Table 1.

Prevalence of common clinical manifestations in TSC patients

Clinical category	Prevalence	Clinical Notes
Neurological manifestations
Epilepsy	83.5–88.4% [20–25]	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 [28].
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 [33]. 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. [38] 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 [38]. Individuals with severe intellectual disability due to TSC have higher levels of verbal disability that do those with severe intellectual disability from other causes [39]. Many individuals with TSC have more than one neuropsychiatric disorder [40, 41].
Autism	25–61% [21, 23, 24, 40, 42–47]	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]
Behavioral problems	Overactivity 45% [50] Impulsivity 42.7% [50] Severe aggression 24.3% [50] Sleep issues 43.9% [50]	Rates of self-injury and aggression in adults with TSC with intellectual disability: 31 and 37.9%, respectively [51]. 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 [50] The relationship between cortical tubers and autism spectrum disorders is mediated by general cognitive impairment [52].
Depression	23.4–56% [42, 45, 49, 53–55]	A UK study [42] 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) [56]. 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 [54]. 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% [53]. Chung et al. [40] demonstrated in a retrospective analysis that behavioral problems and mood disorders can be successfully treated medically in about two-thirds of afflicted individuals.
Renal manifestations
Angiomyolipoma (AML)	51.8% [21]	Recent publications from the TOSCA registry [57] 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 [35]. A strong association between age, AML size, and CKD was observed. In a UK study [42], 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% [60] Severe (Polycystic kidney disease, PKD) 3.5% [21]	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 [61].
Pulmonary manifestations
Lymphangioleiomyomatosis (LAM)	34–81% of female individuals [62], rare in males	A Dutch study [62] 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 [62]. 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) [63]. 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 manifestations
Cardiac rhabdomyoma	34–58% [21]	Rhabdomyoma in TSC are typically, but not exclusively, multifocal.
Aortic aneurysm		Rare, but can develop from early age [64].
Cutaneous manifestations
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% [65]).
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% [65]
Forehead plaque	18.9% [65]
Periungual fibromas	15.1% [65]	Usually appear first in childhood/adolescence.
Ocular manifestations
Retinal hamartomas	30–44% [24, 66]
Chorioretinal hypopigmentation	39% [66]
Other organ manifestations
Hepatic (hepatic AML, hepatic cysts)	9.1% [21]	Associated with renal AML [67, 68]. These were found in 9.1% of individuals in TOSCA.
Pancreatic neuroendocrine tumors	4.1% [69]