Tuberous Sclerosis

Synonyms: Bourneville disease; Bourneville Pringle Syndrome; Pringle's disease; Epiloia; Tuberous Sclerosis Complex; Tuberose sclerosis

Tuberous sclerosis is a multi-system disorder. It is characterised by the formation of hamartomas in many organs, commonly the brain, skin and kidneys, which account for many of the clinical symptoms. The eyes, heart and lungs are also often involved. It can present at any age but commonly presents in childhood. It may be detected antenatally in some cases. It classically presents with skin changes and epilepsy (usually as a result of cortical tubers) before the age of 5 years but the disease can remain latent until adulthood.¹ However, a broad range of clinical symptoms can occur because of variable expressivity.²

• Affects 1 in 5000 to 1 in 10,000 newborns.³
• Approximately 2 million people have tuberous sclerosis worldwide.²

• Tuberous sclerosis is caused by mutations in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16.^3,4
• These are tumour suppressor genes. TSC1 facilitates the production of a protein called hamartin, and TSC2, the protein tuberin. These proteins are thought to have a role in the growth and differentiation of cells and, if their production is affected, may contribute to the formation of the hamartomas.²
• These mutations may be inherited in an autosomal dominant fashion but 60-70% of mutations are sporadic.³

Tuberous sclerosis has a wide spectrum of presentation. Some individuals are severely affected, while others have very few features, or may even have subclinical disease. It typically presents shortly after birth. The clinical features can include:

Epilepsy and neurological problems

• Epilepsy: affects 65% and often starts with infantile spasms.³ It usually occurs secondary to tuber formation in the brain. Complex partial and tonic-clonic seizures can also occur.² Sub-ependymal giant cell astrocytoma (SEGA): 5% of patients with tuberous sclerosis develop a sub-ependymal giant cell astrocytoma (or tumour). These can grow and can lead to hydrocephalus (due to their location at the foramen of Munro).⁵ They can present with headache, vomiting, deterioration in seizure control and focal neurological signs.³
• Subependymal nodules (SEN): can also occur. They are small lesions found in the lining of the ventricles. They do not enlarge and do not cause hydrocephalus.

Skin lesions

About 90% of patients have skin changes.¹ Pictures of some of the lesions are available using the Dermis internet link in the internet and further reading section below.

• Ash leaf macules: areas of depigmentation that may develop during infancy (may be present at birth). They are usually multiple and are found on the trunk. They can be seen more easily using a Wood's lamp. Examine a child with infantile spasms for these. May be found in 8 per 1000 'normal' newborns.¹
• Adenoma sebaceum (facial angiofibromas): small, reddish nodules may appear on the cheeks and nose beginning around age four. These lesions eventually enlarge, coalesce, and produce the characteristic adenoma sebaceum appearance. Diagnostic of tuberous sclerosis.
• Shagreen patch: can occur over the sacrum and back (appear as irregular, thickened skin with orange-peel or leathery texture).²
• Forehead plaques: raised, firm, red and usually pigmented skin lesions.¹
• Café au lait spots: not a diagnostic sign.
• Ungual fibromas: smooth, firm, flesh-coloured growths adjacent to, or arising from underneath the nails. Seen in 15-20%. Usually characteristic of tuberous sclerosis but a single lesion can occasionally occur due to trauma.¹
• Poliosis: a localised patch of white hair that can affect the scalp hair or the eyelids occurs in 60%.¹
• Skin tags: multiple skin tags can occur in the axillae, groins, around the head and neck.
• Confetti lesions: these are a cluster of hypomelanotic lesions that have a reticulated appearance. They can develop anywhere on the skin.²

Renal involvement

• Renal angiomyolipoma (AML): occurs in 60-80% of those with tuberous sclerosis.⁶ May be multiple. They are benign hamartomas of the kidney. Usually asymptomatic in childhood. In adults, they can rupture leading to intraperitoneal or intrarenal/ureteric haemorrhage. This can present as haematuria, abdominal pain and hypovolaemia. Obstruction can occur as they enlarge and renal failure can occur as normal renal tissue is replaced by tumour.
• Polycystic kidney disease: 20% of people with tuberous sclerosis have single or multiple simple renal cysts but around 5% have polycystic kidney disease.⁶
• Renal cell carcinoma: affects < 1% of people with tuberose sclerosis. Can be bilateral and usually presents at younger age. Tends to be slow growing.³

