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| Tuberous sclerosis | |
|---|---|
| Other names | Tuberous sclerosis complex (TSC), Bourneville disease, Bourneville-Pringle disease[1] |
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| Main symptoms and signs of tuberous sclerosis | |
| Specialty | Neurology,medical genetics |
| Prognosis | normal life expectancy |
| Frequency | 7 to 12 per 100,000[2] |
Tuberous sclerosis complex (TSC) is a rare, multi-systemgenetic disorder that causesbenign tumors to grow in various organs, including thebrain,kidneys,heart,liver,eyes,lungs, andskin. Symptoms may includeseizures,intellectual disability, anddevelopmental delay.
TSC hasautosomal dominant inheritance, meaning a child with TSC must also have at least one parent with it. It is caused by amutation of either of twogenes,TSC1 andTSC2, which code for theproteinshamartin andtuberin, respectively. TSC2 mutations are more frequent and have usually more severe symptoms.[3] These proteins act astumor growth suppressors, regulatingcell proliferation anddifferentiation. Without them, tumors are more likely to appear.[4]
Life for individuals with TSC varies depending on the severity of the symptoms, but most patients have normallife expectancy through routine medical care.[4] The prevalence of the disease is estimated to be 7 to 12 in 100,000.[2] The disease is often abbreviated totuberous sclerosis, which refers to the hard swellings in the brains of patients,first described by French neurologistDésiré-Magloire Bourneville in 1880.[5]
The physical manifestations of TSC are due to the formation ofhamartia (malformed tissue such as the cortical tubers),hamartomas (benign growths such as facialangiofibroma and subependymal nodules), and very rarely, canceroushamartoblastomas. The effect of these on the brain leads to neurological symptoms such asseizures,intellectual disability, developmental delay, and behavioral problems.[citation needed]
Three types of brain tumours are associated with TSC:[citation needed]
Classic intracranial manifestations of TSC include subependymal nodules and cortical/subcortical tubers.[6]
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. Onmagnetic resonance imaging (MRI), TSC patients can exhibit other signs consistent with abnormal neuron migration such as radial white matter tracts hyperintense on T2WI and heterotopic grey matter.[citation needed]
Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. Interposed neural tissue is not present. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into asubependymal giant cell astrocytoma, which typically develops in the region of theforamen of Monro, in which case it is at risk of developing an obstructivehydrocephalus.
A variable degree of ventricular enlargement is seen, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monro) or idiopathic in nature.[citation needed]
About 90% of people with TSC develop a range of neurodevelopmental, behavioural, psychiatric, and psychosocial difficulties. The "TSC‐associated neuropsychiatric disorders" are abbreviated TAND. These difficulties are less frequently identified and thus undertreated when compared with the neurological symptoms.[7] Most problems are associated with more severe intellectual delay or associated with childhood and adolescence, and some (for example depressed mood) may be unreported if the person is unable to communicate. TAND can be investigated and considered at six levels: behavioural, psychiatric, intellectual, academic, neuropsychological, and psychosocial.[7]
Behavioural problems most commonly seen include overactivity, impulsivity and sleeping difficulties. Also common are anxiety, mood swings, and severe aggression. Less common are depressed mood, self-injury, and compulsive behaviours.[7]
People with TSC are frequently also diagnosed with psychiatric disorders:autism spectrum disorder (ASD),attention deficit hyperactivity disorder (ADHD),anxiety disorder anddepressive disorder. TSC is one of the most common genetic causes of autism spectrum disorder, which affects nearly half of people with TSC. ASD is more common in TSC2 than TSC1 and more common with earlier and more severe epilepsy, and with lower intellectual ability. ADHD is nearly as frequently seen in TSC as ASD (up to half of all people with TSC). Anxiety and depressive disorders, when they occur, are typically diagnosed in early adulthood and among those intellectually able to express their moods.[7]
The intellectual ability of people with TSC varies enormously. About 40–50% have a normal IQ. A normal IQ is much more commonly seen in TSC1 than TSC2, and profound intellectual disability seen in 34% of TSC2 compared with 10% of TSC1 in one study. Many studies have examined whether early onset, type and severity of epilepsy associates with intellectual ability. Academic issues occur even in people with TSC who have normal intellectual ability. These are often specific learning disorders such asdyscalculia (understanding mathematics), but also include other aspects affecting school life such as anxiety, lack of social skills or low self-esteem.[7]
About half of people with TSC, when assessed for neuropsychological skills, are in the bottom 5th percentile in some areas, which indicates a severe impairment. These include problems withattention (for example, being able to concentrate on two separate things like looking and listening),memory (particularlyrecall,verbal andspatial working memory) andexecutive function (for example,planning,self-monitoring,cognitive flexibility).[7]
Thepsychosocial impacts of TSC include lowself-esteem andself-efficacy in the individual, and aburden on the family coping with a complex and unpredictable disorder.[7]
