Genetics of tuberous sclerosis | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Genetics of tuberous sclerosis

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease.[1] Tuberous sclerosis complex is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, patients with tuberous sclerosis complex may present with a broad range of clinical symptoms because of variable expressivity. Tuberous sclerosis complex may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic spots known as Fitzpatrick patches (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas.

Mutations in either of 2 genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, diagnosis continues to be based on clinical manifestations.[2] . Molecular analysis is helpful in confirming a diagnosis and genetic counseling.

This article elucidates the various neoplasms, along with their clinical significance, and suggest suitable evaluation and management strategies.

Molecular genetics and pathogenesis

Tuberous sclerosis complex has a broad clinical spectrum and affects almost every organ system.[3] Tuberous sclerosis complex is an inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, kidney, liver, lung, and heart.

The hamartomas in the brain called cortical tubers are composed of abnormal glial and neural cells, and the size, number, and location vary among patients. Differences in diffusion properties of white matter between tuberous sclerosis complex and control subjects suggest disorganized and structurally compromised axons with poor myelination. The visual and social cognition systems appear to be differentially involved.[4]

The number of tubers may correlate with the severity of seizures. Other CNS manifestations include SENs and SEGAs. SENs are typically located on the surface of the lateral ventricles, giving a candle-dripping appearance, and they tend to calcify during childhood. SENs occasionally give rise to SEGAs, which develop in the Monro foramen and may cause signs and symptoms of hydrocephalus and increased intracranial pressure as they enlarge.

Skin lesions include ash-leaf spots, confetti lesions, facial angiofibromas, shagreen patches, fibrous plaques, and periungual fibromas. The hypopigmentation of ash-leaf spots is due to smaller melanosomes and defective transfer of melanin to keratinocytes. Fibromas, plaques, and patches are due to fibrosis with abnormal collagen and blood vessel accumulation.

Renal manifestations of tuberous sclerosis complex include angiomyolipomas and renal cysts. Angiomyolipomas, found in 70-80% of patients with tuberous sclerosis complex, are composed of blood vessels, smooth muscle, adipose tissue, and connective tissue. The gene for polycystic kidney disease (PKD), PKD1, is contiguous with the TSC2 gene on chromosome 16, and patients with tuberous sclerosis complex occasionally have symptoms of PKD.

Cardiac involvement is in the form of hamartomas, namely rhabdomyomas.

Pulmonary lesions are lymphangioleiomyomatosis (LAM) and pulmonary cysts. These lesions are composed of blood vessels, adipose tissue, and smooth muscle in abnormal arrangements.

Ocular involvement includes retinal hamartomas or astrocytomas that may calcify but rarely lead to decreased visual acuity or other symptoms.

Phalangeal cysts may develop in the hands and feet, and sclerotic lesions may develop in the pelvis or the spine.

The genes responsible for tuberous sclerosis complex have been identified. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in tuberous sclerosis complex. TSC1 is located on chromosome 9 and was identified in 1997. TSC1 encodes for the protein hamartin; TSC2, encodes for the protein tuberin. Mutations in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression, cause tuberous sclerosis complex.[5]

The function and interaction of hamartin and tuberin are not yet fully understood, although they may function as tumor suppressors. Knudson’s 2-hit model of tumorigenesis mandates that a second-hit mutation and resulting loss of heterozygosity (LOH) of a tumor suppressor gene is necessary for tumor formation. LOH is commonly found in several types of hamartomas formed in the process of tuberous sclerosis, but not in brain lesions that contain characteristic giant cells.[6]

Hamartin and tuberin are believed to have a role in growth and differentiation of cells. Both proteins are found throughout the body and interact with each other. Little attention has been given to the recently discovered role of the TSC1/TSC2 complex in gene transcription via the Wnt signaling pathway; hamartin and tuberin have been found to modulate gene transcription via beta-catenin.[7]

Evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas.[8] Jozwiak et al postulate that ERK activation consistently detected in different tuberous sclerosis–associated tumors is a molecular trigger for the development of these neoplasms.[9] Cardiac rhabdomyoma arising in tuberous sclerosis may progress due to Erk potentiation.[10]

There are more than 450 different disease-causing mutations are known for TSC1 and more than 1300 for TSC2, with most of TSC1 mutations being truncating comprising frameshift, nonsense, and splice mutations.[11] A novel TSC2 mutation was recently described.[12] TSC2 -deficient cells may have increased choline phospholipid metabolism.[13]

Molecular studies suggest that tumor development relies on second-hit events, ie, a storm of them, to produce multifocal renal cell carcinoma in tuberous sclerosis complex.[14]



United States

Tuberous sclerosis complex affects approximately 40,000 people in the United States. The incidence is estimated to be 1 case per 6000 live births, with a prevalence of 1 in 10,000 births. The prevalence of tuberous sclerosis complex was previously estimated to be 1 in 50,000-100,000 births. Revision of the diagnostic criteria and improved recognition of the disease complex by physicians have resulted in an increased prevalence rate. Further evaluation of family members may also result in recognition of tuberous sclerosis complex in people with less severe phenotypes, which also increases the prevalence rate.


Estimates indicate that 2,000,000 people have tuberous sclerosis complex worldwide.