Pulmonary involvement

• Pulmonary lymphangioleiomyomatosis (LAM): tends to affect females (up to 40%), usually presents in adulthood, rare in men and children.⁷ Most patients do not have symptoms. In 1-3% of patients, it can lead to progressive deterioration in respiratory function with changes similar to emphysema. Pneumothoraces can occur.
• Multifocal micronodular pneumocyte hyperplasia (MMPH): occurs in 50% of patients. Affects men and women. Appears as multiple nodules on chest X-ray or CT. Doesn't usually cause symptoms and tends to be an incidental finding. Management is by observation.

Developmental and behavioural problems³

• 40-60% of people with tuberous sclerosis have general developmental delay. It is more likely in those who develop infantile spasms and whose epilepsy is difficult to control.
• There may be associated behavioural and psychological problems, however, these can also occur independently of any learning difficulty.
• Around 25% of those with tuberous sclerosis are diagnosed with autism.
• Disruptive behaviour with hyperactivity ± attention deficit occurs in 50-60%.
• Aggressive behaviour and self-injury may also be present.
• Sleep disturbances and schizophrenia can also occur.²

Cardiac involvement

• Cardiac rhabdomyomas: these are seen in the majority of young children with tuberous sclerosis. Most spontaneously regress with no clinical consequence. However, during puberty, they may enlarge or appear de novo. Therefore, this group should be observed for potential clinical signs (heart failure, arrhythmias, heart murmurs) and monitored using echocardiography.⁸ Cardiac rhabdomyomas may be the first sign of tuberous sclerosis in young children and may be detected antenatally.

Other features

• Hepatic angiomyolipomas can also occur, particularly if there are bilateral renal angiomyolipomas.⁹
• Cyst-like areas can occur within the skeleton, especially the phalanges in the hands and feet. Sclerotic lesions can develop in the pelvis or spine.²
• Pitting of the dental enamel is common.²
• Retinal hamartomas or astrocytomas can also occur but they rarely cause visual symptoms (causes an abnormal red reflex).²

Diagnosis is usually clinical, based on examination and some of the investigations detailed below. Family history should also be determined. It is based on major and minor features:²

• Definite tuberous sclerosis is diagnosed by either 2 major features or 1 major feature and 2 minor features.
• Probable tuberous sclerosis is suggested by 1 major feature and 1 minor feature.
• Possible tuberous sclerosis is either 1 major feature or 2 minor features.

Major features

• Facial angiofibromas or forehead plaque
• Non-traumatic ungual or periungual fibromas
• At least 3 hypomelanotic macules (ash leaf spots)
• Shagreen patch (connective tissue naevus)
• Cortical tuber
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma, single or multiple
• Lymphangiomyomatosis and/or renal angiomyolipoma
• Retinal hamartoma

Minor features

• Multiple randomly distributed pits in dental enamel
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white matter radial migration lines
• Gingival fibromas
• Non-renal hamartoma
• Retinal achromic patch
• Confetti skin lesions
• Multiple renal cysts
• Skin tags
• Positive family history in first degree relative

• Fundoscopy should be performed to look for retinal lesions.
• Examination of the skin with Wood's UV light (shows hypopigmented patches)
• Brain CT or MRI is performed in all patients to look for cortical tubers, SENs and SEGAs. Urgent MRI is needed if sub-ependymal giant cell astrocytoma is suspected. Calcified subependymal nodules do not tend to be enlarging.³ Repeat scanning is carried out at intervals.
• EEG is useful when there is epilepsy but not required without it.
• Renal ultrasound should be carried out as renal tumours are common.
• ECG is used to detect cardiac arrhythmias. Wolff-Parkinson-White syndrome is the commonest arrhythmia in this condition.
• Echocardiography can detect cardiac rhabdomyoma.
• Spirometry, chest X-ray and high resolution CT are needed if respiratory symptoms are present and pulmonary lymphangioleiomyomatosis is suspected.

