|Clinical category||Prevalence||Clinical Notes|
The prevalence rate (32.9%, 35.9%) of pharmacoresistant epilepsy is similar to general population with focal epilepsy [26, 27].|
A mutation in the TSC2 gene is a risk factor for infantile spasms (47.3% vs. 23% with TSC1 in TOSCA) as well as an earlier manifestation of epilepsy, a higher seizure frequency, and pharmacological refractoriness .
|Epileptic spasms||38–49% [21, 22, 26]||Most children with TSC and West syndrome develop symptomatic generalized epilepsy (62%) [29, 30].|
|Cortical tubers||88.2% [20, 18, 24]|
|Subependymal nodules (SEN)||78.2% [20, 18, 24]|
|Subependymal giant cell astrocytoma (SEGA)||24.4% [20, 18, 31, 32]||
SEGAs arise from serially growing SEN, are often greater than 1 cm in diameter, and are generally located near the foramina of Monro .|
While SEGAs generally have a low incidence after adolescence, SEGA growth affected 21–29% past the second decade of life [20, 34] in two studies.
|Neuropsychiatric manifestations (TSC-associated neuropsychiatric disorders [TAND])|
|Intellectual disability||53.6–65% [1, 23, 35–37]||
Joinson et al.  described a bimodal distribution of intellectual impairment in TSC. About two-thirds of the studied individuals had an intelligence quotient (IQ) in the normal range, albeit with an overall negative shift (mean IQ: 93), while 31% had a profound intellectual disability .|
Individuals with severe intellectual disability due to TSC have higher levels of verbal disability that do those with severe intellectual disability from other causes .
Many individuals with TSC have more than one neuropsychiatric disorder [40, 41].
|Autism||25–61% [21, 23, 24, 40, 41,42,43,44,45,46,47]||Intellectual impairment and the presence of infantile spasms are associated with higher risks for both autism and ADHD [36, 48].|
|Attention-deficit hyperactivity disorder (ADHD)||19.6–30% [21, 42, 45, 49]|
Overactivity 45% |
Impulsivity 42.7% 
Severe aggression 24.3% 
Sleep issues 43.9% 
Rates of self-injury and aggression in adults with TSC with intellectual disability: 31 and 37.9%, respectively .|
In TOSCA, significantly higher rates of overactivity and impulsivity were seen in children; in adults, higher rates of anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations were reported 
The relationship between cortical tubers and autism spectrum disorders is mediated by general cognitive impairment .
|Depression||23.4–56% [42, 45, 49, 53–55]||
A UK study  showed that the depression rate among patients with TSC was not higher than that in a matched general population comparator cohort.|
A United States (US) study reported that individuals with TSC had significantly higher depressive symptom scores as compared with the general population (11.6 vs. 5.1 on the Hamilton Depression Inventory—short form) . Depending on the scoring system used, 19% (Hospital Anxiety and Depression Scale; HADS) to 43% (Symptom Checklist-90-Revised) of adults with TSC present elevated depression scores [54, 55].
A study identified HADS scores suggesting anxiety in 56% of adult individuals with TSC .
A study on individuals with TSC in transition from pediatric treatment found frequent sadness and depression in 60% of patients and high anxiety in 40% .
Chung et al.  demonstrated in a retrospective analysis that behavioral problems and mood disorders can be successfully treated medically in about two-thirds of afflicted individuals.
|Angiomyolipoma (AML)||51.8% ||
Recent publications from the TOSCA registry  have hinted at an even higher rate of AML than previously known (51.8% of 2216 individuals) and suggest an earlier onset in early childhood.|
A retrospective, longitudinal Dutch cohort study in 369 individuals with TSC and chronic kidney disease (CKD) or angiomyolipoma of the kidneys reported that during follow-up, 16% of patients achieved CKD stage 3 or higher . A strong association between age, AML size, and CKD was observed. In a UK study , CKD (stages 3–5) was found more frequently in individuals with TSC of all ages than in the general population at the same age intervals. Of note, a peak in the patients over 65 years cohort (42%) was noted.
|Renal cell carcinoma||1–2% [21, 58, 59]||
Incidence is similar compared to the general population.|
Renal cell carcinoma can manifest earlier than in the general population, even in children and young adults.
|TSC renal cystic kidney disease||
Total 50% |
Severe (Polycystic kidney disease, PKD) 3.5% 
PKD is a rare manifestation in TSC. The PKD1 gene is situated next to the TSC2 gene on chromosome 16, so in rare cases a contiguous gene syndrome with severe polycystic kidney disease and early loss of renal function can develop in individuals with TSC.|
Milder, typically asymptomatic forms of TSC renal cystic disease without a certain link to PKD mutations are more common, more commonly in individuals with TSC2 mutations .
|Lymphangioleiomyomatosis (LAM)||34–81% of female individuals , rare in males||
A Dutch study  identified LAM-typical cysts in 52 (28%) of 186 individuals with TSC. Pulmonary cysts were detected much more frequently in females (42%), but also in 13% of males . In general, however, cysts were larger and more numerous in women than in men. Also, considerable cystic changes were detected almost exclusively in women (in 33 women versus in three men).|
Another study found LAM prevalence increasing rates in women with age (27% at the age of 21 years and 81% at the age of 40 years and older) .
A long-term LAM register study from the US showed 26 deaths and 43 lung transplantations occurred over a follow-up of 13 to 17 years in 217 patients. Diagnosis after menopause and better baseline lung function decreased transplantation probability or risk of death. Of note, only 36 of 217 patients had TSC-LAM. The presence of TSC-LAM did not significantly affect time to transplantation or death.
|Cardiac rhabdomyoma||34–58% ||Rhabdomyoma in TSC are typically, but not exclusively, multifocal.|
|Aortic aneurysm||Rare, but can develop from early age .|
|Hypopigmented macules (“Ash-leaf spots”)||66.7–97.2% [21, 65]||
Detection can be eased by Wood light in persons with a light skin tone.|
Hypopigmented macules more rarely manifest as “Confetti-like” lesions (2.8% ).
|Angiofibromas||57.3–74.5% [21, 65]||Usually appear from the 2nd to 5th year of life.|
|Chagrin patches||22.7–48.1% [21, 65]||Connective tissue hamartoma, mostly on dorsal body surfaces such as the lower back region.|
|Molluscum fibrosum pendulans||22.6% |
|Forehead plaque||18.9% |
|Periungual fibromas||15.1% ||Usually appear first in childhood/adolescence.|
|Retinal hamartomas||30–44% [24, 66]|
|Chorioretinal hypopigmentation||39% |
|Other organ manifestations|
|Hepatic (hepatic AML, hepatic cysts)||9.1% ||Associated with renal AML [67, 68]. These were found in 9.1% of individuals in TOSCA.|
|Pancreatic neuroendocrine tumors||4.1% |