tuberous sclerosis tuberous sclerosis tuberous sclerosis complex (tsc) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. a combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease. not to be confused with tuberculosis or tsc (disambiguation). tuberous sclerosisother namestuberous sclerosis complex (tsc),bourneville diseasemain symptoms and signs of tuberous sclerosisspecialtyneurology, medical geneticsprognosisnormal life expectancyfrequency7 to 12 per 100,000 tsc is caused by a mutation of either of two genes, tsc1 and tsc2, which code for the proteins hamartin and tuberin, respectively, with tsc2 mutations accounting for the majority and tending to cause more severe symptoms. these proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation. prognosis is highly variable and depends on the symptoms, but life expectancy is normal for many. the prevalence of the disease is estimated to be 7 to 12 in 100,000. the disease is often abbreviated to tuberous sclerosis, which refers to the hard swellings in the brains of patients, first described by french neurologist désiré-magloire bourneville in 1880. signs and symptoms the physical manifestations of tsc are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules), and very rarely, cancerous hamartoblastomas. the effect of these on the brain leads to neurological symptoms such as seizures, intellectual disability, developmental delay, and behavioral problems. neurological tsc in mri three types of brain tumours are associated with tsc: giant cell astrocytoma: (grows and blocks the cerebrospinal fluid flow, leading to dilatation of ventricles causing headache and vomiting) cortical tubers: after which the disease is named subependymal nodules: form in the walls of ventricles classic intracranial manifestations of tsc include subependymal nodules and cortical/subcortical tubers. 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 (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. 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 a subependymal giant cell astrocytoma, which 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 is seen, either obstructive (e.g. by a subependymal nodule in the region of the foramen of monro) or idiopathic in nature. neuropsychiatric 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. 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. 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. people with tsc are frequently also diagnosed with psychiatric disorders: autism spectrum disorder (asd), attention deficit hyperactivity disorder (adhd), anxiety disorder and depressive 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. schizophrenia (and symptoms like hallucinations or psychosis) is no more common in tsc than the general population. 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 as dyscalculia (understanding mathematics), but also include other aspects affecting school life such as anxiety, lack of social skills or low self-esteem. 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 with attention (for example, being able to concentrate on two separate things like looking and listening), memory (particularly recall, verbal and spatial working memory) and executive function (for example, planning, self-monitoring, cognitive flexibility). the psychosocial impacts of tsc include low self-esteem and self-efficacy in the individual, and a burden on the family coping with a complex and unpredictable disorder. kidneys computed tomography showing multiple angiomyolipomas of the kidney in a patient with lung lymphangioleiomyomatosis on ct: suspected tsc between 60 and 80% of tsc patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called angiomyolipomas frequently causing hematuria. these tumors are composed of vascular (angio–), smooth muscle (–myo–), and fat (–lip-) tissue. although benign, an angiomyolipoma larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. lungs patients with tsc can develop progressive replacement of the lung parenchyma with multiple cysts, known as lymphangioleiomyomatosis (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. heart small tumours of the heart muscle, called cardiac rhabdomyomas, 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 an obstetric 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. 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 of heart 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 cause fainting that is confused with drop seizures, and symptoms of arrhythmia such as palpitations may not be reported in an individual with developmental delay. skin a case of tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern. from top to bottom: hypopigmented macules, shagreen patch and periungual fibroma of tuberous sclerosis. 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: hypomelanic macules ("ash leaf spots") are present in about 90% of people with tsc. these small white or lighter patches of skin may appear anywhere on the body, and are caused by a lack of melanin. they 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. on the scalp, the effect may be a white patch of hair (poliosis). patches smaller than 3mm are known as "confetti" skin lesions. facial angiofibromas are present in about 75% of people with tsc. these are a rash of reddish spots or bumps on the nose and cheeks in a butterfly distribution, which consist of blood vessels and fibrous tissue. this potentially socially embarrassing rash starts to appear during childhood. ungual fibromas: also known as koenen's tumors, these are small fleshy tumors that grow around and under the toenails or fingernails. these are rare in childhood, but common by middle age. they are generally more common on toes than on fingers, develop at 15–29 years, and are more common in women than in men. fibrous cephalic plaques are present in about 25% of people with tsc. these are raised, discoloured areas usually found on the forehead, but sometimes on the face or elsewhere on the scalp. shagreen patches are present in about half of people with tsc, appearing in childhood. they are areas of thick leathery skin that are dimpled like an orange peel, and pigmented, they are usually found on the lower back or nape of the neck, or scattered across the trunk or thighs. the frequency of these lesions rises with age. dental enamel pits are found in almost all adults with tsc. intraoral fibromas are small surface-tumours found in the gums, inside the cheeks or tongue. gum (gingival) fibromas are found in about 20-50% of people with tsc, more commonly in adults. 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 they are in the differential diagnosis of a calcified globe mass on a ct scan. nonretinal lesions associated with tsc include: coloboma angiofibromas of the eyelids papilledema (related to hydrocephalus) pancreas pancreatic neuroendocrine tumours have been described in rare cases of tsc. variability 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. the frequency of signs in children with tsc, grouped by age genetics tsc is inherited in an autosomal dominant fashion. tsc is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. 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 and tsc2. tsc1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. tsc2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. 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 polycystic kidney disease in childhood. tsc2 has been associated with a more severe form of tsc. 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 90%. 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 high penetrance, tsc has wide expressivity. hamartinidentifierssymboltsc1ncbi gene7248hgnc12362omim605284refseqnm_000368uniprotq92574other datalocuschr. 9 q34search forstructuresswiss-modeldomainsinterpro tuberinidentifierssymboltsc2ncbi gene7249hgnc12363omim191092refseqnm_000548uniprotp49815other datalocuschr. 16 p13.3search forstructuresswiss-modeldomainsinterpro pathophysiology hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. the complex appears to interact with rheb gtpase, thus sequestering it from activating