eMedicine Specialties > Radiology > Multisystem

Tuberous Sclerosis

Bennett Greenspan, MD, Instructor of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine
L Keith Jordan, MD, Consulting Staff, Radiology Associates PA; Charles M Glasier, MD, Professor, Departments of Radiology and Pediatrics, University of Arkansas for Medical Sciences; Chief, Magnetic Resonance Imaging, Vice-Chief, Pediatric Radiology, Arkansas Children's Hospital

Updated: May 8, 2009

Introduction

Background

Genetics

Tuberous sclerosis is an autosomal-dominant disorder. Approximately 50% of cases are inherited and 50% are sporadic, although the incidence of sporadic cases may be as high as 80%. Penetrance is believed to be high. The expression is variable. The severity of the disease appears to reflect the variable penetrance. Substantial genetic inhomogeneity exists. The disease is caused by mutations in either the TSC1 gene, on chromosome 9q34, or the TSC2 gene, on chromosome 16p13.3.^1,2,3,4

Clinical appearance

Manifestations of tuberous sclerosis can become apparent in persons of any age, but most patients have clinical symptoms before they are aged 10 years. The classic form of the disease is the triad of seizures, mental retardation, and adenoma sebaceum, which is a papular facial nevus more accurately termed facial angiofibroma. This classic appearance occurs in less than half of patients, probably in one third.

Sagittal T1-weighted MRI in an infant with tuberous sclerosis shows multiple hyperintense cortical and subependymal nodules.

Image in a 15-year-old boy with a right-sided abdominal mass, which is a renal cell carcinoma.

Abnormal radiologic findings are important in diagnosing this disease and include CNS lesions of cortical hamartomas, white-matter abnormalities, and subependymal nodules (ie, hamartomas). Patients also have subependymal giant cell astrocytomas. These intracranial neoplasms can result in obstructive hydrocephalus. Retinal lesions, nonatheromatous vascular stenoses and aneurysms, and mild ventricular enlargement without astrocytomas can be present.

Tuberous sclerosis is a multisystemic disorder. Non-CNS lesions of tuberous sclerosis include cutaneous manifestations. In addition to the lesions mentioned above, these include vitiligo and subungual patches. Findings also are observed in the heart; lungs; kidneys; skeleton; and, occasionally, liver, spleen, and pancreas.

Diagnostic criteria

The Mayo Clinic has developed a more inclusive set of diagnostic criteria. The established definitive criteria include facial angiofibromas, ungual fibromas, retinal hamartomas (phakomas), cortical tubers, subependymal nodules, and multiple renal angiomyolipomas; only 1 must be present for the diagnosis to be made. Presumptive criteria also have been developed; of these, a minimum of 2 must be present because these findings can occur without tuberous sclerosis. The presumptive criteria include cutaneous findings of hypomelanotic nodules or shagreen patches, renal findings of a single angiomyolipoma or multicystic kidney, lung findings of pulmonary lymphangioleiomyomatosis (LAM) or radiographic honeycomb lung, cardiac rhabdomyoma, and a first-degree relative with tuberous sclerosis.⁵

Comprehensive diagnostic criteria have been revised as a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. The following are major features:

Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibroma
Hypomelanotic macules (>3)
Shagreen patch (connective-tissue nevus)
Multiple retinal nodular hamartomas
Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangioleiomyomatosis
Renal angiomyolipoma

When both lymphangioleiomyomatosis and renal angiomyolipoma are present, other features of tuberous sclerosis should be present before a definite diagnosis is made.

The following are minor features:

Multiple randomly distributed pits in dental enamel
Hamartomatous rectal polyps
Bone cysts (radiographic confirmation is sufficient)
Cerebral white-matter radial migration lines
Gingival fibromas
Nonrenal hamartomas
Retinal achromic patches
"Confetti" skin lesions
Multiple renal cysts

Diagnostic criteria are as follows:

Definite - Two major features or 1 major feature plus 2 minor features
Probable - One major feature plus 1 minor feature
Possible - One major feature or 2 or more minor features

Pathophysiology

Tuberous sclerosis is a multisystemic disease.

The pathogenesis of the CNS lesions is not certain, but it is believed to be associated with disordered migration of abnormal or dysgenetic neurons along abnormal glial fibers. Intracranial lesions are classified into 4 major categories as follows:

Cortical tubers: These are considered to be hamartomas.
White-matter abnormalities.
Subependymal nodules: These also are considered to be hamartomas. Periventricular subependymal nodules usually are present at birth and can range from 2-25 mm. Their tendency to become calcified increases with the patient's age.
Subependymal giant cell astrocytomas: These usually occur at the foramina of Monro and are associated with obstructive hydrocephalus. These lesions are uncommon in infants and most common in adolescents.