Mutations in the genes TSC1 or TSC2 had been considered rare in Korean populations. However, that may not be the case, as demonstrated by direct sequencing followed by multiplex ligation–dependent probe amplification analysis.[15]

Based on a meta-analysis of 380 tuberous sclerosis patients, the frequency of TSC1 mutations was found to be twice as high in the American and British populations compared with those from Poland and from the Republic of China.[16] These data should be verified with additional larger studies.


Overall, the most common cause of death in patients with tuberous sclerosis complex is status epilepticus or bronchopneumonia. The next most frequent cause of death is renal failure. Lymphangioleiomyomatosis (LAM) is the most common cause of death in patients with tuberous sclerosis complex, when present.

Morbidity is associated in the following organ systems:


Seizures, hydrocephalus, mental retardation, and autism or pervasive developmental disorder (PDD) are commonly associated with morbidity in children with tuberous sclerosis complex.

Seizures are the most common cause of morbidity and affect more than one half of patients with tuberous sclerosis complex. Infantile spasms affect approximately one third of patients and are often one of the early symptoms of tuberous sclerosis complex. An early age of onset of seizures is associated with risks of refractory seizures and decreased cognitive function. Earlier and more aggressive treatment may improve outcome

The growth of SEGAs may lead to hydrocephalus, although growth is gradual and patients often do not become symptomatic until significant hydrocephalus has developed. Patients may then experience neurologic sequelae, including blindness. Patients often require neurosurgery and shunt placement.

Approximately 50-85% of children with tuberous sclerosis complex have mental retardation. Approximately 0.1-0.7% of patients with mental retardation have tuberous sclerosis complex. Nearly all patients with mental retardation have seizures, although the reverse is not always true. Seizures and mental retardation may be concomitant.

Autism or PDD is present in 15-85% of children. The typical pattern of male bias in autism does not extend to patients with tuberous sclerosis complex.

Various behavioral disorders, including sleep disorders, hyperactivity, aggression, and schizophrenia, may be present in some individuals. Patients with tuberous sclerosis complex who have normal intelligence may be prone to developmental language disorders.


Various skin lesions are present in as many as 95% of patients with tuberous sclerosis complex. Facial angiofibromas, present in 75% of patients, cause the most morbidity because of the disfiguring cosmetic effects.


Approximately 70-80% of patients with tuberous sclerosis complex have either renal cysts, which are more common in children, or angiomyolipomas, which are more common in adults. Renal failure or hypovolemic shock due to bleeding angiomyolipomas may lead to death. Renal failure is the second most common cause of death in patients with tuberous sclerosis complex. The risk of bleeding increases when angiomyolipomas are larger than 4 cm. Rarely, renal lesions undergo differentiation to renal cell carcinoma.


Rhabdomyomas often develop at 22-26 weeks’ gestation. They may cause fetal death due to nonimmune hydrops fetalis. These benign tumors may cause valvular dysfunction, outflow obstruction in 1-2 ventricles, decreased contractility, and cardiomyopathy. Rhabdomyomas may also predispose patients to cardiac arrhythmias. In most patients, if outflow obstruction does not occur during the neonatal period, the lesions frequently resolve spontaneously or shrink after several years. Although cardiac rhabdomyomas are common, they do not usually cause mortality.


Lymphangioleiomyomatosis (LAM) predominantly occurs in females with tuberous sclerosis complex, although fewer than 1% of females are affected. Pulmonary hypertension and fibrosis may lead to cor pulmonale. Pneumothorax or pulmonary failure is often the final cause of death in patients with LAM or pulmonary cysts.


Tuberous sclerosis complex occurs with equal frequency in all races.


No sex predilection is noted in this autosomal dominant disease. Tuberous sclerosis complex in females tends to be associated with higher morbidity and mortality rates because the incidence of lung involvement is higher in females than in males.


Tuberous sclerosis complex is a congenital disorder, although age at diagnosis may range from birth to adulthood. Patients who are not severely affected may be diagnosed only when a family member is discovered to have tuberous sclerosis complex and all family members are evaluated. Younger patients typically present with cardiac rhabdomyomas, brain tumors, ash-leaf spots, or seizures, particularly infantile spasms. Diagnosis at a later age is often due to CNS and dermatologic manifestations.


Clinical features

Children with tuberous sclerosis complex (TSC) may have a broad range of symptoms and signs, ranging from subclinical findings to severe handicaps, because of variable expression.

CNS symptoms

The most common and severe CNS manifestations of tuberous sclerosis complex include seizures, including infantile spasms and mental retardation. These relate to cortical/subcortical glioneuronal tubers, subependymal glial nodules, and subependymal giant cell astrocytomas (SEGA). The cortical tubers in the brain are typically located at the gray-white matter interface, commonly in the frontal and parietal lobes.[17] Seizures may develop during infancy or later. Infantile spasms or a hypsarrhythmia pattern on EEG findings may be present in infants with tuberous sclerosis complex. Other common seizure types in patients with tuberous sclerosis complex are complex partial and tonic-clonic seizures.

TSC2 mutations, and especially TSC2/PKD1 mutations, tend to develop SEGA earlier in childhood and should be screened for SEGA from birth (Kotulska et al, 2014).

