Tuberous Sclerosis Complex

[Bourneville Disease. Includes: Tuberous Sclerosis 1 (TSC1), Tuberous Sclerosis 2 (TSC2)]

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

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

Since the identification of the TSC2 and TSC1 genes, more than 1500 individuals with TSC and their families have had disease-causing mutations identified [Jones et al 1999, Dabora et al 2001, Au et al 2004, Sancak et al 2005, Au et al 2007]. Of all probands in whom mutations were identified, 27% had mutations in TSC1 and 73% had mutations in TSC2.

Clinical testing. Molecular genetic testing of the TSC1 and TSC2 genes is complicated by the large size of the two genes, the large number of disease-causing mutations, and the high rate of somatic mosaicism (10%-25%) [Sampson et al 1997, Verhoef et al 1999].

• Sequence analysis. 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.

  • Jones et al [1999] identified exonic and whole-gene deletions in both TSC1 and TSC2 genes and small mutations in 120 of 150 (80%) individuals with TSC, of which 130 represented simplex cases (i.e., individuals who have no family history of TSC) and 20 were familial cases.

  • In a study of 38 familial cases, 183 simplex cases, and three of unknown status, Dabora et al [2001] identified small mutations in either TSC1 or TSC2 in 166 (74%) probands.

  • Using mutation scanning and direct sequencing to screen for mutations in 325 families who met diagnostic criteria for TSC, Au et al [2007] identified 243 (75%) who had small mutations in either TSC1 or TSC2.

  • Using mutation scanning and direct sequencing, Southern blotting, and FISH analysis in 490 families with TSC, Sancak et al [2005] identified small mutations in either TSC1 or TSC2 in 342 (70%)

• Deletion/duplication analysis

  • Comparing methods to identify large exon(s)/gene deletions in 65 individuals with TSC, Rendtorff et al [2005] concluded that multiple ligation-dependent probe amplification (MLPA) is more sensitive than Southern blot analysis and long range PCR. Using MLPA, they identified large TSC2 exonic or whole-gene deletions in four of 15 (26.7%) families in which no mutation had been identified by sequence analysis and Southern blotting.

  • Using an MLPA method modified from Rendtorff et al [2005] to include all exons of both the TSC1 and TSC2 genes, Kozlowski et al [2007] estimated that large exonic/whole-gene deletion/duplication mutations account for 6.1% of all mutations seen in TSC; 5.6% were TSC2 mutations and 0.5% TSC1 mutations.

Table 1. Molecular Genetic Testing Used in Tuberous Sclerosis Complex

Gene Symbol	% of TSC Attributed to Mutations in This Gene 1	Test Method	Mutation Detection Frequency by Gene, Family History, and Test Method		Test Availability
			Familial Cases	Simplex Cases 2
TSC1	~19%	Sequence analysis	~30%	~15%	Clinical
		Deletion/ duplication analysis 3	0	~0.5%
TSC2	~60%	Sequence analysis	50%	~60%-70%	Clinical
		Deletion/ duplication analysis 3	~0.5%	~5%

1. ~20% of individuals with TSC do not have an identifiable mutation and thus cannot be classified by genetic subtype.

2. Simplex case = single occurrence in a family

3. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Because somatic mosaicism has been reported in seven of 26 (27%) families with a combined TSC/PKD (autosomal dominant polycystic kidney disease) phenotype and six of 62 (10%) probands in another series, DNA testing of other tissues (such as 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 commercial assay is available for testing somatic mosaicism.

• Sequence variants of unknown clinical significance. The interpretation of variants of unknown clinical significance, typically missense mutations, may be difficult. When a sequence variant of unknown clinical significance is detected in a simplex case, examination of DNA from both unaffected parents is recommended; detection of the same variant in one of the parents is strong evidence that it is a benign rather than a pathologic alteration. When a sequence variant of unknown clinical significance is detected in a proband with a family history of TSC, testing other affected and unaffected family members may provide evidence favoring benign vs. pathologic. See ACMG recommendations for interpretation of sequence variations (pdf).

Testing Strategy

Confirmation of the diagnosis in a proband can be accomplished with:

• 1

  Sequence analysis of TSC1 and TSC2.

• 2

  If no mutation is identified, deletion testing 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/ 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 associated with mutations in TSC1 and TSC2.

