Clinical Diagnosis

The diagnostic criteria for tuberous sclerosis complex (TSC) have been revised [Roach & Sparagana 2004]. The new criteria:

• Recognize that individuals with isolated lymphangioleiomyomatosis (LAM) who have associated renal angiomyolipomas do not have TSC [Smolarek et al 1998];
• Have eliminated nonspecific features (e.g., infantile spasms and myoclonic, tonic, or atonic seizures) and have made certain features more specific (e.g., nontraumatic ungual or periungual fibroma; three or more hypomelanotic macules).

Definite TSC. Two major features or one major feature plus two minor features

Probable TSC. One major feature plus one minor feature

Possible TSC. One major feature or two or more minor features

Molecular Genetic Testing

Genes. The only two genes in which mutations are known to cause tuberous sclerosis complex are TSC1 and TSC2 [European Chromosome 16 Tuberous Sclerosis Consortium 1993, van Slegtenhorst et al 1997].

Evidence for additional locus heterogeneity. Molecular genetic testing of TSC1 and TSC2 by sequence analysis and deletion/duplication analysis (to detect exonic or whole-gene deletions) identifies a mutation in approximately 85% of individuals with a definite diagnosis of TSC; approximately 15% of persons with TSC have no mutation identified.

Clinical testing

Molecular genetic testing of TSC1 and TSC2 is complicated by the large size of the two genes, the large number of disease-causing mutations, and the high rate of somatic mosaicism [Sampson et al 1997, Verhoef et al 1999]. Furthermore, TSC1 mutations are primarily small deletions and insertions and nonsense mutations detected by sequence analysis; in contrast, TSC2 mutations also include significant numbers of large (exonic and whole-gene) deletions and rearrangements that cannot be detected by sequence analysis and thus require deletion/duplication analysis for detection.

Somatic mosaicism has been described in numerous individuals with TSC and their parents. However, an estimate of the frequency of somatic mosaicism is complicated by:

• The sensitivity of the methods and the difficulty of detecting low-level mosaicism;
• The relative ease of detecting mosaicism for exonic / whole-gene deletions or duplications and the difficulty in detecting mosaicism for point mutations and small intra-exonic deletions or duplications;
• The likely overestimate of the percent of mosaicism in some studies because only affected persons who did not have a mutation identified by other molecular genetic test methods (sequencing and/or deletion/duplication analysis) were evaluated for mosaicism; and
• The fact that the phenotypes caused by mutations in TSC1 and TSC2 cannot be differentiated clinically; therefore, the proportion of individuals with each phenotype is unknown at the outset of studies screening for somatic mosaicism.

Note: (1) It is difficult to identify with confidence low-level mosaicism for missense and other mutations involving a few nucleotides because most of the sequence variants with a low level of mosaicism may be artifacts possibly introduced by the PCR processes. (2) Levels of mosaicism greater than 20% can be detected in lymphocyte DNA [Qin et al 2010].

The frequency of somatic mosaicism for large deletions and duplications of TSC1 and TSC2 in affected individuals (who did not have a mutation identified by sequencing or other similar methods) has been reported as about 5% (N=165) [Kozlowski et al 2007; Author, personal observation]. The eight individuals with mosaicism had multiexonic rearrangements: seven had deletions in TSC2, one had a duplication in TSC2 [Kozlowski et al 2007].

Using next-generation sequencing of TSC1 and TSC2, Qin et al [2010] identified somatic mosaicism in two of 33 affected individuals who did not have a mutation identified by sequence analysis or deletion/duplication analysis. Both mutations were in TSC2, one a missense mutation and the other a splice site mutation.

Given the 5% detection rate for somatic mosaicism [Kozlowski et al 2007, Qin et al 2010] and given that 15% of persons with TSC do not have a mutation identified in TSC1 or TSC2 by sequence analysis, the authors conclude that at least 1% of persons with TSC have somatic mosaicism for a TSC1 or TSC2 mutation [Author, personal observation].

