Pediatric Annals

Special Issue Article 

Tuberous Sclerosis Complex: A Review

Stephanie Carapetian Randle, MD, MS

Abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present at any age and can affect multiple organ systems. This disorder is usually identified in infants and children based on characteristic skin lesions, seizures, and cellular overgrowth or hamartomas in the heart, brain, and kidneys. Tuberous sclerosis complex is a genetic disorder caused by a mutation in either the TSC1 or TSC2 gene leading to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular hyperplasia. Accurate diagnosis is essential in implementing appropriate surveillance and treatment to patients with this disorder. Specific guidelines for diagnosis, surveillance, and management have been proposed by the International Tuberous Sclerosis Complex Consensus Group. Treatment of tuberous sclerosis complex is in part symptomatic; however, for certain clinical manifestations, specific treatments may be indicated. [Pediatr Ann. 2017;46(4):e166–e171.]

Abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present at any age and can affect multiple organ systems. This disorder is usually identified in infants and children based on characteristic skin lesions, seizures, and cellular overgrowth or hamartomas in the heart, brain, and kidneys. Tuberous sclerosis complex is a genetic disorder caused by a mutation in either the TSC1 or TSC2 gene leading to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular hyperplasia. Accurate diagnosis is essential in implementing appropriate surveillance and treatment to patients with this disorder. Specific guidelines for diagnosis, surveillance, and management have been proposed by the International Tuberous Sclerosis Complex Consensus Group. Treatment of tuberous sclerosis complex is in part symptomatic; however, for certain clinical manifestations, specific treatments may be indicated. [Pediatr Ann. 2017;46(4):e166–e171.]

Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder with an incidence of 1 per 6,000 to 10,000 live births.1,2 TSC was first identified by Friedrich Daniel von Recklinghausen in 1862 in a baby with cardiac “myomatas“ and areas of sclerotic brain tissue.2 In 1880, Bourneville better explained the neurologic features, and observed associated dermatologic abnormalities, and subsequently, the term tuberous sclerosis was used to describe this disorder.2 Since that time, TSC is known to have a variable presentation that classically involves the brain, skin, kidneys, heart, eyes, and lungs, but can affect any organ system. The hallmark of the disease is tumors consisting of glial-neuronal and retinal hamartomas, subependymal giant cell tumors, cardiac rhabdomyomas, renal and extra-renal angiomyolipomas (AML), and pulmonary lymphangioleiomyomatosis (LAM). Despite the typically benign pathology of these tumors, they may lead to secondary outflow abnormalities due to mass effect (ie, hydrocephalus, renal, and cardiac dysfunction) or interruption of the function of the normal tissue (ie, seizures and arrhythmia).

Pathophysiology and Genetics

The clinical manifestations of TSC are a result of dysfunction in cell differentiation, proliferation, and migration during early fetal development. TSC is known to be caused by a mutation in either the TSC1 or TSC2 gene.3–6TSC1 is found on chromosome 9q34 and encodes the protein hamartin, and TSC2 is found on chromosome 16p13 and encodes the protein tuberin.2,5–8 Both hamartin and tuberin are widely expressed throughout normal tissue and together these proteins are involved in the mammalian target of rapamycin (mTOR) pathway. This pathway functions to regulate cell growth, size, and proliferation. Deregulation of the mTOR signaling pathway can result in tissue overgrowth as the TSC2:TSC1 complex stops mTOR activation.8

Approximately 30% of TSC cases are inherited in an autosomal dominant manner, and around 70% of cases are secondary to spontaneous mutations.3,4 A mutation in TSC2 is 4 times more common in de novo cases; however, in familial cases of TSC, the incidence of a mutation in TSC1 is about equal to a mutation in TSC2.4 Although genetic testing may be negative in 10% to 25% of people,3,4,8 it is important in the counseling and management of a patient with TSC and should be considered in a patient with a diagnosis of possible TSC.

Clinical Manifestations

TSC is a multisystem disorder with variable clinical manifestations (Table 1). Frequently the central nervous system, the kidneys, and the skin are affected.1 Common symptoms of central nervous system involvement include seizures and intellectual disability. Renal dysfunction may be secondary to renal angiomyolipomas and most patients with TSC will have hypomelanotic macules, also known as ash leaf spots.1


            Common Clinical Manifestations of Tuberous Sclerosis

Table 1.

