Final Diagnosis -- Tuberous Sclerosis Complex (TSC)


TSC is a genetic neurocutaneous disorder associated with cognitive impairment, cutaneous lesions and a variety of other benign tumors. The common features of TSC included seizures, mental retardation and a myriad of benign hamartomatous tumors including renal angiomyolipomas, facial angiofibromas, cardiac rhabdomyomas and cortical tubers (glioneuronal hamartomas). In addition to facial angiofibromas, other characteristic skin lesions are commonly seen in these patients-hypomelanotic macules (also called ash-leaf spots due to their elliptical shape) and connective tissue nevi (known as Shagreen patches).

Genetics of Tuberous Sclerosis Complex
TSC is an inherited autosomal dominant disease caused by mutations in TSC1(hamartin) and TSC2(tuberin) genes which are identifiable in 60-80% of cases. The TSC1 and TSC2genes function as tumor suppressors to inhibit the mTOR pathway2. In patients with heterozygous mutations a second "hit" results in proliferation of cells forming hamartomas in a variety of organs.

Mutations in TSC2 are more commonly detected in sporadic cases of TSC than are mutation in TSC13. This has been suggested to be due to an ascertainment bias because TSC2 mutations generally have more severe disease and thus these patients are identified and tested more frequently4. The most common types of mutations in TSC2 are small deletions and insertions (35%) followed by nonsense mutations (20%) and large deletions and rearrangements (15%)5. The most common mutations in TSC1 are small deletions and insertions (50%) and nonsense mutations (35%)5. Large deletions are uncommon in TSC1 (<5%). 5% of both TSC1 and TSC2 mutations affect consensus splice donor or acceptor sites.

Approximately two-thirds of patients diagnosed with TSC have sporadic disease occurring in the absence of a family history6. Many of these cases are due to de novo mutations; however, occasional cases are due to inheritance of mutant genes from undiagnosed parents. Due to the wide variability in disease severity, some parents may have subtle features of TSC that are not detected until the diagnosis in a child prompts a careful examination of the parent. It is believed that the presence of a known disease causing mutation in one of these two genes has 100% penetrance but that careful clinical examination may be required to detect features of TSC in some patients. Another explanation for inheritance from an undiagnosed parent to a child is the occasional mosaicism of TSC gene mutations. In such situations, the parent may have very mild to no disease due to a somatic mutation while the affected child might have severe disease due to procession of a germline mutation.

Diagnosis of Tuberous Sclerosis Complex
Diagnosis of TSC is based on clinical findings7,8. However, these criteria were formulated prior to the availability of a genetic testing of TSC1 and TSC2 genes and therefore molecular tests are not included in the diagnostic criteria. Clinical features of TSC are divided into major and minor features (Table 1). Definite TSC is defined as the presence of two major features or one major plus two minor features. Probable TSC is defined as the presence of one major plus one minor feature. Possible TSC is defined as the presence of only one major feature or the presence of two or more minor features.

Exceptions to these diagnostic criteria are in cases of women with both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis as these can both be seen in women affected by lymphangioleiomyomatosis. In such cases the presence of additional TSC features is required for definite TSC. The presence of both white matter radial migration lines and cortical tubers is also counted only once. While seizures are one of the most common findings in patients with TSC, it is not included in the diagnostic criteria due to a lack of sensitivity.

What is the Role of TSC1 and TSC2 genetic testing?
The patient presented above has three major features of TSC (multiple hypomelanotic ash-leaf macules, cortical tubers and subependymal nodules) and therefore meets criteria for definite TSC. Genetic testing for TSC gene mutations was therefore not necessary for a diagnosis of definite TSC. Unfortunately, there remains little guidance for treating physicians in the role of genetic testing as the diagnostic criteria where formulated prior to the availability of clinical TSC gene testing. Recent studies support the use of TSC gene testing for confirmation of TSC in patients with clinically probable or possible TSC9. Negative molecular genetic testing does not exclude a diagnosis of TSC since as many as 25% of patients with definite TSC lack identifiable mutations in TSC1 or TSC210. A second effective use TSC gene testing is for testing parents children diagnosed with sporadic. In such cases it is possible for a parent to carry a disease causing mutation but not meet clinical criteria of TSC. In some instances a parent may have a germline mutation but have mild disease. It is expected that in such cases a careful exam will identify at least some features of TSC. The other possibility is the presence of mosaicism in the parent due to a somatic mutation. These parents may not show any features of TSC but still have the potential to pass a mutated gene on to their children. Identification of a disease causing mutation in a parent could then aid in future family planning and indicate the need to monitor the parent for TSC related morbidity.