Germline mosaicism studies are typically limited to families with two or more affected children and unaffected parents. Of 120 such families, Rose et al [1999] identified six (5%) with mutation-confirmed germline mosaicism. Of these, one mutation was in TSC1 and five in TSC2; mutations were missense, nonsense, and a one-nucleotide insertion or deletion.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.
• Because somatic mosaicism for a mutation in TSC2 has been reported in seven of 26 families with a combined TSC/PKD (autosomal dominant polycystic kidney disease) phenotype and six of 62 probands in another series, DNA testing of other tissues (e.g., tumors, saliva, skin, and/or hair follicles) is warranted when somatic mosaicism is suspected and routine molecular genetic testing has not revealed a mutation. No assay kit or service laboratory for testing somatic mosaicism exists at this time.

Testing Strategy

To confirm the diagnosis in a proband

1.

Perform sequence analysis of TSC1 and TSC2.

2.

If no mutation is identified, perform deletion/duplication analysis of TSC1 and TSC2.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with germline mutations in TSC1 and TSC2.

Pulmonary lymphangioleiomyomatosis (LAM). DNA extracted from lung tissue of some individuals with sporadic LAM harbors mutations of TSC2 or TSC1 not present in the germline [Smolarek et al 1998, Carsillo et al 2000, Sato et al 2002]. Tuberin is strongly expressed in LAM tissues [Johnson et al 2002].

Perivascular epitheloid cell tumors (PEComa). In some PEComa, reported loss of either TSC2 or TSC1 [Pan et al 2008] is evidence to support an oncogenic lineage of PEComa and angiomyolipomas in TSC.

Natural History

Tuberous sclerosis complex (TSC) exhibits variability in clinical findings both among and within families. Females tend to have milder disease than males [Sancak et al 2005, Au et al 2007]. Any organ system can be involved in TSC.

Skin. The skin is affected in virtually 100% of individuals with TSC. Skin lesions include: hypomelanotic macules (87%-100% of individuals), facial angiofibromas (47%-90%), shagreen patches (20%-80%), fibrous facial plaques, and ungual fibromas (17%-87%). Among the skin lesions, the facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems.

Central nervous system. CNS tumors are the leading cause of morbidity and mortality in TSC. The brain lesions of TSC, including subependymal nodules (SENs) [Torres et al 1998], cortical tubers, and subependymal giant cell astrocytomas (SEGAs), can be distinguished with neuroimaging studies. SENs occur in 90% of individuals and cortical or subcortical tubers in 70%. SEGAs occur in 6% to 14% of all individuals with TSC [Torres et al 1998]. These giant cell astrocytomas may enlarge, causing pressure and obstruction and resulting in significant morbidity and mortality.

More than 80% of individuals with TSC have been reported to have seizures, although this percentage may reflect ascertainment bias of more severely involved individuals. TSC is a known cause of the infantile spasm/hypsarrhythmia syndrome. At least 50% of individuals have developmental delay or intellectual disability. 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).

Individuals with TSC are at significant risk for neurodevelopmental and behavioral impairment. The behavioral and psychiatric disorders most commonly observed are part of the autism spectrum disorders.

• Numis et al [2011] reported that 40% of persons with TSC were diagnosed with autism spectrum disorders.
• Ehninger & Silva [2011] suggest that 20%-60% of persons with TSC have autism spectrum disorders.

Hyperactivity or attention deficit hyperactivity disorder (ADHD) and aggression are also commonly observed in individuals with TSC [Baker et al 1998, Gutierrez et al 1998].

Prather & de Vries [2004] observed that the frontal brain systems most consistently disrupted by TSC-related neuropathology lead to abnormalities in regulatory and goal-directed behaviors.

Zaroff et al [2004] reported that early-onset seizures and increased tuber burden are risk factors for cognitive impairment, and that early behavioral assessment and therapeutic intervention, including seizure control, promote better neurobehavioral outcome.

Kidneys. Renal disease is the second leading cause of early death (27.5%) in individuals with TSC. An estimated 80% of children with TSC have an identifiable renal lesion by the mean age of 10.5 years [Ewalt et al 1998].

Five different renal lesions occur in TSC: benign angiomyolipoma (70% of affected individuals); epithelial cysts (20%-30%) [Sancak et al 2005, Au et al 2007]; oncocytoma (benign adenomatous hamartoma) (<1%); malignant angiomyolipoma (<1%); and renal cell carcinoma (<3%) [Patel et al 2005].