Common Clinical Manifestations of Tuberous Sclerosis

Neurologic Manifestations

Neurologic manifestations include epilepsy, intellectual disability, autism spectrum disorder, and behavioral problems. Epilepsy can present at any age; however, the majority of cases present in the first year of life. Epileptic spasms, which were previously called infantile spasms, are seen in about 50% of children with TSC and seizures younger than age 1 year.9 Approximately 10% to 25% of children with epileptic spasms have TSC.9 Epileptic spasms are an age-limited epilepsy syndrome that typically present in children younger than age 1 year, with peak incidence seen in infants age 3 to 7 months.10 Epileptic spasms are typically characterized by symmetric and synchronous clusters of flexion or extension of the neck, trunk, or limbs that typically occur around times of awakening or falling asleep. Epileptic spasms are often associated with a distinctive electroencephalographic pattern described as hypsarrhythmia.10 Treatment of epileptic spasms is often dependent on the cause with leading treatments including adrenocorticotropic hormone, prednisolone, vigabatrin, ketogenic diet, and surgery.10 In patients with TSC and epileptic spasms, vigabatrin is recommended as first-line therapy given its superior efficacy as compared to treatment with steroids.7,9–13 For other types of epilepsy, there is limited evidence to guide any specific treatment to patients with TSC. Children with TSC are at higher risk of developing medically refractory epilepsy, and alternative treatments such as a low carbohydrate diet and epilepsy surgery should be considered.7,12–15 Up to 90% of children with TSC can have TSC-associated neuropsychiatric disorders (TAND), which include autism, attention-deficit/hyperactivity disorder, and intellectual disability.1,16

In patients with TSC, the structural brain abnormalities that are typically found include cortical tubers, subependymal nodules, and subependymal giant cell tumors (SGCT), which are also referred to as subependymal giant cell astrocytomas. Cortical tubers are present in at least 80% of patients with TSC and are comprised of abnormal neurons and glia.17 These areas of focal cortical dysplasia are stable in size throughout life; however, they are related to the development of epilepsy. Subependymal nodules are present in up to 90% of patients with TSC and are intraventricular protrusions comprised of abnormal cells typically found in the lateral ventricles adjacent to the caudate nucleus, which may be calcified.17 SGCT are glioneuronal tumors that are also intraventricular and typically found in the caudothalamic groove, near the foramen of Monro. SGCT are slow-growing benign tumors that may cause obstruction and are seen in 10% to 20% of patients with TSC.1,17 Symptomatic SGCT are present in up to 10% of patients with TSC.18 Signs of obstructive hydrocephalus include headache, emesis, and focal neurologic deficits as well as nonspecific symptoms of fatigue, alteration in mental status, and increase in seizures.17,18

Dermatologic and Dental Manifestations

Dermatologic and dental abnormalities are found in almost all patients with TSC.1,19,20 Of the dermatologic findings, approximately 90% of people with TSC will have hypomelanotic macules (also referred to as “ash leaf spots”), which can be seen at birth or early in infancy.20 Wood's lamp examination may assist in revealing the hypomelanotic macules that may be located throughout the body. Additionally, 75% of people older than age 9 years with TSC will have angiofibromas (previously referred to as adenoma sebaceum).20 This lesion is typically found on the central face and may progress in appearance with time. Initially it will appear as a vascular macule and with time will become more fibrous with dome-shaped papules.20 Other characteristic dermatologic findings include a fibrous cephalic plaque (typically found on the forehead), a shagreen patch (typically found on the low back), confetti skin lesions, and ungual fibromas.1,19,20 Dental manifestations include dental enamel pits and intraoral fibromas.1,19

Cardiovascular Manifestations

At least 50% of newborns with TSC have cardiac rhabdomyomas, a collection of abnormal myocytes, which may be detected on prenatal ultrasound between 20 to 30 weeks' gestation.1,21 These lesions are typically asymptomatic; however, depending on size, location, and number they may obstruct inflow or outflow leading to heart failure or arrhythmia.21 These lesions typically regress within the first 3 years of life.1,21

Renal Manifestations

Renal manifestations of TSC typically include renal cysts, AML, and uncommonly renal cell carcinoma.22 Cysts may be present in up to 45% of patients with TSC and may lead to kidney failure and hypertension.22 AML are benign tumors that are comprised of vascular, smooth muscle, and adipose tissue. AML may be seen in up to 80% of patients with TSC.1,22 Despite the benign nature these tumors, AML are the most common cause of TSC-related death given the risk of hemorrhage and subsequent renal failure requiring long-term dialysis or transplant.22

Ophthalmologic Manifestations

Retinal lesions are common in TSC with retinal astrocytic harmatomas being the most common, seen in up to 50% of patients.23,24 These lesions are comprised of glial astrocytes and blood vessels that are usually benign and typically do not affect visual acuity unless compressing the optic disc.23,24 Other ocular abnormalities include retinal pigmentary changes, palpebral angiofibromas, colobomas, and iris depigmentation.1,23,24

