AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. TSC 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 TSC may present with a broad range of clinical symptoms because of variable expressivity. TSC 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 lesions (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas. Recently, mutations in 2 genes (TSC1 and TSC2) have been determined to cause TSC; however, current diagnostic criteria continue to be based on clinical manifestations.¹

Pathophysiology

TSC has a broad clinical spectrum and affects almost every organ system. Many of the clinical symptoms are due to the development and growth of hamartomas. Cortical tubers in the brain are typically located at the gray-white matter interface, commonly in the frontal and parietal lobes. Cortical tubers are composed of abnormal glial and neural cells, and the size, number, and location vary among patients. 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 are extremely common in patients with TSC. 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 TSC include angiomyolipomas and renal cysts. Angiomyolipomas, found in 70-80% of patients with TSC, 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 TSC occasionally have symptoms of PKD.

Cardiac rhabdomyomas often present at birth or during infancy but may be detected as early as 20 weeks' gestation using fetal ultrasonography. These hamartomas, which are usually multiple and intramural, may cause abnormal valve function, outflow obstruction, decreased contractility, cardiomyopathy, and arrhythmias. Usually, cardiac rhabdomyomas are asymptomatic and spontaneously resolve as the child ages if the rhabdomyoma does not cause outflow obstruction during the neonatal period.

Lymphangioleiomyomatosis (LAM) and pulmonary cysts are 2 pulmonary lesions that may develop. These lesions develop almost exclusively in women in the third or fourth decade of life, although fewer than 1% of females with TSC exhibit these lesions. The lesions are composed of blood vessels, adipose tissue, and smooth muscle in abnormal arrangements. Spontaneous pneumothorax may occur, and pulmonary fibrosis and hypertension may lead to cor pulmonale.

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. Asymptomatic pitting of dental enamel is common in the permanent teeth of patients with TSC.

The genes responsible for TSC have been identified. TSC is caused by a mutation in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression.² TSC1, located on chromosome 9, encodes for the protein hamartin; TSC2, located on chromosome 16, encodes for the protein tuberin. The function and interaction of these proteins 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 cells³.

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 is given to the recently discovered role of the TSC1/TSC2 complex in gene transcription via the Wnt signaling pathway. Recently, hamartin and tuberin have been found to modulate gene transcription via beta-catenin.⁴

Recent evidence also suggests that extracellular signal-regulated kinase (ERK) is specifically implicated in the pathogenesis of hamartomas.⁵ 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.⁶

Frequency

United States

TSC 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 TSC 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 TSC in people with less severe phenotypes, which also increases the prevalence rate. Unaffected parents of children with TSC have a recurrence risk of 1-2% in subsequent pregnancies. Affected parents have a 50% chance of transmission to offspring because of the autosomal dominant inheritance pattern. Incidence of gonadal mosaicism is approximately 10-25%. Approximately 0.1-0.7% of patients with mental retardation have TSC.

International

Estimates indicate that 2,000,000 people have TSC worldwide.

Mortality/Morbidity

Overall, the most common cause of death in patients with TSC is status epilepticus or bronchopneumonia. The next most frequent cause of death in patients with TSC is renal failure. Morbidity is associated in the following organ systems:

• CNS manifestations: Seizures, hydrocephalus, mental retardation, and autism or pervasive developmental disorder (PDD) are commonly associated with morbidity in children with TSC.
• • Seizures are the most common cause of morbidity and affect more than one half of patients with TSC. Infantile spasms affect approximately one third of patients and are often one of the early symptoms of TSC. The risks of refractory seizures and decreased cognitive function, with earlier age of seizure onset, are higher. 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 TSC have mental retardation. 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 with TSC. The typical pattern of male bias in autism does not extend to patients with TSC.
  • Various behavioral disorders, including sleep disorders, hyperactivity, aggression, and schizophrenia, may be present in some individuals. Patients with TSC who have normal intelligence may be prone to developmental language disorders.
• Dermatologic manifestations: Various skin lesions are present in as many as 95% of patients with TSC. Facial angiofibromas, present in 75% of patients, cause the most morbidity because of the disfiguring cosmetic effects. Previously treated with dermal abrasion techniques, they are currently treated more successfully using laser therapy.
• Renal manifestations: Approximately 70-80% of patients with TSC 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 TSC, following status epilepticus or bronchopneumonia in some patients with mental retardation. The risk of bleeding increases when angiomyolipomas are larger than 4 cm. Rarely, renal lesions undergo differentiation to renal cell carcinoma.
• Cardiac manifestations: 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.
• Pulmonary manifestations: LAM predominantly occurs in females with TSC, although fewer than 1% of females are affected. However, LAM is the most common cause of death in patients with TSC, when present. 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.