Benign angiomyolipomas comprise abnormal blood vessels, sheets of smooth muscle, and mature adipose tissue. In children, angiomyolipomas tend to increase in size or number over time. Benign angiomyolipomas can cause life-threatening bleeding and can replace renal parenchyma, leading to end-stage renal disease (ESRD).

Renal cysts have an epithelial lining of hypertrophic hyperplastic eosinophilic cells.

Some affected individuals have features of both TSC2 and autosomal dominant polycystic kidney disease type 1 (PKD1). In these individuals, progressive enlargement of the cysts may compress functional parenchyma and lead to ESRD [Martignoni et al 2002]. Individuals with the TSC2/PKD1 contiguous gene syndrome are also at risk of developing the complications of PKD1, which include cystic lesions in other organs (e.g., the liver) and Berry aneurysms.

Malignant angiomyolipoma and renal cell carcinoma (RCC) may result in death. Although rare, these two tumors are much more common in TSC than in the general population [Pea et al 1998]. It is estimated that 2%-5% of persons with TSC will develop RCC. The age of diagnosis of RCC in those with TSC is 28-30 years which is much earlier than the age of diagnosis for sporadic RCC [Borkowska et al 2011, Crino et al 2006]. Note: Common imaging techniques may not distinguish fat-poor angiomyolipomas from RCC. Immunologic staining for HMB-45 for angiomyolipomas and cytokeratin for RCC is recommended

Heart. Cardiac rhabdomyomas are present in 47%-67% of individuals with TSC [Jones et al 1999, Dabora et al 2001, Sancak et al 2005]. These tumors have been documented to regress with time and eventually disappear. The cardiac rhabdomyomas are often largest during the neonatal period. In a meta-analysis of the literature, Verhaaren et al [2003] concluded that:

• Surgical intervention immediately after birth is only necessary when cardiac outflow obstruction occurs; and
• If cardiac outflow obstruction does not occur at birth, the individual is unlikely to have health problems from these tumors later.

Lung. Lymphangiomyomatosis (LAM) of the lung which primarily affects women is estimated to occur in approximately 30% of individuals with TSC, a five- to tenfold higher incidence than for sporadic LAM [Costello et al 2000, Franz et al 2001, Moss et al 2001, McCormack 2008]. Because the diagnosis of LAM is age-dependent, Kinder et al [2010] estimate that LAM occurs in up to 40% of women with TSC.

The mean age of diagnosis for TSC LAM is 28 years compared to 35 years for sporadic LAM.

Individuals with sporadic LAM may present with shortness of breath or hemoptysis. Chest radiographs reveal a diffuse reticular pattern and CT examination shows diffuse interstitial changes with infiltrates and cystic changes. Pneumothorax and chylothorax may occur. Some individuals progress to respiratory failure and death.

It is suggested that LAM associated with TSC is milder than sporadic LAM because persons with TSC LAM account for only about 15% of registrants in the NHLBI LAM Foundation [McCormack 2008]. Furthermore, persons with TSC LAM have less severe lung cysts than persons with sporadic LAM [Avila et al 2007].

Multifocal micronodular pneumonocyte hyperplasia (MMPH), characterized by multiple nodular proliferations of type II pneumocytes, was first described in association with TSC in 1991 [Popper et al 1991]. Muir et al [1998] described 14 individuals with MMPH (12 females and two males): seven had TSC/LAM; two had TSC only; three had LAM only; and two had neither. Fewer than 50 cases of MMPH have been reported to date in persons with TSC.

Avila et al [2007] reported 12% of persons with TSC LAM had multiple non-calcified nodules in the lung scans compared to 1% of persons with sporadic LAM. Furthermore, the nodules in sporadic LAM are mostly atypical adenomatoid hyperplasia.

Eye. The retinal lesions of TSC are hamartomas (elevated mulberry lesions or plaque-like lesions) and achromic patches (similar to the hypopigmented skin lesions). One or more of these lesions may be present in up to 75% of affected individuals. Although these lesions are usually asymptomatic, a few persons with TSC have had progressively enlarging retinal astrocytic hamartomas with total exudative retinal detachment and neovascular glaucoma [Shields et al 2004].