Pulmonary Manifestations

Pulmonary manifestations of TSC are typically only seen in adult women with the clinical manifestation of LAM. LAM is characterized by proliferation of bundles of smooth muscle cells and resultant cystic changes in the lung parenchyma.1,25 Clinically, this can manifest as exertional dyspnea, recurrent pneumothoraces, thoracic lymphadenopathy, and hemoptysis. LAM is seen in up to 35% to 80% of women with TSC by age 40 years. Around 10% of men with TSC will develop LAM; however, they are usually asymptomatic.1,25 Other pulmonary manifestations include multifocal micronodular pneumocytic hyperplasia in up to 60% of patients with TSC and rarely clear cell lung tumor.25

Other Manifestations

Extrarenal AML are rarely seen in the liver (10%–25%), adrenal glands (25%), pancreas, and endocrine system.1 These lesions are typically best visualized on abdominal magnetic resonance imaging (MRI).26 Skeletal abnormalities are rare, however, and may include hyperostosis of the inner table of the calvaria, cystic lesions, and scoliosis.26

Evaluation and Diagnosis

If a diagnosis of TSC is suspected, the initial screening evaluation includes a detailed assessment of the patient (Table 2).1


            Evaluation for Suspected Tuberous Sclerosis Complex

Table 2.

Evaluation for Suspected Tuberous Sclerosis Complex

A diagnosis of TSC can be made based on clinical features, genetic findings, or a combination of the two. There is no pathognomonic finding in TSC and for that reason a clinical diagnosis is made based on a combination of features. In 2012, the International TSC Consensus Group revised the clinical criteria for the diagnosis of TSC (Table 3).1 A definite clinical diagnosis is made based on having two major features or one major and two or more minor features. A probable clinical diagnosis is made based on having either one major feature or at least two minor features.1


            Clinical Diagnostic Criteria of Tuberous Sclerosis

Table 3.

Clinical Diagnostic Criteria of Tuberous Sclerosis

Now that reliable and comprehensive genetic testing is available for pathogenic TSC1 and TSC2 mutations, a genetic diagnosis can be made.1 A pathogenic mutation is defined as a mutation that prevents protein synthesis or inactivates the function of the TSC1 and TSC2 proteins. A subset of patients, 10% to 25%, will have no mutation identified.8

Surveillance and Management

Once a diagnosis of TSC is made, continued surveillance is needed to assess for organ dysfunction, new lesions, or growth of previously identified lesions (Table 4).7 Optimal care for patients with TSC includes a multidisciplinary approach and may require involvement from the primary care provider, neurology, dermatology, cardiology, nephrology, ophthalmology, dentistry, neurosurgery, neurodevelopmental pediatrics, pulmonology, and genetics.


            Surveillance and Follow-Up Testing After a Tuberous Sclerosis Diagnosis

Table 4.

Surveillance and Follow-Up Testing After a Tuberous Sclerosis Diagnosis

Neurologic Management

To screen for development of SGCT, surveillance MRI of the brain with and without contrast should be performed every 1 to 3 years until age 25 years.1 As SGCT are thought to develop in childhood and adolescence, surveillance MRIs are only needed after age 25 years if there is an asymptomatic SGCT. If a symptomatic SGCT or evidence of a SGCT with increasing ventricular enlargement is present, more frequent neurologic and neurosurgical monitoring is needed. The best treatment of SGCT is still under investigation; however, either surgical resection or treatment with a mTOR inhibitor may be indicated.7,27

For treatment of epileptic spasms, there is strong evidence to support the use of vigabatrin as first-line treatment in patients with TSC.9–11 Other than in the treatment of epileptic spasms, there is little evidence to support a specific treatment of epilepsy.12 Patients with TSC are at increased risk of development of medically refractory epilepsy and dietary therapy, epilepsy surgery, or vagus nerve stimulation may be helpful in treatment.13,15,28

Dermatologic Management

For certain skin lesions, topical mTOR inhibitors, laser treatment or surgical treatment may be an option.19,20 Should the skin lesions not be disfiguring or providing discomfort, intervention may not be necessary and clinical monitoring may be sufficient.