Race

TSC occurs with equal frequency in all races.

Sex

No sex predilection is noted in this autosomal dominant disease. TSC 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.

Age

TSC 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 TSC 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

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.

A family history of TSC may not be discovered if TSC is caused by a spontaneous mutation or if a family member has subclinical disease. Obtain a history and detailed physical evaluation of family members. This includes a history of TSC, seizures, mental retardation, skin manifestations, or other findings consistent with TSC.

Clinical symptoms of TSC in 4 patients with an identical TSC2 mutation were assessed.⁷ 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, TSC 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.

Usefulness of tuberous sclerosis complex diagnostic criteria in pediatric patients

The Tuberous Sclerosis Complex 1998 Consensus Conference clinical criteria represented an important advance in the diagnosis of TSC.⁸ However, many findings regarded as highly specific for TSC are not apparent until late childhood or adulthood.⁹ Physicians should be aware of the criteria frequency in different stages of TSC in children.

• CNS symptoms: The most common and severe CNS manifestations of TSC include seizures, including infantile spasms, and mental retardation. Other symptoms include autism or PDD, aggressive behavior, schizophrenia, and sleep disturbances. Sleep disturbances may be displayed by decreased overall sleep time and frequent nocturnal awakenings.
• Dermatologic symptoms: Hypopigmented lesions (ie, ash-leaf spots) are typically the first dermatologic manifestations of TSC. Other possible lesions include confetti lesions, facial angiofibromas, shagreen patches, periungual or ungual fibromas, and café au lait spots.
• Renal symptoms: 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 may cause heart failure or arrhythmia, even in the presence of normal echocardiogram findings. Patients with rhabdomyomas are usually asymptomatic. Rhabdomyomas often regress with time, although the patient remains at risk for arrhythmia.
  • A case report of molecular confirmation identified multiple cardiac rhabdomyomas as a sole symptom of TSC.
  • A child was described with multiple cardiac rhabdomyomas that were identified using routine fetal ultrasonography.¹⁰ Molecular genetic studies identified a TSC2 gene missense mutation. At age 6 years, he had no skin manifestations of TSC, although CT scan of the brain revealed 2 periventricular calcifications consistent with the molecular diagnosis. Molecularly confirmed TSC 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 TSC.
• Pulmonary symptoms: These predominantly affect females, although fewer than 1% of females with TSC have pulmonary pathology. When present, symptoms include dyspnea, hemoptysis, and development of spontaneous pneumothorax.
• Oral symptoms: Most oral fibromas in TSC are gingival.¹¹ Nearly all patients have dental pits.

Physical

In 1998, the National Institutes of Health Consensus Conference on Tuberous Sclerosis Complex developed revised diagnostic criteria, as follows:¹²

• 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

• Major features include cortical tubers, SENs, SEGAs, 3 or more ash-leaf spots, facial angiofibromas or forehead plaques, shagreen patches, ungual or periungual fibromas in the absence of trauma, cardiac rhabdomyomas, LAM, renal angiomyolipomas, or retinal hamartomas.
• Minor features include dental pits, gingival fibromas, confetti skin lesions, bone cysts, hamartomatous rectal polyps, multiple renal cysts, other nonrenal hamartomas, achromic lesions of the retina, and radial migration lines of cerebral white matter.

