Tuberous Sclerosis Complex (TSC)

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: TSC1 (HGNC:12362) TSC2 (HGNC:12363)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 12/17/2021
• Curation Status: Released (1.1.4)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
TSC1	tuberous sclerosis (0001734)	191100	Moderate Actionability
TSC2	tuberous sclerosis (0001734)	613254	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from TSC-related lesions / Evaluation by specialist with imaging to guide possible use of mTORi therapy	2	3C	2B	2	9CB

Severity of Outcome

Prevalence of the Genetic Condition

Tuberous sclerosis complex (TSC) affects approximately one in 6000 to 10,000 births, with a prevalence of one in 11,000 to 14,000 after the age of 10 years. True incidence is not known due to mildly affected or asymptomatic individuals who are underdiagnosed.

Clinical Features (Signs / symptoms)

TSC is characterized by the pervasive formation of benign tumors in the brain, skin, kidneys, heart, lungs, retina, and other organs. These masses consist of cysts, lesions, nodules, or tubers that present in a range of numbers, sizes, and locations, which may lead to early and severe symptoms, or which may result in mild symptoms that are undiagnosed or misdiagnosed well into adulthood. Clinical features may present dynamically over the course of an individual’s life. Brain lesions include subependymal nodules (SEN), cortical tubers, and subependymal giant cell astrocytomas (SEGAs). When SEGAs develop they produce complications either through growth and invasion of surrounding cerebral tissue or through blockage of the flow of cerebrospinal fluid. Development and progression of benign brain tumors including tubers, SEN, and SEGAs may be associated with epilepsy, intellectual disability, and behavioral disorders. Seizures are a common feature of TSC; the first seizure types to occur can be infantile spasms, focal seizures, or both, and the infantile spasms are frequently not associated with hypsarrhythmia. Seizures in adults can begin at any age, can worsen, or can abate over the individual’s lifespan, and seizure seismology can change over time. TSC-associated neuropsychiatric disorders (TAND) is an umbrella term encompassing interrelated neuropsychiatric manifestations common in TSC, including behavioral (such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD)), psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties and disorders. Kidney manifestations include angiomyolipomas (AMLs) with complications of hemorrhagic rupture, cortical cysts, chronic renal insufficiency (due to AMLs or polycystosis), and malignant lesions. Adult females may develop pulmonary lymphangioleiomyomatosis (LAM), which can lead to terminal respiratory insufficiency. Presenting symptoms of LAM can include progressive shortness of breath, recurrent pneumothoraces and deterioration of lung function. Cardiac rhabdomyoma may also be present, particularly in the prenatal or neonatal period. Disfiguring skin lesions are common, but do not result in serious medical problems. Eye lesions, which include hamartomas, are occasionally symptomatic.

Natural History (Important subgroups & survival / recovery)

The clinical presentation of TSC is variable and the progression and severity of organ involvement can vary according to the individual’s age, genotype, and treatment. Females tend to have milder disease than males. Pathogenic variants in TSC2 are more commonly identified in individuals with a negative family history and are more likely to be associated with severe disease than TSC1 pathogenic variants. Although mosaic individuals may experience fewer findings of TSC, they may develop any manifestation of TSC.

Many manifestations can be associated with severe morbidity and potentially death. In at least two-thirds of individuals, TSC is diagnosed in the first year of life when an infant presents with epileptic seizures; cortical tumors may be detected. Epilepsy is a major manifestation in childhood and may be accompanied by behavioral and neuropsychiatric manifestations that continue into adulthood. The leading cause of premature death (32.5%) among individuals is a complication of severe intellectual disability (e.g., status epilepticus and bronchopneumonia). Renal disease is the second leading cause of early death (27.5%). Kidney damage develops mainly before 20 years of age but with consequences that must be managed into adulthood. SEGAs tend to develop in adolescence or very early adulthood and may remain dormant or enlarge at any time, causing significant morbidity and mortality. The mean age of diagnosis for females who develop LAM is 28 years. LAM is commonly associated with renal AMLs. TAND issues are common and are often the most impactful aspect of TSC, yet they are the least likely to be addressed and controlled by existing treatments.