Cardiac Management

The need for cardiac screening is dependent on the presence of an intracardiac rhabdomyoma. Should one be present prenatally or in infancy, an echocardiogram should be performed every 1 to 3 years until regression has been demonstrated.7,21 The natural course of most intracardiac rhabdomyomas is spontaneous regression over a period of months to years.21 Medical or surgical management of heart failure may be indicated.21

Renal Management

If there is an AML measuring greater than 3 cm in diameter, a mTOR inhibitor is recommended as first-line treatment; however, with more significant dysfunction, dialysis or transplant may be needed.7,22 Abdominal MRI is the preferred modality for surveillance and detection of AML, as they may be “fat poor” and missed on a renal ultrasound.7,22

Ophthalmologic Management

The majority of ocular hamartomas are not progressive and do not affect vision; however, if they become more aggressive or fluid filled, they have the ability to cause retinal detachment and treatment with laser photocoagulation may be indicated.23 Most frequently, the ocular lesions are left untreated and monitored clinically.

Pulmonary Management

In certain patients with LAM and moderate to severe lung disease, a mTOR inhibitor may be considered; however, certain patients may be a candidate for lung transplant.7,25 Preventing complications related to pulmonary disease may be integral in minimizing morbidity related to TSC.26

Prognosis

Morbidity and mortality in TSC is most often related to problems in the central nervous system (epilepsy, obstructive hydrocephalus, and neuropsychiatric issues), renal system (hemorrhage and renal failure), and the pulmonary system (shortness of breath and recurrent pneumothoracices).26 A recent study of 284 patients with TSC had 16 patients that died of complications related to TSC.26 In this cohort, the median age of death was 33 years, with none in the pediatric age range. Mortality was associated with learning disabilities, renal disease, and pulmonary disease, as well as epilepsy as manifested by sudden unexplained death in epilepsy.26

Conclusions

TSC is a multiorgan genetic disorder predominantly affecting the brain, kidneys, heart, skin, and lungs. It is an important disorder for general practitioners to recognize given the multisystem involvement, the high incidence of seizures (including epileptic spasms), and renal AML, which have specific treatments. Approved guidelines for surveillance and management are published.1,7 Patients with TSC will likely need evaluation by many subspecialized practitioners and coordinating this care early is important.2

References

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Common Clinical Manifestations of Tuberous Sclerosis

Organ System Symptom or Sign (% of Affected Patients)
Neurologic Epilepsy (90)1,2,12,13,29 Cortical brain malformations (90)1,2,4 Tuberous sclerosis complex associated neuropsychiatric disorder(90)1,16
Dermatologic Hypomelanotic macules (90)1,19
Renal Renal angiomyolipomas (75–80)1,22
Cardiac Intracardiac rhabdomyomas (66–75 of newborns)1,21
Ocular Retinal abnormalities (90)23
Pulmonary Lymphangioleiomyomatosis (35–80 of women by age 40 years)23

Evaluation for Suspected Tuberous Sclerosis Complex

Organ System Evaluation Recommendations
Skin, teeth, eyes Perform a detailed clinical examination
Brain Brain MRI with and without contrast, EEG, TAND checklist/screen
Heart ECHO, EKG
Kidneys Hypertension screen, evaluate function with GFR, renal ultrasound orabdominal MRI (preferred)
Lungs Baseline PFTa, HRCTa
Genetics Obtain a three-generation family history, consider genetic testing

Clinical Diagnostic Criteria of Tuberous Sclerosis

Major Features Minor Features
Hypomelanotic macules (≥3, at least 5 mm diameter) “Confetti” skin lesions
Angiofibromas (≥3) or fibrous cephalic plaque Dental enamel pits (≥3)
Ungual fibromas (≥2) Intraoral fibromas (≥2)
Shagreen patch Retinal achromic patch
Multiple retinal hamartomas (≥2) Multiple renal cysts
Cortical dysplasiaa Nonrenal hamartomas
Subependymal nodules --
Subependymal giant cell tumor --
Cardiac rhabdomyoma --
Lymphangioleiomyomatosis --
Angiomyolipomas (≥2) --

Surveillance and Follow-Up Testing After a Tuberous Sclerosis Diagnosis

Organ System Recommendations
Skin, eyes Annual clinical examination
Teeth Bi-annual clinical examination
Brain Brain MRI every 1–3 years until age 25 years, EEG based on clinical need, TAND screen annually
Heart ECHO every 1–3 years until regression of rhabdomyoma, EKG every 3–5 years
Kidneys Annual blood pressure measurement, annual GFR measurement, abdominal MRI every 1–3 years
Lungs PFT annually,a HRCT every 5–10 years or every 2–3 yearsa
Authors

Stephanie Carapetian Randle, MD, MS, is an Assistant Professor of Pediatric Neurology and Epilepsy, University of Washington and Seattle Children's Hospital.

Address correspondence to Stephanie Carapetian Randle, MD, MS, 4800 Sand Point Way NE, Seattle, WA 98105; email: stephanie.randle@seattlechildrens.org.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/19382359-20170320-01

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