Between 26% and 80% of TSC patients have benign tumors of the kidneys calledangiomyolipomas, withhematuria being the most frequent presenting symptom.[8] TSC angiomyolipomas differ from non-TSC angiomyolipomas in age of presentation (31.5 years vs 53.6 years), mean tumor size (8.2 cm vs 4.5 cm), and percentage of cases requiring surgical intervention (50% vs 28%).[8] Although benign, an angiomyolipoma larger than 4 cm is at risk for a potentially catastrophic hemorrhage, either spontaneously or with minimal trauma.[citation needed]
Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts, known aslymphangioleiomyomatosis (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported.[9]
Small tumours of theheart muscle, called cardiacrhabdomyomas, are rare in the general population (perhaps 0.2% of children) but very common in people with TSC. Around 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several. The vast majority of children with at least one rhabdomyoma, and nearly all children with multiple rhabdomyomas will be found to have TSC. Prenatal ultrasound, performed by anobstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. Rhabdomyoma vary in size from a few millimetres to several centimetres, and are usually found in the lower chambers (ventricles) and less often in the upper chambers (atria). They grow in size during the second half of pregnancy, but regress after birth, and are seen in only around 20% of children over two years old.[10]
Most rhabdomyomas cause no problems but some may cause heart failure in the foetus or first year of life. Rhabdomyomas are believed to be responsible for the development ofheart arrhythmia later in life, which is relatively common in TSC. Arrhythmia can be hard to spot in people with TSC, other than by performing routine ECG. For example, arrhythmia may causefainting that is confused withdrop seizures, and symptoms of arrhythmia such as palpitations may not be reported in an individual with developmental delay.[10]
Some form of dermatological sign is 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:
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 aCT scan.[13]
Nonretinal lesions associated with TSC include:
Pancreatic neuroendocrine tumours have been described in rare cases of TSC.[14]
Individuals with TSC 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 TSC.
TSC is a genetic disorder with anautosomal dominant pattern of inheritance, variable expressivity, and incompletepenetrance.[12][16] 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 roughly 20% of individuals diagnosed with the disease. So far, it has been mapped to two genetic loci,TSC1 andTSC2.[17]
TSC1 encodes for the protein hamartin, is located onchromosome 9 q34, and was discovered in 1997.[18]TSC2 encodes for the protein tuberin, is located onchromosome 16 p13.3, and was discovered in 1993.[19]TSC2 is contiguous withPKD1, the gene involved in one form ofpolycystic kidney disease (PKD). Grossdeletions affecting both genes may account for the 2% of individuals with TSC who also develop polycystic kidney disease in childhood.[20]TSC2 has been associated with a more severe form of TSC.[21] However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused byTSC2 range from 55% to 90%.[3]
TSC1 andTSC2 are bothtumor suppressor genes that function according toKnudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its highpenetrance, TSC has wideexpressivity.[citation needed]
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Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact withRHEBGTPase, thus sequestering it from activatingmTOR signalling, part of thegrowth factor (insulin) signalling pathway. Thus, mutations at theTSC1 andTSC2 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 angiofibroma, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of theforamina of Monro.[citation needed]
Molecular genetic studies have defined at least two loci for TSC. InTSC1, the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. No missense mutations occur inTSC1. InTSC2, the gene abnormalities are on chromosome 16p13. This gene encodes tuberin, a guanosine triphosphatase–activating protein. The specific function of this protein is unknown. InTSC2, 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.[citation needed]
Cells from individuals with pathogenic mutations in the TSC2 gene display abnormal accumulation ofglycogen that is associated with depletion oflysosomes andautophagic impairment. The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation ofmTORC1 and is restored, in cultured cells, by the combined use ofPKB/Akt and mTORC1 pharmacological inhibitors.[22]
Tuberous sclerosis complex is diagnosed with clinical andgenetic tests. There are many different mutations in the TSC1 and TSC2 genes that have been identified in individuals with TSC. A pathogenic mutation in the gene prevents the proteins from being made or inactivates the proteins. If such a pathogenic mutation is found then this alone is sufficient to diagnose TSC. However, some mutations are less clear in their effect, and so not sufficient alone for diagnosis. Between 1 in 10 and 1 in 4 of individuals with TSC have no mutation that can be identified. Once a particular mutation is identified in someone with TSC, this mutation can be used to make confident diagnoses in other family members.[11]
For clinical diagnosis, there isn't onesign that is unique (pathognomonic) to TSC, nor are all signs seen in all individuals. Therefore, several signs are considered together, classed as either major or minor features. An individual with two major features, or one major feature and at least two minor features can be given a definite diagnosis of TSC. If only one major feature or at least two minor features are present, the diagnosis is only regarded as possibly TSC.[11]