All patients with tuberous sclerosis complex who have mental retardation have seizures, but not all patients with seizures have mental retardation. Intelligence may be normal, or children may have mild, moderate, or severe mental retardation.

Other symptoms include autism or pervasive developmental disorder (PDD), aggressive behavior, schizophrenia, and sleep disturbances. Sleep disturbances may be displayed by decreased overall sleep time and frequent nocturnal awakenings.

Dermatologic symptoms

Skin findings are very common in tuberous sclerosis complex and should be regarded as signs of this pivotal systemic disease.

Hypomelanotic macules are overwhelmingly the most common early finding in tuberous sclerosis complex.[18] . These hypopigmented lesions are described as ash-leaf spots. These are best observed using a Wood lamp. A Fitzpatrick patch or ash-leaf spot may be observed in the general population, but the presence of at least 3 spots constitutes one of the major diagnostic criteria. These macules often come in other shapes, although most are polygonal, usually 0.5-2 cm in diameter, and resemble a thumbprint. In honor of their deceased describer, Thomas Fitzpatrick, they are termed Fitzpatrick patches.[19]

Infants with seizures or other stigmata of tuberous sclerosis complex should be evaluated for these hypomelanotic macules and for other associated findings. Confetti lesions are also hypomelanotic lesions that cluster and have a reticulated or network appearance. They may develop anywhere on the skin.

Facial angiofibromas and forehead plaques usually present in patients older than 2 years. Facial angiofibromas are erythematous lesions located on the cheeks, nose, and chin, often sparing the upper lip. Growth is often increased during puberty, and angiofibromas are sometimes confused with acne. The presence of one or both of these lesions constitutes one of the major diagnostic criteria. The relationship between the presence of a forehead plaque and CNS involvement may be statistically significant in patients with tuberous sclerosis complex.[20] If true, forehead plaque may be considered as a novel cutaneous marker of CNS involvement in tuberous sclerosis complex at an early stage.

A shagreen patch is a connective tissue hamartoma located in the lower back region. A shagreen patch has an orange peel or leathery texture and often presents in children aged 2-6 years but may not appear until puberty.

Genetics of Tuberous Sclerosis 4

Fig. 4. A shagreen patch is a connective tissue hamartoma with a leathery texture and is found most commonly in the lower back region.

Ungual or periungual fibromas (see the image below) may appear in adolescents or adults with tuberous sclerosis complex. Fibromas may cause distortion of the nail or nailbed. They can occur as an isolated sign of tuberous sclerosis complex with TSC1 germline mutation.[21]


Fig. 7. Periungual fibroma on the thumb of a patient with tuberous sclerosis complex (TSC).

Periungual fibromas may bleed and may produce pain and nail distortion.[22]

Café au lait spots occasionally develop in patients with tuberous sclerosis complex, although they are usually less common in patients with tuberous sclerosis complex than in those with neurofibromatosis.

Renal symptoms

Renal angiomyolipomas are considered one of the major diagnostic features of tuberous sclerosis complex. Angiomyolipomas are mesenchymal neoplasms that occur sporadically or are associated with tuberous sclerosis complex; they are generally considered to be benign. Malignant angiomyolipomas are rare; most are found to be epithelioid upon histopathological examination. A renal angiomyolipoma with a malignant epithelioid component was recently described in a patient with tuberous sclerosis complex.[23] Renal cysts are also common, and 40-80% of patients with tuberous sclerosis complex have either renal angiomyolipomas or renal cysts. The presence of hypovolemic shock may result from bleeding angiomyolipomas. Renal failure may also be evident.

Flank pain is the most common renal symptom. Other symptoms include hematuria, hypertension, and, rarely, hemorrhagic shock or renal failure, which may develop in severe cases. Renal symptoms are rare during childhood and are not present in all patients with renal disease.

Cardiac symptoms

Cardiac rhabdomyomas are often present at birth or during infancy but may be detected as early as 20 weeks’ gestation using fetal ultrasonography. These are usually multiple and intramural, may cause abnormal valve function, outflow obstruction, decreased contractility, cardiomyopathy, and arrhythmias. Usually they are asymptomatic and spontaneously regress as the child ages. However, they may cause cause outflow tract obstruction during the neonatal period.Cardiac rhabdomyomas may cause heart failure or arrhythmia, even in the presence of normal echocardiogram findings.

A case report of molecular confirmation identified multiple cardiac rhabdomyomas as a sole symptom of tuberous sclerosis complex. A child was described with multiple cardiac rhabdomyomas that were identified using routine fetal ultrasonography.[24] Molecular genetic studies identified a TSC2 gene missense mutation. At age 6 years, he had no skin manifestations of tuberous sclerosis complex, although CT scan of the brain revealed 2 periventricular calcifications consistent with the molecular diagnosis. Molecularly confirmed tuberous sclerosis complex in a child with multiple cardiac rhabdomyomas and no other clinical manifestations of the disease had not been previously described. All infants with multiple cardiac rhabdomyomas were proposed to be given a tentative diagnosis of tuberous sclerosis complex.

