Tuberous sclerosis

(medicine) A familial neurocutaneous syndrome characterized in its complete form by epilepsy, adenoma sebaceum, and mental deficiency, and pathologically by nodular sclerosis of the cerebral cortex. Also known as Bourneville's disease.

Definition

Tuberous sclerosis (TS) is a hereditary neurological condition that affects all ages. The name arises from the potato stem-shaped growths that occur in the brain, also known as tubers. These growths often involve overgrowth of nerves or the connective tissue within them, which is described by the term sclerosis.

Description

TS is also known by the names tuberous sclerosis complex and Bourneville's disease. Neurological symptoms may include tubers and other non-cancerous growths in the brain, cancerous brain tumors, seizures, and mental retardation or developmental delay.

Nearly everyone with TS has some symptoms affecting their skin. These include light-colored patches called ash-leaf spots, acne-type growths on the face, nail beds, and the body, and shagreen patches. Other common symptoms of TS are kidney cysts, kidney growths, and heart tumors that may develop at a very young age or even before birth.

Demographics

According to the National Institute of Neurological Disorders and Stroke (NINDS), TS affects about 1 in 6,000 newborns. As many as 25,000 to 45,000 people in the United States and 1-2 million people worldwide have the disorder. Its true incidence may be higher because mildly affected individuals may not come to medical attention. TS has been reported in all ethnic groups and races with equal frequency.

Two genes for TS have been identified, and males and females are equally affected with the condition. About one third of people with TS have an affected parent as well.

Causes and symptoms

Always known to be hereditary, mutations in two different genes are now known to cause TS. These genes are TSC1 and TSC2, and were discovered in 1993 and 1997 on chromosomes 16 and 9 respectively. TS is inherited in an autosomal dominant manner, meaning that an affected individual has a 50/50 chance to pass a disease-causing mutation to his or her children, regardless of their gender. As a result, strong family histories of TS are common.

TSC1 and TSC2 normally code for specific proteins, hamartin and tuberin, which are felt to be necessary for neurological functioning. Reduced amounts of these proteins in the brains of people with TS may contribute to the neurological complications associated with the condition.

The most common neurological symptoms in TS include seizures, learning and behavioral problems, and hydrocephalus. Seizures affect about 85% of people at some point in their lives. They can begin in very early childhood as infantile spasms, sometimes with hypsarrhythmia. The presence of these spasms at an early age often means more significant learning problems and more significant epilepsy later on.

Learning problems are not a certainty with TS; about 50% of people with the condition are known to have developmental delay or mental retardation. People with TS have an increased chance to develop certain behavioral disorders. Autism is seen in about 25–50% of people with TS, and this is felt to have a major influence on an individual's daily functioning. Parents of children with TS often raise concerns about autism or autistic-type characteristics, because this has a significant impact on routine activities like attending school. Though scientific studies have been done to find exact neurological causes for autism in TS, none has provided consistent results.

A unique brain finding in TS is the cortical tuber, which is seen in about 90% of people with the condition. The number and size of tubers in a person can correlate with the degree of learning problems and seizures they may experience. Other brain findings in TS include subependymal hamartomas. Some of these may grow in childhood and block the normal flow of spinal fluid, causing hydrocephalus. Brain tumors like subependymal giant cell astrocytomas are a cause of health complications and death in TS.

Since skin changes are so common in TS, they can be some of the first signs of the condition that are noticed. Ash-leaf spots are the most common skin finding, followed by facial angiofibromas. These angiofibromas may cause slight disfigurement, but more often are a cosmetic concern. Darkened skin patches called cafe-au-lait spots may also occur, along with skin tags. Fortunately, none of the skin symptoms usually cause serious medical complications.

Kidney disease can be a serious medical concern in TS; it is the most frequent cause of death in people with TS older than 30 years. The most common renal finding is the angiomyolipoma, which is more commonly found in women at a younger age. Though these growths are non-cancerous, they can enlarge and disturb normal kidney function. Kidney cysts may occur, again more commonly in younger women. These cysts may be numerous and similarly disrupt normal kidney function as a result. Renal cell carcinoma can be a further symptom of TS, and kidney transplants may be necessary for any significant renal complication.

Cardiac rhabdomyomas are typically seen in early childhood, but occasionally may even be seen on a prenatal ultrasound. Most rhabdomyomas disappear with age, remaining stable and causing no symptoms; others may cause heart rhythm problems. Vascular disease may also be a part of TS, with some people having aneurysms of the abdomen and other areas of the body.

