Synonyms: Bourneville's disease; Bourneville-Pringle disease; Pringle's disease; epiloia; tuberous sclerosis complex; tuberose sclerosis

Tuberous sclerosis is a multisystem 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.

Epidemiology

• It affects 1 in 5,000 to 1 in 10,000 newborns.¹
• Approximately 2 million people have tuberous sclerosis worldwide.²

Genetics

Tuberous sclerosis is caused by mutations in either the TSC1 gene on chromosome 9, or the TSC2 gene on chromosome 16.^1,3 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
The mutations may be inherited in an autosomal dominant fashion but 60-70% of mutations are sporadic.¹

Presentation

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.⁴ Some individuals are severely affected, while others have very few features, or may even have subclinical disease because of variable expressivity.²

Epilepsy and neurological problems

• Epilepsy affects 65% and often starts with infantile spasms.¹ It usually occurs secondary to tuber formation in the brain. Complex partial and tonic-clonic seizures can also occur.²
• Subependymal giant cell astrocytoma (SEGA) may develop in 5% of patients with tuberous sclerosis. 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.¹
• Subependymal nodules (SENs) 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.⁴ Pictures of the lesions are available in the 'Internet and further reading' section, below.

• Ash leaf macules are areas of depigmentation that may develop during infancy (they 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 1,000 'normal' newborns.⁴
• Adenoma sebaceum (facial angiofibromas) are small, reddish nodules that 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 patches can occur over the sacrum and back (they appear as irregular, thickened skin with orange-peel or leathery texture).²
• Forehead plaques are raised, firm, red and usually pigmented skin lesions.⁴
• Ungual fibromas are smooth, firm, flesh-coloured growths adjacent to, or arising from underneath, the nails. They are seen in 15-20%. Usually they are characteristic of tuberous sclerosis but a single lesion can occasionally occur due to trauma.⁴
• Poliosis is a localised patch of white hair that can affect the scalp hair or the eyelids and occurs in 60%.⁴
• Skin tags can occur in the axillae, groins, and around the head and neck.
• Confetti lesions 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 They may be multiple. They are benign hamartomas of the kidney. Usually, they are 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 is found in around 5% of patients with tuberous sclerosis. 20% of people with tuberous sclerosis have single or multiple simple renal cysts.⁶
• Renal cell carcinoma affects <1% of people with tuberose sclerosis. It can be bilateral and usually presents at a younger age. It tends to be slow-growing.¹

Pulmonary involvement

• Pulmonary lymphangioleiomyomatosis (LAM) tends to affect females (up to 40%). It usually presents in adulthood and is 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. It affects men and women. It appears as multiple nodules on CXR or CT scan. It doesn't usually cause symptoms and tends to be an incidental finding. Management is by observation.

Developmental and behavioural problems¹

• 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 are seen in the majority of young children with tuberous sclerosis. They may be the first sign of tuberous sclerosis in young children and may be detected antenatally. 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

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

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 features¹⁰

• Facial angiofibromas or forehead plaque.
• Nontraumatic ungual or periungual fibromas.
• At least 3 hypomelanotic macules (ash leaf spots).
• Shagreen patch (connective tissue naevus).
• Cortical tuber.
• Subependymal nodule (SEN).
• Subependymal giant cell astrocytoma (SEGA).
• 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 a first-degree relative.

Investigations

• Fundoscopy should be performed to look for retinal lesions.
• Examination of the skin with Wood's ultraviolet (UV) light (shows hypopigmented patches).
• Brain CT or MRI scanning is performed in all patients to look for cortical tubers, subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs). Urgent MRI is needed if SEGA is suspected. Calcified subependymal nodules do not tend to be enlarging.¹ Repeat scanning is carried out at intervals.
• Electroencephalography (EEG) is useful when there is epilepsy but not required without it.
• Renal ultrasound should be carried out as renal tumours are common.¹⁰
• Electrocardiogram (ECG) is used to detect cardiac arrhythmias. Wolff-Parkinson-White syndrome is the most common arrhythmia in this condition.
• Echocardiography can detect cardiac rhabdomyoma.
• Spirometry, CXR and high-resolution CT scanning are needed if respiratory symptoms are present and pulmonary lymphangioleiomyomatosis is suspected.