TSC may present a severe physical, mental, and financial burden to both the individuals with TSC and their caregivers. Management of stress associated with TSC, and its complexities is crucial to the mental well-being of the individual with TSC and caregivers.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

The population prevalence of pathogenic variants associated with TSC was not found. Of the more than 10,000 individuals with TSC and their families in whom pathogenic variants have been identified, ~26% of probands had a pathogenic variant in TSC1 and ~74% had a pathogenic variant in TSC2.

Tier 3

Unknown

Two thirds of affected individuals have the altered TSC1 or TSC2 gene as the result of a de novo pathogenic variant.

Tier 3

Unknown

Approximately 10-20% of individuals with TSC have no pathogenic variant identified. Low-level mosaic pathogenic variants have been identified in some individuals with clinical signs of TSC in whom standard next generation sequencing (NGS) or pre-NGS testing was normal. Intronic splice site pathogenic variants are also important to identify as a potential cause for TSC. A recent report of 53 people with TSC with no pathogenic variant identified, reported that mosaicism was observed in the majority (58%) and then followed by intronic pathogenic variants, which were seen in 40% of the study population.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

After detailed evaluation of those known to have TSC1 or TSC2 pathogenic variants, the penetrance of TSC is now thought to be 100%. Rare instances of apparent non-penetrance have been reported; however, molecular studies revealed the presence of two different pathogenic variants in the family and the existence of germline mosaicism in others.

Tier 3

>= 40 %

Reported rates of phenotypic manifestations include:

• Skin: hypomelanotic macules (~90%), confetti skin lesions (range - 3% of children to ≤58% overall), facial angiofibromas (75-86%), shagreen patches (~50%), and ungual fibromas (20% overall but ≤80% in older affected adults)

• Central nervous system: SENs (80%), cortical tubers (90%), SEGAs (5%-20%), focal seizures and epileptic spasms in infants, typically between three and eight months old (63-78%). More than 80% of individuals have seizures, though this may reflect ascertainment bias

• TAND: ASD (16-61%), ADHD (21%-60%), intellectual disability (44-64%), self-injury (27%), aggression (50%)

• Kidneys: 80% of children have identifiable renal lesion by age 10.5 years. Types of renal lesions include: benign AML (70-80%), cysts (10-20% of children, 14-45% of adults), oncocytoma (<1%), malignant AML (<1%), and renal cell carcinoma (<3%). AMLs associated with TSC have a rupture and hemorrhage rate ranging from 21% to 100%.

• Lung: LAM occurs in 30-40% of females, though a more recent study suggests LAM diagnosis is age dependent and occurs in up to 80% of females by age 40 years. LAM is observed in 10-12% of males, though symptomatic LAM in males is very rare.

• Eye: retinal astrocytic hamartomas (30%-50% overall, bilateral in 43%, multiple in 40%), achromic patches (39%).

• Cardiac: Fetal cardiac rhabdomyoma (50-80%). Most partially or completely regress during the first 2-4 years of life.

Tier 3

Unknown

A systematic review including 3542 children with TSC found that ASD was associated with a history of seizures (OR 3.79, 95%CI 1.77-8.14), infantile spasms compared with other seizure types (OR 3.04, 95%CI 2.17-4.27), onset of any seizure type during infancy (OR 2.65, 95%CI 1.08-6.54) and male sex (OR 1.62, 95%CI 1.23-2.14). There was no association with tuber number, tuber location or genotype (genotype information only available for 1770 children).

Tier 1

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was found.

Expressivity

TSC exhibits both inter- and intrafamilial variability in clinical expressivity.

Tier 3

Females with pathogenic variants on the carboxy terminus of the TSC2 gene product may have increased incidence and/or severity of LAM.

Tier 3

Pathogenic variants in TSC2 are more commonly identified in individuals with a negative family history and are more likely to be associated with severe disease than TSC1 pathogenic variants.

Tier 3

Some pathogenic missense variants in TSC2 are associated with milder disease, which have been identified in individuals with a family history of TSC.

Tier 3

Renal cysts are more common in patients with pathogenic variants in TSC2 than in TSC1, especially if the TSC2 pathogenic variant is truncated.

