Tuberous sclerosis

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Tuberous sclerosis
Classifications 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 (meaning "hard swellings") is a rare genetic disorder primarily characterized by a triad of seizures, mental retardation, and skin lesions (called facial angiofibroma). This "classic" Vogt triad is present in 30-50% of cases; in particular, up to 30% of those with tuberous sclerosis reportedly have normal mentation. Tuberous sclerosis, along with Neurofibromatosis type I, Neurofibromatosis type II (a.k.a. MISME syndrome), Sturge-Weber, and Von Hippel-Lindau compromise the Phakomatoses or neurocutaneous syndromes, all of which have neurologic and dermatologic lesions. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

Individuals with tuberous sclerosis may experience none or all of the symptoms with varying degrees of severity. Tuberous sclerosis is a multi-system disease that can affect the brain, kidneys, heart, eyes, lungs, and other organs. Small benign tumors may grow on the face and eyes, as well as in the brain, kidneys, and other organs. Neuroimaging studies may be able to confirm the diagnosis. Seizures most often begin in the first year of life.

Tuberous sclerosis' acronym is T.S.C. (Tuberous sclerosis complex) so as to avoid confusion with Tourette syndrome.

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 2 Causes 3 Diagnosis 4 Pathophysiology 5 Management 6 Prognosis 7 Epidemiology 8 History 9 Notes 10 References 11 External links 11.1 Support groups

[edit] Signs and symptoms

Tuberous sclerosis is a multisystem disorder that affects many organs including the brain, kidneys, lungs, heart, skin and eyes. Many symptoms only appear in late childhood or adulthood, and there is a wide variation in severity.

[edit] Central nervous system

About 50% of people with TSC have learning difficulties ranging from mild to profound^[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] 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.^[4]

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 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:

• 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.
• Facial angiofibromas: 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.
• 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.
• 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.
• Other skin features that 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 that may appear 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] Causes

Tuberous sclerosis (TSC) is a genetic disorder caused by mutations on either of two genes TSC1 and TSC2. It has an autosomal dominant pattern of inheritance and penetrance is 100%. The incidence is between 1/6,000 and 1/10,000. One third of cases are inherited; the rest are new mutations.

TSC1 is located on chromosome 9 q34 and encodes for the protein hamartin. It was discovered in 1997.^[5] TSC2 is located on chromosome 16 p13.3 and encodes for the protein tuberin. It was discovered in 1993.^[6] TSC2 is contiguous with PKD1 (which causes one form of polycystic kidney disease). Gross deletions affecting both genes may account for the 2% of individuals with TSC who develop PKD in childhood.^[7]

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. Of the two, TSC2 has been associated with a more severe form of TSC.^[8] However, the difference is subtle and statistical and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 ranges from 55% to 80-90%.^[9] Current genetic tests have difficulty locating the mutation in approximately 20% of individuals.

Hamartin Identifiers Symbol(s) TSC1 Entrez 7248 OMIM 605284 RefSeq NM_000368 UniProt Q92574 Other data Locus Chr. 9 q34

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

[edit] Diagnosis

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

Diagnostic Criteria for Tuberous Sclerosis Complex^[10]

Major Features
	Location	Sign	Onset[11]	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^{[12] [13]}

• 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^[1]. 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.^[10]

[edit] Pathophysiology

Hamartin/tuberin function as a complex, whose biological activity appears to be a Rheb GTPase. They function within the growth factor (insulin) signalling pathway and are involved in suppressing mTOR signalling.

[edit] Management

Drug therapy for some of the manifestations of TSC is currently in the developmental stage.^[14] Community TSC is a distributed computing project to find drugs to treat TSC. Volunteers are welcome.

[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.^[12]

Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.^[15] 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.^[16] 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] Epidemiology

Tuberous sclerosis occurs in all races and ethnic groups, and in both genders. The incidence has been estimated to be as high as 1:6,000 live births, and total population prevalence as high as 8–9 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 invention of CT and ultrasound scanning have enabled the identification of non-symptomatic signs in the brain and kidneys. 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 angiobribroma. The prevalence figures have steadily increased from 1:150,000 in 1956, 1:100,000 in 1968, 1:70,000 in 1971, 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.^{[1] [17]}

[edit] History

1835 The French dermatologist Pierre François Olive Rayer published an atlas of skin diseases. It contains 22 large coloured plates with 400 figures presented in a systematic order. On page 20, fig. 1 is a drawing that is regarded as the earliest description of tuberous sclerosis.^[18] Entitled "végétations vasculaires", Rayer notes these are "small vascular, of papulous appearance, widespread growths distributed on the nose and around the mouth".^[19] No mention is made of any medical condition associated with the skin disorder.

1862 The German physician Friedrich Daniel von Recklinghausen, who was working as an assistant in the Institute for Pathological Anatomy in Berlin,^[20] presented a case to the city's Obstetrical Society. The heart of an infant who "died after taking a few breaths" had several tumours, which he called "myomata". He also noted the brain had a "a great number of scleroses".^[18] These were almost certainly the cardiac rhabdomyomas and cortical tubers of tuberous sclerosis, yet he failed to recognise a distinct disease.^[21] Von Recklinghausen's name would instead become associated with neurofibromatosis after a classic paper in 1881.^[20]