Lung problems are a part of TS, and affect women more often. Lymphangioleimyomas of the lung are common and affect about 1-4% of people with TS by interfering with normal lung function. Hormones may be a factor because pregnancy, menstruation, and estrogen have been associated with a worsening of these symptoms in some women. Interestingly, pulmonary problems have been associated with a milder case of TS, often with fewer learning problems and seizures.

Other symptoms of TS include growths on the retinas called hamartomas, which are not usually problematic. There have been no typical ages in which eye involvement occurs in TS.

Diagnosis

Up until the discovery of TSC1 and TSC2, the diagnosis of TS was made on a clinical basis. Criteria for clinical diagnosis were updated in 1998 at the Tuberous Sclerosis Complex Consensus Conference.

Revised diagnostic criteria for tuberous sclerosis complex (TSC)

The major features include:

• facial angiofibromas or forehead plaque
• non-traumatic ungual or periungual fibroma
• hypomelanotic macules (more than three)
• shagreen patch
• multiple retinal nodular hamartomas
• cortical tuber
• subependymal nodule
• subependymal giant cell astrocytoma
• cardiac rhabdomyoma, single or multiple
• lymphangioleimyomatosis
• renal angiomyolipoma

The minor features include:

• 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

Definite TSC: Either two major features, or one major feature plus two minor features. Probable TSC: One major plus one minor feature. Possible TSC: Either one major feature, or two or more minor features.

Most brain findings in TS can be identified with magnetic resonance imaging (MRI) or computed tomography (CT) scans. Seizures can be documented from electroencephalogram (EEG) monitoring. Skin changes are often found by using a Woods lamp, which makes them more obvious during a physical examination. Routine ultrasounds of the kidney often find and help monitor cysts and angiomylipomas. Cardiac involvement may be seen as early as a prenatal ultrasound, or with an echocardiogram in early life. Electrocardiograms may be necessary to help detect heart rhythm problems. For women in particular, a CT scan of the chest is important to detect lung lymphangiomyomatosis. For all, an ophthalmology examination is important to detect retinal involvement.

Genetic testing is available for TS via gene sequencing. It is useful for confirming a clinical diagnosis, prenatal diagnosis, or family testing when there is an identified TSC mutation in the family. Sequencing of the TSC1 and TSC2 genes is not perfect; it detects about 80% of people with TS. An informative test result is one that identifies a known mutation in either gene, and this confirms that the person has TS. A negative test result does not identify a mutation in either gene. This either means that the tested individual does not have TS, or has a mutation that cannot be found through testing and truly has the diagnosis.

Treatment team

Treatment for people with TS is usually very specific to the person, since symptoms vary greatly. The typical treatment team for someone with TS may include a neurologist, neurosurgeon, medical geneticist, genetic counselor, dermatologist, cardiologist, pulmonologist, nephrologist, ophthalmologist, social worker, and a primary care provider. Often times there are pediatric specialists in these fields who aid in the care for children. Care providers in pediatric development are particularly important, such as speech-language therapists and pediatric neuropsychologists.

Treatment

There is no cure for tuberous sclerosis. Therefore, treatment is based upon symptoms.

Seizures may be treated with various anti-epilepsy medications. Those with significant seizures may be tried on a ketogenic diet, which consists of frequent meals of high-fat foods. While challenging, the ketogenic diet yields good results in some cases.

Learning or behavioral problems are often serious issues, but awareness and developmental interventions often help families with TS. Pediatricians who have an interest in child development are a good resource, particularly if a child with TS is showing signs of autism.

Hydrocephalus can be serious and even lead to learning problems if left untreated, so surgery to drain accumulated fluid in the brain may be necessary. While most growths in the brain are non-cancerous, brain tumors are typically treated as they would be in someone without TS.

Since most skin complications of TS cause no medical problems, treatment is not often necessary. Some angiofibromas, particularly on the face, may be problematic and require removal. Laser treatments may also be effective to reduce the appearance of some skin changes.

Many kidney growths cause no health problem in TS, but some individuals may have kidney cysts similar to those found in polycystic kidney disease (Type 1). In these cases, kidney function may be disturbed and the person might need a kidney transplant after some time. Those with renal cell carcinoma would be treated as anyone with this complication.