Tier 3

Intervention Effectiveness

Patient Management

Recommended management following initial diagnosis of TSC include:

• Obtain three generation pedigree

• During infancy, educate parents to recognize infantile spasms and focal seizures

• Perform comprehensive assessment for all levels of potential TAND manifestations

• Provide parent/caregiver education and training about TAND

• Provide psychological and social support to families and caregivers

• Provide counseling to patients and families about sudden unexpected death in epilepsy (SUDEP)

• Provide counseling regarding the risk of pregnancy and exogenous estrogen use

• In adults, inquire about tobacco exposure, connective tissue disease manifestations, signs of chyle leak, and pulmonary manifestations of dyspnea, cough, and spontaneous pneumothorax

• Sudden and unexpected change in behavior should prompt physical evaluation to look at potential medical causes (e.g., SEGA, seizures, renal disease, medications)

• Patients should be informed of the risk and clinical signs of a hemorrhagic rupture of an AML and the nearest medical centers able to treat these acute ruptures should be identified.

Tier 2

Recommended evaluations following initial diagnosis of TSC include:

• Obtain MRI of the brain to assess for the presence of tubers, SEN, migrational defects, and SEGA. If MRI is not available or cannot be performed, CT or head ultrasound (in neonates or infants when fontanels are open) may be used

• One guideline recommends obtaining baseline EEG while awake and asleep for all patients. Another guideline recommends EEG only in those with suspected epileptic seizure activity

• Obtain MRI of the abdomen to assess for AMLs and renal cysts. If MRI is not available, abdominal CT is next preferred modality

• Screen for hypertension by obtaining accurate blood pressure

• Evaluate renal function by determination of glomerular filtration rate (GFR)

• Perform baseline chest CT in all females, and symptomatic males, starting at age 18 years or older. Ultra-low-dose CT acquisition protocols are recommended when possible

• Perform detailed clinical dermatologic inspection/examination, ideally using Wood’s lamp

• Perform detailed clinical dental inspection/examination at the time of diagnosis, time of eruption of the first tooth or no later than 12 months of age

• Obtain echocardiography in pediatric patients, especially if younger than three years. One guideline recommends echocardiography in adults if symptomatic

• Obtain electrocardiography at all ages to assess for underlying conduction defects

• Perform complete ophthalmologic evaluation, including dilated fundoscopy, to assess for retinal findings and visual field defects.

Tier 2

Children should be referred initially to a pediatric neurologist with expertise in epilepsy associated with TSC. Adults should be evaluated by an adult neurologist with expertise in epilepsy associated with TSC.

Tier 2

It is recommended to offer vigabatrin as first-line treatment to infants with infantile spasms due to TSC. If vigabatrin is ineffective, offer a steroid. Both the guideline and systematic review identified one study evaluating vigabatrin vs hydrocortisone in 22 infants (age range one month to two years) with TSC. This small study found in the initial phase that 11 of 11 participants (100%) treated with vigabatrin were spasm free as compared with 5 of 11 participants (45%) treated with hydrocortisone (Peto OR 13.8, 95%CI 2.21 to 86.35). Time to achieve cessation of spasms was 4 days for those 11 responders taking vigabatrin (range 0.5 to 14 days, median 2 days) and 13 days (range 3 to 30 days, median 23.5 days) for those 5 responders taking hydrocortisone (weighted mean difference -8.8, 95% CI -19.2 to 1.6). Ten of 11 participants who responded to vigabatrin remained spasm free; this information was not available for the 5 responders to hydrocortisone.

Tier 1

In at risk infants diagnosed with TSC and epileptiform activity on EEG, pre-emptive treatment with vigabatrin before the onset of clinical seizures may provide additional benefit of preventing or delaying seizure onset. A recent study, evaluating infants with TSC age ≤ 4 months without previous seizures, found that preventative vigabatrin treatment resulted in reduced risk of seizures, infantile spasms, and drug-resistant epilepsy; however, there was no significant difference in the prevalence of developmental delay (p=0.9) or autism (p=0.8) at age two years.

Tier 2

Antiseizure medications for seizure types other than infantile spasms in TSC should generally follow that of other epilepsies. Introduction of everolimus as add-on therapy should be considered if TSC-associated seizures are refractory to two antiseizure medications. Treatment with mechanistic target of rapamycin inhibitors (mTORi) appears to be dose-responsive. It appears to be safe in young children aged less than 3 years.