Pulmonary symptoms

Lymphangiomyomas (LAM) and pulmonary cysts develop almost exclusively in women in the third or fourth decade of life, and are present in fewer than 1% of females with tuberous sclerosis complex. LAM produces cystic lung disease adroitly characterized as a type of perivascular epithelioid cell tumor.[25]

Symptoms include dyspnea, hemoptysis, and development of spontaneous pneumothorax. Pulmonary fibrosis and hypertension may lead to cor pulmonale.

Oral symptoms

Most oral fibromas in tuberous sclerosis complex are gingival.[26] Asymptomatic pitting of dental enamel is common in the permanent teeth of patients with tuberous sclerosis complex. Nearly all patients have dental pits. They are more easily detected when teeth are stained.

Miscellaneous manifestations

A retinal hamartoma or astrocytoma may cause an abnormal red reflex that is sometimes confused with retinoblastoma. Visual acuity is typically not affected.

A rectal hamartoma or polyp is occasionally detected using a digital rectal examination.

A low-grade hypothalamic papillary tumor recently described may extend the spectrum of neoplasms with tuberous sclerosis complex.[27]

Children with tuberous sclerosis complex may rarely develop a chordoma, a cancer that arises from notochordal remnants.[28] TSC1 and TSC2 mutations have been postulated to contribute to chordoma etiology.



The diagnosis of tuberous sclerosis complex is made on the clinical basis. In 1998, the National Institutes of Health Consensus Conference on Tuberous Sclerosis Complex developed revised diagnostic criteria, as follows:[29]

Definitive diagnosis — The presence of 2 major features or 1 major feature plus 2 minor features

Probable diagnosis — The presence of 1 major feature plus 1 minor feature

Possible diagnosis — The presence of 1 major feature or 2 minor features

Diagnostic criteria for tuberous sclerosis complex have been revised.[30] Recognize that individuals with isolated lymphangioleiomyomatosis (LAM) who have associated renal angiomyolipomas do not have tuberous sclerosis complex.

Major features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), 3 or more ash-leaf spots (see the first image below), facial angiofibromas or forehead plaques (see the second image below), shagreen patches, ungual or periungual fibromas in the absence of trauma, cardiac rhabdomyomas, lymphangioleiomyomatosis (LAM), renal angiomyolipomas, or retinal hamartomas.

Genetics of Tuberous Sclerosis 3

Fig 3. Ash-leaf spots are hypomelanotic lesions that are observed more easily with the use of a Wood lamp.

Genetics of Tuberous Sclerosis 2

Fig 2. Forehead plaque in a patient with tuberous sclerosis complex (TSC). The presence of either a forehead plaque or a facial angiofibroma constitutes one of the major diagnostic criteria for TSC.

Minor features include dental pits, gingival fibromas, confetti skin lesions (see the image below), bone cysts, hamartomatous rectal polyps, multiple renal cysts, other nonrenal hamartomas, achromic lesions of the retina, and radial migration lines of cerebral white matter.

Genetics of Tuberous Sclerosis 5

Fig 5. Confetti skin lesions are hypomelanotic lesions that cluster and appear reticulated.

Many findings regarded as highly specific for tuberous sclerosis complex are not apparent until late childhood or adulthood.[31] Physicians should be aware of the criteria frequency at different stages of tuberous sclerosis complex in children.

Molecular analysis can detect mutations in about 85% of cases and the rest do not have a detectable mutation. Molecular analysis is also complicated by the fact that the genes are large and many different disease causing mutations occur. It can be used to confirm diagnosis in clinically diagnosed cases and is quite useful for genetic counseling and prenatal diagnosis when a mutation in an affected parent is known. Information regarding gene testing is available online from GeneTests.

Phenotypic variation is observed even with the same genotype (same genetic mutation). Clinical symptoms of tuberous sclerosis complex in 4 patients with an identical TSC2 mutation were assessed.[32] Epilepsy, depigmented spots, and periventricular calcification and cortical tubers were evident in all 4 patients; cardiac rhabdomyoma and angiomyolipoma of the kidneys were evident in 3 patients; and mental retardation and forehead fibroma were evident in 2 patients. Thus, tuberous sclerosis complex symptoms varied in patients with the identical type of TSC2 mutation. The main symptoms were present in all or most patients; the clinical picture also differed based on age.

Tuberous sclerosis complex is most often diagnosed in children, with an average age at diagnosis of 7.5 years (range, birth to 73 y) in one retrospective study.[33] Eighty-one percent were diagnosed with tuberous sclerosis complex before age 10 years in this retrospective evaluation of 243 patients at Massachusetts General Hospital in Boston.


Tuberous sclerosis complex is inherited in an autosomal dominant pattern. Therefore a detailed family history should be obtained when a child is diagnosed with tuberous sclerosis complex, looking for subclinical symptoms and bearing in mind the major and minor clinical features. This should be followed by a detailed clinical examination to look for major/minor criteria of tuberous sclerosis complex. A parent affected with tuberous sclerosis complex has a 50% chance of transmitting the disease to each offspring.

About two thirds of cases are sporadic as a result of new mutations. If the parents are determined to be unaffected after careful evaluation, they still have a recurrence risk of 1-2% in subsequent pregnancies due to possible gonadal mosaicism. Incidence of gonadal mosaicism is approximately 10-25%.

