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Tuberous sclerosis

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Title: Tuberous sclerosis  
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Tuberous sclerosis

Tuberous sclerosis
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 191100
DiseasesDB 13433
MedlinePlus 000787
eMedicine neuro/386 derm/438 ped/2796 radio/723
MeSH D014402

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung and kidney disease. TSC 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 postmortem. 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.


  • Signs and symptoms 1
    • Central nervous system 1.1
    • Kidneys 1.2
    • Lungs 1.3
    • Heart 1.4
    • Skin 1.5
    • Eyes 1.6
    • Variability 1.7
  • Genetics 2
  • Pathophysiology 3
  • Diagnosis 4
  • Management 5
  • Prognosis 6
  • Epidemiology 7
  • History 8
  • References 9
  • External links 10

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 TSC 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 TSC.[4] Other conditions, 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 TSC:

  • Giant cell astrocytoma: (grows and blocks the cerebrospinal fluid (CSF) flow, leading to dilatation of ventricles causing headache and vomiting)
  • Cortical tubers: after which the disease is named.
  • Sub-ependymal nodules: form in the walls of ventricles.

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, TSC 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. There is no interposed neural tissue. 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 (SEGA). A SEGA 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, 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 TSC 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 AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. AMLs are found in about 1 in 300 people without TSC. However, those are usually solitary, whereas in TSC they are commonly multiple and bilateral.

Approximately 20-30% of people with TSC will 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 TSC 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 LAM is monoclonal metastasis from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM recurring following lung transplant.[6]


Rhabdomyomas are benign tumors of striated muscle. A cardiac rhabdomyoma can be discovered using echocardiography in approximately 50% of people with TSC. 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 will 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 TSC in the child, especially if there is a family history of TSC.


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

  • Facial angiofibromas ("adenoma sebaceum"): A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution. They consist of blood vessels and fibrous tissue. This potentially socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.
  • Periungual fibromas: Also known as Koenen's tumors, these are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These are very rare in childhood but common by middle age. They are generally more common on toes than on fingers, develop at 15–29 years and are more common in women than in men. They can be induced by nail-bed trauma.
  • Hypomelanic macules ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of melanin. These are usually the only visible sign of TSC at birth. In fair-skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.
  • Forehead plaques: Raised, discolored areas on the forehead.
  • Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel,pigmented and usually found on the lower back or nape of the neck. They can also be scattered across the trunk or thighs. The frequency of these lesions rises with age.
  • Other skin features are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders, café au lait spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.


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.

Non-retinal lesions associated with TSC include


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[7]


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.[8] Two thirds of TSC 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 approximately 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.[9] TSC2 encodes for the protein Tuberin, is located on chromosome 16 p13.3 and was discovered in 1993.[10] 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 TSC who also develop PKD in childhood.[11] TSC2 has been associated with a more severe form of TSC.[12] However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 80-90%.[13]

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 percent penetrance, TSC has wide expressivity.


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. TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system (CNS) 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 TSC. 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.


There are no pathognomonic clinical signs for tuberous sclerosis. Many signs are present in individuals who are healthy (although rarely), or who have another disease. A combination of signs, classified as major or minor, is required in order to establish a clinical diagnosis.

Diagnostic Criteria for Tuberous Sclerosis Complex[14]
Major Features
Location Sign Onset[15] Note
1 Head Facial angiofibromas or forehead plaque Infant – adult
2 Fingers and toes Nontraumatic ungual or periungual fibroma Adolescent – adult
3 Skin Hypomelanotic macules Infant – child More than three.
4 Skin Shagreen patch (connective tissue nevus) Child
5 Brain Cortical tuber 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 10 and 11 together count as one major feature.
Minor Features
Location Sign Note
12 Teeth Multiple randomly distributed pits in dental enamel
13 Rectum Hamartomatous rectal polyps Histologic confirmation is suggested.
14 Bones Bone cysts
15 Brain Cerebral white-matter "migration tracts" Radiographic confirmation is sufficient. 5 and 15 together count as one major feature.
16 Gums Gingival fibromas
17 Liver, spleen and other organs Nonrenal hamartoma Histologic confirmation is suggested.
18 Eyes Retinal achromic patch
19 Skin "Confetti" skin lesions
20 Kidneys Multiple renal cysts Histologic confirmation is suggested.
21 Lungs Multifocal micronodular pneumocyte hyperplasia[16] Adult

