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      Drugs & Diseases > Pediatrics: Genetics and Metabolic Disease

      Genetics of Tuberous Sclerosis Workup

      Updated: Sep 02, 2021
      • Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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      Workup

      Laboratory Studies

      Some recommend annual urinalysis and electrolyte testing to detect progression of renal lesions in patients with tuberous sclerosis complex (TSC), although this testing is controversial.

      Testing to determine genetic mutations is now available only on a clinical basis. Once a person affected with tuberous sclerosis complex is found to have a mutation in either of the 2 genes, at-risk family members may be tested. 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. [41] FLAIR images confirmed the cystic character of some of these cortical tubers.

      Renal cell carcinomas were divided in TSC into three different morphologic groups (Yang et al, 2014). The largest group were classified as "TSC-associated papillary renal cell carcinomas."

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      Imaging Studies

      Brain MRI or CT scanning

      Brain MRI is recommended for the detection and follow-up imaging of cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Perform MRI during the initial diagnostic workup and then every 1-3 years in children with tuberous sclerosis complex. 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 tuberous sclerosis complex 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. The clinical presentation of TSC is highly variable and not well understood. SEGAs are found to be linked with autistic spectrum disorders in patients with TSC, suggesting that SEGA formation may also predispose. [42]

      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 tuberous sclerosis complex. Perform subsequent surveillance studies in children or adults with tuberous sclerosis complex 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. Avoid CT as much as possible to minimize radiation. Benign angiomyolipomas are found in 50-80% of patients with tuberous sclerosis complex. The lesions are usually bilateral, and the average size is 9 cm. Angiomyolipomas are more common in adults with tuberous sclerosis complex, whereas renal cysts are more common in children.

      Echocardiography

      Obtain an echocardiogram at initial evaluation and in adults with tuberous sclerosis complex 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 tuberous sclerosis complex. 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 adult females with tuberous sclerosis complex, 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 lymphangioleiomyomatosis (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.

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      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 tuberous sclerosis complex, 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 tuberous sclerosis complex 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 tuberous sclerosis complex 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 tuberous sclerosis complex and known ophthalmologic lesions.

      Funduscopic examination may reveal retinal hamartomas or astrocytomas in 50-80% of individuals with tuberous sclerosis complex. 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 tuberous sclerosis complex. PFT results in individuals with tuberous sclerosis complex usually demonstrate an obstructive pattern.

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      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.

      Periungual fibromas are nonencapsulated neoplasms composed of stellate fibroblasts admixed with vertically oriented dense collagen and blood vessels. Histologic variants of periungual fibromas in tuberous sclerosis complex have been classified as angiomatous, fibrotic, and intermediate mixed subtypes, depending on the relative proportion of vascular and stromal components. [30]

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