OVERVIEW: What every practitioner needs to know

Are you sure your patient has tuberous sclerosis? What are the typical findings for this disease?

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that affects multiple organ systems and is primarily characterized by the development of benign neoplasms of the brain, skin and kidneys. The incidence of TSC may be as high as 1 in 5,800. TSC is inherited in 30% of cases and is the result of spontaneous mutation in 70%. There are two distinct genes causative of TSC: TSC1 located on chromosome 9q34 and TSC2 located on chromosome 16p33.3. TSC1 encodes for a protein called hamartin, while TSC2 encodes for a protein called tuberin. These two proteins interact to form a complex that has been shown to be important in several intracellular signaling pathways. TSC has near 100% penetrance but has wide phenotypic variability. Patients with mutations in TSC1 may have a milder phenotype than those with mutations in TSC2.

Clinical Diagnostic Criteria

The diagnosis of TSC is generally made on the basis of clinical criteria. Genetic testing is available, but poor sensitivity limits its clinical utility.

  • To be diagnosed with definite TSC, a patient must have two major features or one major feature plus two minor features.

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  • To be diagnosed with probable TSC, a patient must have one major feature plus one minor feature.

  • To be diagnosed with possible TSC, a patient must have one major feature or two or more minor features.

    Major Features

    Facial angiofibromas or forehead plaque

    Nontraumatic ungual or periungual fibromas

    Hypomelanotic macules (three or more)

    Shagreen patch (connective tissue nevus)

    Multiple retinal nodular hamartomas

    Cortical tuber 1

    Subependymal nodule

    Subependymal giant cell astrocytoma

    Cardiac rhabdomyoma, single or multiple

    Lymphangiomyomatosis 2

    Renal angiomyolipoma 2

    Minor Features

    Multiple randomly distributed pits in dental enamel

    Hamartomatous rectal polyps 3

    Bone cysts 4

    Cerebral white matter radial migration lines 1,2

    Gingival fibromas

    Nonrenal hamartoma 3

    Retinal achromic patch

    “Confetti” skin lesions

    Multiple renal cysts 3

  • When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis.

  • When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned.

  • Histologic confirmation is suggested.

  • Radiographic confirmation is sufficient.

Clinical Manifestations

Cutaneous Findings

Skin lesions are very common in TSC and are often the presenting manifestation leading to diagnosis.

The most common skin manifestation of TSC is hypomelanotic macules, previously termed ash leaf lesions. These occur in up to 97% of patients. These are often present at birth and often become more numerous with age. They can occur anywhere on the skin but tend to be most prominent on the trunk and buttocks. Hypomelanotic macules are not specific to TSC.

Facial angiofibromas (previously termed adenoma sebaceum) are pink or reddish papular lesions involving the cheeks and naso-labial folds, sparing the upper lip, typically in a malar distribution. They are seen in up to three quarters of patients with TSC. They most commonly appear during preschool age and become more prominent over time.

Forehead fibrous plaques are seen in about 20% of patients with TSC. These are slightly elevated brownish or flesh-colored plaques made up of coalesced nodules.

Shagreen patches are irregular areas of raised, roughened skin often described as having an orange peel-like texture. They are seen in about one half of patients and generally become apparent around puberty. They are most commonly located in the lumbosacral region but can appear elsewhere.

Periungual or subungual fibromas are pink or flesh-colored nodules that grow in the finger or toe nail beds in patients with TSC. They are seen in about 20% of patients with TSC and are more likely to be found in adolescents or adults.

Cardiac manifestations

Cardiac rhabdomyomas are the most common cardiac manifestation of TSC . These may be seen in half to 2/3 of newborns with TSC, although most cause no significant medical problems and regress spontaneously with age. When symptomatic, cardiac rhabdomyomas may present with heart failure, arrhythmia or murmurs.

Renal manifestations

The most common renal complication of TSC is the growth of angiomyolipomas, which occur in up to 80% of TSC patients. These are benign tumors composed of immature smooth muscle cells, fat cells and abnormal blood vessels. They are typically multiple and involve both kidneys at the time of diagnosis. Most remain asymptomatic. When symptomatic, angiomyolipomas typically present with either renal failure or hypertension on the basis of encroachment on normal kidney tissue or hemorrhage due to aneurysm formation. Hemorrhage can be a life-threatening complication and is most commonly seen in angiomyolipomas over 4 cm in diameter. Angiomyolipomas greater than 3 to 4 cm are often treated with embolization.

Renal cysts are also common in TSC, and, like angiomyolipomas, usually affect both kidneys. Renal cysts are more likely to present with hypertension and renal insufficiency or failure and are less likely to present with hemorrhage. A relationship between TSC and renal carcinoma has been postulated but not yet been clearly established.

Pulmonary manifestations

Lymphangioleiomyomatosis (LAM) is a condition characterized by proliferation of atypical smooth muscle-like cells in the lungs and diffuse, progressive cystic destruction of lung tissue. It typically presents with dyspnea, hemoptysis, chest pain, chylothorax and/or pneumothorax, most commonly in young adult women with TSC. LAM is a chronic, sometimes progressive illness with a 10-year survival rate of about 90%.