Microscopic examination reveals giant cell clusters with varying degrees of neuronal and astrocytic differentiation of all 4 of the CNS lesions described above.

Renal lesions include cysts: angiomyolipomas and renal cell carcinoma. Renal cysts typically are multiple and bilateral. Angiomyolipomas, which are considered hamartomas, are benign lesions that contain varying amounts of smooth muscle, blood vessels, and mature adipose tissue. Usually, a significant amount of lipid is present. These lesions can enlarge over time.

Thoracic manifestations include cardiac rhabdomyomas, which often are present at birth. Pulmonary manifestations typically are present late in the disease. These produce cystic changes that are characterized by interstitial smooth muscle proliferation, which can result in interstitial thickening; alveolar destruction; and, eventually, chronic fibrosis or honeycomb lung, with complications of pneumothorax, pulmonary hypertension, and cor pulmonale. These abnormalities can be clinically indistinguishable from lymphangioleiomyomatosis.

Frequency

United States

The prevalence of tuberous sclerosis in the United States is approximately 1 case per 10,000 persons.

Mortality/Morbidity

Mortality can result from obstructive hydrocephalus caused by the development of subependymal giant cell astrocytomas.

Cardiac rhabdomyoma is a rare lesion, but 50% of these tumors occur in patients with tuberous sclerosis. Cardiac rhabdomyoma may be fatal in infants. Other morbidities are related to the type of lesion or disease present.

Morbidity in CNS lesions: Seizures are a fairly common clinical manifestation and occur in most patients with tuberous sclerosis. Infantile spasms are a type of seizure that frequently occurs in babies with tuberous sclerosis. Mental impairment or retardation occurs in a substantial number of patients. Although histologically benign, giant cell astrocytomas typically cause obstructive hydrocephalus. These tumors may be locally aggressive because of rapid growth and an associated mass effect. Hemorrhage may occur within the tumor, causing rapid enlargement.
Morbidity in renal lesions: Multiple cysts or angiomyolipomas can cause hypertension. Bleeding, from angiomyolipomas or renal cell carcinoma, can occur and cause flank pain. Severe renal involvement may result in renal failure, which may necessitate dialysis.
Morbidity in cardiopulmonary disease: One or more cardiac rhabdomyomas may develop. These tumors can interfere with both electrical conduction and muscular contraction and can result in congestive heart failure. In the lungs, cystic and interstitial changes can occur; these changes may be indistinguishable from those of lymphangioleiomyomatosis. Also, these changes can result in spontaneous pneumothorax in as many as 50% of patients with pulmonary involvement. Patients also may have pulmonary hypertension, cor pulmonale, end-stage fibrosis, or honeycomb lung.

Age

Patients often have seizures in infancy or childhood. Patients who have seizures before they are aged 5 years are more likely to have mental retardation than other patients. Most patients have clinical symptoms before they are aged 10 years.

Anatomy

Alterations in the brain anatomy can occur as a result of cortical tubers, white-matter lesions, or subependymal nodules. Development of subependymal giant cell astrocytomas may result in hydrocephalus.

Renal lesions, both angiomyolipomas and renal cell carcinoma, can distort the renal collecting systems or cause renal enlargement.

Cardiac rhabdomyomas can cause enlargement or other abnormalities of the heart.

Pulmonary disease can cause cystic and interstitial changes, which can result in alveolar destruction and end-stage fibrosis.

Orbital lesions, such as retinal hamartomas or phakomas, commonly become calcified and may produce a white retinal light reflection termed leukokoria, a common sign in retinoblastoma.

Several skeletal lesions can cause anatomic changes. Ungual angiofibromas cause erosion of the tufts of the distal phalanges. Periosteal thickening generally occurs in the metacarpals and metatarsals, but it can also occur in the long bones. Bone islands are also observed.

Presentation

Manifestations of tuberous sclerosis can become apparent in persons of any age, but most patients have clinical symptoms before they are aged 10 years. The severity of the disease appears to reflect the variable penetrance. The classic form of the disease is the triad of seizures; mental retardation; and adenoma sebaceum, which is a papular facial nevus more accurately termed facial angiofibroma. This classic appearance occurs in less than half the patients, probably in one third.

Seizures occur in most patients. Mental impairment or retardation can be observed in 40-82% of patients, and in almost all patients with seizures, the seizures begin before the patient is aged 2 years.

Renal cystic disease may appear as bilateral flank masses. Severe renal involvement may result in renal failure in patients aged 10-30 years. Patients may present with flank pain or hematuria resulting from hemorrhage within an angiomyolipoma, renal cell carcinoma, or a perinephric area.

