How TSC is Diagnosed

To diagnose TSC with certainty, physicians rely on a constellation of features, rather than any single manifestation.

Tuberous sclerosis complex (TSC) is often difficult to diagnose. The disorder is well known for causing a wide variety of symptoms, which often differ from one individual to another. TSC may affect any or all major organs, but these manifestations are not always outwardly apparent or easily recognizable, especially in very young children with TSC. Further complicating diagnosis is the fact that no single manifestation of TSC is unique to the disorder. In fact, many features commonly associated with TSC are also seen in individuals who don't have the disorder.

To diagnose TSC with certainty, physicians rely on a constellation of features, rather than any single manifestation. In general, the more TSC-related features that an individual has, the more likely it is that they have the disorder. However, not all clinical features are considered equally significant diagnostically.

To make distinctions about the significance of features and to reach a clinical diagnosis, physicians rely on very specific diagnostic criteria, first developed in 1979 and revised most recently in 1998.

The diagnostic criteria for TSC distinguish between major features and minor features of the disorder. The major features include 11 clinical findings that are seen very frequently in people with TSC and significantly less often in the general population. The minor features include 9 clinical findings that are seen more frequently in people with TSC, but are also relatively common in the general population.

Diagnostic Criteria

Major Features

• Facial angiofibromas or forehead plaque
• Nontraumatic ungual or periungual fibroma
• Hypomelanotic macules (more than three)
• Shagreen patch
• Cortical tuber¹
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Multiple retinal nodular hamartomas
• Cardiac rhabdomyoma (single or multiple)
• Lymphangioleiomyomatosis²
• Renal angiomyolipoma²

Minor Features

• Multiple randomly distributed pits in dental enamel
• Hamartomatous rectal polyps²
• Bone cysts²
• Cerebral white matter radial "migration tracts"¹
• Gingival fibromas
• Nonrenal hamartoma^{3, 4}
• Retinal achromic patch
• "Confetti" skin lesions
• Multiple renal cysts³

In light of these criteria, diagnosis of an individual suspected of having TSC is based on a careful physical examination, during which a physician examines the skin for various TSC-related abnormalities, as well as the fingernails and toenails for periungual fibromas, and the teeth and gums for dental pits and/or gingival fibromas. For infants and individuals with pale skin, physicians may use a Wood's lamp, or ultraviolet light, to locate hypomelanotic macules of the skin. This extensive physical exam is combined with a review of images of the brain, created using computed tomography (CT) or magnetic resonance imaging (MRI), to identify cortical tubers and subependymal nodules. Physicians also use ultrasound images of the heart and kidneys to identify tumors in those organs.

Based on their clinical findings, physicians use the diagnostic criteria to determine the level of certainty of a diagnosis. If the TSC evaluation reveals either two major features or one major and two minor features, the physician considers the diagnosis definite. If the physician identifies one major and one minor feature, the diagnosis is considered probable. And if either one major or two or more minor features are found, the diagnosis is considered possible.

In some cases, physicians examining infants and very young children identify a combination of features sufficient to call a TSC diagnosis definite. However, many individuals, especially those mildly affected, can be diagnosed with certainty only later in life, once symptoms that weren't present earlier begin to appear.

In addition to physical and imaging examinations, individuals suspected of having TSC typically undergo genetic testing. In most cases, a genetic test for TSC can determine if an individual has a mutation in one of the two genes known to be associated with the disorder. Although a negative test result cannot rule out the disorder, a positive result can confirm a diagnosis.

Citations

1: When cerebral cortical dysplasia (abnormal non-cancerous cells in the cerebral cortex) and cerebral white matter migration tracts (lines of immature neurons that didn't reach the cerebral cortex when the brain developed) occur together, they should be counted as one rather than two features of TSC.
2: When both lymphangioleiomyomatosis and renal angiomyolipomas are present, other features of TSC should be present before a definite diagnosis is made.
3: Histologic (viewing cells under a microscope) confirmation is suggested.
4: Radiographic (x-ray, CT, MRI and other imaging) confirmation is sufficient.
Adapted from Roach et al. (1998) Journal of Child Neurology 13, 624-628