Tuberous sclerosis

Not to be confused with tuberculosis.
Tuberous sclerosis complex
Tuberous sclerosis complex (TSC),
Bourneville disease

A case of tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern
Classification and external resources
Specialty neurology, medical genetics
ICD-10 Q85.1
ICD-9-CM 759.5
OMIM 613254 191100; 613254
DiseasesDB 13433
MedlinePlus 000787
eMedicine neuro/386 derm/438 ped/2796 radio/723
Patient UK Tuberous sclerosis
MeSH D014402
Orphanet 805

Tuberous sclerosis is a rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. Tuberous sclerosis is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.[1]

The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm, and pale gyri, called "tubers", in the brains of patients post mortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville's disease (English /bɔərnˈvl/) or Bourneville–Pringle disease (after Bourneville and John James Pringle).

Signs and symptoms

The physical manifestations of tuberous sclerosis are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules), and very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizures, intellectual disability, developmental delay, and behavioral problems. Symptoms also include trouble in school and concentration problems.

Central nervous system

Tuberous sclerosis in MRI

About 50% of people with tuberous sclerosis have learning difficulties ranging from mild to significant,[2] and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism, with an even higher proportion showing features of a broader pervasive developmental disorder.[3] A 2008 study reported self-injurious behavior in 10% of people with tuberous sclerosis.[4] Other behaviors and disabilities, such as ADHD, aggression, behavioral outbursts, and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.

Three types of brain tumours may be associated with tuberous sclerosis:

Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.[5]

The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. On magnetic resonance imaging, tuberous sclerosis patients can exhibit other signs consistent with abnormal neuron migration such as radial white matter tracts hyperintense on T2WI and heterotopic gray matter.

Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. Interposed neural tissue is not present. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma, which typically develops in the region of the foramen of Monro, in which case it is at risk of developing an obstructive hydrocephalus.

A variable degree of ventricular enlargement is seen, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monro) or idiopathic in nature.


Computed tomography showing multiple angiomyolipomas of the kidney in a patient with lung lymphangioleiomyomatosis on CT: suspected tuberous sclerosis

Between 60 and 80% of tuberous sclerosis patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called angiomyolipomas (AML) frequently causing hematuria. These tumors are composed of vascular (angio–), smooth muscle (–myo–), and fat (–lip-) tissue. Although benign, an angiomyolipoma larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Angiomyolipomas are found in about one in 300 people without tuberous sclerosis. However, those are usually solitary, whereas in tuberous sclerosis they are commonly multiple and bilateral.

About 20-30% of people with tuberous sclerosis have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease.

Very rare (< 1%) problems include renal cell carcinoma and oncocytomas (benign adenomatous hamartoma).


Patients with tuberous sclerosis can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called lymphangioleiomyomatosis (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in tuberous sclerosis-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of tuberous sclerosis-related lymphangioleiomyomatosis recurring following lung transplant have been reported.[6]


Rhabdomyomas are benign tumors of striated muscle. A cardiac rhabdomyoma can be discovered using echocardiography in around 50% of people with tuberous sclerosis. However, the incidence in the newborn may be as high as 90% and in adults as low as 20%. These tumors grow during the second half of pregnancy and regress after birth. Many disappear entirely; alternatively, the tumor size remains constant as the heart grows, which has much the same effect.

Problems due to rhabdomyomas include obstruction, arrhythmia, and a murmur. Such complications occur almost exclusively during pregnancy or within the child's first year. Prenatal ultrasound, performed by an obstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. This rare tumour is a strong indicator of tuberous sclerosis in the child, especially if a family history of tuberous sclerosis exists.


Some form of dermatological sign is present in 96% of individuals with tuberous sclerosis. Most cause no problems, but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:


Retinal lesions, called astrocytic hamartomas (or "phakomas"), which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. Astrocytic hamartomas can calcify, and they are in the differential diagnosis of a calcified globe mass on a CT scan.

Nonretinal lesions associated with tuberous sclerosis include:


Pancreatic neuroendocrine tumours have been described in rare cases of tuberous sclerosis.[7]


Individuals with tuberous sclerosis may experience none or all of the clinical signs discussed above. The following table shows the prevalence of some of the clinical signs in individuals diagnosed with tuberous sclerosis.

The frequency of signs in children with tuberous sclerosis, grouped by age[8]


Tuberous sclerosis is inherited in an autosomal dominant fashion.

Tuberous sclerosis is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and complete penetrance.[9] Two-thirds of tuberous sclerosis cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease. So far, it has been mapped to two genetic loci, TSC1 and TSC2.

TSC1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997.[10] TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993.[11] TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with tuberous sclerosis who also develop polycystic kidney disease in childhood.[12] TSC2 has been associated with a more severe form of tuberous sclerosis.[13] However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of tuberous sclerosis caused by TSC2 range from 55% to 90%.[14]

TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its 100% penetrance, tuberous sclerosis has wide expressivity.

Symbol TSC1
Entrez 7248
HUGO 12362
OMIM 605284
RefSeq NM_000368
UniProt Q92574
Other data
Locus Chr. 9 q34
Symbol TSC2
Entrez 7249
HUGO 12363
OMIM 191092
RefSeq NM_000548
UniProt P49815
Other data
Locus Chr. 16 p13.3


Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. (The complex appears to interact with RHEB GTPase, thus sequestering it from activating mTOR signalling, part of the growth factor (insulin) signalling pathway.) Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors. Tuberous sclerosis affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.