• CNS manifestations
• • Seizures may develop during infancy or later. Infantile spasms or a hypsarrhythmia pattern on EEG findings may be present in infants with TSC. Other common seizure types in patients with TSC are complex partial and tonic-clonic seizures.
  • All patients with TSC 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.
• Dermatologic manifestations
• • Ash-leaf spots or hypopigmented lesions are typically the first dermatologic manifestation of TSC. The lesion is best observed using a Wood lamp. An ash-leaf spot may be observed in the general population, but the presence of at least 3 lesions constitutes one of the major diagnostic criteria.
  • Hypomelanotic macules are overwhelmingly the most common early finding in TSC.¹³ Infants with seizures or other stigmata of TSC 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 TSC.¹⁴ If true, forehead plaque may be considered as a novel cutaneous marker of CNS involvement in TSC 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.
  • Ungual or periungual fibromas may appear in adolescents or adults with TSC. Fibromas may cause distortion of the nail or nailbed.
  • Café au lait spots occasionally develop in patients with TSC, although they are usually less common in patients with TSC than in those with neurofibromatosis.
• Renal manifestations: Renal angiomyolipomas are considered one of the major diagnostic features of TSC. Angiomyolipomas are mesenchymal neoplasms that occur sporadically or are associated with TSC; 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 TSC.¹⁵ Renal cysts are also common, and 40-80% of patients with TSC have either renal angiomyolipomas or renal cysts. The presence of hypovolemic shock may result from bleeding angiomyolipomas. Renal failure may also be evident.
• Cardiac manifestations: Arrhythmias due to cardiac rhabdomyomas may be noted. Signs of cardiac failure are rare but possible.
• Pulmonary manifestations: Evidence of pneumothorax (including absence of breath sounds) due to progression of LAM may be observed.
• 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.
  • Dental pits in permanent teeth usually occur randomly on multiple teeth. They are more easily detected when teeth are stained.
  • Gingival fibromas can be noted upon visual inspection of the oral cavity.
  • A rectal hamartoma or polyp is occasionally detected using a digital rectal examination.

Causes

TSC is inherited in an autosomal dominant pattern. A parent with TSC has a 50% chance of transmitting the disease to offspring. Sporadic mutations are estimated to occur in approximately two thirds of cases.

• Mutations in two genes, TSC1 and TSC2, have been identified as causes of TSC. TSC1 is located on chromosome 9 and was identified in 1997. This gene encodes for the protein hamartin. The protein tuberin is encoded by the gene TSC2. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in TSC. Approximately 50% of familial cases are due to TSC1, and the remaining 50% are due to TSC2. A mutation in the TSC2 gene is responsible for 75% of sporadic cases.
• Currently, TSC is a clinical diagnosis because genetic testing is still expensive and rarely performed. Family members may also be tested on a clinical basis if a mutation is detected. Information regarding gene testing is available online from GeneTests.
• Criteria for germline mosaicism have recently been outlined. Parents without evidence of either major or minor criteria of TSC who have 2 or more children with TSC meet the criteria for germline mosaicism. For this reason, parents who have no manifestations of TSC but who have one child with TSC should receive counseling regarding the 1-2% chance of having another child with TSC. The incidence of germline mosaicism is estimated to be approximately 10-25%.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to 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.¹⁶ 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 TSC may be similar to those in Cowden syndrome, Birt-Hogg-Dube syndrome, and multiple endocrine neoplasia type 1.¹¹

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Some recommend annual urinalysis and electrolyte testing to detect progression of renal lesions, although this testing is controversial.
• Currently, testing to determine genetic mutations is available only on a research basis. Once a mutation is discovered, family members may be tested on a clinical basis. Because testing is not yet widely available, the diagnosis is likely to remain clinically based for years to come. Further research in genetic testing is ongoing. 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 (TSC).¹⁷ FLAIR images confirmed the cystic character of some of these cortical tubers.

Imaging Studies

• Brain MRI or CT scanning
• • Brain MRI is recommended for the detection and follow-up imaging of cortical tubers, SENs, and SEGAs. Perform MRI during the initial diagnostic workup and then every 1-3 years in children with TSC. 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 TSC 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. 
• 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 TSC. Perform subsequent surveillance studies in children or adults with TSC 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. Benign angiomyolipomas are found in 50-80% of patients with TSC. The lesions are usually bilateral, and the average size is 9 cm. Angiomyolipomas are more common in adults with TSC, whereas renal cysts are more common in children.  
• Echocardiography
• • Obtain an echocardiogram at initial evaluation and in adults with TSC 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 TSC. 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 individuals with TSC as clinically indicated. Obtain pulmonary CT scans in women with TSC 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 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

