Tuberous sclerosis
From Wikipedia, the free encyclopedia
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| 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 is a rare genetic disorder characterized by a triad of signs: seizures, mental retardation, and small benign facial skin tumors (angiofibromas). 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. The acronym for Tuberous Sclerosis is TSC (Tuberous Sclerosis Complex), to avoid confusion with Tourette syndrome.
The disease is caused by the proliferation of small benign tumors in the brain, as well as on the face and eyes, and in the kidneys, lungs, and other organs. Seizures and mental retardation are associated with the disturbance in brain function.
Tuberous sclerosis was traditionally considered one of a family of disorders called neurocutaneous syndromes, or phakomatoses; however this nomenclature has lost support, since distinct genetic causes have been found for the various disorders. (Other disorders included in this family were Neurofibromatosis type I, Neurofibromatosis type II (a.k.a. MISME syndrome), Sturge-Weber, and Von Hippel-Lindau.)
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[edit] History
Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial tumors (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 generally credited with having first characterized the disease, and he coined the name tuberous sclerosis. The neurologist Vogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).[1]
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.[1] The proteins associated with TSC1 and TSC2, Harmartin and Tuberin, function as a complex in the signalling pathway that regulates cell division (see below). 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.[2]
[edit] Pathophysiology
Small benign tumors grow on the face and eyes, as well as in the brain, kidneys, lungs and other organs. One third of all cases are inherited; they show an autosomal dominant pattern of inheritance, and penetrance is 100%. Based on this inheritance, the disease has been mapped to two genetic loci, TSC1 and TSC2. However, current genetic tests have difficulty locating the mutation in approximately 20% of individuals diagnosed with the disease.
Of the two loci, TSC2 has been associated with a more severe form of TSC.[3] 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%.[4]
TSC2 is located on chromosome 16 p13.3 and encodes for the protein Tuberin. It was discovered in 1993.[5] TSC1 is located on chromosome 9 q34 and encodes for the protein Hamartin. It was discovered in 1997.[6]
Hamartin and Tuberin function as a complex which is involved in the control of 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 division, and therefore a predisposition to forming tumors. The characteristic facial tumors usually have a butterfly distribution, which suggests that exposure to sunlight may be the precipitating factor in skin tumor formation.
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 the wide expressivity of the disease.
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.[7]
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[edit] Epidemiology
Tuberous sclerosis occurs in all races and ethnic groups, and in both genders. The incidence is estimated to be between 0.1 and 0.16 cases per 1000 live births; total population prevalence is 8 to 9 cases per 100,000. 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 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][9]
[edit] Clinical presentation
Since the advent of CT and ultrasound diagnosis, the "classic" Vogt triad of signs is now present in only 30–50% of cases. Up to 30% of people diagnosed with TSC reportedly have normal mentation. Seizures, when present, usually begin in the first year of life. Many symptoms appear in late childhood or adulthood. A given individual diagnosed with the disease may have a variable number of the symptoms, and may experience them with varying degrees of severity.
[edit] Central nervous system
About 50% of people with TSC have learning difficulties ranging from mild to profound,[10] 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.[11] Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.
Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.[12]
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 Monroe, 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.
[edit] Kidneys
Between 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called angiomyolipomas (AML). 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).
[edit] 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. (Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes, Chromosomes & Cancer. Dec. 2003. 38(4):376-81)
[edit] Heart
Rhabdomyomas are benign tumors of striated heart 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.
[edit] Skin
Some form of dermatological sign (pictures) 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: A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution.[1] 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: 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, cafe-au-lait spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.
[edit] Eyes
Retinal lesions, called astrocytic hamartomas, 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)
[edit] 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.
[edit] 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.
| Major Features | ||||
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| Location | Sign | Onset[14] | 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 | Lymphangiomyomatosis | 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[15][16]
- 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.[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.[13]
[edit] 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.[15]
Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.[17] 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.[18] 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.
[edit] Management
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Drug therapy for some of the manifestations of TSC is currently in the developmental stage.[19] Community TSC is a distributed computing project to find drugs to treat TSC. Volunteers are welcome.
[edit] References
- ^ a b Curatolo (2003), chapter: "Hisorical Background".
- ^ Rott HD, Mayer K, Walther B, Wienecke R (03 2005). Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis) (German). Tuberöse Sklerose Deutschland e.V. Retrieved on 2007-01-08.
- ^ 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. PMID 11112665.
- ^ 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. PMID 16114042.
- ^ (1993) "Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium". Cell 75 (7): 1305-15. PMID 8269512.
- ^ van Slegtenhorst M, et al (1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science 277 (5327): 805-8. PMID 9242607.
- ^ 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. PMID 7894481.
- ^ a b c Curatolo (2003), chapter: "Diagnostic Criteria".
- ^ O'Callaghan F (1999). "Tuberous sclerosis.". BMJ 318 (7190): 1019-20. PMID 10205080.
- ^ Ridler K, et al (2006). "Neuroanatomical Correlates of Memory Deficits in Tuberous Sclerosis Complex". Cerebral Cortex. PMID 16603714.
- ^ Harrison JE, Bolton, PF (1997). "Annotation: Tuberous sclerosis". Journal of Child Psychology and Psychiatry 38: 603-614. PMID 9315970.
- ^ 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.
- ^ a b Roach E, Sparagana S (2004). "Diagnosis of tuberous sclerosis complex.". Journal of Child Neurology 19 (9): 643-9. PMID 15563009.
- ^ Crino P, Nathanson K, Henske E (2006). "The Tuberous Sclerosis Complex.". New England Journal of Medicine 355 (13): 1345-56. PMID 17005952.
- ^ a b Tuberous Sclerosis Fact Sheet. National Institute of Neurological Disorders and Stroke (2006-04-11). Retrieved on 2006-10-03.
- ^ Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. Tuberous Sclerosis Association (April 2002). Retrieved on 2006-10-03.
- ^ 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.
- ^ 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. PMID 17003820.
- ^ Yates JR. Tuberous sclerosis. Eur J Hum Genet. 2006 Jul 26; PMID 16868562
[edit] Further reading
- Paolo Curatolo (Editor) (2003). Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898683-39-5.
- NINDS Tuberous Sclerosis Information Page
- GeneTests at NIH/UW tuberous-sclerosis
[edit] External links
- 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
[edit] Support groups
- United Kingdom: The Tuberous Sclerosis Association. Awareness month is October.
- United States: Tuberous Sclerosis Alliance. Awareness month is May.
- Canada: Tuberous Sclerosis Canada. Awareness month is May.
- Australasia: Australasian Tuberous Sclerosis Society.
- Brazil: Associação Brasileira de Esclerose Tuberosa (Brazilian Tuberous Sclerosis Association) (Portuguese)
- Taiwan: Taiwan Tuberous Sclerosis Complex