Yet another use of genetic testing for TSC is prenatal screening of parent with a family history of TSC. Such prenatal testing can be used to aid the selection of embryos in IVF or in screening of an already conceived fetus. It is important however, for parents to know that such testing is not able to predict the severity of the disease4,11. Also, a negative result may not exclude the possibility of disease as low level mosaicism is often not detected by conventional testing12 .

When genetic testing is to be performed sequential testing of TSC1 and TSC2 genes is the most efficient method. In cases of sporadic TSC, initial sequencing of TSC2 is the best test as the majority of cases will be identified. If TSC2 sequencing is negative reflex testing of TSC1 sequencing is then warranted. If TSC2 and TSC1 sequencing is negative then analysis of TSC2 then TSC1 for deletion and duplication should be performed by another method such as array based comparative genomic hybridization (CGH).

While molecular genetic testing was not required in this patient to make the diagnosis of TSC, it is confirmatory. The finding of the c.1628delC frameshift causing deletion has not been previously reported. However, as this single nucleotide deletion result in a frameshift it is almost certainly disease causing. Based on the American College of Medical Genetics and Genomics, this mutation would be considered a category 2 mutation. Other ACMG categories are summarized in Table 2. Based on this evidence the detected sequence variant in TSC2 in this patient is almost certainly the cause of his disease.


  1. Richards CS, Bale S, Bellissimo DB, et al. "ACMG recommendations for standards for interprestationand reporting of sequence variations: Revisions 2007." Genet Med. 2008. 10(4):294-300.
  2. Hengstschlager M, Rodman DM, Miloloza A et al. "Tuberous sclerosis gene products in proliferation control." Mutat Res. 2001. 488(3):233-239.
  3. Niida Y, Lawrence-Smith N, Banwell A et al. "Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis." Hum Mutat. 1999. 14(5):412-422.
  4. Jansen FE, Braams O, Vincken KL et al. "Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations." Neurology. 2008. 70(12):908-915.
  5. Plon SE and Owens J. "Tuberous sclerosis complex." accessed 10/26/2011.
  6. Osborne JP, Fryer A, Webb D. "Epidemiology of tuberous sclerosis." Ann N Y Acad Sci. 1991. 615:125-127.
  7. Roach ES, Gomez MR, Northrup H. "Tuberous Sclerosis Complex consensus conference: revised clinical diagnostic criteria." J Child Neurol. 1998. 13(12):624-628.
  8. Roach ES, DiMario FJ, Kandt RS, Northrup H. "Tuberous sclerosis consensus conference: Recommendations for diagnostic evaluation." J Child Neurol. 1999. 14:401-407.
  9. Yates JRW, MacLean C, Higgins JNP et al. "The tuberous sclerosis 2000 study: presentation, initial assessments and implications for diagnosis and management." Arch Dis Child. 2011. 96:1020-1025.
  10. Sancak O, Nellist M, Goebloed M et al. "Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: Genotype - phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex." Eur J Hum Genet. 2005. 13:731-741.
  11. Smalley SL, Burger F, Smith M. "Phenotypic variation of tuberous sclerosis in a single extended kindred." J Med Genet. 1994. 31(10)761-765.
  12. Qin W, Kozlowski P, Taillon BE et al. "Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex." Hum Genet. 2010. 127(5):573-582.

Contributed by Christopher C. Griffith MD, PhD and Jeffrey A. Kant MD, PhD

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