Most rhabdomyomas cause no problems, but some may need surgery to keep their hearts working well. Surgery may also be required for someone with a severe heart rhythm problem.

People with lung function problems may need to be treated with medications, hormone therapy, or surgery if necessary.

Visual complaints are not as common for people with TS, since retinal growths do not usually cause symptoms. In rarer cases, vision may be disturbed and treated like someone without TS.

Clinical trials

As of early 2004, there were two clinical studies recruiting subjects in the United States. Both were at the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health in Bethesda, Maryland. One study was studying skin tumors in people with TS, and the other was studying disease progression in people with TS who have lymphangioleimyomatosis. More information about these trials can be found at www.clinicaltrials.gov.

Prognosis

Prognosis for someone with tuberous sclerosis is highly dependent upon symptoms they experience. Those who die may do so as a result of significant neurological, pulmonary or cardiac complications. People with TS often have routine medical appointments dealing with symptoms as they arise.

Many people with TS survive into adulthood, and studies are attempting to learn more about long-term prognosis as people with TS age. It is challenging to gain this information because older people with milder forms of TS may not present for medical care frequently, or may not even know they have the condition.

Resources

BOOKS

Curatolo, Paolo, Peter G. Procopis, Isabelle Rapin, and John Stobo Prichard. Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. Mac Keith Publishers, 2003.

Gomez, Manuel Rodriguez, Julian R. Sampson, and Vicky Holets Whittemore. Tuberous Sclerosis Complex, 3rd ed. Oxford University Press, 1999.

Parker, James N., and Philip M. Parker. The Official Patient's Sourcebook on Tuberous Sclerosis: A Revised and Updated Directory for the Internet Age. Icon Health Publishers, 2002.

PERIODICALS

Curatolo, Paolo, Magda Verdecchia, and Roberta Bombardieri. "Tuberous sclerosis complex: a review of neurological aspects." European Journal of Paediatric Neurology 6 (2002): 15-23.

Franz, David Neal. "Diagnosis and Management of Tuberous Sclerosis Complex." Seminars in Pediatric Neurology 5, no. 4 (December 1998): 253-268.

Lendvay, Thomas S., and Fray F. Marshall. "The Tuberous Sclerosis Complex and its Highly Variable Manifestations." Clinical Urology 169, no. 5 (May 2003): 1635-1642.

McClintock, William M. "Neurologic Manifestations of Tuberous Sclerosis Complex." Current Neurology and Neuroscience Reports 2 (2002): 158-163.

Sparagana, Steven P., and E. Steve Roach. "Tuberous sclerosis complex." Current Opinion in Neurology 13 (2000): 115-119.

Walz, Nicolay Chertkoff, Anna Weber Byars, John C. Egelhoff, and David Neal Franz. "Supratentorial Tuber Location and Autism in Tuberous Sclerosis Complex." Journal of Child Neurology 17, no. 11 (November 2002): 830-832.

WEBSITES

GeneTests/GeneReviews.http://www.genetests.org.

National Institute of Neurological Disorders and Stroke.http://www.ninds.nih.gov/index.htm.

Online Mendelian Inheritance in Man.http://www.ncbi.nlm.nih.gov/omim/.

Tuberous Sclerosis International (Worldwide Organisation of Tuberous Sclerosis Associations).http://www.stsn.nl/tsi/tsi.htm.

ORGANIZATIONS

Tuberous Sclerosis Alliance. 801 Roeder Road, Suite 750, Silver Spring, MD 20910. 301-562-9890 or 800-225-6872; Fax: 301-562-9870. ntsa@ntsa.org. http://www.tsalliance.org.

The Tuberous Sclerosis Association, U.K. Janet Medcalf, P.O. Box 9644, Bromsgrove, England B61 OFP. +44 (0)1527 871898; Fax: +44 (0)1527 579452. http://www.tuberous-sclerosis.org.

The Australasian Tuberous Sclerosis Association. 5 Parer Avenue, Condell Park, Australia NSW 200. 1300 733 435 (Australia only). atss@netspace.net.au. http://atss.customer.netspace.net.au/index.htm.

Deepti Babu, MS, CGC

Definition

Tuberous sclerosis is a genetic disorder in which noncancerous (benign) tumors grow on the brain, skin, kidneys, eyes, heart, and lungs.