Extrarenal angiomyolipomas (AMLs). Although rare, extrarenal angiomyolipomas have been reported [Elsayes et al 2005]. In a retrospective study of sonographic and CT images, Fricke et al [2004] identified eight hepatic AMLs in 62 individuals with TSC (13%).

Dworakowska & Grossman [2009] summarized case reports of persons with TSC who had neuroendocrine tumors (NETs): the majority of tumors were pituitary adenomas (ACTHoma and GHoma), parathyroid adenomas and hyperplasia, and pancreatic adenomas (insulinoma and islet cell neoplasm). More recently single case reports have included gastrinoma, pheochromocytoma, and carcinoids. Several individuals had a TSC2 mutation and/or loss of heterozygosity in the islet cell neoplasms.

Genotype-Phenotype Correlations

Except for the TSC2/PKD1 contiguous gene deletion syndrome (see Clinical Description), the phenotypes caused by mutations in TSC1 and TSC2 were initially considered to be identical; however, with more genotype/phenotype data available, it is now known that TSC2 mutations produce a more severe phenotype than TSC1 mutations [Dabora et al 2001, Lewis et al 2004, Sancak et al 2005, Au et al 2007].

• A higher percentage of individuals with more severe TSC phenotypes have a de novo TSC2 mutation compared to a de novo TSC1 mutation [Jones et al 1999, Dabora et al 2001, Sancak et al 2005, Au et al 2007].
• Simplex cases (i.e., a single occurrence in a family) are more likely to have a TSC2 mutation and familial cases have an almost equal proportion of TSC1 and TSC2 mutations [Au et al 2007]. Jones et al [1997] and Jones et al [1999] reported a decreased proportion of mutations in TSC1 among individuals with TSC who have no family history of TSC; this may represent a true biologic phenomenon, or ascertainment of individuals with de novo mutations in TSC1 may be decreased because of the somewhat less severe phenotype.
• Al-Saleem et al [1998] reported a greater risk of renal malignancy in individuals with mutations in TSC2.
• Jones et al [1997] and Jones et al [1999] found a higher frequency of intellectual disability in individuals with a mutation in TSC2.
• Autistic disorder, low IQ, and infantile spasms are more frequently associated with a TSC2 mutation [Lewis et al 2004].
• Strizheva et al [2001] suggested that females with mutations on the carboxy terminus of tuberin, the TSC2 gene product, may have increased incidence and/or severity of lymphangiomyomatosis [Strizheva et al 2001].
• The type of TSC1 or TSC2 mutation (protein truncation vs missense) and the location of the mutation do not predict the severity of the phenotype. The exception is that some missense TSC2 mutations (i.e., p.Arg905Gln and p.Gln1503Pro) are associated with milder disease phenotypes [Khare et al 2001, Jansen et al 2006].

Renal cysts occur in individuals with the following:

• TSC1 mutations
• Small TSC2 mutations (single- to few-base pair insertions, deletions, and point mutations)
• A contiguous gene syndrome involving large gene deletions and rearrangements of both TSC2 and PKD1, which are arranged tail to tail in close proximity on chromosome 16p13.3. Note: Mutation of PKD1 causes autosomal dominant polycystic kidney disease (ADPKD).

Penetrance

After detailed evaluation of each individual known to have a TSC1 or TSC2 mutation, the penetrance of TSC is now thought to be 100%. Rare instances of seeming non-penetrance have been reported; however, molecular studies have revealed the presence of two different TSC-causing mutations in the family and the existence of germline mosaicism in others [Connor et al 1986, Webb & Osborne 1991, Rose et al 1999].

Variable expressivity. Variable expressivity occurs in part because TSC is autosomal dominant at the level of the organism but autosomal recessive at the cellular level. Both TSC1 and TSC2 have properties consistent with tumor suppressor genes functioning according to Knudson's "two hit" hypothesis [Knudson 1971]. The clinical variability results from the random nature of the second "hit" in individuals who have a germline mutation. Given that tuberin (the product of TSC2) and hamartin (the product of TSC1) are subjected to regulation through multiple cell signaling pathways, both genetic and environmental factors acting on these pathways are expected to influence the disease expression in individuals with TSC who, by definition, have only one functional copy of TSC1 or TSC2.

