Genetics of Tuberous Sclerosis

Updated: Oct 19, 2023
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Practice Essentials

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. [1] It 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. Regarding the genetic sources of epilepsy, tuberous sclerosis complex is among the most common. Epilepsy affects 90% of patients with the neurocutaneous condition, first becoming evident in most such individuals in the initial 2 years of life. [2]  Tuberous sclerosis complex provides a model for genetic epilepsy development and modification. [3]

Anticonvulsant medication is the first treatment option for seizures, and neurosurgery is rarely required for refractory seizures. Magnetic resonance imaging (MRI), electroencephalography (EEG), and positron emission tomography (PET) scans to localize brain lesions are important prior to neurosurgery.

Mutations in either of two genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, diagnosis continues to be based on clinical manifestations. [4] . 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.

Signs and symptoms of tuberous sclerosis complex

The most common and severe central nervous system (CNS) manifestations of tuberous sclerosis complex include seizures, such as infantile spasms, and mental retardation.

Hypomelanotic macules are overwhelmingly the most common early finding in tuberous sclerosis complex, [5] while renal angiomyolipomas are considered one of the major diagnostic features. Flank pain is the most common renal symptom.

Cardiac rhabdomyomas are often present at birth or during infancy but may be detected as early as 20 weeks' gestation using fetal ultrasonography.

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

Most oral fibromas in tuberous sclerosis complex are gingival, [7] and nearly all patients have dental pits.

Workup in tuberous sclerosis complex

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 the TSC1 or TSC2 gene, at-risk family members may be tested.

Brain MRI is recommended for the detection and follow-up imaging of cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs).

For renal evaluation, ultrasonography is usually preferred over computed tomography (CT) scanning and MRI because of availability and cost. In addition, ultrasonography is more sensitive in detecting renal lesions than CT scanning.

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

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.

Management of tuberous sclerosis complex

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.

Lymphangioleiomyomatosis (LAM) may respond to therapy using progesterone and oophorectomy.

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 angiotensin-converting enzyme (ACE) inhibitor may be the first drug of choice.

Kidney surgery for angiomyolipomas usually consists of enucleation or partial nephrectomy. Renal arterial embolization is an additional treatment option.

Some believe that early epilepsy surgery is associated with seizure freedom in children with tuberous sclerosis complex and intractable epilepsy. [8]



Molecular genetics and pathogenesis

Tuberous sclerosis complex has a broad clinical spectrum and affects almost every organ system. [9] 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. [10]

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. [11]  (A rare heterozygous TSC2 mutation found in a boy aged 18 months, his mother, and other family members led to an atypical phenotype not meeting consensus clinical criteria for TSC diagnosis. [12] )

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. [13]

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. [14]

Evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas. [15] 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. [16] Cardiac rhabdomyoma arising in tuberous sclerosis may progress due to Erk potentiation. [17]

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. [18] A novel TSC2 mutation was recently described. [19]  TSC2 -deficient cells may have increased choline phospholipid metabolism. [20]  Severe clinical tuberous sclerosis complex in infants is predicted by TSC2 pathogenic variants. [21]

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. [22]  Angiofibromas may result from ultraviolet ray–induced mutations. [23]  As determined using MRI, a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume exists in association with TSC1 versus TSC2. [21]




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. [24]

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. [25] 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 the complex, with high rates of infantile spasms having been linked to TSC2 mutation. [26]  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.