Description

The name tuberous sclerosis refers to characteristics of the benign tumors that grow within the brain. The tumors have root-like or tuberous appendages. Over time, the tumors undergo sclerosis, meaning they calcify and grow hard.

Symptoms of tuberous sclerosis may be identifiable at birth or may develop over time.

Demographics

In the United States, as of the early 2000s, there are between 25,000 and 40,000 individuals with tuberous sclerosis. Globally, about 1 to 2 million individuals have the disease. The disease occurs in about one out of every 6,000 newborns. There is no gender, racial, or ethnic predilection.

Causes and Symptoms

Tuberous sclerosis occurs when at least one of two genes (either TSC-1 on chromosome 9 or TSC-2 on chromosome 16) is defective. Normally, the two genes produce proteins called hamartin and tuberin, respectively. These proteins seem to serve as inhibitors of tumor growth. When the TS genes are defective or absent, the proteins are either absent or deficient, which allows tumor growth.

Most cases of tuberous sclerosis occur due to spontaneous mutations. This means that the disease does not occur due to the inheritance of an abnormal gene, but rather because the baby's gene is defective for some reason other than inheritance.

Symptoms

The tumors of tuberous sclerosis occur throughout the body, including the brain, heart, lungs, kidneys, eyes, and skin. Other symptoms include seizures, developmental delay, behavior problems, and skin problems.

KIDNEYS. Cysts on the kidneys tend to appear during the second or third decade of life. In most cases, they do not interfere with kidney functioning. Rarely, there are so many cysts that the kidneys functioning is impaired, or the cysts bleed, resulting in anemia. Fatty growths within the kidneys (called angiolipomas) may grow so large that they cause pain and/or kidney failure. Rarely, malignant tumors of the kidney (renal cell carcinoma) occur within an existing angiolipoma.

BRAIN. Several types of brain tumors can grow, resulting in blockage of the flow of cerebrospinal fluid, fluid backup, headaches, and visual disturbances.

HEART. Benign tumors in the heart (rhabdomyomas) may block circulation or may exist uneventfully.

EYES. White areas in the retina, called phakomas, are characteristic of the disease (and may aid in diagnosis) but do not result in visual disturbances.

SKIN. A variety of skin disorders are noted in tuberous sclerosis, including areas of under-pigmented skin (hypomelanic macules); reddish bumps on the face (facial angiofibromas); raised patches on the forehead (called forehead plaques); areas of rough, thickened skin on the neck or back (shagreen patches); tiny fleshy bumps around or under the toe- or fingernails (ungula or subungual fibromas); skin tags (molluscum fibrosum); flat brown patches.

BEHAVIOR. About 33 to 50 percent of all tuberous sclerosis patients have problems such as learning disabilities, severe mental retardation, attention deficit disorder, obsessive-compulsive disorder, autism, aggression, rage, or self-harming behavior.

Diagnosis

Tuberous sclerosis is diagnosed when the characteristic tumors are noted in the skin, heart, brain, or kidneys. Many patients come to the healthcare provider's attention after they have begun to have seizures. Further examination with CT and/or MRI scans, ultrasound, and Wood's lamps to view the eyes will reveal the presence of the characteristic tumors of tuberous sclerosis.

Treatment

As of 2004, no cure was available for tuberous sclerosis. Antiseizure medications may be prescribed, as well as medications to treat attention deficit disorder and obsessive-compulsive disorder. Skin lesions may be removed or reduced via dermabrasive or laser procedures. Surgery may be performed to remove enlarging kidney tumors, to avoid the advent of kidney failure.

Prognosis

Most individuals with tuberous sclerosis have a normal lifespan. The prognosis for their quality of life depends on the severity of their behavioral and cognitive symptoms. Individuals whose symptomatology is confined to kidneys or skin (as opposed to having multiple behavioral symptoms) may do very well.

Prevention

As of 2004, there was no way to prevent tuberous sclerosis.

Parental Concerns

Parents of child with tuberous sclerosis should be prepared to answer any questions their child or the child's siblings may have about the disease. Siblings may fear they will catch the disease or perhaps caused it, and may need to reassured that they are not at fault.

Resources

Books

Haslam, Robert H. A. "Neurocutaneous syndromes." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2004.

"Neurocutaneous Disorders." In Textbook of Clinical Neurology. Edited by Christopher G. Goetz. Philadelphia: Saunders, 2003.