Anticipation

Anticipation has not been observed in TSC.

Nomenclature

Terms used in the past to describe findings in tuberous sclerosis that are now outdated or inappropriate but have not yet been eliminated from the medical literature include the following:

• Adenoma sebaceum. Used previously to describe facial lesions that are now better characterized as facial angiofibromas because the lesions have no "sebaceous" elements
• Myomata. Replaced by the more precise terms cardiac rhabdomyomas and cortical tubers
• White ash leaf spots. Used previously to describe the hypopigmented macules; now discouraged because the hypopigmented macules can be any shape or size. Hypopigmented macules of a certain size and shape are not more or less indicative of an association with tuberous sclerosis complex.
• Epiloia. Used to describe individuals with TSC and epilepsy

Prevalence

The incidence of TSC may be as high as one in 5,800 live births [Osborne et al 1991]. A high mutation rate (1:25,000) is estimated [Sampson et al 1989].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with tuberous sclerosis complex (TSC), the following evaluations were recommended by the Clinical Issues Panel at the Tuberous Sclerosis Consensus Conference in July 1998 (revision in Roach & Sparagana [2004]; click for full text):

• Medical history, especially for features of TSC
• Family history, especially for features of TSC
• Physical examination with use of a Woods lamp (ultraviolet light) in a darkened room and special attention to dermatologic findings
• Cranial CT/MRI
• Renal ultrasonography
• Ophthalmologic examination
• Electrocardiography and echocardiography if cardiac symptoms indicate
• Electroencephalography if concern for seizures is present
• Neurodevelopmental and behavioral evaluation
• Chest CT for adult females
• Medical genetics consultation

Treatment of Manifestations

Subependymal giant cell astrocytomas (SEGAs). Early identification of an enlarging giant cell astrocytoma permits medical therapy with mTOR inhibitors which were FDA approved as a treatment for enlarging giant cell astrocytomas in November 2010 after several clinical trials determined efficacy [Franz et al 2006, Krueger et al 2010]. Therapy with mTOR inhibitors obviates the need for neurosurgical intervention in many individuals.

Seizures. Early control of seizures is thought to prevent subsequent epileptic encephalopathy and reduce cognitive behavioral consequences [Muzykewicz et al 2009, Bombardieri et al 2010]. The efficacy of different treatments for infantile spasms varies among individuals. Despite earlier studies suggesting the contrary, a recent retrospective review found that vigabatrin controlled infantile spasms in 73% of children with TSC [Camposano et al 2008]. (See Prevention of Secondary Complications regarding vigabatrin therapy.)

The seizures in TSC may be resistant to polydrug therapy with anticonvulsants. A number of small studies have reported excellent results after epilepsy surgery [Avellino et al 1997, Baumgartner et al 1997, Weiner et al 1998, Romanelli et al 2002, Thiele 2004].

• Jarrar et al [2004] found that unifocal-onset seizures and mild to no developmental delay at the time of surgery predict excellent long-term outcome.
• Romanelli et al [2004] discussed the use of electroencephalographic techniques, functional neuroimaging, and invasive cortical mapping to aid the surgeon in evaluating options for surgical resection in individuals with TSC who have multifocal epileptogenic zones.
• Kagawa et al [2005] found that increased radiolabeled alpha-methyl-L-tryptophan uptake on PET scans identifies epileptogenic tubers with 83% accuracy, thus enhancing successful epilepsy surgery.
• Weiner et al [2006] used a three-staged bilateral surgical approach in 22 persons with TSC. They suggest that this approach can help identify both primary and secondary epileptogenic zones in young persons with multiple tubers.

Renal angiomyolipoma. Angiomyolipomas can become painful from hemorrhage into the tumor. Several investigators have determined that size greater than 3.5-4.0 cm in diameter is the best indicator of an angiomyolipoma that is likely to hemorrhage and thus require intervention.