• Electroencephalography
• • 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 TSC, 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 TSC entering the first grade. In children and adults with a history of developmental delay, perform repeated evaluations as clinically indicated.
• Electrocardiography
• • Obtain ECGs with the same frequency as echocardiograms (ie, initial evaluation, as indicated in adults with TSC 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 TSC and known ophthalmologic lesions.
  • Funduscopic examination may reveal retinal hamartomas or astrocytomas in 50-80% of individuals with TSC. 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 TSC. PFT results in individuals with TSC 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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).⁶
• 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 eMedicine topic Hypertension in the Pediatric Cardiac Disease and Critical Care Medicine Volume.
• Rapamycin (sirolimus) may be useful in tuberous sclerosis treatment.¹⁸ 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 this agent are in progress.^{19, 20, 21}

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 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.
• 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. They were previously treated with repeated dermal abrasion, but laser therapy is currently recognized to have improved efficacy and outcome.

Consultations

• Neurosurgeon: 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.
• Neurologist: 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.
• Cardiologist: 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.
• Ophthalmologist: An ophthalmologist may perform a thorough funduscopic examination to assess for evidence of retinal hamartomas or astrocytomas.
• Genetic counselor: A genetic counselor is particularly helpful when parents of children with TSC are contemplating future pregnancies.
• Other specialists: A pulmonologist may assist with management of LAM in females with TSC. Consult a nephrologist for individuals with symptomatic renal disease. Consultation with a neuropsychologist is helpful in assessing intellectual ability in a child with TSC. Neuropsychologists may also assist in management of various behavioral problems, such as autism or PDD, schizophrenia, aggressive behavior, or sleep disturbances. Finally, a social worker may assist families and individuals in coping with this chronic disorder.

Diet

• 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 TSC 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.²²

Activity

• Activity is not restricted in patients with TSC 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

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Drug Category: Anticonvulsant agents

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.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit patients with 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 (TSC) 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 TSC 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 PFT.
• Routinely monitor patients on anticonvulsant medications for adequacy of seizure control.
• Patients with behavioral or psychiatric disorders require routine outpatient follow-up evaluation.

In/Out Patient Meds

• Various anticonvulsant medications, such as carbamazepine, valproic acid, or lamotrigine,²³ may be used for seizure control.²⁴ 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.

Transfer

• 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.

Deterrence/Prevention

• TSC 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 is under investigation, with mutational analysis currently available on a research basis. Prenatal testing may be available in the future.

Complications

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

Prognosis

• TSC has a wide clinical spectrum, and some patients are affected subclinically with no decrease in life expectancy or quality of life.
• A decreased life expectancy is noted in some individuals with TSC. 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.

Patient Education

• Instruct patients, parents, and family members regarding seizure precautions. A medical identification bracelet may be useful.
• Educate patients and their families regarding the symptoms of increased intracranial pressure and hydrocephalus so that medical attention may be sought quickly.
• Provide genetic counseling to assist in family planning.
• An excellent resource for patients and their family members for information and support is the Tuberous Sclerosis Alliance. The contact information is as follows:

  Tuberous Sclerosis Alliance
  801 Roeder Road, Suite 750
  Silver Spring, MD 20910
  Telephone: 1-800-225-6872
  Fax: 1-301-562-9870
  email: info@tsalliance.org

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize signs or symptoms of tuberous sclerosis complex (TSC)
• Failure to recognize the presence of increased intracranial pressure and to provide appropriate treatment
• Failure to obtain appropriate screening or surveillance studies
• Failure to provide genetic counseling to patients, parents, or family members
• Failure to screen first-degree relatives for TSC once an individual is diagnosed with TSC

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Facial angiofibroma, previously termed adenoma sebaceum, in a patient with tuberous sclerosis complex (TSC).
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Media file 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.
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Media type:  Photo

Media file 3:  Ash-leaf spots are hypomelanotic lesions that are observed more easily with the use of a Wood lamp.
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Media type:  Photo

Media file 4:  A shagreen patch is a connective tissue hamartoma with a leathery texture and is found most commonly in the lower back region.
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Media type:  Photo

Media file 5:  Confetti skin lesions are hypomelanotic lesions that cluster and appear reticulated.
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Media type:  Photo

Media file 6:  MRI in a patient with tuberous sclerosis complex (TSC) demonstrates the presence of a tuber and subependymal nodules.
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Media type:  MRI

Media file 7:  Periungual fibroma on the thumb of a patient with tuberous sclerosis complex (TSC).
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: May 15, 2008