Web Sites

"Tuberous Sclerosis Fact Sheet." National Institute of Neurological Disorders and Stroke (NINDS). Available online at www.ninds.nih.gov/disorders/tuberous_sclerosis.htm (accessed January 9, 2005).

[Article by: Rosalyn Carson-DeWitt, MD]

Not to be confused with tuberculosis.

Tuberous sclerosis
Classification and external resources
Earliest illustration, from Rayer's atlas of skin diseases, 1835.
ICD-10	Q85.1
ICD-9	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 genetic disease that causes benign tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems, skin abnormalities, lung and kidney disease. TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour 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.

Contents 1 Signs and symptoms 1.1 Central nervous system 1.2 Kidneys 1.3 Lungs 1.4 Heart 1.5 Skin 1.6 Eyes 1.7 Variability 2 Genetics 3 Pathophysiology 4 Diagnosis 5 Management 6 Prognosis 7 Epidemiology 8 History 9 Notes 10 References 11 External links

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, developmental delay and behavioral problems.

Central nervous system

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 type of brain tumours may be associated with TSC: i. Giant cell astrocytoma: (grows and blocks the CSF flow leading to dilatation of ventricles causing headache and vomiting) ii. Cortical tubers: after which the disease is named. iii. 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 (radial white matter tracts hyperintense on T2WI, 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 Monroe) or idiopathic in nature.

Kidneys

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 tissue (angio–), smooth muscle (–myo–), and fat (–lipoma). 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).

Lungs

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]

Heart

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.

Skin

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 socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.
• Ungual or subungual 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.
• 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, usually found on the lower back or nape of the neck.
• 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.

Eyes

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 in is in the differential diagnosis of a calcified globe mass on a CT scan.

Non-retinal lesions associated with TSC include

• Coloboma
• Angiofibromas of the eyelids
• Papilledema (related to hydrocephalus)

Variability

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 clinical signs in children with tuberous sclerosis, grouped by age^[7]

Genetics

Tuberous sclerosis is inherited in an autosomal dominant fashion.

Tuberous sclerosis is a genetic disorder with an autosomal dominant pattern of inheritance, and penetrance is variable.^[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 Identifiers Symbol TSC1 Entrez 7248 HUGO 12362 OMIM 605284 RefSeq NM_000368 UniProt Q92574 Other data Locus Chr. 9 q34

Tuberin Identifiers Symbol TSC2 Entrez 7249 HUGO 12363 OMIM 191092 RefSeq NM_000548 UniProt P49815 Other data Locus Chr. 16 p13.3

Pathophysiology

This section requires expansion.

Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. (The complex appears to be a Rheb GTPase which suppresses 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.

Diagnosis

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.

In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves^[16][17]

• 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^[update], preimplantation diagnosis is not widely available.^[14]

Management

Drug therapy for some of the manifestations of TSC is currently in the developmental stage.^[18] For example, a 2008 study found that treatment with rapamycin rescued learning and memory deficits in a mouse model of tuberous sclerosis.^[19] Community TSC is a distributed computing project to find drugs to treat TSC.^{[citation needed]} 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.

Prognosis

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 mental retardation, 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.^[16]

Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.^[20] 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.^[21] 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.

Epidemiology

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.^[22] 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]

History

Main article: Timeline of tuberous sclerosis

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).^[23]

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.^[23] 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.^[24]