1880 The French neurologist Désiré-Magloire Bourneville, an assistant to Jean Martin Charcot at La Salpêtrière, published a report describing a patient, with a condition he called "Sclérose tubéreuse des circonvolution cérébrales". In addition to the acne common in a 15 year old girl, Marie had "confluent vascular-papulous eruption of the nose, the cheeks, the face". She had learning difficulties, she could not walk or talk, and had epilepsy. She was admitted to the hospital where she had a large number of seizures and a mild fever. These were treated with quinquina, bromide of camphor, amyl nitrite, and the application of leeches behind the ears.^[22] Despite treatment, she died in her hospital bed. The postmortem examination disclosed hard, dense tubers in the cerebral convolutions, which Bourneville concluded were the source (focus) of her seizures.^[18]

1881 Bourneville and Édouard Brissaud examined a 4 year old boy at La Bicétre. As before, this patient had cortical tubers, epilepsy and learning difficulties. In addition he had a heart murmur and, on postmortem examination, had tiny hard tumours in the ventricle walls in the brain (subependymal nodules) and small tumours in the kidneys (angiomyolipomas).^[23]

1890 The Scottish dermatologist John James Pringle described a 25 year old woman with subnormal intelligence and a facial lesion.^[24] The eponym "Pringle's adenoma sebaceum" gained widespread acceptance both to describe the facial rash and also as a synonym for TSC. This was unfortunate for two reasons. Firstly, he wasn't the first to use the term - Félix Balzer pubished papers in 1885 and 1886 using the French equivalent "adénomes sébacés".^[25] Secondly, it is a misnomer since they are neither adenoma nor derived from sebaceous glands. The accepted term is now angiofibroma.^[26]

1908 The German paediatric neurologist Heinrich Vogt established the diagnostic criteria.^[27][28] Vogt's triad of epilepsy, idiocy, and adenoma sebaceum held for 60 years until research by Manuel Gomez discovered that fewer than a third of patients with TSC had all three symptoms.^[18]

[edit] Notes

1. ^ ^{a b c} Paolo Curatolo (2003). “Diagnostic Criteria”, Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898-68339-5.
2. ^ Ridler K, et al (2006). "Neuroanatomical Correlates of Memory Deficits in Tuberous Sclerosis Complex". Cerebral Cortex. PMID 16603714.
3. ^ Harrison JE, Bolton, PF (1997). "Annotation: Tuberous sclerosis". Journal of Child Psychology and Psychiatry 38: 603-614. PMID 9315970.
4. ^ 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.
5. ^ van Slegtenhorst M, et al (1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science 277 (5327): 805-8. PMID 9242607.
6. ^ (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.
7. ^ 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.
8. ^ 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.
9. ^ 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.
10. ^ ^{a b} Roach E, Sparagana S (2004). "Diagnosis of tuberous sclerosis complex.". Journal of Child Neurology 19 (9): 643-9. PMID 15563009.
11. ^ Crino P, Nathanson K, Henske E (2006). "The Tuberous Sclerosis Complex.". New England Journal of Medicine 355 (13): 1345-56. PMID 17005952.
12. ^ ^{a b} Tuberous Sclerosis Fact Sheet. National Institute of Neurological Disorders and Stroke (2006-04-11). Retrieved on 2006-10-03.
13. ^ Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. Tuberous Sclerosis Association (April 2002). Retrieved on 2006-10-03.
14. ^ Yates JR. Tuberous sclerosis. Eur J Hum Genet. 2006 Jul 26; PMID 16868562
15. ^ 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.
16. ^ 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.
17. ^ O'Callaghan F (1999). "Tuberous sclerosis.". BMJ 318 (7190): 1019-20. PMID 10205080.
18. ^ ^{a b c d} Paolo Curatolo (2003). “Hisorical Background”, Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898-68339-5.
19. ^ Rayer, Pierre François (1835). Traité des maladies de la peau / atlas (in French). Paris: J.-B. Baillière, 20. Retrieved on 2006-12-09.
20. ^ ^{a b} Ole Daniel, Enersen. Friedrich Daniel von Recklinghausen. Who Named It?. Retrieved on 2006-12-10.
21. ^ Jansen F, van Nieuwenhuizen O, van Huffelen A (2004). "Tuberous sclerosis complex and its founders.". J Neurol Neurosurg Psychiatry 75 (5): 770. PMID 15090576.
22. ^ Bourneville, Désiré-Magloire (1880). "Sclérose tubéreuse des circonvolution cérébrales: Idiotie et épilepsie hemiplégique". Archives de neurologie, Paris 1: 81-9l. Retrieved on 2006-12-10.
23. ^ Bourneville, Désiré-Magloire, Brissaud, Édouard (1881). "Encéphalite ou sclérose tubéreuse des circonvolutions cérébrales". Archives de neurologie, Paris 1: 390-412. (as cited in Curatolo 2003)
24. ^ Pringle, John James (1890). "A case of congenital adenoma sebaceum". British Journal of Dermatology, Oxford 2: 1-14. (as cited in Curatolo 2003)
25. ^ Ole Daniel, Enersen. Bourneville-Pringle disease. Who Named It?. Retrieved on 2006-12-10.
26. ^ Sanchez N, Wick M, Perry H (1981). "Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related pathologic entities". J Cutan Pathol 8 (6): 395-403. PMID 6278000.
27. ^ Ole Daniel, Enersen. Heinrich Vogt. Who Named It?. Retrieved on 2006-12-11.
28. ^ Vogt, Heinrich (1908). "Zur Diagnostik der tuberösen Sklerose". Zeitschrift für die Erforschung und Behandlung des jugendlichen Schwachsinns auf wissenschaftlicher Grundlage, Jena 2: 1-16. (as cited in Curatolo 2003 and fully cited by Who Named It?)

[edit] References

• 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
• GeneReviews: Tuberous Sclerosis Complex

[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.

[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)