Basics
Description
- Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by a spectrum of signs and symptoms that present over a patient 's lifetime, including neurologic disorders, multisystem tumor growth, and dermatologic manifestations.
- First described by Bourneville in 1880, the classic diagnostic triad of adenoma sebaceum, intellectual disability, and seizures has been revised to include other manifestations because many patients with tuberous sclerosis do not exhibit this triad.
Epidemiology
Incidence
Current estimates suggest an incidence of 1 in 5,000 to 1 in 15,000 births. 60 " 70% of cases reflect sporadic mutation; 30 " 40% of cases are familial.
Risk Factors
Genetics
- 2 clearly identified loci for familial and sporadic cases based on linkage analyses are 9q34 and 16p13, corresponding to TSC1 and TSC2 genes, respectively. TSC1 encodes the protein hamartin and TSC2 encodes the protein tuberin. Together, hamartin and tuberin join to form a regulatory complex of mTOR (the serine-threonine kinase, mammalian target of rapamycin). Permanent activation of mTOR through mutations in the genes coding for these proteins causes dysregulation of cellular growth, differentiation, and migration, leading to the clinical symptoms and multisystem cellular overgrowth seen in TSC.
- >1,000 mutations in these genes are known to exist, leading to highly variable phenotypes in this disorder.
- TSC2 mutations: more common in sporadic cases, associated with more severe phenotypes
- 10 " 15% of cases meeting clinical criteria have no identifiable gene mutations.
Etiology
Tuberous sclerosis is either inherited in an autosomal dominant pattern or results from a spontaneous/sporadic mutation.
Diagnosis
History
- Primary symptoms include seizures, intellectual disability, and skin lesions.
- All types of seizures are seen in TSC. Seizures may begin at any time and are present in 70 " 80% of patients. In infancy, infantile spasms are a common presenting seizure; 1/3 of patients develop infantile spasms.
- Intellectual disability and neurobehavioral abnormalities (e.g., autism, which is present in 25% of patients) may manifest as developmental delay, but some patients are without cognitive defect.
- Skin lesions may appear in infancy or during early childhood.
- It is important to obtain a full family history, reviewing involved systems.
- Inquire about history of seizures, mental retardation, skin lesions, and cardiac or renal disease/cancers.
- Screening for symptoms of hydrocephalus (headache, vomiting) is important: 10% of patients develop CSF obstruction from subependymal giant cell tumors.
- Women are primarily affected by pulmonary lymphangiomyomatosis, which may manifest as dyspnea or pneumothorax in early adulthood.
Physical Exam
- Maintain a high level of suspicion for tuberous sclerosis in any patient presenting with the following:
- Infantile spasms or childhood seizures
- Autism
- Intellectual impairment/developmental delay
- Peculiar skin lesions
- Ash leaf and cafe au lait spots are small (often <5 mm) but may be found anywhere on skin and are often present at birth. Examination with a Wood lamp may help to identify hypopigmented lesions (e.g., ash leaf spots).
- Cardiac rhabdomyomas (however, not all these patients will ultimately be diagnosed with TSC)
- Facial angiofibromas are typically found around the nose and cheeks and look like acne; they develop in later childhood to adolescence. They neither itch nor suppurate.
- Ungual fibromas appear around the nail bed.
- Shagreen patches are brownish, leathery skin patches near the sacrum.
- Funduscopic examination may reveal whitish-yellow areas in epipapillary and peripapillary regions around the optic nerve head. They rarely impair vision. Papilledema may be seen with hydrocephalus.
- Signs of heart failure or tachyarrhythmia may be seen in infants with cardiac tumors.
- Flank pain, nausea, vomiting, and hematuria may suggest renal involvement.
- Procedures: Dilated funduscopic examination may also aid in full visualization of the optic nerve head.
- Definite diagnosis requires 2 major or 1 major plus 2 minor features:
- Major criteria: facial angiofibroma, ungual fibroma, shagreen patch, hypomelanotic papule (ash leaf spot), cortical tuber, subependymal giant cell tumor, retinal hamartoma, cardiac rhabdomyoma, renal angiomyolipoma, lymphangiomyomatosis
- Minor criteria: pitting in tooth enamel, hamartomatous rectal polyps, bone cysts, cerebral white matter radial migration lines, gingival fibromas, retinal achromic patch, "confetti " skin lesions (grouped lightly pigmented spots), multiple renal cysts
- As with other dominant, multisystem conditions, the findings in TSC have variable penetrance, and clinical manifestations may appear at different developmental points.
- Although seizures and intellectual disability are common in TSC, they vary, are nonspecific, and so are not considered in the diagnostic criteria.
Diagnostic Tests & Interpretation
Lab
- Blood and CSF lab test results are typically normal unless renal function is significantly compromised by renal cysts or renal angiomyolipomas.
- ECG may reveal cardiac dysrhythmias, present in 47% of persons with cardiac rhabdomyomas.
- In patients with intellectual disability or seizures, EEG helps to evaluate cerebral activity.
- In infants with suggestive history, an EEG may help diagnose infantile spasms, which are associated on EEG with a highly disorganized pattern of large-amplitude, asynchronous, sharp waves termed hypsarrhythmia.
