Tuberous Sclerosis

Diagnosis. 1

Clinical manifestations. 1

Management and screening. 1

Definition

Progressive, genetic disease characterised by:

• Hypopigmented macules of the skin

• Migrational errors of the brain

• Seizures

• Cognitive impairment

• Hamartomas of multiple organ systems including – skin, kidney, brain, lung, heart

Epidemiology

• 1/6800 to 1/17300

• Onset in infancy

• Autosomal dominant, M=F

• High spontaneous mutation rate, 40% familial, 60% sporadic

Aetiology

• Inactivation of either:

o TSC1 gene on chromosome 9q – encoding hamartin

o TSC2 gene on chromosome 16p – encoding tuberin

• Both protein part of a complex that is an important negative regular of mTOR pathway

• Mosaicism can occur

Diagnosis

• Genetic testing can identify mutations in 85-90% of patients

Cerebral imaging

CT

• Cortical tubers – Hypodense to isointense

o Calcification in most with age.

• SEN – calcification

• SEGA - Mixed density with moderate enhancement in most.

MRI

• Cortical tubers

o Adults – isointense to cortex on T1 (unless calcification), outer margin may be hyperintense and subcortical component hypointense

- Mixed signal on T2, deeper component more hyperintense

- Occasional contrast enhancement (3-5%)

• Subependymal nodules

o Small nodules protruding from the wall of lateral ventricles

o Change with age – in adults isointense with white matter

o Most calcify – seen on SWI, hypointense on T2

o Contrast enhancement variable, 50% show significant enhancement (does not indicate malignancy)

o Growth (>20%) on subsequent scans may indicate SEGA

• White matter lesions

o 100% of patients

o Streaky linear or wedge shaped lesions (T2 hyperintense in adults) along radial bands from the ventricles to the under surface of cortical tubers

o Small round syst-like lesions in 50% of patients – resemble CSF

• SEGA

o Most found around the foramen of Munro

o Mixed intensity on T1 and T2

o Nearly all enhance strongly

o Rarely invade brain

o Look for associated hydrocephalus

• Other

o Cerebellar tubers

Clinical criteria:

Clinical manifestations

Neurological

Symptoms

• Intellectual disability

• Epilepsy(80-90%)

o Most onset in first year of life

o Most common cause of infantile spasms

o Treated with vigabatrin and ACTH

• Behavioural abnormalities

o Autism 25-50%

• Spectrum from mild/no symptoms to severe

Pathology

• Cortical/subcortical tubers

• White matter abnormalities

• Subependymal hamartomas (SEN)

o Grow over time, usually only into adolescence – then calcify

• Subependymal giant cell astrocytoma (SEGA)

o Transform from SEN

o 6-14% of patients

o Usually benign but locally invasive

Renal

• Renal angiomyolipomas (75%)

o Most present by 10 years of age

• Renal cysts (20%)

Cardiac

• Rhabdomyomas (30-50%)

o Rarely symptomatic

- Can obstruct valves or disrupt conduction system

o Tend to regress after infancy

Dermatological

• Hypomelanotic macules (61-97%)

o A few mm up to several cm

o Oval, ‘ash-leaf’ shape

• Angiofibromas

o Adenoma sebaceum – small, red-pink skin lesions in butterfly pattern on the face, onset mid-late childhood in 70%

o Fibrous plaques

• Shagreen patches – thick, flesh coloured macules in the lumbosacral region

• Ungual fibromas and angiofibroma’s of the nailbed.

Pulmonary

• Lymphangiomyomatosis (LAM) - (24-49% of adult females)

o Onset ~30-35years, progressive

o Normal structure of the lungs replaced by multiple cysts

o Exacerbated by oestrogen

o Significant cause of mortality

Visual

• Retinal hamartoma (40-50%)

• May impair vision – most asymptomatic

Management and screening

mTOR inhibitors

• Everolimus and sirolimus

• (In Australia Everolimus is PBS subsidised for SEGA or visceral tumours)

• Demonstrated to reduce progression of disease in a number of organs

Screening and treatment considerations

	Screening	Treatment comments
Brain	Asymptomatic patients <25yrs – MRI brain to monitor for SEGA – 1-3 years Known large or growing SEGA – MRI brain – frequency is dependent on specific circumstances Infants up to 24 months - regular EEG’s (even in asymptomatic) to detect early seizures. Patients >24 months - Consider EEG if clinical or behavioural change Perform screening of TSC associated neuropsychiatric disorders (e.g. Autism, ADHD, Anxiety, Depression)	mTOR inhibitors can be considered for enlarging or symptomatic SEGA Surgery or VP shunting for large SEGA Seizures may respond particularly well to vigabatrin
Renal	MRI of abdomen every 1-3 years - to assess for progression of angiomyolipoma and renal cystic disease Renal function - Annual	Large (>4cm) lesions may need treatment (surgery or ablation). mTOR inhibitors may also help shrink renal lesions.
Respiratory	Females - Baseline HRCT chest in all females at age 18 then every 5 years to menopause if asymptomatic (more often if symptomatic or known lung disease) Male – At age 18 years if symptomatic then only need repeat testing if known lung disease or new symptoms Respiratory function tests in any patient with changes on imaging or symptoms. VEGF levels can be measured to monitor progress in affected patients.	Avoid oestrogen exposure (note risk with pregnancy) mTOR inhibitors can be considered for symptomatic disease
Heart	Echo every 1-3 years in asymptomatic paediatric patients or until regression of cardiac rhabdomyomas Frequency/necessity of Echo monitoring unclear in adults (probably only if symptomatic or ECG abnormality) Consider ECG ever 3-5 years in asymptomatic patients	Cardiac lesions rarely require intervention and usually spontaneously regress.
Skin	Annual skin check	Angiofibroma will respond to mTOR inhibitors (generally cosmetic treatment) Avoid sun exposure which worsens lesions.
Dental	Annual dental check (jaw/oral fibromas)
Eye	Annual ophthalmic examination in childhood. ?Frequency in adulthood