Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.1
• GENE/GENE PANEL: TSC1, TSC2
• Condition: Tuberous Sclerosis Complex (TSC)
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• TSC1 ⇔ MONDO:0001734 (tuberous sclerosis 1; tsc1): Assertion Pending
• TSC2 ⇔ MONDO:0001734 (tuberous sclerosis 2; tsc2): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: TSC1 ⇔ MONDO:0001734 (OMIM:191100) TSC2 ⇔ MONDO:0001734 (OMIM:613254)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
SEGA development / mTOR inhibitor treatment	2	2N	2B	2	8NB
Morbidity and mortality from masses / Imaging to detect masses when intervention is effective	2	3N	2B	3	10NB
LAM development in women / mTOR inhibitor treatment	2	2N	2B	2	8NB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

TSC affects approximately one in 6000 births, with a prevalence of one in 11,000 to 14,000 after the age of 10 years. [1, 2, 3]

Clinical Features

Tuberous sclerosis complex (TSC) is a rare, slowly progressive disorder characterized by disorganized cellular growth, abnormal differentiation, and 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. Kidney manifestations include angiomyolipomas (AMLs) with complications of hemorrhagic rupture, cortical cysts, chronic renal insufficiency (due to AMLs or polycystosis), and malignant lesions. Adult women with TSC may develop pulmonary lymphangioleiomyomatosis (LAM), which can lead to terminal respiratory insufficiency. Brain lesions include subependymal nodules (SEN), cortical tubers, and subependymal giant cell astrocytomas (SEGAs) affecting 80%, 90%, and 5-15% of TSC patients, respectively. 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 such as autism and ADHD. Prevalence rates of autism spectrum disorder (ASD) in TSC range from 24% to 60% with an approximately equal male to female ratio. In adulthood, high rates of anxiety symptoms and depressed mood are reported. Disfiguring skin lesions are common, but do not result in serious medical problems. Eye lesions are occasionally symptomatic. [1, 3, 4, 5, 6, 7]

Natural History

Tuberous sclerosis complex (TSC) exhibits variability in clinical findings both among and within families. Females tend to have milder disease than males. Any organ system can be involved and TSC2 mutations produce a more severe phenotype than TSC1 mutations. Patients with mild symptoms tend to live long, productive lives, while individuals with more severe forms of TSC may have serious disabilities. In at least two-thirds of cases, TSC is diagnosed in the first year of life when an infant with TSC presents with epileptic seizures; cortical tumors may be detected. Cardiac rhabdomyoma may also be present particularly in the neonatal period, requiring surveillance until regression during childhood. 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 with TSC 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 affects 48-80% of patients, developing mainly before 20 years of age but with consequences that must be managed well into adulthood. Whether TSC is a risk factor for development of malignant kidney tumors is a subject of debate; such tumors occur in TSC at a rate of 0.5-4%. Although present in a minority of cases, 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 women who develop TSC LAM is 28 years. [1, 2, 5, 7]

2. How effective are interventions for preventing harm?

Patient Management

At diagnosis all individuals should undergo magnetic resonance imaging (MRI) of the brain, abdominal imaging, renal function tests, blood pressure assessment, echocardiogram, and a detailed dermatologic, dental and ophthalmologic exam. Also, a baseline pulmonary function test, 6-minute walk test, and high-resolution tomography (HRCT) in women 18 years or older. (Tier 2) [1, 6, 8]

Newly diagnosed adults should undergo an assessment of cognitive, behavioral, and vocational profiles to determine a based profile for future evaluations. Psychosocial needs should be also determined. (Tier 2) [8]

SEGAs associated with increasing ventricular enlargement, or with unexplained changes in neurological status or neuropsychiatric symptoms, require intervention (surgical resection or medical therapy with mTOR inhibitors) or more frequent clinical monitoring and reimaging. In two large prospective studies, the mTOR inhibitor everolimus significantly decreased the volume (>50%) of SEGAs in 35% to 42% at 6 months of treatment. (Tier 2) [8, 9]