Criteria for germline mosaicism have recently been outlined. Parents without evidence of either major or minor criteria of tuberous sclerosis complex who have 2 or more children with tuberous sclerosis complex meet the criteria for germline mosaicism.

Mutations in two genes, TSC1 and TSC2, have been identified as causes of tuberous sclerosis complex. Approximately 50% of familial cases are due to mutations in TSC1, and the remaining 50% are due to TSC2. A mutation in the TSC2 gene is responsible for 75% of sporadic cases.

Currently, tuberous sclerosis complex is a clinical diagnosis but genetic testing is useful for prenatal diagnosis if the affected parent has a detectable mutation. It may be useful in suspected cases of gonadal mosaicism.

The family should be referred to a genetics clinic for genetic counseling of all of the above issues.

The genetic counselor can provide information to the patient and the family about the natural history, inheritance, recurrence risk and resources.

Diagnostic Considerations

The following should be considered:

  • Autism
  • Cardiac arrhythmia
  • Epilepsy
  • Infantile spasms
  • Other causes of mental retardation

Hypomelanotic macules of tuberous sclerosis complex (TSC) must be distinguished from vitiligo, which may reflect a systemic process that includes other autoimmune diseases and ocular and neurological abnormalities.[34] In particular, Alezzandrini syndrome and Vogt-Koyanagi-Harada syndrome exemplify this relationship. In addition, the macules of tuberous sclerosis occasionally require distinction from progressive systemic sclerosis (scleroderma), and, in endemic regions, leprosy.

The multiple oral papules in tuberous sclerosis complex may be similar to those in Cowden syndrome, Birt-Hogg-Dube syndrome, and multiple endocrine neoplasia type 1.[26]

Neuroendocrine tumors of the pancreas have been described in only 9 TSC cases.[35] However, there may be a common molecular pathway between these 2 entities.

Differential Diagnoses


  • Pervasive Developmental Disorder
  • Pneumothorax
  • Polycystic Kidney Disease
  • Retinoblastoma
  • Schizophrenia and Other Psychoses
  • Sleep Disorder: Problems Associated With Other Disorders

Laboratory Studies

Some recommend annual urinalysis and electrolyte testing to detect progression of renal lesions in patients with tuberous sclerosis complex (TSC), although this testing is controversial.

Testing to determine genetic mutations is now available only on a clinical basis. Once a person affected with tuberous sclerosis complex is found to have a mutation in either of the 2 genes, at risk family members may be tested. Current information is available online from GeneTests.

MRI with the fluid-attenuated inversion recovery (FLAIR) sequence of cystlike cortical tubers was performed in patients with tuberous sclerosis complex.[36] FLAIR images confirmed the cystic character of some of these cortical tubers.

Renal cell carcinomas were divided in TSC into three different morphologic groups (Yang et al, 2014). The largest group were classified as «TSC-associated papillary renal cell carcinomas.»

Imaging studies

Brain MRI or CT scanning

Brain MRI is recommended for the detection and follow-up imaging of cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Perform MRI during the initial diagnostic workup and then every 1-3 years in children with tuberous sclerosis complex. MRI may be performed less frequently in adults without lesions and as clinically indicated in adults with lesions. In addition, perform MRI in family members if results of physical examinations are negative or are not definitive for a diagnosis. MRI is preferred over CT scanning because of improved depiction of lesions and the lack of radiation exposure on repeat examinations.

Cortical tubers, best detected using T2-weighted MRI sequences, often develop in the gray-white junction. On T2-weighted images, cortical tubers demonstrate increased signal intensity and are often wedge shaped (tuber) or linear shaped (radial migration lines). Conversely, cortical tubers demonstrate decreased signal intensity on T1-weighted images. Previously believed to be pathognomonic, cortical tubers are no longer considered specific for tuberous sclerosis complex because isolated cortical dysplasia may demonstrate similar radiologic features. The number of tubers detected using MRI appears to be correlated with the severity of mental retardation or seizures.

SENs are located in the ventricles and often become calcified. The lesions are best detected using CT, although they are sometimes found using MRI or plain radiography if they are calcified. SENs demonstrate a candle-dripping appearance.

SENs may grow and give rise to SEGAs. A SEGA may cause obstruction, with evidence of hydrocephalus or mass effect in some patients. The lesions usually appear in the region of the Monro foramen, are partially calcified, and are often larger than 2 cm. Detection of SEGAs is slightly more sensitive using MRI than using CT scanning. The clinical presentation of TSC is highly variable and not well understood. SEGAs are found to be linked with autistic spectrum disorders in patients with TSC, suggesting that SEGA formation may also predispose (Kothare et al, 2014).

Renal ultrasonography, CT scanning, or MRI

Ultrasonography is usually preferred over CT scanning and MRI because of availability and cost. Ultrasonography is more sensitive in detecting renal lesions than CT scanning. Perform a study at initial diagnosis or evaluation and also in family members of patients with tuberous sclerosis complex. Perform subsequent surveillance studies in children or adults with tuberous sclerosis complex every 1-3 years. In those with renal lesions, perform studies every 6-12 months until no further growth occurs or lesions begin to regress.