In some cases, DNA extracted from lung tissue in individuals with sporadic pulmonary lymphangioleiomyomatosis (LAM) harbors mutations of TSC2 or TSC1 not present in the germline [Smolarek et al 1998, Carsillo et al 2000, Sato et al 2002]. The role of mutations in TSC1 and TSC2 in this process is not yet fully determined. Evidence that TSC1 and TSC2 probably have a limited role in the complex process of LAM development includes:

• Only a small percentage (2.3%) of individuals with TSC develop LAM.

• Tuberin is strongly expressed in LAM tissues [Johnson et al 2002].

In some perivascular epitheloid cell tumors (PEComa), loss of either TSC2 or TSC1 has been reported [Pan et al 2008] as 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, which include subependymal glial nodules [Torres et al 1998], cortical tubers, and subependymal giant cell astrocytomas, can be distinguished with neuroimaging studies. Subependymal glial nodules occur in 90% of individuals and cortical or subcortical tubers in 70%. Goodman et al [1997] have suggested that the cortical tuber count detected on MRI may be a marker to predict the severity of cerebral dysfunction. They found moderately to severely affected individuals to be five times more likely to have more than seven cortical tubers detected on MRI than those more mildly affected. Subependymal giant cell astrocytomas 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 mental retardation. The leading cause of premature death (32.5%) among individuals with TSC is a complication of severe mental retardation (e.g., status epilepticus and bronchopneumonia).

Individuals with TSC have a great risk of neurodevelopmental and behavioral impairment. The behavioral and psychiatric disorders common in TSC include pervasive developmental disorder (PDD) and autism. Two recent literature reviews [Curatolo et al 2004, Wiznitzer 2004] suggest that about 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders depending on diagnostic tools used. Hyperactivity or attention deficit hyperactivity disorder (ADHD) and aggression are also commonly observed in 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 for 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]. Cook et al [1996] reported that three out of 136 individuals with TSC had RCCs; Patel et al [2005] identified only one RRC (0.5%) out of 206 renal masses from individuals with TSC.

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: (1) surgical intervention immediately after birth is only necessary when cardiac outflow obstruction occurs; and that (2) if cardiac outflow obstruction does not occur at birth, the individual is unlikely to have health problems from these tumors later.

Lung. Lymphangiomyomatosis of the lung is estimated to occur in 1%-6% of individuals and primarily affects women between age 20 and 40 years. Individuals 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.

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.

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. These lesions are usually asymptomatic.

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%).

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 appears 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 individuals with 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 they have a 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], Jones et al [1999] found a higher frequency of mental retardation in individuals with mutations in TSC2.

• Autistic disorder, low IQ, and infantile spasms are more frequently associated with TSC2 mutations [Lewis et al 2004].

• Strizheva et al [2001] suggested that females with mutations on the carboxy terminus of the TSC2 gene product (tuberin) may have increased incidence and/or severity of lymphangiomyomatosis [Strizheva et al 2001].

• The type of mutation (protein truncation vs missense) and the location of the mutation do not predict the severity of the phenotype in either TSC1 or TSC2. 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 the TSC2 gene and the PKD1 gene that are arranged tail to tail in close proximity on chromosome 16p13.3

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 cases of seeming non-penetrance have been reported; however, molecular studies have resolved these cases, revealing two different TSC-causing mutations in the family and the existence of germline mosaicism in others [Connor et al 1986, Webb & Osborne 1991].

Variable expressivity. Variable expressivity occurs because TSC is autosomal dominant at the level of the organism but autosomal recessive at the cellular level. Both the TSC1 and TSC2 genes 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 and hamartin 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, Panel 1, at the Tuberous Sclerosis Consensus Conference in July 1998 and revised recently [Roach & Sparagana 2004]:

• 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 seizures are present

• Neurodevelopmental and behavioral evaluation

• Chest CT for adult females

Treatment of Manifestations

CNS. Early identification of an enlarging giant cell astrocytoma permits removal before symptoms develop and before it becomes locally invasive, and is the reason for performing routine brain imaging of children and adolescents with documented subependymal nodules [Weiner et al 1998].

The efficacy of different treatment options for infantile spasms varies between individuals. Early studies suggested that more than 90% of individuals with TSC and infantile spasms did respond to vigabatrin compared to 54% of individuals without TSC [Aicardi et al 1996].

In a Cochrane Review of 11 randomized controlled trials of single drug use to treat infantile spasms, Hancock et al [2003] concluded that vigabatrin was not superior to other anticonvulsants; however, because of the insufficient number of individuals in these studies, the authors were unable to provide a statistically significant conclusion.