Notes

1. ^ "Tuberous Sclerosis Fact Sheet". NINDS. 2006-04-11. http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. Retrieved 2007-01-09.  (Some text copied with permission.)
2. ^ Ridler K, et al. (2006). "Neuroanatomical Correlates of Memory Deficits in Tuberous Sclerosis Complex". Cerebral Cortex 17 (2): 261. doi:10.1093/cercor/bhj144. PMID 16603714. 
3. ^ Harrison JE, Bolton, PF (1997). "Annotation: Tuberous sclerosis". Journal of Child Psychology and Psychiatry 38 (6): 603–614. doi:10.1111/j.1469-7610.1997.tb01687.x. PMID 9315970. 
4. ^ Staley BA, Montenegro MA, Major P et al. (2008). "Self-injurious behavior and tuberous sclerosis complex: frequency and possible associations in a population of 257 patients". Epilepsy Behav 13 (4): 650. doi:10.1016/j.yebeh.2008.07.010. PMID 18703161. 
5. ^ Ridler K, et al. (2004). "Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex". Journal of Child Neurology 19 (9): 658–665. PMID 15563011. 
6. ^ Henske EP. (2003). "Metastasis of benign tumor cells in tuberous sclerosis complex". Genes, Chromosomes & Cancer 38 (4): 376–381. doi:10.1002/gcc.10252. PMID 14566858. 
7. ^ ^{a b c} Curatolo (2003), chapter: "Diagnostic Criteria".
8. ^ Northrup H, Au K (5 December 2005). "Tuberous Sclerosis Complex". GeneReviews. http://www.geneclinics.org/profiles/tuberous-sclerosis/details.html. Retrieved 2007-09-02. 
9. ^ van Slegtenhorst M, de Hoogt R, Hermans C, et al. (1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science 277 (5327): 805–8. doi:10.1126/science.277.5327.805. PMID 9242607. 
10. ^ European Chromosome 16 Tuberous Sclerosis Consortium (1993). "Identification and characterization of the tuberous sclerosis gene on chromosome 16". Cell 75 (7): 1305–15. PMID 8269512. 
11. ^ Brook-Carter PT, et al. (1994). "Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome". Nature Genetics 8 (4): 328–32. doi:10.1038/ng1294-328. PMID 7894481. 
12. ^ Dabora SL, et al. (2001). "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs". American Journal of Human Genetics 68 (1): 64–80. doi:10.1086/316951. PMID 11112665. PMC 1234935. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1234935&blobtype=pdf. 
13. ^ Rendtorff ND, et al. (2005). "Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations". Human Mutation 26 (4): 374–83. doi:10.1002/humu.20227. PMID 16114042. 
14. ^ ^{a b} Roach E, Sparagana S (2004). "Diagnosis of tuberous sclerosis complex". Journal of Child Neurology 19 (9): 643–9. PMID 15563009. http://www.medscape.com/viewarticle/495642. 
15. ^ Crino P, Nathanson K, Henske E (2006). "The Tuberous Sclerosis Complex". New England Journal of Medicine 355 (13): 1345–56. doi:10.1056/NEJMra055323. PMID 17005952. 
16. ^ ^{a b} "Tuberous Sclerosis Fact Sheet". National Institute of Neurological Disorders and Stroke. 2006-04-11. http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. Retrieved 2006-10-03. 
17. ^ "Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex" (PDF). Tuberous Sclerosis Association. April 2002. http://www.tuberous-sclerosis.org/publications/clinicalguidelinessummary.pdf. Retrieved 2006-10-03. 
18. ^ Yates JR. Tuberous sclerosis. Eur J Hum Genet. 2006 Jul 26; PMID 16868562
19. ^ Ehninger D, Han S, Shilyansky C et al. (2008). "Reversal of learning deficits in a Tsc2^+/- mouse model of tuberous sclerosis". Nat Med 14 (8): 843. doi:10.1038/nm1788. PMID 18568033. Lay summary – Science News (2008-06-23). 
20. ^ Shepherd C, Gomez M, Lie J, Crowson C (1991). "Causes of death in patients with tuberous sclerosis". Mayo Clin Proc 66 (8): 792–6. PMID 1861550. 
21. ^ Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. (2006). "Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors". Kidney International 70 (10): 1777. doi:10.1038/sj.ki.5001853. PMID 17003820. 
22. ^ O'Callaghan FJK, Shiell AW, Osborne JP, Martyn CN (1998). "Prevalence of tuberous sclerosis estimated by capture-recapture analysis". Lancet 351 (9114): 1490. doi:10.1016/S0140-6736(05)78872-3. 
23. ^ ^{a b} Curatolo (2003), chapter: "Historical Background".
24. ^ Rott HD, Mayer K, Walther B, Wienecke R (March 2005). "Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis)" (in German) (PDF). Tuberöse Sklerose Deutschland e.V. http://www.tsdev.de/92001/Uploaded/hhehn%7Cgeschichte_der_tsc2005.pdf. Retrieved 2007-01-08. 

References

• Ingole J; Jain AP: Tuberous Sclerosis with Unusual Presentation in an Adult: JIACM 2005; 6(1): 79-81
• Paolo Curatolo (Editor) (2003). Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898683-39-5. 
• tuberous-sclerosis at NIH/UW GeneTests

External links

• 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

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