Ophthalmologic manifestations

Several retinal abnormalities can be seen in patients with TSC; however, they are usually asymptomatic and only rarely cause any functional vision loss. Retinal hamartomas are seen in about half of patients with TSC. Punched out areas of retinal depigmentation may also be seen. Patients with TSC may also develop angiofibromas of the eyelid, strabismus or colobomas.

Central nervous system manifestations

Neurologic complications of TSC are very common and are a prominent source of morbidity and mortality.

Cortical tubers are seen in up to 95% of patients with TSC. They are composed of disorganized neurons and dysmorphic giant astrocytes. The border zone between gray and white matter becomes indistinct, and the normal six-layered lamination pattern of neurons in the cortex is lost. The number of cortical tubers has been shown to be correlated with the severity of seizures and cerebral dysfunction.

Lesions in the white matter are also commonly seen in TSC. These lesions may represent areas of demyelination, dysmyelination, hypomyelination, and/or heterotopic neurons or glia along paths of cortical migration.

Subependymal nodules are seen in the majority of patients with TSC. Subependymal nodules are hamartomatous growths along the walls of the lateral ventricles composed of dysplastic astrocytes and auroral cells located in the subependymal region.

Subependymal giant-cell tumors (SGCTs, previously called subependymal giant cell astrocytomas or SEGAs) are low-grade glioneuronal tumors that are seen in approximately 15% of patients with TSC. They typically originate near the foramen of Monro, and as a result, often cause obstructive hydrocephalus and may require surgical resection or medical therapy with everolimus.

Seizures and epilepsy are extremely common in patients with TSC, with reported incidences probably over 95%. Seizures most typically begin during infancy or early childhood, with the incidence decreasing with increasing age. Seizures can be generalized or partial in onset. Infantile spasms are seen in approximately 1/3 of patients with TSC.

Cognitive and behavioral manifestations

Behavioral and cognitive impairments are common in TSC, with approximately 1/2 of patients showing some degree of intellectual impairment and over 60% diagnosed with behavioral problems such as autism, pervasive developmental disorder (PDD), obsessive compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD). Approximately 70% of patients with TSC fall into a normal distribution with mean scores 12 points below those of unaffected siblings, while about 30% of patients cluster around IQs in the profoundly impaired range (IQs less than 20). Those with normal IQs may have academic problems or learning disabilities.

In patients with TSC, the incidence of autism is probably around 25%, with approximately 40% to 50% meeting diagnostic criteria for autism or PDD. Autism and PDD are more prevalent in patients with TSC and global intellectual impairment than those with normal intelligence. Approximately half of patients with TSC meet diagnostic criteria for ADHD.

What other disease/condition shares some of these symptoms?

Many of the features associated with TSC can be seen in isolation and are not necessarily indicative of a diagnosis of TSC. For instance, hypopigmented macules may be present in as many as 1% of all newborns, and are usually of no clinical significance.

There is some clinical overlap between the renal disease of TSC and polycystic kidney disease (PKD). TSC patients with extensive renal cysts may occasionally be misdiagnosed as having polycystic kidney disease. Additionally, in rare instances, patients will have a mutation that affects both the TSC2 and PKD1 genes, and those patients will manifest features of both TSC and polycystic kidney disease.

What caused this disease to develop at this time?


What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Genetic testing for TSC1 and TSC2 is commercially available; however, sensitivity is limited. Mutations will only be detected in about ¾ of patients who meet clinical criteria for the diagnosis of TSC. As such, negative genetic testing does not rule out TSC. Patients with mutations in the TSC1 gene may have a milder phenotype than those with TSC2 mutations; however, there remains broad phenotypic variability in either instance. As a result, this information is of limited utility in counseling patients and families and does not alter management.

Would imaging studies be helpful? If so, which ones?

  • An MRI of the brain should be performed with and without gadolinium at the time of diagnosis to evaluate for cortical tubers, subependymal nodules, SGCTs, white matter abnormalities, and hydrocephalus. Subsequently, an MRI should be obtained every 1 to 3 years in children and adolescents with TSC. If a SGCT is identified, consideration should be given to increasing monitoring frequency.

    A renal ultrasound should be performed at diagnosis to evaluate for the presence of renal cysts and/or angiomyolipomas. Renal ultrasound should be repeated every 1 to 3 years, with the frequency dependent on the presence or absence of lesions. If large lesions (>3 cm) are detected or there is concern of malignancy, then CT or MRI should be considered.

    Cardiac ultrasound to evaluate for rhabdomyomas should be considered for infants with TSC and heart murmur, arrhythmia and/or signs of heart failure.

If you are able to confirm that the patient has tuberous sclerosis, what treatment should be initiated?

  • Due to the complexities of the manifestations of TSC and the need for access to multiple medical disciplines, patients are best served by evaluation and management through a multidisciplinary clinic with familiarity and expertise in the care of patients with TSC.