Management

• A multidisciplinary approach is required to this multisystem 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 TS Alliance in the USA.¹¹
• The needs of the whole family should be considered.
• Social support, including advice about benefits and disability living allowance, should be available.

Medical

• Drugs may be required for specific problems like management of epilepsy. However, some anti-epileptic drugs may exacerbate the behavioural problems associated with tuberous sclerosis.¹
• Some patients with lymphangioleiomyomatosis (LAM) benefit from the use of beta₂ 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

• 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 subependymal giant cell astrocytoma (SEGA) or a renal cell carcinoma is diagnosed.
• Arterial embolisation or renal sparing surgery may be needed if there is a bleeding renal angiomyolipoma.¹
• Surgery may also be considered in difficult to control epilepsy.¹²
• Lung transplantation is a possibility in patients with severe LAM.⁷

Follow-up

This should take place at least annually, or more frequently if problems are encountered.¹Assessment 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 imaging.⁶
• Pulmonary complications.
• Developmental and psychological problems.

Prognosis

Because of the wide clinical spectrum, 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.^12,13
• If significant hydrocephalus develops, this can lead to neurological sequelae and blindness.²

The prognosis of subependymal giant cell tumour is excellent. This should be monitored clinically and radiologically and removed if growing or causing symptoms.⁵

Genetic counselling and screening

A child of someone with tuberous sclerosis has a 50% chance of inheriting the disease.²
Patients, 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.

The future

Trials are looking at drugs (e.g. rapamycin) that may slow down the growth of the hamartomas responsible for the features of the disease. In theory these 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.¹⁴
Prenatal testing may also become available.²

Document references

1. Clinical guidelines for the care of patients with Tuberous Sclerosis Complex, Tuberous Sclerosis Association (2002); (summary)
2. Schwartz RA et al; Tuberous Sclerosis, eMedicine, Mar 2010
3. Tuberous Sclerosis, Online Mendelian Inheritance in Man (OMIM)
4. Stables G, Sheehan-Dare; The Dermatological Features of Tuberous Sclerosis and their Treatment. Fact-Sheet No. 25 of the Tuberous Sclerosis Association, 2000
5. Crimmins D; Subependymal Giant Cell Tumours in Tuberous Sclerosis Complex. Tuberous Sclerosis Association Fact Sheet 26, 2006
6. Kingswood JC; Monitoring kidney problems in tuberous sclerosis. Fact-sheet No.24 of the Tuberous Sclerosis Association, 2001
7. Johnson S, Tattersfield A; Lung Problems in Tuberous Sclerosis Complex. Tuberous Sclerosis Association Fact Sheet 41, 2003
8. Jozwiak S, Kotulska K, Kasprzyk-Obara J, et al; Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics. 2006 Oct;118(4):e1146-51. Epub 2006 Aug 28. [abstract]
9. Fricke BL, Donnelly LF, Casper KA, et al; Frequency and imaging appearance of hepatic angiomyolipomas in pediatric and adult patients with tuberous sclerosis. AJR Am J Roentgenol. 2004 Apr;182(4):1027-30. [abstract]
10. Curatolo P, Bombardieri R, Jozwiak S; Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. [abstract]
11. Guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis, Tuberous Sclerosis Association (2003); (assessments needed in TSC, when to do them, and recommended tests)
12. Weiner HL, Carlson C, Ridgway EB, et al; Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics. 2006 May;117(5):1494-502. [abstract]
13. Jansen FE, Vincken KL, Algra A, et al; Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology. 2008 Mar 18;70(12):916-23. Epub 2007 Nov 21. [abstract]
14. Paghdal KV, Schwartz RA; Sirolimus (rapamycin): from the soil of Easter Island to a bright future. J Am Acad Dermatol. 2007 Dec;57(6):1046-50. Epub 2007 Jun 21. [abstract]

Internet and further reading

• Tuberous Sclerosis, DermIS (Dermatology Information System)