• A multidisciplinary approach is required to this multi-system disease.
• Attention to schooling and behavioural disorders will be required along with developmental, psychological and behavioural assessment. A statement of special educational need may be required. Guidelines for the assessment of cognitive and behavioural problems in tuberous sclerosis have been drawn up after a consensus workshop in 2003 and are endorsed by the Tuberous Sclerosis Association in the UK and the TSAlliance in the USA.¹⁰
• The needs of the whole family need to be considered.
• Social support, including advice about benefits and disability living allowance should be considered.

Medical management

• Drugs may be required for specific problems like management of epilepsy. However, some anti-epileptic drugs may exacerbate the behaviour problems associated with tuberous sclerosis.³
• Some patients with LAM benefit from the use of beta 2 agonist inhalers such as salbutamol.⁷
• Chest drain insertion may be needed in a pneumothorax.
• Hormone treatments such as progesterone, buserelin and tamoxifen have been trialled in LAM and may be helpful in some people.⁷
• Antihypertensives may be needed in renal disease.

Surgical treatment/other interventions

• Facial angiofibromas respond to laser treatment.
• Either laser, diathermy, cryotherapy or surgery can remove ungual fibromas but they tend to recur.
• Skin tags can be removed using cryotherapy.
• Fibrous plaques and shagreen patches can be treated with laser ± plastic surgery.
• Surgical excision is needed if a sub-ependymal giant cell astrocytoma or a renal cell carcinoma is diagnosed.
• Arterial embolisation or renal sparing surgery may be needed if there is a bleeding renal angiomyolipoma.³
• Surgery may also be considered in difficult to control epilepsy.¹¹
• Lung transplantation is a possibility in patients with severe LAM.⁷

This should take place at least annually, or more frequently if problems are encountered.³Assessment and investigation should look for any problems relating to:

• Epilepsy
• Neurological problems
• Cardiac symptoms
• Skin lesions
• Renal complications: blood pressure, renal function, haemoglobin, urine dipstick for blood and protein, regular ultrasound imaging⁶
• Pulmonary complications
• Developmental and psychological problems

• Because of the wide clinical spectrum in tuberous sclerosis, some patients have no decrease in life expectancy or quality of life.²
• The most common cause of death is status epilepticus or bronchopneumonia. Renal failure is another common cause.²
• Epilepsy can be difficult to control and can contribute to developmental delay. Functional outcome is improved when seizures are controlled at an early age.^11,12
• The prognosis of sub-ependymal giant cell tumour is excellent. They should be monitored clinically and radiologically and removed if they are growing or causing symptoms.⁵ If significant hydrocephalus develops, they can lead to neurological sequelae and blindness.²
• Developmental delay, autism or pervasive developmental disorder are common, as are behavioural disorders.
• Cardiac rhabdomyomas do not usually cause death.

A child of someone with tuberous sclerosis has a 50% chance of inheriting the disease.²Patients, parents and family members who are considering having children should be referred to a clinical geneticist.

• Tuberous sclerosis is usually a clinical diagnosis and family members are normally screened clinically. Genetic testing is very expensive and may not be widely available.
• Brain MRI can be carried out if clinical examination is negative.
• Renal ultrasound may also be carried out as renal lesions occur in up to 80% of patients.
• Echocardiography is not usually required in adults as cardiac rhabdomyomas tend to disappear by adulthood.
• Fundoscopy can also be carried out to look for retinal lesions.

Trials are underway looking at drugs such as rapamycin with the hope that they will slow down the growth of the hamartomas responsible for the features of the disease. The theory is that such drugs will help to regulate cell growth in place of the proteins that are normally produced by the genes TSC1 and TSC2 which are faulty in tuberous sclerosis.¹³ Prenatal testing may also be available in the future.²