The clinical and genetics diagnostic criteria of 2012 are summarized in the table below.
|MAJOR FEATURES||MINOR FEATURES|
|1. Hypomelanotic macules (≥3. at least 5·mm diameter)||1. “Confetti” skin lesions|
|2. Angiofibromas (≥3) or fibrous cephalic plaque||2. Dental enamel pits (>3)|
|3. Ungual fibromas (≥2)||3. Intraorallibromas (≥2)|
|4. Shagreen patch||4. Retinal achromatic patch|
|5. Multiple retinal hamartomas||5. Multiple renal cysts|
|6. Cortical dysplasias*||6. Nonrenal hamartomas|
|7. Subependymal nodules|
|8. Subependymal giant cell astrocytoma|
|9. Cardiac rhabdomyoma|
|10. Lymphangioleiomyomatosis (LAM)**|
|11. Angiomyolipomas (≥2)**|
|Definite diagnosis: Two major features or one major feature with ≥ 2 minor features.
Possible diagnosis: Either one major feature or ≥2 minor features.
* Includes tubers and cerebral white matter radial migration lines.
**A combination of the two major Clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a Definite Diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (e.g., out of frame insertion or deletion or nonsense mutation), prevents protein synthesis (e.g., large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment. Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a Definite Diagnosis of TSC.
Note that approximately 15% of individuals with TSC have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC or have any effect on the use of Clinical Diagnostic Criteria to diagnose TSC. Clinical genetic testing identifies gene mutations in 75-90% of DNA samples that are submitted for testing from individuals who have a definite diagnosis of TSC based on accepted diagnostic criteria. For the remaining 10-25% of TSC patients there are several explanations for why we cannot find an underlying mutation. There may be a mutation in the TSC1 or TSC2 gene that we cannot detect because it only occurs in some of the patient’s cells but not all of the cells. This situation is called mosaicism meaning that the genetic complement of different cells is different in different cells of the body. Another reason we may not find a mutation is that the mutation may be in sections of the gene that we do not test because we do not understand how changes in these parts of the genes can cause disease.