Hypertension may develop as a result of renal disease.

Preferred Examination

CT and MRI of the brain are the most sensitive screening imaging studies. Currently, MRI is considered the modality of choice for the evaluation of the brain in patients with diagnosed or suspected tuberous sclerosis. CT is the modality of choice for evaluating renal lesions because of its ability to delineate cystic from solid lesions and lipid-containing angiomyolipomas.^6,7

Limitations of Techniques

CT is much less sensitive than MRI in the identification of cortical hamartomas and neuronal migration streaks. MRI is less sensitive than CT in the identification of calcifications of the brain. CT cannot be used to differentiate non–lipid-containing angiomyolipomas from other renal tumors.

Differential Diagnoses

Angiomyolipoma, Kidney
Autosomal Dominant Polycystic Kidney Disease
Autosomal Recessive Polycystic Kidney Disease
Lymphangioleiomyomatosis
Renal Cell Carcinoma

Radiography

Findings

Abnormal radiologic findings are important in diagnosing this disease and include CNS lesions of cortical hamartomas, white-matter abnormalities, and subependymal nodules (ie, hamartomas).

Most findings detectable on plain radiographs are musculoskeletal or thoracic. One half of the patients with tuberous sclerosis have musculoskeletal lesions. Changes include osteoporosis and cystic defects in the metacarpals, metatarsals, and/or phalanges. Erosions of the tufts of the distal phalanges, the result of ungual angiofibromas, may be observed. A periosteal reaction is observed in tubular bone; some authors characterize this reaction as having an undulating appearance. Heterogeneous sclerosis can affect the entire axial skeleton. Multiple bone islands with an apparent natural propensity for the diploic space may be observed. Macrodactyly and expansile-enhanced bone density that is restricted to a single rib are described. Plain skull films often reveal sclerosis or widening of the diploic space, which is related to the administration of phenytoin.

Chest radiographs rarely can depict evidence of interstitial fibrosis or honeycombing. Occasionally, the appearance of the chest is compatible with its appearance in lymphangioleiomyomatosis (LAM). The connection between tuberous sclerosis and LAM is unclear. Pneumothorax is an infrequent complication in interstitial fibrosis and LAM. Approximately one fourth of patients can have cardiac rhabdomyomas, which places these patients at risk for congestive heart failure.

Renal angiomyolipomas occur in 50-90% of patients but only rarely contain enough adipose tissue to be observed on plain radiographs. Findings on excretory urograms or retrograde pyelograms can vary widely, depending on the number and size of cysts or angiomyolipomas. These findings include bilateral renal enlargement or distortion of the collecting systems caused by cysts or angiomyolipomas. Hamartomatous polyps can be present in the colon. Gastric polyposis also can occur; this can be depicted on barium studies.

Specificity with respect to plain radiographic findings in patients with tuberous sclerosis is problematic because many of these lesions occur in other conditions; however, conventional radiographic findings often support the diagnosis of tuberous sclerosis.

Degree of Confidence

Occasionally, plain radiographs depict lucencies caused by fat in the angiomyolipoma; this finding can suggest the diagnosis of tuberous sclerosis. Distortion of the renal collecting system as a result of multiple cystic lesions may be indistinguishable from findings in autosomal dominant polycystic kidney disease.

False Positives/Negatives

Findings on excretory urograms and retrograde pyelograms can include bilateral renal enlargement or distortion of the collecting system; these can mimic the findings in autosomal-dominant polycystic kidney disease.

Computed Tomography

Axial nonenhanced CT image in a patient with tuberous sclerosis reveals subependymal calcifications. A hypointense right frontal lesion represents a white matter lesion or tuber; it extends from the lateral ventricle through the cerebral cortex.

Hyperattenuating cutaneous lesion in the left frontal region represents a calcified shagreen patch.

Axial CT image obtained at the same level as in Image 1 above reveals no enhancement in this white matter lesion in the right frontal lobe after the intravenous administration of contrast material.

Contrast-enhanced head CT scan reveals a low-attenuating cortical tuber (arrow) in a 10-year-old patient with tuberous sclerosis.

Nonenhanced head CT scan reveals bilateral calcified subependymal nodules at the foramina of Monro.

Image obtained in the same patient as in Image above, who presented at age 16 years with progressive headaches, papilledema, and vomiting, shows a giant cell astrocytoma at the right foramen of Monro.

Nonenhanced CT scan shows large right retinal tuber in an infant with tuberous sclerosis.

Axial nonenhanced CT scan obtained in the same patient as in Image above shows multiple hyperattenuating subependymal tubers.