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. Patients with LAM should be educated and warned regarding the signs and risk of pneumothorax and told to seek urgent medical attention in the event of symptoms. (Tier 2) [1, 6]

The onset of respiratory symptoms (unexplained dyspnea, pneumothorax) should result in pulmonary imaging regardless of the sex of the patient. In select patients, treatment with an mTOR inhibitor may be used to stabilize or improve pulmonary function. In a 1-year randomized double-blind placebo-controlled trial of sirolimus in 89 patients with LAM, the between-group difference in the mean change in 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) [1, 6, 8]

Patients with TSC who would like to become pregnant should have a genetic consultation before any conception and should be informed of risks during pregnancy. (Tier 2) [1]

Surveillance

Ongoing periodic surveillance is needed after initial diagnosis for optimal care and prevention of secondary complications associated with TSC. (Tier 2) [8]

It is imperative to monitor for TSC-specific neuropsychiatric features and their impact on daily living at each follow-up clinic visit, with a minimum frequency of once per year. (Tier 2) [8]

Annual screening and monitoring of renal lesions and blood pressure is indicated in all patients with TSC. Preventive treatment such as mTOR inhibitor therapy for AMLs meeting appropriate criteria may be considered. In a double-blind, placebo-controlled, phase III trial of patients with TSC or sporadic LAM, the AML response rate was 42% (33 of 79 [95% CI 31-53%]) for the mTOR everolimus and 0% (0 of 39 [0-9%]) for placebo (response rate difference 42% [24-58%]; p<0·0001). (Tier 2) [1, 8]

A skin survey should be performed annually to assess skin lesions. Early intervention is indicated for bleeding, symptomatic, or potentially disfiguring lesions. (Tier 2) [8]

HRCT imaging for pulmonary LAM should be repeated in previously asymptomatic women every 5-10 years after baseline or at least by 30 to 40 years of age. (Tier 2) [1, 6, 8]

For early detection, MRI surveillance for SEGAs should be performed every 1-3 years until age 25, or more frequently in developmentally or cognitively disabled patients who cannot reliably report symptoms. Individuals without SEGAs by the age of 25 years do not need continued surveillance, but those with asymptomatic tumors should continue to be monitored by MRI for life because of the possibility of growth. (Tier 2) [8]

Circumstances to Avoid

Patients with LAM should refrain from smoking. (Tier 2) [6]

Patients with TSC who have renal AMLs and/or pulmonary LAM should avoid estrogenic treatments, which are risk factors for AML progression and/or spontaneous rupture, and for more rapid degeneration of respiratory function in LAM. For those without symptoms, counseling on smoking risks and estrogen use should also occur in adolescents and adults (Tier 2) [1, 8]

Nephrectomy should be avoided due to the high incidence of complications and risk of renal insufficiency or failure. (Tier 2) [8]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant
Two thirds of affected individuals have the altered TSC1 or TSC2 gene as the result of a de novo mutation. [2]

Prevalence of Genetic Variants

No information on population prevalence of genetic mutations was found. About 30% of patients with definite clinical TSC and an identifiable mutation have a TSC1 mutation; the rest have a TSC2 mutation. (Tier 3) [2, 10]

Approximately 15-20% of persons with TSC have no mutation identified. (Tier 3) [2, 10]

Penetrance

In a study of 103 clinically diagnosed TSC patients (all with seizure onset at less than 3 years of age), 90% of whom had confirmed TSC1 or TSC2 mutations, it was estimated that 40% of individuals had ASD. (Tier 5) [11]

