clinical topic updates
Genetic Influences on the Severity of Tuberous Sclerosis Complex
Tuberous sclerosis complex (TSC) is a rare, multisystem, genetic disorder resulting from mutations in TSC1 and TSC2. Genetic testing may be helpful; however, it remains difficult to establish a correlation between TSC severity and genotype at the individual level.
Director, Pediatric Epilepsy Program
“It has been shown by several groups that a mutation in TSC2 generally carries a more severe phenotype than TSC1. However, one of the challenges in TSC is that there can be substantial phenotypic variability, with significantly different clinical manifestations occurring even among individuals with the same pathogenic variant.”
It has been shown by several groups that a mutation in TSC2 generally carries a more severe phenotype than TSC1. However, one of the challenges in TSC is that there can be substantial phenotypic variability, with significantly different clinical manifestations occurring even among individuals with the same pathogenic variant. This can occur even in a family in which all people have the same inherited form of TSC. In my practice, I see some families with up to 6 people with TSC, affecting 2 or 3 generations, and some are very mildly affected while others are severely
affected—despite all sharing the same mutation.
This phenotypic variability makes the prediction of clinical manifestations difficult. If an individual has TSC and is mildly affected, there is no guarantee that their offspring would also be as mildly affected. If you look at larger research cohorts with TSC populations, patients with TSC2 mutations do have more severe clinical manifestations than patients with TSC1 mutations, but this is not as clear at the individual level. Some of the most mildly affected patients have a TSC2 mutation, and some of the more severely affected patients have a TSC1 mutation. The factors that lead to phenotypic variability represent a big gap in our knowledge and understanding of TSC and require further study.
Another area of research interest with TSC1 and TSC2 relates to oncogenesis in the sense that, even though TSC1 and TSC2 are in the mammalian target of rapamycin pathway, patients with TSC typically have benign growths, not cancer. So, when TSC1 or TSC2 are mutated, patients develop these benign tumors, whereas when other proteins in that pathway become mutated, the result is cancer.
Our group has been analyzing malignancy in TSC over the years, and, although we do not necessarily think that overall malignancy rates are higher in TSC, there are 3 malignancies that are all quite rare in the general population and usually present in patients who are in their 60s or 70s that can also develop in some children with TSC (ie, pancreatic neuroendocrine tumors, renal cell carcinoma, and chordoma). Now, this is not at all common, and I would not want patients with TSC or their families to worry about malignancy or to worry that they are going to develop one of these malignancies that we sometimes see. But it is something that can happen, albeit rarely, and we are trying to figure out what that means about both TSC and malignancy.
de Vries PJ, Belousova E, Benedik MP, et al; TOSCA Consortium and TOSCA Investigators. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis. 2018;13(1):157. doi:10.1186/s13023-018-0901-8
Moavero R, Mühlebner A, Luinenburg MJ, Craiu D, Aronica E, Curatolo P. Genetic pathogenesis of the epileptogenic lesions in tuberous sclerosis complex: therapeutic targeting of the mTOR pathway. Epilepsy Behav. 2021 Jan 8;107713. doi:10.1016/j.yebeh.2020.107713
Ogórek B, Hamieh L, Hulshof HM, et al; EPISTOP Consortium Members. TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study. Genet Med. 2020;22(9):1489-1497. doi:10.1038/s41436-020-0823-4
Reyna-Fabián ME, Hernández-Martínez NL, Alcántara-Ortigoza MA, et al. First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with tuberous sclerosis complex reveals numerous novel pathogenic variants. Sci Rep. 2020;10(1):6589. doi:10.1038/s41598-020-62759-5
Vail EA, Rakowski SK, Numis AL, Thiele EA. Role of mutational analysis in diagnosis of tuberous sclerosis complex. Clin Genet. 2009;75(3):282-285. doi:10.1111/j.1399-0004.2008.01129.x