- Later in childhood, patients with tuberous sclerosis may develop Lennox-Gastaut syndrome, which consists of developmental delays, seizures, and a characteristic EEG pattern of slow (i.e., ≤2.5 Hz), generalized spike-wave complexes.
Imaging
- Subependymal or other cerebral calcifications on CT, often found in the course of emergent evaluation of new seizures, suggest TSC " consider MRI.
- Guidelines suggest MRI of the brain with gadolinium administration yearly or in alternate years until age 21 years and every 2 " 3 years thereafter. Imaging will identify tubers, subependymal nodules, hydrocephalus, and giant cell tumors. These appear hyperintense on T-weighted images and may enhance with gadolinium.
- Echocardiogram can detect cardiac rhabdomyomas in infants with tuberous sclerosis; prenatal ultrasound commonly identifies these tumors.
- CT of the lungs is indicated in women with TSC to screen for lymphangiomyomatosis.
- Renal ultrasound (every 1 " 2 years) or CT will demonstrate renal lesions.
Pathologic Findings
Findings reflect the primary tissue in which lesions are identified:
- Brain
- 3 characteristic lesions are cortical tubers, subependymal nodules, and subependymal giant cell tumors.
- In tubers, the cerebral cortical architecture is disrupted, and these regions may undergo calcification, which can be visible on skull radiographs or brain CT.
- Subependymal nodules consist of large abnormal astrocytes emanating from the lateral ventricular surface.
- Subependymal giant cell tumors are low-grade benign astrocytic neoplasms.
- Skin
- Facial angiofibromas may be mistaken for acne and are highly suggestive of tuberous sclerosis; they appear as pinkish-yellow plaques on the malar regions and nasolabial folds.
- Ash leaf spots are hypopigmented hypomelanotic macules occurring anywhere on the body.
- Ungual fibromas are fleshy growths along the lateral borders of the nail bed.
- Shagreen patches are areas of shaggy leathery skin typically in the lumbosacral area.
- Retina
- Whitish-yellow angiomyolipomas or hamartomas occur near the optic nerve head or the retinal periphery and may calcify.
- Heart
- Rhabdomyomas in the ventricular wall occur in infancy and contain abundant nodules of large eosinophilic cells; this is the most common type of cardiac tumor of infancy and early childhood which 4% of the time will occur in the absence of TSC.
- Kidney
- Renal cysts, polycystic kidneys, angiomyolipomas, and, more rarely, renal carcinomas
- Other organ systems
- Less commonly affected are the lungs, GI tract, spleen, vascular bed, and lymphatic system.
Differential Diagnosis
Neurocutaneous syndromes in which skin lesions, intellectual disability, and seizures are characteristic features should be considered:
- Neurofibromatosis
- Sturge-Weber syndrome
- von Hippel-Lindau disease
- Neurocutaneous melanosis
- Albright syndrome
- Incontinentia pigmenti
- Linear sebaceous nevus
Treatment
Medication
- Everolimus (a rapamycin analog) is an immunosuppressant agent that inhibits mTOR, thereby inhibiting the cellular proliferation seen in tuberous sclerosis patients. It has been approved by FDA for management of subependymal giant cell tumors, and its use in targeting other tuberous sclerosis complications is under investigation.
- Anticonvulsant therapy as needed. Infantile spasms may be treated with adrenocorticotropic hormone or vigabatrin.
- Medical management of heart failure or cardiac dysrhythmias is indicated in tuberous sclerosis patients with cardiac rhabdomyomas.
Ongoing Care
Prognosis
Cognitive disability unfortunately will not improve unless the cognitive impairment results from uncontrolled seizures. Seizure control is medically refractory in up to 40% of cases, and some children require epilepsy surgery to remove cortical tubers or subependymal nodules. Cardiac tumors may also require surgical intervention. Renal angiomyolipomas can be embolized angiographically or surgically corrected. Subependymal giant cell astrocytomas that cause hydrocephalus may require resection.
Additional Reading
- Au KS, Ward CH, Northrup H. Tuberous sclerosis complex: disease modifiers and treatments. Curr Opin Pediatr. 2008;20(6):628 " 633. [View Abstract]
- Crino PB. The pathophysiology of tuberous sclerosis complex. Epilepsia. 2010;51(Suppl 1):27 " 29. [View Abstract]
- Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657 " 668. [View Abstract]
- Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010;41(5):199 " 208. [View Abstract]
- Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801 " 1811. [View Abstract]
Codes
ICD09
ICD10
SNOMED
- 7199000 tuberous sclerosis syndrome (disorder)
- 36025004 Fibrous skin tumor of tuberous sclerosis (disorder)
FAQ
- Q: Can tuberous sclerosis be transmitted in subsequent pregnancies?
- A: An affected patient with the tuberous sclerosis gene mutation has a 50% chance of transmitting the mutation to his or her children.
- Q: Is genetic testing available?
- A: Molecular genetic testing for mutations at the TSC1 and TSC2 loci are available but are not required for diagnosis because not all clinical cases of TSC have identifiable mutations.
- Q: Will my child need brain surgery?
- A: In the event of refractory seizures, removal of cortical tubers may help seizure control. Surgery may also be indicated in cases of obstructive hydrocephalus. If a brain tumor is detected by MRI, neurosurgical evaluation is indicated.