In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves[17][18]

  • Taking a personal and family history.
  • Examining the skin under a Wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas) and the mouth (dental pits and gingival fibromas).
  • Cranial imaging with non enhanced CT or, preferably, MRI (cortical tubers and subependymal nodules).
  • Renal ultrasound (angiomyolipoma or cysts).
  • An echocardiogram in infants (rhabdomyoma).
  • Fundoscopy (retinal nodular hamartomas or achromic patch).

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

  • Definite – Either two major features or one major feature plus two minor features.
  • Probable – One major plus one minor feature.
  • Suspect – Either one major feature or two or more minor features.

Due to the wide variety of mutations leading to TSC, there are no simple genetic tests available to identify new cases. Nor are there any biochemical markers for the gene defects.[7] 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.[14]


Drug therapy for some of the manifestations of TSC is currently in the developmental stage.[19] For example, a 2008 study found that treatment with rapamycin rescued learning and memory deficits in a mouse model of tuberous sclerosis.[20] Community TSC is 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. Majority of patients will require some medications to control symptoms, e.g., anti-epileptics 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. 20 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."[23]


The prognosis for individuals with TSC 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.[17]

A study of 30 TSC patients in Egypt found that "...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."[24]

Leading causes of death include renal disease, brain tumour, lymphangioleiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.[25] 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 (LAM) is only a risk for females with AMLs.[26] In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas (SEGA). 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 even 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.[27] 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 non-symptomatic 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.[7]


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 that 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).[28]

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.

Two genetic loci associated with tuberous sclerosis, TSC1 and TSC2, were discovered in 1997 and 1992 respectively. This has enabled the use of genetic testing as a diagnostic tool.[28] The proteins associated with TSC1 and TSC2, harmartin and tuberin, function as a complex in the mTOR signalling pathway that controls cell growth and cell division. The importance of this pathway in cancer therapy has stimulated further research into tuberous sclerosis.

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.[29]


  1. ^ "Tuberous Sclerosis Fact Sheet". NINDS. 11 April 2006. Retrieved 9 January 2007.  (Some text copied with permission.)
  2. ^ Ridler K, Suckling J, Higgins NJ, de Vries PJ, Stephenson CM, Bolton PF, Bullmore ET (2007). "Neuroanatomical correlates of memory deficits in tuberous sclerosis complex". Cereb. Cortex 17 (2): 261–71.  
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  4. ^ Staley BA, Montenegro MA, Major P, Muzykewicz DA, Halpern EF, Kopp CM, Newberry P, Thiele EA (2008). "Self-injurious behavior and tuberous sclerosis complex: frequency and possible associations in a population of 257 patients". Epilepsy Behav 13 (4): 650–3.  
  5. ^ Ridler K, Suckling J, Higgins N, Bolton P, Bullmore E (2004). "Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex". J. Child Neurol. 19 (9): 658–65.  
  6. ^ Henske EP (2003). "Metastasis of benign tumor cells in tuberous sclerosis complex". Genes Chromosomes Cancer 38 (4): 376–81.  
  7. ^ a b c Curatolo (2003), chapter: "Diagnostic Criteria".
  8. ^ Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJ, Stephens K, Northrup H, Koenig MK, Au KS. "Tuberous Sclerosis Complex". GeneReviews [Internet].  
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External links

  • tuberous-sclerosis at NIH/UW GeneTests
  • GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex
  • The Tuberous Sclerosis Alliance in the United States offers a comprehensive Web site, online discussion groups, and free publications.
  • The HUGO Gene Nomenclature Committee web pages for TSC1 and TSC2 provide a selection of links for further genetic research.
  • The Rothberg Institute For Childhood Diseases have a distributed computing project called CommunityTSC
  • Dermatlas: Images of Tuberous sclerosis
  • Mass General Hospital's Living with TSC
  • The Tuberous Sclerosis Association in the UK has a comprehensive Web site
  • Cancer.Net: Tuberous Sclerosis Syndrome
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