It is recommended that persons with symptomatic angiomyolipomas greater than 3.5-4.0 cm be considered for prophylactic renal arterial embolization or renal sparring surgery (i.e., enucleation or partial nephrectomy) [Oesterling et al 1986, Steiner et al 1993, van Baal et al 1994].

One study suggested that angioembolization in multifocal AML was warranted to rapidly stabilize acute hemorrhage and preserve kidney function when nephrectomy was not feasible [Faddegon & So 2011].

Alternative treatments including focused ablation and pharmacologic therapies including anti-angiogenics and mTOR inhibitors may be safer and equally effective. These options are currently being explored.

Other trials have demonstrated efficacy of mTOR inhibitors for renal angiomyolipomas and LAM [Bissler et al 2008; McCormack et al 2011]. The FDA has not approved use of mTOR inhibitors for treatment of the renal and lung issues in people with TSC.

In a review of over 100 persons with renal angiomyolipomas, Sooriakumaran et al [2010] concluded that selective arterial embolization effectively controlled hemorrhage acutely, but was of limited value in long-term management of persons with TSC. A review suggested that active surveillance is a reasonable option for persons with slow-growing angiomyolipomas [Mues et al 2010]. (See Surveillance.)

LAM. LAM affects almost exclusively women of childbearing age in whom estrogen is suspected to be involved in stimulating growth of smooth muscle cells in the lung. Medroxy-progesterone treatment and/or oophorectomy reduce the production of estrogen; however, response to treatment is highly individual. Oxygen therapy is necessary with impaired lung function. Persons with severe disease require lung transplantation.

Other trials have demonstrated efficacy of mTOR inhibitors for renal angiomyolipomas and LAM [Bissler et al 2008, McCormack et al 2011]. The FDA has not approved use of mTOR inhibitors for treatment of the renal and lung issues in people with TSC.

Prevention of Secondary Complications

For those on vigabatrin therapy, visual field testing at the onset of therapy, at three-month intervals for the first 18 months, and every six months afterward is recommended because of the risk for peripheral visual field restriction [Willmore et al 2009].

Surveillance

The following routine monitoring is recommended for individuals with TSC:

• Cranial CT/MRI every one to three years for asymptomatic children and adolescents and every five years in asymptomatic adults
  
  For children and adolescents with documented subependymal nodules (SENs) routine brain imaging permits early identification and intervention before the size of tumors causes a neurosurgical emergency [Weiner et al 1998, Krueger et al 2010].
• Renal imaging:
  • Ultrasonography every one to three years in persons with no previously identified renal lesions
  • Semiannual ultrasonography in individuals with angiomyolipomas less than 3.5-4.0 cm in diameter
  • Renal CT/MRI if large or numerous renal tumors are detected by renal ultrasound examination
• Electroencephalography for seizure management as needed
• The 2005 TS Alliance Conference-generated consensus clinical guidelines on neurodevelopmental and behavioral evaluations for children with TSC [de Vries et al 2005; click for full text]:
  • Assessment of neurodevelopment and neurocognition at various times in childhood and early adulthood, each with a specific purpose (e.g., to identify autism in the first 3 years; to determine educational needs prior to school entry; to evaluate for academic progress, and emergence of ADHD and neurocognitive deficits in middle childhood; to plan transitions into secondary school and out of children’s services)
  • Assessment of neurodevelopment and neurocognition in response to rapid/sudden/unexpected changes in learning and/or behavior which are typically associated with medical issues such as SEGAs, epilepsy, angiomyolipomas, renal failure
• Echocardiography, if cardiac symptoms indicate
• Pulmonary evaluation:
  • The TS Alliance recommends a high resolution CT (HRCT) scan of all women with TSC at least once after age 18 years.
  • Routine pulmonary function tests every 6 to 12 months and HRCT scans every one to three years depending on symptoms and other clinical factors.

Note: (1) Individuals with retinal lesions seldom develop progressive visual loss; therefore, ophthalmologic evaluations beyond those required for routine health care maintenance are unnecessary. (2) Routine dermatologic evaluations are unnecessary for most individuals. Those who may benefit from treatments should be referred to an experienced specialist.

