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Tuberous Sclerosis Complex

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

Summary

Disease characteristics. Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, mental retardation/developmental delay), kidney (angiomyolipomas, cysts), and heart (rhabdomyomas, arrhythmias). CNS tumors are the leading cause of morbidity and mortality, while renal disease is the second leading cause of early death.

Diagnosis/testing. The diagnosis of TSC is based on clinical findings. Two causative genes, TSC1 and TSC2, have been identified. Molecular testing for both genetic subtypes is available on a clinical basis.

Management.  Treatment of TSC includes routine brain imaging of children with subependymal nodules and removal of enlarging giant cell astrocytomas before symptoms develop. Vigabatrin and other anticonvulsants are used to treat infantile spasms; selected individuals have benefitted from epilepsy surgery. Prophylactic renal arterial embolization or renal sparing surgery is considered for individuals with angiomyolipomas greater than 3.5 to 4.0 cm to prevent pain and/or hemorrhage. Surveillance includes renal ultrasonography every one to three years and renal CT/MRI if large or numerous tumors are detected, semiannual renal sonography in individuals with small angiomyolipomas, cranial CT/MRI every one to three years, and electroencephalography for seizure management.

Genetic counseling. TSC is inherited in an autosomal dominant manner. Two-thirds of affected individuals have TSC as the result of a de novo gene mutation. The offspring of an affected individual have a 50% risk of inheriting the altered TSC gene. Prenatal testing using molecular genetic techniques is available if the disease-causing allele has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

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

• The new criteria recognize that individuals with isolated lymphangiomyomatosis who have associated renal angiomyolipomas do not have TSC [Smolarek et al 1998].
• The new criteria 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

Major Features

• Facial angiofibromas or forehead plaque
• Nontraumatic ungual or periungual fibromas
• Hypomelanotic macules (three or more)
• Shagreen patch (connective tissue nevus)
• Multiple retinal nodular hamartomas
• Cortical tuber ¹
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma, single or multiple
• Lymphangiomyomatosis ²
• Renal angiomyolipoma ²

Minor Features

• Multiple randomly distributed pits in dental enamel
• Hamartomatous rectal polyps ⁴
• Bone cysts ⁵
• Cerebral white matter radial migration lines ^1,3,5
• Gingival fibromas
• Nonrenal hamartoma ⁴
• Retinal achromic patch
• "Confetti" skin lesions
• Multiple renal cysts ⁴

1. Cerebral cortical dysplasia and cerebral white matter migration tracts occurring together are counted as one rather than two features of TSC.
2. When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis must be present before TSC is diagnosed.
3. White matter migration lines and focal cortical dysplasia are often seen in individuals with TSC; however, because these lesions can be seen independently and are relatively nonspecific, they are considered a minor diagnostic criterion for TSC [Roach & Sparagana 2004].
4. Histologic confirmation is suggested.
5. Radiographic confirmation is sufficient.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

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, over 1000 individuals with TSC and their families have had disease-causing mutations identified [Au, Rodriguez et al 1998 ; Jones et al 1999 ; Dabora et al 2001 ; Au et al 2004 ; Sancak et al 2005]. Of all probands in whom mutations were identified, 27% had mutations in TSC1 and 73% had mutations in TSC2.

Clinical uses

• Confirmatory diagnostic testing
• Prenatal diagnosis
• Determination of recurrence risk (for genetic counseling purposes)

Clinical testing

• 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 deletions and rearrangements that cannot be detected by sequence analysis.

  • Jones et al (1999) identified large deletions and subtle 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 in which the status was unknown, Dabora et al (2001) identified subtle mutations in 166 (74%) probands.
  • Using SSCA and direct sequencing to screen for mutations in 351 families, including roughly 10% that did not meet diagnostic criteria for TSC, Au et al (2004) identified subtle mutations in 219 individuals (62.4%).
  • Using SSCP, DHPLV, DGGE, direct sequencing, Southern blotting, and FISH analysis in 490 famillies with TSC, Sancak et al (2005) identified subtle mutations in 342 (70%).

  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].

• Genomic microarray analysis/FISH.  Genomic microarray analysis includes evaluation of numerous clinically relevant loci using numerous FISH-validated BAC clones for the presence or absence of the tested region of DNA. One tested region includes the TSC2 gene (~45 kb) on chromosome 16p13.3. Because of the size of the area tested, genomic microarray analysis or a single FISH probe cannot detect the majority of TSC2 gene deletions or duplications. Therefore, genomic microarray analysis or a single FISH probe is most appropriate for testing DNA from individuals who have TSC and other findings consistent with a contiguous gene deletion or duplication syndrome, and not appropriate for testing individuals who have TSC without other syndromic features.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in TSC TSC Genetic Subtype Test Method Mutation Detection Rate  1 Test Availability Familial Cases Simplex Cases TSC1 Sequence analysis ~30% ~15% Clinical TSC2 50% ~60%-70% Clinical

1. 20%-30% of individuals with TSC do not have an identifiable mutation and thus cannot be classified by genetic subtype.

