eMedicine Specialties > Radiology > Multisystem

Tuberous Sclerosis

Author: Bennett Greenspan, MD, Instructor of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine
Coauthor(s): 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
Contributor Information and Disclosures

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.

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

Other Problems to Be Considered

Giant cell astrocytoma
Rhabdomyoma
Epilepsy in patients with mental retardation

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