Tier 2

A systematic review identified one study (117 participants, age range 0-65 years) where participants were selected based on the need for intervention for progression of SEGA, rather than presence of seizures. In the everolimus group (n=78, median age 9.5 years, range 1-23.9 years), 27 individuals (35%) had seizures on baseline EEG. In the placebo group (n=39, median age 7.1 years, range 0.8-26.6 years), 13 individuals (33%) had seizures on baseline EEG. The median change of seizure frequency with oral (systemic) administration of everolimus was -.29 in 24 hours (95% CI -4.0 to -1.0) in the treatment group versus -4.1 in 24 hours (95% CI -10.9 to 5.8) in the placebo group. A meta-analysis, including two additional randomized controlled trials, also showed that mTORi compared to the placebo significantly reduced seizure frequency (RR= 2.12, 95%CI 1.41,3.19, p=0.0003).

Tier 1

Surgical resection should be performed for acutely symptomatic SEGA. Cerebrospinal fluid diversion (shunt) may also be necessary. For large tumors, if clinical condition enables, neoadjuvant treatment with mTORi may facilitate surgery. Minimally invasive surgical techniques may increase surgical safety in selected patients.

Tier 2

Either medical treatment with mTORi or surgical resection may be used for growing but otherwise asymptomatic SEGA. Optimal outcome is associated with early detection and treatment.

Tier 2

A systematic review and a meta-analysis identified one study (117 participants) using oral (systemic) everolimus which found that significantly more participants in the treatment arm achieved a 50% reduction in SEGA tumor volume (RR= 27.85, 95% CI 1.74 to 444.82, p=0.02).

Tier 1

The onset of respiratory symptoms (unexplained dyspnea, pneumothorax) should result in pulmonary imaging regardless of the sex of the patient.

Tier 2

The mTORi sirolimus is recommended as the first-line treatment for qualifying patients with LAM. A substantial proportion of patients with TSC who are discovered to have LAM may already be taking everolimus for other indications. In these circumstances, given the extensive molecular similarity and evidence of efficacy in an open-label phase 2 study, it is recommended to continue treatment with everolimus and serial PFT monitoring rather than switching to sirolimus. In a 1-year randomized double-blind placebo-controlled trial of sirolimus in 89 patients with LAM (proportion of patients with TSC not provided), the between-group difference in the mean change in forced expiratory volume in 1 second (FEV(1)) was about 11% of baseline, favoring sirolimus. The sirolimus group improved in measures of forced vital capacity, quality of life, and functional performance, although not in the 6-miniute walk test.

Tier 2

Trans-arterial embolization followed by corticosteroids is the first-line therapy for AML presenting with acute hemorrhage. Efficacy of this type of embolization is reported to be 93% in patients with AML (of unspecified etiology) and is associated with the onset of post-embolization syndrome in 35% of patients. Although both nephrectomy and embolization will resolve the condition, the risk of renal failure in patients with TSC was noted to be seven times higher with nephrectomy.

Tier 2

For asymptomatic, growing AML measuring larger than 3 cm in diameter, treatment with an mTORi is now the recommended first-line therapy. Treatment should continue if there is clinical benefit or until unacceptable toxicity occurs.

Tier 2

A systematic review and a meta-analysis identified two studies (235 participants) using oral everolimus and found that significantly more participants in the treatment arm (109 participants) achieved a 50% reduction in renal AML size (RR=24.69, 95% CI 3.51-173.41, p=0.001).

Tier 1

Topic mTORi treatment is recommended for flat or minimally elevated skin lesions. Many individuals show improvement in TSC-related skin lesions while taking a systemic mTORi for other manifestations of TSC. Evidence is currently lacking to demonstrate an additive benefit of topical sirolimus (rapamycin) in patients on systemic therapy. Topical sirolimus is safe and effective for treating facial angiofibromas and it may also improve other TSC skin lesions.

Tier 2

A systematic review identified two studies (224 participants) and found that the proportion of participants who showed a skin response was significantly increased in the treatment arms (RR= 5.78, 95% CI 2.30 to 14.52, p=0.0002). One study (28 participants) used topical (skin) administration of rapamycin. There was a tendency towards improvement in participants’ perception of their skin appearance although it was not significant (RR=1.81 95%CI 0.80-4.06).

