Diagnosis of Tuberous Sclerosis Complex

E. Steve Roach MD; Steven P. Sparagana MD

Disclosures

J Child Neurol. 2004;19(9):643-649. 

In This Article

Clinical Features of Tuberous Sclerosis Complex

The cutaneous lesions of tuberous sclerosis complex include hypomelanotic macules, the shagreen patch, ungual fibromas, and facial angiofibromas (Figure 1). One or more of these skin lesions occur in over 90% of individuals with tuberous sclerosis complex, although none is pathognomonic.[4]

Cutaneous features of tuberous sclerosis complex include A, hypomelanotic macules and poliosis (in this case, the area of hypopigmentation and poliosis is unusually large; a more typical hypomelanotic macule is evidently inferior to the large lesion); B, facial angiofibromas (adenoma sebaceum); C, the shagreen patch, and D, an ungual fibroma. B reproduced with permission from Roach ES, Delgado MR: Tuberous sclerosis. Dermatol Clin 1995;13:151-161.

Hypomelanotic macules (ash leaf spots) are found in over 90% of patients with tuberous sclerosis complex (see Figure 1). They are usually present at birth but are often difficult to see in the newborn without an ultraviolet light. Other pigmentary abnormalities include the "confetti" lesions (an area with stippled hypopigmentation, typically on the extremities) and poliosis of the scalp hair or eyelids. Hypomelanotic macules are not specific for tuberous sclerosis complex because one or two of these lesions are relatively common in normal individuals.[8]

Facial angiofibromas (see Figure 1) occur in about three fourths of patients but often appear several years after the diagnosis has been established by other means. These lesions typically become apparent during the preschool years as a few small red papules on the malar region; they gradually become larger and more numerous, sometimes extending down the nasolabial folds or onto the chin. Angiofibromas contain both vascular and connective tissue elements. Although facial angiofibromas are a strong indication of tuberous sclerosis complex when found with other manifestations, these lesions also occur in individuals with multiple endocrine neoplasia type I and thus are not pathognomonic for either condition.

The shagreen patch (see Figure 1) is most commonly found on the back or flank area; it is an irregularly shaped, slightly raised, or textured skin lesion. The lesion is found in 20 to 30% of patients with tuberous sclerosis complex and occasionally other individuals. It might not be apparent in young children.

Ungual fibromas (see Figure 1) are nodular or fleshy lesions that arise adjacent to or from underneath the nails. The lesion is usually considered specific for tuberous sclerosis complex, although a single lesion occasionally occurs after trauma. Ungual fibromas are seen in about 20% of unselected patients with tuberous sclerosis complex and are more likely to be found in adolescents or adults than in younger children. Sometimes the fibroma itself is not visible but creates a prominent longitudinal groove in the fingernail, a finding that also has diagnostic significance.

The frequency of retinal hamartomas in tuberous sclerosis complex varies with the expertise and technique of the examiner. Under ideal circumstances, up to 87% of patients with tuberous sclerosis complex have retinal lesions, but especially in uncooperative children, these lesions can be difficult to identify without dilating the pupils and the use of indirect ophthalmoscopy.[1] Retinal lesions vary from the classic mulberry lesions (Figure 2) adjacent to the optic disk to the plaquelike hamartoma or depigmented areas. Most retinal lesions are clinically insignificant, but occasional patients have visual impairment owing to a large macular lesion, and rare patients have visual loss owing to retinal detachment, vitreous hemorrhage, or hamartoma enlargement. Some patients have a pigmentary defect of the iris.

A retinal astrocytoma ("mulberry lesion") adjacent to the optic nerve is typical of those found with tuberous sclerosis complex. Reproduced with permission from Roach ES: Neurocutaneous syndromes. Pediatr Clin North Am 1992;39:591-620.

Roughly two thirds of newborns with tuberous sclerosis complex have one or more cardiac rhabdomyomas, but few of these lesions are clinically important. Cardiac rhabdomyomas are often multiple (Figure 3) but shrink over time and are identified much less often in older children and adults.[10] These lesions are sometimes evident on prenatal ultrasonographic testing, and most of the patients with cardiac dysfunction present soon after birth with heart failure, usually owing to either obstruction of blood flow by an intraluminal tumor or to inadequate normal myocardium to maintain perfusion. Some patients stabilize and improve after medical treatment; others require surgery. A few children later develop cardiac arrhythmias.

Ultrasonic demonstration of multiple cardiac rhabdomyomas ( arrows ). Reproduced with permission from Roach ES, Delgado MR: Tuberous sclerosis. Dermatol Clin 1995;13:151-161.

Renal angiomyolipomas occur in about 75 to 80% of patients with tuberous sclerosis complex over the age of 10 years; most of these lesions are histologically benign tumors with varying amounts of vascular tissue, fat, and smooth muscle (Figure 4).[11] Bilateral tumors or multiple tumors per kidney are typical. The prevalence of renal tumors increases with age, and tumors larger than 4 cm are much more likely to become symptomatic than smaller tumors. Renal cell carcinoma or other malignancies are less common.

A large angiomyolipoma of the lower pole of a kidney removed at surgery; several smaller angiomyolipomas ( arrows ) are evident in the same specimen. Reproduced with permission from Weiner DM et al.[1]

Single or multiple renal cysts are also a feature of tuberous sclerosis complex; these tend to appear earlier than the renal tumors. Larger cysts are easily identified with ultrasonography or computed tomography (CT), and the combination of renal cysts and angiomyolipomas is characteristic of tuberous sclerosis complex. Individual renal cysts can disappear.