Interpretation of test results used in diagnosis of individuals suspected of having TSC

• For issues to consider in interpretation of sequence analysis results, click here .
• Mosaicism for a mutation is a confounding variable in molecular testing that could result in diagnostic errors. 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%) of individuals in another series.

Testing Strategy for a Proband

Evidence suggests that a higher percentage of individuals with a more severe TSC phenotype have de novo TSC2 mutations [Jones et al 1999 ; Dabora et al 2001 ; Sancak et al 2005 ; Au & Northrup, unpublished observations].

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]. The role of the TSC1 and TSC2 genes in this process is not yet fully determined. Several lines of evidence support the conclusion that the actions of TSC1 and TSC2 are probably limited in the complex process of LAM development: (1) only a small percentage (2.3%) of individuals with TSC develop LAM [Castro et al 1995]; (2) Johnson et al (2002) demonstrated strong tuberin expression in LAM tissues.

Clinical Description

Natural History

Tuberous sclerosis complex (TSC) exhibits variability in clinical findings both among and within families. 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 fibromata (17%-87%) [Butterworth & Wilson 1941 , Nickel & Reed 1962 , Lagos & Gomez 1967 , Nevin & Pearce 1968 , Rogers 1988 , Fitzpatrick 1991 , Gomez 1991 , Haines et al 1991]. 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% [Gomez 1988 , Houser et al 1991]. 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 [Gomez 1988]. 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 [Shepherd et al 1991].

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 a l (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 [Shepherd et al 1991]. 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], oncocytoma (benign adenomatous hamartoma) (<1%), malignant angiomyolipoma (<1%), and renal cell carcinoma (<3%) [Cook et al 1996 , 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.

Renal cysts have an epithelial lining of hypertrophic hyperplastic eosinophilic cells [Stillwell et al 1987].

Some affected individuals have a combined phenotype with features of 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 renal failure [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 [Jozwiak et al 1994 , Jones et al 1999 , Dabora et al 2001 , Sancak et al 2005]. These tumors have been documented to regress with time and eventually disappear [Webb et al 1993]. 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 (2) that 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 the ages of 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) has been reported in some individuals with TSC [Kobayashi et al 2005].

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 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 contiguous gene deletion syndrome, 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 TSC1 mutations produce a less severe phenotype than TSC2 mutations [Au, Rodriguez et al 1998 ; Dabora et al 2001 ; Lewis et al 2004 ; Sancak et al 2005]. The exception is that some missense TSC2 mutations are associated with milder disease phenotypes [Khare et al 2001].

• Al-Saleem et al (1998) reported a greater risk of renal malignancy in individuals with mutations in TSC2.
• Jones et al (1997 , 1999) found a higher frequency of mental retardation in individuals with mutations in TSC2.
• Jones et al (1997 , 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.
• Autistic disorder, low IQ, and infantile spasms are more common with TSC2 mutations [Lewis et al 2004].

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 [Brook-Carter et al 1994]

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].

Penetrance

After careful, 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 nonpenetrance have been reported; however, molecular studies have resolved these cases, revealing two different TSC 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 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 , Henske et al 1995 , Carbonara et al 1996 , Sepp et al 1996]. The clinical variability occurs secondary to the random nature of the second "hit" in individuals who have a germline mutation.

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 is now discouraged because the hypopigmented macules can be any shape or size. Hypopigmented macules of a certain size and shape are no more or less indicative of an association with tuberous sclerosis
• 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].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Many of the features of tuberous sclerosis complex (TSC) are nonspecific and can be seen as isolated findings or as a feature of another disease.

Skin.   Hypopigmented macules have been observed in 0.8% of newborns in some studies and in most cases have no medical significance [Alper & Holmes 1983]. A study by Vanderhooft et al (1996) determined that three or more hypopigmented macules are much more likely to be seen in an individual who will be diagnosed with TSC. Other diseases with hypopigmented macules as part of the phenotype include vitiligo, nevus depigmentus, nevus anemicus, piebaldism, and Vogt-Koyanagi-Harada syndrome. Associated findings can usually distinguish these diseases from TSC.

A single facial angiofibroma likewise is not diagnostic of TSC. On physical examination, acne vulgaris, acne rosacea, or multiple trichoepithelioma can be mistaken for angiofibromas, but biopsy easily distinguishes among them.

The shagreen patch of TSC does not differ from other connective tissue nevi, which are rare but are seen sporadically or in families.

Ungual fibromas can result from trauma, but generally traumatic ungual fibromas are single lesions and their presence can be explained (e.g., by a particular manner of holding a golf club). Ungual fibromas must be distinguished from epithelial inclusion cysts, verruca vulgaris, and infantile digital fibromatosis.

CNS.   Multiple lesions [cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), or radial migrating lines] in the CNS are definitive features of TSC.

Kidneys.   Renal cysts are seen commonly in the population (1%-2%), but uncommonly in individuals younger than 30 years of age [Becker & Schneider 1975 , Northrup et al 1993].