Evaluation of Relatives at Risk

Identifying affected relatives permits monitoring for early detection of problems associated with TSC, thus leading to earlier treatment and better outcomes. If the family-specific mutation is known, molecular genetic testing can be used to identify those at-risk relatives who are affected; otherwise, examination should be undertaken for the findings of TSC (see Diagnosis).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Approximately 20 clinical trials are testing the effect of drugs on manifestations of TSC. Some are already closed, others still in progress (see Clinical Trials).

SEGAs

• Oral rapamycin therapy induced regression of astrocytomas associated with TSC in five persons [Franz et al 2006]; however, some tumors returned to the pretreatment size and some increased to a size greater than pretreatment size following cessation of treatment. Subsequent resumption of rapamycin treatment resulted in tumor regression.
• A Phase I/II trial (NCT00411619) that began in 2006 to study the safety and efficacy of treatment with oral everolimus (RAD001) on giant cell astrocytoma showed marked reduction in giant cell astrocytoma volume and seizure frequency [Krueger et al 2010]. Improved quality of life was observed.

Infantile spasms. A randomized, controlled trial (NCT00441896) that began in 2007 to study the safety and efficacy of oral ganaxolone in controlling infantile spasms has been completed.

Renal angiomyolipoma. A Phase II rapamycin trial (NCT00126672) to examine safety and efficacy of sirolimus (rapamycin) on renal angiomyolipomas began in 2005.

Note: Using the natural Tsc2 mutant rat (Eker rat) model, Kenerson et al [2005] reported significant reduction of renal tumor size in rats treated with rapamycin; however, they also detected evidence for rapamycin-resistant lesions in rats with prolonged therapy.

A clinical trial in the UK showed sustained regression of renal angiomyolipomas in persons with TSC and simplex cases (i.e., a single occurrence in a family) with LAM following two years of treatment with sirolimus (rapamycin) [Davies et al 2011].

LAM

• A Phase III clinical trial (NCT00414648) between late 2006 and 2011 concluded that sirolimus (rapamycin) stabilized lung function and reduced serum VEGF-D levels in persons with LAM [McCormack et al 2011]. The study showed reduced LAM symptoms and improved quality of life in the treatment group compared to the placebo group. Discontinuation of treatment resulted in decline in lung function. Adverse events were more common with the treatment group than the placebo group; however, the frequency of serious adverse events did not differ significantly between the two groups.
• Recent clinical trials using rapamycin for treatment of renal angiomyolipomas in persons with TSC reported decrease in tumor volume during treatment, but increase in tumor volume after treatment stopped, thus requiring further treatment to control tumor growth [Bissler et al 2008, Davies et al 2008]. Lung function in persons with LAM improved in Bissler’s study, but not in Davies’ study, suggesting the need for larger multicenter trials.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Tuberous sclerosis complex (TSC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About one third of probands with TSC have an affected parent.
• Two thirds of individuals have the altered TSC1 or TSC2 gene as the result of a de novo mutation.
• Recommendations for the evaluation of parents of a child with no apparent family history of tuberous sclerosis include thorough skin examination, retinal examination, brain imaging, renal ultrasound examination, and molecular genetic testing if the disease-causing mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If a parent is affected or has the disease-causing mutation identified in the family, the risk to the sibs is 50%.
• If neither parent has any findings indicative of TSC or if neither parent has the disease-causing mutation detectable in DNA extracted from leukocytes, sibs of a proband have a 1% to 2% recurrence risk because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with tuberous sclerosis has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has the disease-causing mutation, his/her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

The penetrance of TSC1 and TSC2 mutations is thought to be 100%. However, TSC exhibits extreme variability in clinical findings both among and within families. See Penetrance.

Although some genotype-phenotype correlations are known, using results of molecular genetic testing to predict phenotype can be difficult. See Genotype-Phenotype Correlations.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who have a disease-causing mutation.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

• Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).
  
  Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• Fetal imaging studies. For families in which a disease-causing mutation has not been identified, high-resolution ultrasound examination for tumors is possible; however, its sensitivity is unknown. Fetal MRI may be of use in the evaluation of TSC in fetuses at 50% risk.
  
  Note: The cardiac tumors are generally not detected until the third trimester.