At least 1% of patients with tuberous sclerosis complex develop symptomatic pulmonary dysfunction, and many others probably have asymptomatic lung lesions on diagnostic studies later in life. The classic pulmonary lesion of tuberous sclerosis complex is lymphangioleiomyomatosis; other patients have multifocal micronodular pneumocyte hyperplasia. Pulmonary disease is five times more common in female than in male patients. Spontaneous pneumothorax, dyspnea, cough, and hemoptysis are typical symptoms of pulmonary tuberous sclerosis complex, although these do not often develop before the third or fourth decade. CT of the chest commonly demonstrates lung lesions even in adults without symptoms.

Both renal angiomyolipomas and pulmonary lymphangiomyomatosis are strongly associated with tuberous sclerosis complex, but neither is specific; moreover, they tend to occur together in the absence of other signs of tuberous sclerosis complex. Thus, when both conditions occur in the same patient, they should be counted as one major feature of tuberous sclerosis complex, not two. Either condition can be considered a major feature of tuberous sclerosis complex without the other, but the diagnosis should not rest solely on the presence of these two lesions.[1]

The predominant neurologic manifestations of tuberous sclerosis complex are mental retardation, epileptic seizures, and behavioral abnormalities, but affected individuals with little or no neurologic impairment are common.[2,3] Neurologic lesions probably result from impaired neuronal migration along radial glial fibers and from abnormal proliferation of glial elements.

Neuropathologic lesions of tuberous sclerosis complex include subependymal nodules, cortical hamartomas, areas of focal cortical hypoplasia, and heterotopic gray matter.[7,12] Although all of the superficial cerebral lesions of tuberous sclerosis complex are sometimes lumped together as cortical tubers, the actual pathologic picture is more complex. A classic tuber is a dysplastic lesion of a gyrus that has a firm, nodular feel; it often occurs at the apex of a gyrus but does not always enlarge the gyrus. However, areas of focal cortical dysplasia that are not nodular and are less sharply demarcated are common, ranging from grossly visible defects of the cortical mantle to microscopic disruption of the cytoarchitecture.

Various types of seizures occur in 80 to 90% of patients. Most patients with mental retardation have epilepsy, but there are exceptions. On the other hand, many people with tuberous sclerosis complex have epilepsy but have normal intelligence. The number of subependymal lesions does not correlate with the clinical severity of tuberous sclerosis complex, but patients with numerous lesions of the cerebral cortex shown by magnetic resonance imaging (MRI) tend to have more cognitive impairment and more difficulty with seizure control.[13,14] Children with infantile spasms are more likely to exhibit long-term cognitive impairment, but these patients, in turn, have more cortical lesions demonstrated by MRI.

The likelihood of mental retardation in patients with tuberous sclerosis complex is probably overestimated. Webb and colleagues, for example, found only 10 patients with mental retardation among 26 patients with tuberous sclerosis complex in a population survey.[15] The severity of intellectual dysfunction ranges from borderline to profound mental retardation. Autism and various behavioral disturbances, including hyperactivity, aggressiveness, and frank psychosis, are common, either as isolated problems or in combination with epilepsy or intellectual deficit.[16]

The calcified subependymal nodules (Figure 5) that characterize tuberous sclerosis complex are best demonstrated with cranial CT. Subependymal nodules arise adjacent to the ventricular wall and characteristically protrude into the ventricular lumen. They are most often found in the lateral ventricles and seem to occur more often anteriorly. Superficial cerebral lesions can sometimes be seen with cranial CT but are far more obvious with T2-weighted MRI (Figure 6). Cerebellar anomalies occur in about a fourth of patients with tuberous sclerosis complex. Nodular subependymal lesions that have not yet calcified produce a high-signal lesion with T2-weighted scans. Evidence of abnormal neuronal migration can be seen in some patients as a high-signal linear lesion running perpendicular to the cortex on T2-weighted scans.

Computed tomographic scan from a child with tuberous sclerosis complex demonstrates typical calcified subependymal nodules, a large calcified parenchymal lesion, and smaller low-density cortical lesions. Reproduced with permission from Roach ES, Kerr J, Mendelsohn D, et al: Diagnosis of symptomatic and asymptomatic gene carriers of tuberous sclerosis by CCT and MRI. Ann N Y Acad Sci 1991;615:112-122.

Noncontrast T2-weighted magnetic resonance image from a child with tuberous sclerosis demonstrates extensive high-signal cortical lesions typical of tuberous sclerosis. Reproduced with permission from Miller VS, Roach ES: Neurocutaneous syndromes, in Bradley WG, Daroff RB, Fenichel GM, Marsden CD (eds): Neurology in Clinical Practice, 3rd ed. Newton, MA, Butterworth-Heinemann, 1999, 1665-1700.

Subependymal giant cell astrocytoma occurs in 6 to 14% of individuals with tuberous sclerosis complex and is more likely to develop during childhood. Unlike the more common cortical tubers, giant cell astrocytomas (Figure 7) can enlarge and cause symptoms such as increased intracranial pressure, new focal neurologic deficits, or deterioration of seizure control.[17] Acute or subacute onset of neurologic dysfunction rarely results from sudden obstruction of the ventricular system by an intraventricular subependymal giant cell astrocytoma or from hemorrhage into the tumor itself. Giant cell tumors are usually benign but locally invasive, and surgery, performed early, can be curative.

A, Gadolinium-contrast T1-weighted magnetic resonance image (MRI) from a child with tuberous sclerosis complex shows an enhancing subependymal giant cell astrocytoma protruding into the left frontal horn. B, Another patient's MRI with gadolinium demonstrates a huge subependymal giant cell astrocytoma filling much of the lateral ventricle.

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