Ultrasonography, CT scanning, or MRI may reveal evidence of benign or malignant angiomyolipomas, renal cysts, or, rarely, renal cell carcinoma. Avoid CT as much as possible to minimize radiation. Benign angiomyolipomas are found in 50-80% of patients with tuberous sclerosis complex. The lesions are usually bilateral, and the average size is 9 cm. Angiomyolipomas are more common in adults with tuberous sclerosis complex, whereas renal cysts are more common in children.


Obtain an echocardiogram at initial evaluation and in adults with tuberous sclerosis complex as clinically indicated. In children with previously detected lesions, obtain an echocardiogram every 6-12 months until lesions cease growing or begin to regress.

Cardiac rhabdomyomas occur in 50-70% of patients with tuberous sclerosis complex. Tumors almost always regress as the child ages. Occasionally, lesions are not detected using echocardiography, although they may still cause arrhythmia.

Pulmonary CT scanning or plain radiography

Obtain a CT scan of the lung in adult females with tuberous sclerosis complex beginning at age 18 years, even in the absence of symptoms. Pulmonary pathology is almost nonexistent in males. The average age of onset of pulmonary symptoms is in the early fourth decade of life.

Pulmonary lesions that may be detected on CT scans include lymphangioleiomyomatosis (LAM), clear cell tumors, and multifocal multinodular pneumocyte hyperplasia.

Plain radiography of the chest may reveal a honeycomb appearance due to the presence of multiple subpleural cysts.

Other tests


EEG is not diagnostically helpful; obtain EEGs only in patients with a history of doubtful seizures.

EEG may reveal a hypsarrhythmia pattern in an infant with infantile spasms.

Onset of partial seizures is often localized to the frontal and temporal regions.

The interictal sleep EEG was recently recognized to have high sensitivity and positive predictive value in the neurologic outcome and seizure control of patients with tuberous sclerosis complex, with abnormal EEG results correlating with a worse outcome.

Neurodevelopmental testing

Perform neurodevelopmental testing in children at the time of diagnosis and in children with tuberous sclerosis complex entering the first grade. In children and adults with a history of developmental delay, perform repeated evaluations as clinically indicated.


Obtain ECGs with the same frequency as echocardiograms (ie, initial evaluation, as indicated in adults with tuberous sclerosis complex and cardiac lesions, and every 6-12 mo in children with known cardiac lesions).

Various arrhythmias or conduction defects may be noted on ECGs.

Funduscopic examination

Perform a funduscopic examination during the initial workup, when evaluating family members, and as clinically indicated in patients with tuberous sclerosis complex and known ophthalmologic lesions.

Funduscopic examination may reveal retinal hamartomas or astrocytomas in 50-80% of individuals with tuberous sclerosis complex. The lesions may have a rounded or multinodular appearance. Initially, lesions are semitranslucent or translucent but often calcify and become whitish with time.

An abnormal red reflex may also be present and may be confused with retinoblastoma.

Papilledema may be detected in the presence of increased intracranial pressure.

Pulmonary function testing

Some recommend performing pulmonary function tests (PFTs) in postpubertal females with tuberous sclerosis complex. PFT results in individuals with tuberous sclerosis complex usually demonstrate an obstructive pattern.

Histologic findings

Tubers are dysplastic disorganized regions within the cortex, with a loss of structured pattern. The gray-white border is usually blurred. Astrocytes, neurons, and giant cells appear abnormal. The surrounding unaffected areas appear completely normal.

SENs and SEGAs are also composed of neurons, giant cells, and astrocytes. SENs and SEGAs are denser than tubers; therefore, they are sometimes confused with malignant tumors.

Periungual fibromas are nonencapsulated neoplasms composed of stellate fibroblasts admixed with vertically oriented dense collagen and blood vessels. Histologic variants of periungual fibromas in tuberous sclerosis complex have been classified as angiomatous, fibrotic, and intermediate mixed subtypes, depending on the relative proportion of vascular and stromal components.[22]

Medical care

Medical care is aimed at seizure control using various anticonvulsants. Begin treatment with monotherapy and increase the dose gradually until seizures are well controlled or the dose is limited by adverse effects. If the first drug is ineffective, try a different anticonvulsant agent while the first drug is gradually weaned, rather than directly initiating multidrug therapy. A second anticonvulsant may be added if monotherapy with various medications fails. Treatment is desirable before seizures, representing new indications for antiepileptic therapy in children with tuberous sclerosis complex (TSC).[9]

Lymphangioleiomyomatosis (LAM) may respond to therapy using progesterone and oophorectomy. Therefore, treatment in females with evidence of pulmonary disease should begin with progesterone.

Consider inotropic agents in patients with evidence of decreased contractility and cardiomyopathy due to rhabdomyoma.

Antihypertensive medication may be required in patients with renal disease and subsequent hypertension. An ACE inhibitor may be the first drug of choice. For more information, see the topic Hypertension in the Pediatric Cardiac Disease and Critical Care Medicine Volume.