A retrospective study suggested levetiracetam can be used as adjunctive antiepileptic therapy in treatment of TSC [Collins et al 2006].

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.

Kidney. Several investigators have determined that the size of an angiomyolipoma is the best indicator of those tumors that are likely to be symptomatic (i.e., cause pain and/or hemorrhage) and thus require intervention. Pain usually results from hemorrhage into the tumor. Angiomyolipomas greater than 3.5 to 4.0 cm in diameter have the greatest risk of hemorrhage. It is recommended that those with symptomatic angiomyolipomas greater than 3.5 to 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].

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 are used to reduce the production of estrogen but the response to treatment is highly individual. Oxygen therapy is necessary with impaired lung function and patients with severe disease require lung transplantation.

Surveillance

The following routine follow up is recommended for individuals with TSC:

• Cranial CT/MRI every one to three years for children and adolescents

• Renal ultrasonography every one to three years in persons with no previously identified renal lesions

• Semiannual renal sonography in individuals with angiomyolipomas less than 3.5 to 4.0 cm

• Renal CT/MRI, if large or numerous renal tumors are detected by renal ultrasound examination

• Electroencephalography for seizure management as needed

• Neurodevelopmental and behavioral evaluations for children at the time of school entry and in response to educational or behavioral concerns

• Echocardiography, if cardiac symptoms indicate

• Chest CT, if pulmonary symptoms indicate

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.

Testing 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

Several clinical trials to test the effect of drugs on manifestations of TSC are underway:

Giant cell astrocytoma

• 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) began in December 2006 to study the safety and efficacy of everolimus (RAD001) on giant cell astrocytoma. Patient recruitment is ongoing.

Infantile spasms. A randomized, controlled trial (NCT00441896) began in 2007 to study the safety and efficacy of ganaxolone in controlling infantile spasms. Patient recruitment is ongoing.

Renal angiomyolipoma. A Phase II rapamycin trial (NCT00126672) began in 2005 and is to continue until 2010 to examine safety and efficacy of sirolimus on renal angiomyolipomas.

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.

LAM

• A Phase III clinical trial (NCT00414648) began in late 2006 and is to continue through 2011 to assess effects of rapamycin on pulmonary disease in those with LAM.

• Recent clinical trials using rapamycin for renal angiomyolipoma in persons with TSC and LAM 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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, Testing of Relatives at Risk for information on testing 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. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

High-risk pregnancies

• Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained from chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
  
  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 available, but 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 to have TSC is 50%.

Preimplantation genetic diagnosis (PGD) is available and has been used for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Tuberin has GTPase-activating protein functions for the small G-proteins (Rap1a and Rab5) [Xiao et al 1997] and functions as a major regulator of small G-protein Rheb and downstream pathway on protein translation, growth and cell proliferation [Inoki et al 2003].

Hamartin interacts with the ezrin-radxin-moesin (ERM) family of actin-binding proteins [Lamb et al 2000]. Hamartin also regulates the cell cycle through interacting with CDK [Astrinidis et al 2003]. Growing of neurites, synapse formation and axon development are also regulated by hamartin [Floricel et al 2007, Knox et al 2007]. In addition, hamartin was shown to be suppressed by TNFα activated IKKβ phosphorylation at Ser511 resulting in dissociation of tuberin hamartin complex, activating S6K and VEGF production [Lee et al 2007].

Hamartin and tuberin form heterodimers, suggesting that they may act in concert to regulate cell proliferation [Plank et al 1998, van Slegtenhorst et al 1998]. 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, MTOR/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].

All TSC1 mutations and 70% of TSC2 mutations are predicted to produce truncated protein products that fail to regulate protein translation and subsequently lead to uncontrolled cell growth and cell proliferation to cause a focal malformation consisting of disorganized arrangement of tissue types that are normally present in the anatomical area (hamartias) and hamartomas formation [Au et al 2004].

The type of mutation (protein truncation vs missense) does not predict the severity of the phenotype.

• Almost all TSC1 mutations are predicted to cause truncation of the hamartin protein; the location of the TSC1 mutation does not appear to associate with disease severity.

• 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. Disease severity does not seem to associate with the location of the TSC2 mutation.

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, both genetic and environmental factors targeting these pathways are expected to influence disease expression in individuals who have only one functional copy of TSC1 or TSC2.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Revision History

• 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