  • Coordinated multidisciplinary care should include specialists from genetics, neurology, neurosurgery, radiology, ophthalmology, dermatology, plastic surgery, neuropsychology, and oncology.

  • In addition to screening imaging, as discussed above, patients with TSC should undergo, at a minimum, annual follow-up with a complete general examination, neurologic examination, skin evaluation, ophthalmologic exam, assessment of growth parameters, and academic and developmental screening.

    Specific treatments are dependent on the manifestations present in individual patients.


    One of the most challenging aspects of management of TSC patients is treatment of epilepsy. Choice of therapy is dependent on a number of factors including seizure type, severity, age, and EEG findings. Vigabatrin is the treatment of choice for infants with infantile spasms and TSC, though ACTH may be nearly as effective. Patients with TSC may develop partial or generalized epilepsies, and medical therapies are tailored specifically to each patient. Many patients require multi-drug regimens and/or the addition of the ketogenic diet or vagal nerve stimulator. For patients with medically intractable seizures, surgery is increasingly becoming an option, particularly for patients with an identifiable primary epileptogenic focus.


    SGCTs causing hydrocephalus, showing growth on serial imaging or causing focal neurologic deficit, may be considered for treatment. Previously, surgical resection or radiation were the only options available. Secondary malignancy has been increasingly recognized as a risk of radiation therapy in TSC as well as other tumor predisposition syndromes (such as NF1 and NF2), and is less commonly used. Recently, everolimus, an mTOR inhibitor, was approved as medical therapy for patients with TSC and SGCTs for whom surgical resection is not desired. Other mTOR inhibitors are currently in clinical trial.

    Renal Cysts

    Because of the risk of spontaneous hemorrhage, it is recommended that patients with angiomyolipomas over 3 to 4 cm be considered for either transcatheter arterial embolization, or partial or total nephrectomy. Preliminary data suggests that therapy with mTOR inhibitors may have a role in decreasing the size of angiomyolipomas, and trials are in progress.


    Hormonal manipulation, brochodilation therapy, and alpha-interferon are all used for the treatment of LAM with unclear benefit. Recent trials of sirolimus have shown promise, and it is undergoing further evaluation.


    No treatment is necessary for asymptomatic cardiac rhabdomyomas, as they will all undergo spontaneous regression. However, in rare instances surgical resection may be required in symptomatic infants.

What are the adverse effects associated with each treatment option?


What are the possible outcomes of tuberous sclerosis?

There is very broad phenotypic variability among patients with TSC. As such, it is difficult to make accurate predictions regarding outcome for any specific individual diagnosed with the disorder. Neurologic disease, particularly SGCTs and status epilepticus and renal disease including renal cell carcinoma and hemorrhage into an angiomyolipoma, are the most common causes of premature death in TSC.

What causes this disease and how frequent is it?


How do these pathogens/genes/exposures cause the disease?

  • The TSC1 gene encodes for a protein called hamartin, and the TSC2 gene encodes for a protein called tuberin. Hamartin and tuberin interact to form a heterodimer. The functions of the hamartin-tuberin protein complex are not yet fully elucidated, but it appears to integrate multiple cell signaling cues and is a critical negative regulator of the mTOR pathway. It appears to be an important regulator of cell proliferation and cell survival via both mTOR dependent ANT and mTOR independent pathways.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?


Are additional laboratory studies available; even some that are not widely available?


How can this disease be prevented?


What is the evidence?

Au, KS, Williams, AT, Gambello, MJ. “Molecular genetic basis of tuberous sclerosis complex: from bench to bedside”. J Child Neurol. vol. 19. 2004. pp. 699-709. (A review of the molecular and genetic pathophysiologic mechanisms of TSC.)

Krueger, DA, Care, MM, Holland, K. “Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis”. N Engl J Med. vol. 363. 2010. pp. 1801-11. (An open-label, prospective clinical trial of everolimus in the treatment of TSC-associated SEGAs in 28 patients. Treatment resulted in significant reduction of tumor size and seizure frequency.)

Krueger, DA, Franz, DN. “Current management of tuberous sclerosis complex”. Paediatr Drugs. vol. 10. 2008. pp. 299-313. (A recent review of management strategies for neurologic, behavioral, pulmonary and renal manifestations of TSC.)

Roach, ES, DiMario, FJ, Kandt, RS, Northrup, H. “Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association”. J Child Neurol. vol. 14. 1999. pp. 401-7. (Consensus guidelines regarding the use of diagnostic studies in patients newly diagnosed with TSC, for serial monitoring of patients with an already-established diagnosis, and for family members of affected individuals.)

Yates, JR, Maclean, C, Higgins, JN. “The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management”. Arch Dis Child. vol. 96. 2011. pp. 1020-5. (This paper presents data regarding the presenting clinical features as part of a longitudinal study of 125 children with TSC.)

Ongoing controversies regarding etiology, diagnosis, treatment