Rapamycin (sirolimus) may be useful in tuberous sclerosis treatment.[37] It binds to its intracellular receptor, FK506-binding protein 12 (FKBP12), and inhibits the activity of the mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in numerous cell processes linked to cell growth control. Investigational studies with sirolimus and everolimus are in progress.[38, 19, 39, 40, 41, 42] Successful everolimus treatment of a huge subependymal giant cell astrocytoma in a 10-year old boy with TSC has been described. Everolimus treatment may be a therapeutic option alternative to surgery.[43]

Preventative antiepileptic treatment of 45 infants with TSC and high risk of epilepsy was found to markedly improve neurodevelopmental outcome and reduce the incidence of drug-resistant seizures.[44]

Surgical Care

Anticonvulsant medication is the first treatment option, and neurosurgery is rarely required for refractory seizures. The best outcome has been noted in patients with fewer lesions. MRI, EEG, and positron emission tomography (PET) scans to localize the lesions are important prior to neurosurgery. Growth of subependymal giant cell astrocytomas (SEGAs) may result in increased intracranial pressure and hydrocephalus. People with increased intracranial pressure require immediate surgery to remove the obstructing lesions. Ventriculoperitoneal (VP) shunt placement is sometimes required.

However, magnetic source imaging and (18)fluorodeoxyglucose PET/MRI coregistration may be able to noninvasively localize the epileptogenic zones in many children with tuberous sclerosis complex and intractable epilepsy, with a 67% seizure-free rate postoperatively.[45] Some believe that early epilepsy surgery is associated with seizure freedom in children with tuberous sclerosis complex and intractable epilepsy.

Partial nephrectomy, enucleation, or renal arterial embolization: Angiomyolipomas may progress and lead to renal failure or bleeding, with resultant hemorrhagic shock. In general, any symptomatic lesion or a lesion larger than 3.5-4 cm should be closely monitored, and surgical treatment should be considered. The goal of surgical treatment is to spare the kidneys as much as possible because new lesions may develop in the future. Therefore, surgical treatment usually consists of enucleation or partial nephrectomy. Renal arterial embolization is an additional treatment option.

Oophorectomy and progesterone therapy are believed to have a beneficial impact on LAM in females. In individuals with end-stage lung disease, lung transplantation is sometimes performed, although it is not always successful.

Cardiac surgery for the removal of rhabdomyomas is rarely required but is performed when cardiac failure is caused by outflow obstruction. Cardiac rhabdomyomas usually spontaneously regress as the individual ages, thus obviating the need for cardiac surgery in older individuals.

Facial angiofibromas may require cosmetic therapy. Previously treated with dermal abrasion techniques, they are currently treated more successfully using laser therapy.

Genetics of Tuberous Sclerosis 1

Fig. 1. Facial angiofibroma, previously termed adenoma sebaceum, in a patient with tuberous sclerosis complex (TSC).



Consult with a neurosurgeon immediately if any suggestion or evidence of increased intracranial pressure is present. Surgery is required to relieve the obstruction and to reduce intracranial pressure. Neurosurgery is rarely required for treatment of epilepsy.


A neurologist may be consulted to assist with seizure management and anticonvulsant medication. In addition, a neurologist may assist with obtaining baseline and serial neurologic examinations to assess for neurologic deficits.


Consultation with a cardiologist is recommended so that initial and surveillance echocardiograms can be obtained to assess cardiac rhabdomyomas. Cardiac surgery is rarely required for removal of rhabdomyomas.


An ophthalmologist may perform a thorough funduscopic examination to assess for evidence of retinal hamartomas or astrocytomas.

Genetic counselor

Consultation with a genetic counselor is recommended when a child/adult is first diagnosed with tuberous sclerosis complex to review the natural history, inheritance, recurrence risks, and the possibility of molecular/genetic testing. The counselor spends adequate time to explain the above in nonmedical terms and may refer the family to other consumer resources. Genetic consultation is particularly helpful when parents of children with tuberous sclerosis complex are contemplating future pregnancies.

Other specialists

A pulmonologist may assist with management of LAM in females with tuberous sclerosis complex. Consult a nephrologist for individuals with symptomatic renal disease. Consultation with a neuropsychologist is helpful in assessing intellectual ability in a child with tuberous sclerosis complex. Neuropsychologists may also assist in management of various behavioral problems, such as autism or pervasive developmental disorder (PDD), schizophrenia, aggressive behavior, or sleep disturbances. Finally, a social worker may assist families and individuals in coping with this chronic disorder.


No specific diet is recommended for most patients.

A ketogenic diet is recommended for some patients for seizure control. Patient compliance with this diet may be difficult to obtain because of limited choices and unpleasant tastes. A ketogenic diet is most useful in patients who have seizures that are difficult to control using multidrug therapy.

A combination of a ketogenic diet and valproic acid is contraindicated because of the increased risk of hepatotoxicity.

Children with tuberous sclerosis complex show high responsiveness to musical stimuli despite otherwise delayed development in language, cognition, and motor skills. The use of music as therapeutic intervention has been suggested.[46]


Activity is not restricted in patients with tuberous sclerosis complex who do not have a history of seizures.

Patients with a history of seizures should avoid certain activities, such as scuba diving and rock climbing.

Driving restrictions for people with seizures vary by state, and physicians should be aware of local regulations.