Tier 1

For protuberant skin lesions, consider surgical approaches (e.g., excision, lasers), especially if skin lesions do not improve using mTORi or if earlier intervention is indicated.

Tier 2

It is recommended that mTORi therapy be discontinued during the perioperative period. Individuals undergoing major surgical procedures while on mTORi therapy should be informed about potential impairment of wound healing.

Tier 2

Surveillance

Ongoing surveillance recommendations include:

• Obtain brain MRI every 1-3 years in asymptomatic patients younger than age 25 years. There is no consensus when to stop routine brain MRIs, though recent studies reveal that known SEGAs may enlarge during adulthood, and in rare instances newly present in adulthood

• One guideline recommends obtaining routine EEG in asymptomatic infants every 6 weeks up to age 12 months and every 3 months up to age 24 months. Another guideline recommends routine EEG in individuals with known or suspected seizure activity

• Annual screening for TAND

• Obtain MRI of the abdomen to assess for progression of AML and renal cystic disease every 1 to 3 years (imaging frequency should be informed by growth rate and size of lesion) through the lifetime of the patient. MRI is recommended for greater accuracy, but in stable lesions it can be alternated with ultrasound. If MRI is not available, CT can still provide useful information, but careful consideration is warranted due to risks of cumulative radiation, especially in pediatric patients

• Assess renal function including determination of GFR, proteinuria and blood pressure at least annually

• For adult females with a negative screening chest CT who remain asymptomatic, repeat to screen for presence of LAM every 5-7 years through menopause

• Perform annual skin examinations for children. Adult dermatologic evaluation frequency depends on the cutaneous manifestation

• Obtain an echocardiography every 1-3 years in asymptomatic pediatric patients until regression of cardiac rhabdomyomas is documented

• Obtain electrocardiography every 3-5 years in asymptomatic patients of all ages to monitor for conduction defects

• Perform annual ophthalmic evaluation for those with or without visual symptoms at baseline.

Tier 2

Circumstances to Avoid

Avoid routine use of hormonal therapy or doxycycline for the treatment of LAM.

Tier 2

Avoid tobacco smoke exposure including the use of electronic cigarettes and vaping.

Tier 2

Individuals on mTORi therapy should receive the recombinant varicella vaccine regardless of age and avoid all live vaccines.

Tier 2

Sun protection is recommended (ideally using sunblock with SPF 30+), for both children and adults.

Tier 2

Total nephrectomy should be avoided due to the high incidence of complications and increased risk of future renal insufficiency, end-stage renal failure, and the poor prognosis that results from chronic kidney disease.

Tier 2

Nature of Intervention

Nature of Intervention

Because of the variability of TSC, comprehensive ongoing investigations of different organ systems are needed, including MRI of the brain and abdomen, electrocardiography, chest CT in females, ophthalmological examination including dilated fundoscopy, and other evaluations including dermatological and dental examination. Adverse events of systemic therapy with mTORi are typically mild to moderate, including patients treated at young ages. However, it is not uncommon for adverse events, such as stomatitis, hyperlipidemia, and hyperglycemia, to necessitate dose reduction or temporary suspension of treatment. Amenorrhea can be caused by mTORi, though most cases are transient, manageable and do not lead to interruption of treatment. Adverse effects of topical sirolimus are generally mild, such as application-site skin irritation, dry skin, or acne. Vigabatrin has possible side effects that include potential retinal toxicity associated with peripheral vision loss, which appears to be correlated with total cumulative dose.

Context: Adult Pediatric

Chance to Escape Clinical Detection

TSC can be discovered on investigation after the onset of infantile spasms. However, infantile spasms are commonly misdiagnosed initially, often leading to long lead-times between onset and initiation of effective treatment; this long lead-time is associated with worse developmental outcomes.

Context: Adult Pediatric

Tier 3

One study found that 30 out of 45 females who were diagnosed with TSC as adults, actually met the clinical criteria for TSC in childhood. Although these females had minimal morbidity during childhood, they were at risk of life-threatening pulmonary and renal manifestations.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			TSC1			191100	0001734	0008612
TSC2			613254	0001734	0013199

References List

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