Renal angiomyolipomas (AMLs) are rare tumors sometimes observed in individuals with no other medical problems. Studies have shown that such sporadic AMLs can have loss of heterozygosity (LOH) for the TSC2 gene and surrounding markers, leading to the conclusion that they occur as a result of loss of function of the TSC2 gene in individuals not affected with tuberous sclerosis.

Lungs.   Some women who have lymphangiomyomatosis (LAM) also have angiomyolipomas but no other findings of TSC. These individuals do not transmit TSC or lymphangiomyomatosis to their offspring. Individuals affected with lymphangiomyomatosis and angiomyolipomas who have no other features of TSC do not meet diagnostic criteria for TSC [Roach & Sparagana 2004].

Heart.   Infants with cardiac rhabdomyomas have a 50% chance of being affected with TSC. The other 50% have cardiac rhabdomyomas as an isolated finding. Potentially, sporadically occurring cardiac rhabdomyomas could also have a mechanism similar to the sporadic AMLs described above.

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

It is recommended that individuals suspected of having tuberous sclerosis complex (TSC) have the following initial evaluation to establish the diagnosis and to identify potential complications for timely treatment. The evaluation and management plan described below was developed 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].

More recently 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, due to an insufficient number of individuals in these studies, the authors were unable to provide a statistically significant conclusion.

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.

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 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].

Surveillance

It is recommended that individuals known to have TSC have the following routine follow-up evaluations:

• Renal ultrasonography every one to three years
• Renal CT/MRI, if large or numerous renal tumors are detected by renal ultrasound examination
• Semiannual renal sonography in individuals with angiomyolipomas less than 3.5 to 4.0 cm
• Cranial CT/MRI every one to three years for children and adolescents
• Electroencephalography for seizure management
• Neurodevelopmental and behavioral evaluations at the time of school entry and in response to educational or behavioral concerns in children
• Echocardiography, if cardiac symptoms indicate
• Chest CT, if pulmonary symptoms indicate

Individuals with retinal lesions seldom develop progressive visual loss; therefore, ophthalmologic evaluations beyond those required for routine health care maintenance are unnecessary.

Routine dermatologic evaluations are unnecessary for most individuals. Those who may benefit from treatments should be referred to an experienced specialist.

Agents/Circumstances to Avoid

None is known.

Testing of Relatives at Risk

Identifying relatives who are themselves affected permits monitoring for early detection of problems associated with TSC, thus leading to earlier treatment and better outcomes.

Therapies Under Investigation

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 phase I/II trial testing safety of rapamycin in treating AMLs in individuals with TSC, TSC with LAM, and LAM is currently underway (began July 2003) in the Tuberous Sclerosis Clinic at the Children's Hospital of the University of Cincinnati. Another clinical trial led by Dr. Frank McCormack using rapamycin for treating individuals with LAM, the Sirolimus Multicenter International Lymphangiomyomatosis Efficacy and Safety (SMILES) Trial will begin in late 2005 to assess benefits on pulmonary disease and determine changes in other TSC lesions (e.g., tubers, facial angiofibromas).

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

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 upon 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%-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 upon the genetic status of the proband's parents. If a parent is found to be affected or to have the disease-causing mutation, family members of the parent are at risk.

Related Genetic Counseling Issues

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. Thus, results from molecular genetic testing cannot be used to predict phenotype.

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 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.

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 ofgenes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 about ten to 12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

• 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.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies.  When cardiac lesions consistent with rhabdomyoma are identified on fetal ultrasound examination, the risk to the fetus of developing TSC is 50%.

Preimplantation genetic diagnosis (PGD) is available and has been utilized for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Molecular Genetic Pathogenesis

Tuberin has GTPase-activating protein functions for the small G-proteins (Rap1a and Rab5) [Wienecke et al 1995 , 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].

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 the remaining 70%-80% TSC2 mutations are predicted to produce non-functional truncated products that fail to regulate protein translation and subsequently lead to uncontrolled cell growth and cell proliferation to form hamartias and hamartomas [Au et al 2004].

Variability of TSC phenotypes can in part be explained by occurrence of different mutation types in tuberin and hamartin as suggested by genotype-phenotype correlation studies [Dabora et al 2001 ; Lewis et al 2004 ; Sancak et al 2005 ; Au et al, unpublished observations].

TSC1

Normal allelic variants: The TSC1 gene is approximately 50 kb in size and consists of 23 exons. The first two exons are non coding and alternatively spliced. The gene has no known structural homologies to other known gene families. TSC1 exhibits polymorphic variants in the coding regions and it is not known whether these variants affect the expression or function of hamartin [van Slegtenhorst et al 1997 ; Au, Pollum et al 1998].

Pathologic allelic variants: More than 300 TSC1 mutations have been identified in individuals/families with TSC [European Chromosome 16 Tuberous Sclerosis Consortium 1993 , van Slegtenhorst et al 1997 , Jones et al 1999 , Dabora et al 2001 , Au et al 2004 , Sancak et al 2005]. Most mutations are unique, but a few "warm spots" are known including specific codons in exon 15. Other mutations are scattered throughout the exons and splite sites. Mutation types by percentage are shown in Table 2 . Large