How is TSC Diagnosed?
In 2012, the International Tuberous Sclerosis Complex Consensus Conference reviewed prevalence and specificity of TSC-associated clinical manifestations and updated the TSC diagnostic criteria from 1998. Clinical features of TSC continue to be a principal means of diagnosis but include additional clarification and simplification. In addition, TSC may now be diagnosed via genetic testing.
The clinical and genetic diagnostic criteria of 2012 are summarized below:
|MAJOR FEATURES||MINOR FEATURES|
|1. Hypomelanotic macules (≥3. at least 5·mm diameter)||1. “Confetti” skin lesions|
|2. Angiofibroma (≥3) or fibrous cephalic plaque||2. Dental enamel pits (>3)|
|3. Ungual fibromas (≥2)||3. Intraoral fibromas (>2)|
|4. Shagreen patch||4. Retinal achromatic patch|
|5. Multiple retinal hamartomas||5. Multiple renal cysts|
|6. Multiple cortical tubers and/or radial migration lines||6. Nonrenal hamartomas|
|7. Subependymal giant cell astrocytoma||7. Sclerotic bone lesions|
|8. Subependymal nodule (>2)|
|9. Cardiac rhabdomyoma|
|10. Lymphangioleiomyomatosis (LAM)**|
|11. Angiomyolipomas (>2)**|
|Definite TSC: Two major features or one major feature with 2 minor features.
Possible TSC: Either one major feature or > 2 minor features.
**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.
More About the Genetics of TSC
Genes are the biochemical instructions found inside the cell, not unlike the programs found inside computers. Human beings have 22 pairs of chromosomes, as well as a pair of sex chromosomes. Females have two X chromosomes and males have an X and a Y chromosome. Our genes come in pairs, with one copy inherited from the mother and the other from the father. All people have variations in their genes – some of which cause diseases and others increase risk for developing some diseases, and some variations cause no problems at all. Some of these variations have been passed down from one parent, and some variations are unique to individual human beings.
TSC is caused by a change or variation (called a mutation when it causes disease) in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. TSC is an autosomal dominant genetic disorder. This means an individual with TSC has a mutation in one copy of either of the TSC genes that then causes the disease. Many genetic disorders such as TSC can be sporadic, meaning the disorder has not previously occurred in that family. Such sporadic occurrences are the result of a new genetic mutation and account for approximately two-thirds of all cases of TSC. The remaining one-third of cases are the result of a TSC gene containing a mutation being passed along (inherited) from either the mother or the father to their child.
Individuals with TSC have a 50% chance of passing their condition on to each of their children. If parents are unaffected, the chance of a sibling of someone diagnosed with TSC also having TSC is approximately 1% to 2%. The ability to differentiate between an inherited and sporadic occurrence of TSC sometimes relies on a thorough evaluation of the family members of the individual with TSC. This may involve evaluation of the parents, as well as some or all of the siblings.
There are no known cases of an individual having a mutation in both genes, and TSC does not skip a generation. It is possible for a member of the family to have such a mild case of TSC as to seem unaffected. At this point, the severity or risk of specific TSC features cannot be predicted by knowing an individual’s genetic mutation.
Significant progress in understanding the function(s) of the TSC genes has translated into clinical trials to test medications for their ability to stop tumor growth and to impact the neurologic features of TSC, including seizures and cognition. The TSC genes work together as a complex in a specific signaling pathway in cells that regulate cell growth. Ongoing basic and clinical research are moving rapidly forward, hopefully to the day when the symptoms of TSC can be prevented.
Genetic Testing of TSC
Genetic testing allows individuals with TSC, family members and healthcare providers to know exactly what mutation in either the TSC1 or TSC2 gene caused TSC. This information may be helpful for a number of reasons. In some cases, the identification of a TSC1 or TSC2 mutation will facilitate a definite genetic diagnosis of TSC in an individual who has not yet developed enough symptoms for a clinical diagnosis. In approximately 15% of individuals with TSC, no mutation is identified in either TSC1 or TSC2. While a negative DNA test result cannot rule out a diagnosis of TSC, a positive result confirms the diagnosis. In other cases, an individual may have a definite diagnosis of TSC, and family members may wish to know their own genetic status without undergoing extensive clinical evaluations. Upon identifying the TSC mutation in the individual with a definite diagnosis of TSC, any other family member can be easily tested to determine whether he or she is also affected. In addition, the availability of DNA mutation results makes reproductive decision-making possible.
Despite advancing knowledge about TSC mutations, it is not possible to predict the severity of symptoms in a person with a new diagnosis of TSC. A person can have TSC and have very few or mild symptoms, while a family member with TSC can have more severe or extensive symptoms. It is thought, however, that most people who have a TSC mutation will have some signs or symptoms if examined carefully by a physician familiar with the diagnosis of TSC. The distinction between sporadic TSC and familial (or inherited) TSC is important, as it affects the risk that other persons in the family are affected. Therefore, immediate family members of a person newly diagnosed with TSC should be thoroughly examined.
Another factor that complicates the genetics of TSC is germline mosaicism. Germline mosaicism occurs when an individual has cells in his or her germline (egg or sperm cells) that carry a genetic mutation, but not in cells in other parts of the body. While quite rare, individuals with germline mosaicism may have one or more children with TSC but not have any clinical symptoms of TSC.
Given the complicated nature of TSC genetics, all families who have an affected relative with TSC should receive a referral to a genetic counselor or geneticist to discuss their unique genetic risk to either have TSC or to have a child with TSC.