Low-risk pregnancies. When cardiac lesions consistent with rhabdomyoma are identified on fetal ultrasound examination, the risk to the fetus with no known family history of TSC of having TSC is 50%.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Molecular Genetic Pathogenesis

Most TSC1 mutations and 70% of TSC2 mutations are predicted to produce truncated protein products that fail to translate into normal proteins. Subsequently these mutations lead to uncontrolled cell growth and cell proliferation resulting in the formation of hamartias (a focal malformation consisting of disorganized arrangement of tissue types that are normally present in the anatomical area) and hamartomas [Au et al 2004].

With a few exceptions, the type of mutation (protein truncation vs missense) does not predict the severity of the phenotype.

Approximately 70% of TSC2 mutations are predicted to cause complete loss or truncation of the tuberin protein and the remaining 30% involve change of a single or a few amino acids in tuberin. A few missense mutations (e.g., p.Arg905Gln and p.Gln1503Pro) have been suggested to cause less severe disease phenotypes [Khare et al 2001, Jansen et al 2006]. Location of the TSC2 mutation does not seem to associate with disease severity.

These observations are consistent with more signal pathway kinases targeting tuberin than hamartin to dissociate the heterodimer complex, thereby releasing suppression of mTOR functions in growth and cell proliferation.

The clinical variability results in part from the random nature of the second "hit" in individuals who have a germline mutation. Additionally, because tuberin and hamartin are subjected to multiple cell signaling pathway regulation, the quantity and quality of both genetic and environmental factors targeting these pathways are expected to modify disease expression in individuals who have only one functional copy of TSC1 or TSC2.

Hamartin and tuberin form heterodimers, suggesting that they act in concert to regulate cell proliferation [Plank et al 1998, van Slegtenhorst et al 1998, Han & Sahin 2011]. Most recently, tuberin and hamartin were shown to be key regulators of the AKT pathway and to participate in several other signaling pathways including the MAPK, AMPK, b-catenin, calmodulin, MTORC1/S6Kinase, CDK, and cell cycle pathways [Kozma & Thomas 2002, Astrinidis et al 2003, El-Hashemite et al 2003, Harris & Lawrence 2003, Yeung 2003, Au et al 2004, Birchenall-Roberts et al 2004, Li et al 2004, Mak & Yeung 2004]. The hamartin tuberin complex can also regulate mTORC2 complex activity that affects cytoskeleton formation and AKT activation [Han & Sahin 2011].

Published Guidelines/Consensus Statements

1. de Vries P, Humphrey A, McCartney D, Prather P, Bolton P, Hunt A; TSC Behaviour Consensus Panel. Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis. Available online. 2005. Accessed 11-21-11. [PubMed: 15981129]
2. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. Available online. 2004. Accessed 11-18-11.

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Suggested Reading

1. Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010a;41:199–208. [PubMed: 21210335]
2. Franz DN, Krueger DA, Care MM, Holland-Bouley K, Agricola K, Tudor C, Mangeshkar P, Byars AW, Sahmoud T Everolimus for subependymal giant-cell astrocytomas (SEGAs) in tuberous sclerosis (TS). Abstract 2004. Chicago, IL: American Society of Clinical Oncology 46^th Annual Meeting. 2010b.
3. Sampson JR. Tuberous sclerosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 233. New York, NY: McGraw-Hill. Available at www​.ommbid.com. Accessed 11-18-11.
4. Steffann J, Munnich A, Bonnefont JP. Tuberous sclerosis (TSC). Atlas of Genetics and Cytogenetics Oncology and Haematology. Available at atlasgeneticsoncology.org. 2002. Accessed 11-18-11.

Revision History

• 23 November 2011 (me) Comprehensive update posted live
• 7 May 2009 (me) Comprehensive update posted live
• 5 December 2005 (me) Comprehensive update posted to live Web site
• 27 September 2004 (cd) Revision: FISH clinically available for TSC2 deletions
• 29 August 2003 (me) Comprehensive update posted to live Web site
• 3 December 2002 (bp) Revisions
• 18 April 2001 (me) Comprehensive update posted to live Web site
• 13 July 1999 (pb) Review posted to live Web site
• 5 February 1999 (hn) Original submission