| Major Features | ||||
|---|---|---|---|---|
| Location | Sign | Onset[23] | Note | |
| 1 | Skin | Hypomelanoticmacules | Infant – child | At least three, at least 5 mm in diameter. |
| 2 | Head | Facial angiofibromas or fibrous cephalic plaque | Infant – adult | At least three angiofibromas |
| 3 | Fingers and toes | Ungualfibroma | Adolescent – adult | At least two |
| 4 | Skin | Shagreen patch (connective tissuenevus) | Child | |
| 5 | Eyes | Multipleretinalnodularhamartomas | Infant | |
| 6 | Brain | Cortical dysplasias | Fetus | (includes tubers and cerebral white matter radial migration lines) |
| 7 | Brain | Subependymalnodule | Child – adolescent | |
| 8 | Brain | Subependymal giant cellastrocytoma | Child – adolescent | |
| 9 | Heart | Cardiacrhabdomyoma | Fetus | |
| 10 | Lungs | Lymphangioleiomyomatosis | Adolescent – adult | |
| 11 | Kidneys | Renalangiomyolipoma | Child – adult | At least two. Together,10 and11 count as one major feature. |
| Minor Features | ||||
| Location | Sign | Note | ||
| 1 | Skin | "Confetti" skin lesions | ||
| 2 | Teeth | Dental enamel pits | At least three | |
| 3 | Gums | Intraoral fibromas | At least two | |
| 4 | Eyes | Retinal achromic patch | ||
| 5 | Kidneys | Multiplerenal cysts | ||
| 6 | Liver, spleen and other organs | Nonrenalhamartoma | ||
TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routineultrasound. In infancy, epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. The white patches on the skin may also first become noticed. In childhood, behavioural problems andautism spectrum disorder may provoke a diagnosis. During adolescence, the skin problems appear. In adulthood, kidney and lung problems may develop. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.[24]
Tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required.[citation needed]
In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.[25]
The various symptoms and complications from TSC may appear throughout life, requiring continued surveillance and adjustment to treatments. The following ongoing tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.[25]
The mTOR inhibitoreverolimus was approved in the US for treatment of TSC-related tumors in the brain (subependymal giant cell astrocytoma) in 2010 and in the kidneys (renalangiomyolipoma) in 2012.[26][27] Oral everolimus (rapalog) reduces tumour size, is effective in terms of response to skin lesions and does not increase the risk of adverse events.[28] Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC.[29][30] In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.[31]
Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients.[32][33]Embolization and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. Surgical treatments for symptoms oflymphangioleiomyomatosis (LAM) in adult TSC patients include pleurodesis to preventpneumothorax andlung transplantation in the case of irreversible lung failure.[25]
Other treatments that have been used to treat TSC manifestations and symptoms include aketogenic diet for intractable epilepsy and pulmonary rehabilitation for LAM.[34] Facial angiofibromas can be reduced withlaser treatment and the effectiveness of mTOR inhibitor topical treatment is being investigated. Laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation.[35]
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.[4]
A study of 30 TSC patients in Egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD [autism spectrum disorders]. 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."[36]
Leading causes of death include renal disease, brain tumour,lymphangioleiomyomatosis of the lung, andstatus epilepticus orbronchopneumonia in those with severe intellectual disability.[37] Cardiac failure due torhabdomyomas is a risk in the fetus or neonate but is rarely a problem subsequently. Kidney complications such asangiomyolipoma and cysts are common and more frequent in females than males and inTSC2 thanTSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis is only a risk for females with angiomyolipomas.[38] In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.[citation needed]
Detection of the disease should be followed by genetic counselling. It is also important to realize that though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of TSC is important.[39]
TSC occurs in all races and ethnic groups, and in both sexes. Thelive-birthprevalence is estimated to be between 10 and 16 cases per 100,000. A 1998 study[2] estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. Prior to the invention ofCT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower, and the disease associated with those people diagnosed clinically with learning disability, seizures and facial angiofibroma. Whilst still regarded as arare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals affected worldwide.[15]
TSC first came to medical attention when dermatologists described the distinctive facial rash (1835 and 1850). A more complete case was presented byvon Recklinghausen (1862), who identified heart and brain tumours in a newborn who had only briefly lived. However,Bourneville (1880) is credited with having first characterized the disease, coining the name "tuberous sclerosis", thus earning theeponym Bourneville's disease. The neurologistVogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).[40]
Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described byGomez (1979). The invention ofmedical ultrasound,CT andMRI has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability.[citation needed]
In 2002, treatment withrapamycin 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 TSC.[41]
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