).
- Radial bands sign: abnormal signal intensity extending in a radial manner, representing cells of varying degrees of neuronal and astrocytic differentiation as well as difficult-to-classify cells.
Images
Treatment
- Paraventricular tumors should be followed.
- Tubers grow minimally, but
- SEGA progress should be removed if they are symptomatic.
- A transcallosal approach or ventriculoscopic removal are options.
- Infantile myoclonus may respond to steroids.
- Better seizure control, not cure, is the goal in TSC.
- Seizures are treated with AEDs.
- Surgery for intractable seizures may be considered when a particular lesion is identified as a seizure focus.
- VNS
- Everolimus
- Patients ≥3 years of age with increasing size of SEGA lesions have shown sustained reduction of SEGA volume on mTOR inhibitor.
- Off license use to control seizure
- EXIT trial for treatment
- Can use Rapamacin to treatment it but if you stop it can regrow
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