In three studies of TSC patients selected first by clinical diagnosis and then by TSC1 or TSC2 mutation, the following characteristics were documented.
•Median age at diagnosis was 10 to 13 years; overall range was 0 to 64 years.
•Skin involvement included: hypomelanotic macules (92-96% of individuals), facial angiofibromas (63-80%), shagreen patches (44-55%), forehead plaques (33-41%), and ungual fibromas (20-37%).
•SENs occurred in 89-95%, cortical or subcortical tubers occurred in 88-91%, and SEGAs occurred in 12-31% of all individuals with TSC-related mutations.
•80-95% of individuals with mutations had seizures, and 48-76% had intellectual disability.
•Renal AMLS affected 42-56% and renal cysts (any grade) affected 23-27% of adults. (Tier 5) [12, 13, 14]

In two studies of TSC patients selected first by clinical diagnosis and then by TSC1 or TSC2 mutation, LAM occurred in 12-39% of adult females with TSC. (Tier 5) [15, 13]

Relative Risk

No information on relative risk was found.

Expressivity

The TSC clinical phenotype is extremely variable. Some individuals have only superficial skin problems or mild seizures while others show severe physical effects and profound intellectual disability. Variability has also been noted in monozygotic twins. (Tier 3) [3, 5]

4. What is the Nature of the Intervention?

Nature of Intervention

Because of the variability of TSC, non-invasive but comprehensive investigations of different organ systems are needed, like a neurological examination, MRI of the brain, cardiology examination, ultrasound of the heart, ophthalmological examination, dermatological examination, and ultrasound or CT-scan of the abdomen. Some patients may require treatment with mTOR inhibitors, which may be accompanied by adverse events of moderate risk such as infection, metabolic disturbances, hematologic abnormalities, non-infectious pneumonitis, and renal dysfunction.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

TSC has a highly variable phenotype with only one third of patients having the classical triad of epilepsy, learning difficulties, and facial angiofibromas. Those who do not have epilepsy or learning difficulties may have mild cutaneous features of TSC that can be overlooked. Diverse, non-specific, clinical manifestations as well as a high probability of a spontaneous mutation can cause some individuals with TSC to go unrecognized or misdiagnosed for years. (Tier 4) [2, 6, 7]

Date of Search: 07.21.2015

Reference List

1. Rouviere O, Nivet H, Grenier N, Zini L, Lechevallier E. Kidney damage due to tuberous sclerosis complex: management recommendations. Diagn Interv Imaging. (2013) 94(3):225-37.

2. Tuberous Sclerosis Complex. Gene Reviews. (2011) Website: http://www.ncbi.nlm.nih.gov/books/NBK1220/

3. Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res. (2009) 53(10):852-73.

4. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. (2013) 49(4):243-54.

5. de Vries P, Humphrey A, McCartney D, Prather P, Bolton P, Hunt A. Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis. Eur Child Adolesc Psychiatry. (2005) 14(4):183-90.

6. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, Popper H, Bonetti F, Kingswood C. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. (2010) 35(1):14-26.

7. Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. (2011) 27(8):1571-83.

8. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. (2013) 49(4):255-65.

9. Roth J, Roach ES, Bartels U, Jozwiak S, Koenig MK, Weiner HL, Franz DN, Wang HZ. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol. (2013) 49(6):439-44.

10. Mayer K, Fonatsch C, Wimmer K, van den Ouweland AM, Maat-Kievit AJ. Clinical utility gene card for: tuberous sclerosis complex (TSC1, TSC2). Eur J Hum Genet. (2014) 22(2).

11. Numis AL, Major P, Montenegro MA, Muzykewicz DA, Pulsifer MB, Thiele EA. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology. (2011) 76(11):981-7.

12. Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, Wheless JW, Baumgartner JE, Roa BB, Wilson CM, Smith-Knuppel TK, Cheung MY, Whittemore VH, King TM, Northrup H. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. (2007) 9(2):88-100.

13. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS, Reeve MP, Thiele E, Egelhoff JC, Kasprzyk-Obara J, Domanska-Pakiela D, Kwiatkowski DJ. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. (2001) 68(1):64-80.

14. Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, Zonnenberg B, Verhoef S, Halley D, van den Ouweland A. 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(6):731-41.

15. McCormack F, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, Franz DN. Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysis. Chest. (2002) 121(3 Suppl):61S.