Molecular genetic studies have defined at least two loci for tuberous sclerosis. In TSC1, the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. No missense mutations occur in TSC1. In TSC2, the gene abnormalities are on chromosome 16p13. This gene encodes tuberin, a guanosine triphosphatase–activating protein. The specific function of this protein is unknown. In TSC2, all types of mutations have been reported; new mutations occur frequently. Few differences have yet been observed in the clinical phenotypes of patients with mutation of one gene or the other.


No pathognomonic clinical signs for tuberous sclerosis complex are seen. Many signs are present in individuals who are healthy (although rarely), or who have another disease. In order to meet diagnostic criteria for tuberous sclerosis complex, an individual must either have: 1) Two or more major criteria; or 2) One major criterion along with two or more minor criteria.

Diagnostic Criteria for Tuberous Sclerosis Complex[15]
Major Criteria
Location Sign Onset[16] Note
1 Head Facial angiofibromas or fibrous cephalic plaque Infant – adult At least three
2 Fingers and toes Nontraumatic ungual or periungual fibroma Adolescent – adult At least two
3 Skin Hypomelanotic macules Infant – child At least three, at least 5 mm in diameter.
4 Skin Shagreen patch (connective tissue nevus) Child
5 Brain Cortical dysplasias (includes tubers and cerebral white matter radial migration lines) Fetus
6 Brain Subependymal nodule Child – adolescent
7 Brain Subependymal giant cell astrocytoma Child – adolescent
8 Eyes Multiple retinal nodular hamartomas Infant
9 Heart Cardiac rhabdomyoma Fetus Single or multiple.
10 Lungs Lymphangioleiomyomatosis Adolescent – adult
11 Kidneys Renal angiomyolipoma Child – adult At least two. Together, 10 and 11 count as one major feature.
Minor Criteria
Location Sign Note
12 Teeth At least three randomly distributed pits in dental enamel
13 Skin "Confetti" skin lesions, 1–2 mm hypomelanotic papules
14 Gums Intraoral fibromas
15 Liver, spleen and other organs Nonrenal hamartoma Histologic confirmation is suggested.
16 Eyes Retinal achromic patch
17 Kidneys Multiple renal cysts Histologic confirmation is suggested.


In infants, the first clue is often the presence of seizures, delayed development, or white patches on the skin. A full clinical diagnosis involves:[18][19]

The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:

Due to the wide variety of mutations leading to tuberous sclerosis, no simple genetic tests are available to identify new cases, nor are any biochemical markers known for the gene defects.[8] However, once a person has been clinically diagnosed, the genetic mutation can usually be found. The search is time-consuming and has a 15% failure rate, which is thought to be due to somatic mosaicism. If successful, this information can be used to identify affected family members, including prenatal diagnosis. As of 2006, preimplantation diagnosis is not widely available.


Drug therapy for some of the manifestations of tuberous sclerosis is currently in the developmental stage.[20] For example, a 2008 study found that treatment with rapamycin rescued learning and memory deficits in a mouse model of tuberous sclerosis.[21] CommunityTSC was a distributed computing project to find drugs to treat TSC. The patients usually have relapse of symptoms in the clinical course. Unless any vital function is affected, life expectancy is good. A majority of patients require some medications to control symptoms, e.g., antiepileptics to control seizures. In 2010, everolimus was approved for the treatment of subependymal giant cell astrocytoma.

Other drugs used include:

NHS England has been criticised for delays in deciding on a policy for the prescription of everolimus. Twenty doctors addressed a letter to the board in support of the charity Tuberous Sclerosis Association, saying, "around 32 patients with critical need, whose doctors believe everolimus treatment is their best or only option, have no hope of access to funding. Most have been waiting many months. Approximately half of these patients are at imminent risk of a catastrophic event (renal bleed or kidney failure) with a high risk of preventable death."[24]


The prognosis for individuals with tuberous sclerosis depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe intellectual disability, uncontrollable seizures, and kidney failure. Those individuals with mild symptoms generally do well and live long, productive lives, while individuals with the more severe form may have serious disabilities. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.[18]

A study of 30 tuberous sclerosis patients in Egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."[25]

Leading causes of death include renal disease, brain tumour, lymphangioleiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.[26] Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate, but is rarely a problem subsequently. Kidney complications such as angiomyolipoma (AML) and cysts are common, and more frequent in females than males and in TSC2 than TSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis is only a risk for females with angiomyolipomas.[27] In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.

Detection of the disease should prompt one for genetic counselling. It is also important to know that though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of tuberous sclerosis is important.


Tuberous sclerosis occurs in all races and ethnic groups, and in both genders. The live-birth prevalence is estimated to be between 10 and 16 cases per 100,000. A 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected.[28] These estimates are significantly higher than those produced by older studies, when tuberous sclerosis was regarded as an extremely rare disease. The reason is that the invention of CT and ultrasound scanning have enabled the diagnosis of many nonsymptomatic cases. Prior to this, the diagnosis of tuberous sclerosis was largely restricted to severely affected individuals with Vogt's triad of learning disability, seizures, and facial angiofibroma. The total population prevalence figures have steadily increased from 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to the present figure of 1:12,500 in 1998. Whilst still regarded as a rare disease, it is common when compared to many other genetic diseases.[8]


Désiré-Magloire Bourneville

Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial rash (1835 and 1850). A more complete case was presented by von Recklinghausen (1862), who identified heart and brain tumours in a newborn who had only briefly lived. However, Bourneville (1880) is credited with having first characterized the disease, coining the name "tuberous sclerosis", thus earning the eponym Bourneville's disease. The neurologist Vogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).[29]

Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described by Gomez (1979). The invention of medical ultrasound, CT and MRI has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability.

In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with tuberous sclerosis.[30]


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