Medication summary

Medical care is aimed at seizure control using various anticonvulsants. Future prospects are exciting. For example, everolimus appears to be of value in treating the subependymal giant-cell astrocytomas, with a documented reduction in tumor volume, decreased hydrocephalus and intracranial pressure, and a decrease in seizure frequency; this may be a better option than neurosurgery.[41, 40, 42] It also appears to have a favorable effect on renal angiomyolipoma in these patients.[47] Use of mammalian target of rapamycin inhibitors as effective treatment of various aspects of tuberous sclerosis complex has been stressed.[48] However, adverse events may occur, the commonest with everolimus being infections; although such infections are rarely serious, one patient developed grade IV pleuropneumonia and Streptococcus pneumoniae sepsis, while a second patient died after developing Escherichia coli sepsis.[49]

Antineoplastic, Mtor Kinase Inhibitor

Class summary

Immunosuppressant, which forms an inhibitory complex with the immunophilin FKBP12, which binds to and inhibits the ability of mTOR to phosphorylate downstream substrates, such as the S6Ks and 4EBPs.

Everolimus (Afinitor)

Rapamycin-derivative kinase inhibitor. Reduces cell proliferation and angiogenesis by inhibition of mTOR pathway. Indicated for subependymal giant cell astrocytoma (SEGA) associated with TS that cannot be treated with surgery.

Anticonvulsant agents

Class summary

These agents are used to prevent seizures and to terminate clinical and electrical seizure activity. Effective management requires a detailed and accurate classification of seizure types. The goal of treatment is monotherapy, although multidrug therapy is sometimes needed in patients with refractory seizures.

Carbamazepine (Tegretol)

Useful in the treatment of partial and generalized tonic-clonic seizures. Administer a low dose initially, with gradual increases as needed for clinical effect. Therapeutic serum concentration is 4-12 mcg/mL.

Valproic acid (Depakene, Depakote)

Useful in the treatment of all seizure types. Although mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect. Therapeutic serum concentration is 50-100 mcg/mL.

Lamotrigine (Lamictal)

Useful in the treatment of partial seizures or secondarily generalized seizures. Dose depends on use as monotherapy or as an add-on agent. Dose must be increased slowly.

Further inpatient care

Admit patients with tuberous sclerosis complex (TSC) who have evidence of increased intracranial pressure for medical treatment and surgical intervention.

Patients who present with status epilepticus may require admission for medical treatment and observation.

Further outpatient care

Patients with tuberous sclerosis complex require regular follow-up care. Evaluation must include a detailed review of manifestations, including seizures, flank pain, hematuria, and school and behavioral issues, as well as blood pressure measurement and funduscopic examination.

Patients with tuberous sclerosis complex require surveillance testing based on the schedule outlined in Workup. Testing includes MRI or CT scanning of the brain; electroencephalography; echocardiography; electrocardiography; renal ultrasonography, CT scanning, or MRI; pulmonary CT scanning; and pulmonary function testing (PFT).

Routinely monitor patients on anticonvulsant medications for adequacy of seizure control.

Patients with behavioral or psychiatric disorders require routine outpatient follow-up evaluation.

Inpatient & outpatient medications

Various anticonvulsant medications, such as carbamazepine, valproic acid, or lamotrigine,[50] may be used for seizure control.[51] The goal is monotherapy, although many patients require multidrug therapy for adequate seizure control.

The first drug of choice for treatment of infantile spasms is vigabatrin, although it is not yet available in the United States. Other drugs used to treat infantile spasms include prednisone and corticotropin.

Antihypertensive medications, such as ACE inhibitors, are needed in patients with renal disease and resultant hypertension.

Occasionally, infants or young children with cardiac rhabdomyomas develop heart failure. Inotropic support may be required in some of these patients.


Immediate transfer is indicated if a patient has evidence of increased intracranial pressure or hydrocephalus and a neurosurgeon is not available.

Transfer the patient during the initial workup or surveillance testing if consulting specialists or imaging studies, such as CT scan, MRI, or ultrasonography, are not available.


Tuberous sclerosis complex cannot be prevented because it is inherited in an autosomal dominant pattern or arises from a spontaneous mutation.

Genetic counseling is important for patients, parents, and family members who are considering having children. Genetic testing/mutational analysis is currently available and prenatal diagnosis is possible if a mutation in the affected parent has been detected.


  • Increased intracranial pressure and hydrocephalus
  • Mental retardation
  • Seizures
  • Schizophrenia, aggressive behavior, or other behavior disorders
  • Autism or pervasive developmental disorder (PDD)
  • Renal failure or hemorrhagic shock due to bleeding angiomyolipomas
  • Pneumothorax or obstructive lung disease
  • Cardiac arrhythmia or heart failure
  • Death


Tuberous sclerosis complex has a wide clinical spectrum. Some patients are affected subclinically with no decrease in life expectancy or quality of life. Cognitive outcome in tuberous sclerosis complex appears to depend more on the age of the seizure onset rather than on the tuber count.[52]

A decreased life expectancy is noted in some individuals with tuberous sclerosis complex. This is often related to treatable or preventable causes of death, such as pulmonary or renal disease. Appropriate surveillance studies with any necessary early intervention may improve quality of life and life expectancy.


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