Clinical characteristics.

Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.

Diagnosis/testing.

The diagnosis of TSC is established in a proband with one of the following:

• Two major clinical features
• One major clinical feature and two or more minor features
• Identification of a heterozygous pathogenic variant in TSC1 or TSC2 by molecular genetic testing

Management.

Treatment of manifestations: For enlarging SEGAs: mTOR inhibitors; neurosurgery when size causes life-threatening neurologic symptoms. For seizures: vigabatrin and other anti-seizure drugs, and on occasion, epilepsy surgery. For renal angiomyolipomas >4 cm, or >3 cm and growing rapidly: mTOR inhibitors are the recommended first line of therapy with secondary therapy options being embolization, renal sparing surgery, or ablative therapy. For facial angiofibromas: topical mTOR inhibitors. For symptomatic cardiac rhabdomyomas: surgical intervention or consideration of mTOR inhibitor therapy. For LAM: mTOR inhibitors. For TSC-associated neuropsychiatric disorder (TAND): refer to a suitable professional to provide appropriate treatment, which may include ABA therapy and consideration of medication for those with ADHD.

Prevention of secondary complications: For those on vigabatrin therapy, vision testing within four weeks of therapy initiation, at three-month intervals while on treatment, and three to six months after treatment is discontinued.

Surveillance: Brain MRI every one to three years in asymptomatic individuals with TSC younger than age 25 years to monitor for new occurrence of SEGAs; those with asymptomatic SEGA in childhood should continue to be imaged periodically in adulthood; for those with large or growing SEGA or SEGA causing ventricular enlargement, more frequent brain MRIs as deemed clinically appropriate; screening for TAND at least annually with comprehensive formal evaluation for TAND at key developmental time points; EEG in asymptomatic infants every six weeks up to age 12 months, every three months up to age 24 months, and in individuals with known or suspected seizure activity; MRI of the abdomen to assess for progression of angiomyolipoma and renal cystic disease every one to three years; assess renal function (glomerular filtration rate and blood pressure) at least annually; echocardiogram every one to three years in asymptomatic infants and children with cardiac rhabdomyomas until regression is documented; clinical screening for LAM symptoms (exertional dyspnea and shortness of breath) at each clinic visit in women older than age 18 years or those who report respiratory symptoms; high-resolution computed tomography (HRCT) every five to seven years through menopause in asymptomatic individuals at risk for LAM (adult females age >18 years) who have no evidence of lung cysts on baseline HRCT examination;for those with evidence of cystic lung disease consistent with LAM, follow-up scan intervals are determined on a case-by-case basis; annual dermatologic examination; dental examination every six months; annual ophthalmology evaluation.

Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy.

Evaluation of relatives at risk: Identifying affected relatives enables monitoring for early detection of problems associated with TSC, which leads to earlier treatment and better outcomes.

Genetic counseling.

TSC is inherited in an autosomal dominant manner. Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

TSC should be suspected in individuals with either one major clinical feature or two or more minor features, as listed below.

Establishing the Diagnosis

The clinical diagnosis of TSC can be established in a proband based on clinical diagnostic criteria [Northrup et al 2021] or the molecular diagnosis can be established in a proband with a heterozygous pathogenic (or likely pathogenic) variant in TSC1 or TSC2.

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Clinical Description

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

Phenotype Correlations by Gene

TSC2 pathogenic variants produce a more severe phenotype than TSC1 pathogenic variants. A higher percentage of individuals with more severe features of TSC have a de novo TSC2 pathogenic variant versus a de novo TSC1 pathogenic variant [Au et al 2007]. Individuals representing simplex cases (i.e., a single occurrence in a family) are more likely to have a TSC2 pathogenic variant, while those with familial TSC have an almost equal proportion of TSC1 and TSC2 pathogenic variants [Au et al 2007].

Individuals with a TSC2 pathogenic variant are at greater risk for:

• Renal malignancy [Yang et al 2014]
• Intellectual disability[Kothare et al 2014]
• Autistic disorder, low IQ, and infantile spasms [Numis et al 2011]

Genotype-Phenotype Correlations

TSC2

• Females with pathogenic variants on the carboxy terminus of tuberin, the TSC2 gene product, may have increased incidence and/or severity of lymphangioleiomyomatosis [Strizheva et al 2001].
• Some pathogenic TSC2 missense variants – including but not limited to p.Arg622Trp, p.Arg905Gln, p.Ser1036Pro, p.Arg1200Trp, p.Gln1503Pro, p.Gly1579Ser, and p.Arg1713His (see Table 5) – are associated with milder disease phenotypes [Khare et al 2001, O'Connor et al 2003, Mayer et al 2004, Jansen et al 2006, Wentink et al 2012, Farach et al 2017, Fox et al 2017]. Many of the variants associated with a milder disease phenotype have been identified in individuals with a family history of TSC.
• Renal cystic disease may be more severe in individuals with small TSC2 pathogenic variants (single- to few-base pair insertions, deletions, and single-nucleotide variants).

Penetrance

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

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 1:5,800 live births [Osborne et al 1991], but is generally estimated at between 1:6000 and 1:10,000 live births [Northrup et al 2021]. A high mutation rate (1:250,000 per gene per generation) is estimated [Sampson et al 1989].

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 conditions 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 conditions from TSC.

Angiofibromas. A single facial angiofibroma or even two is not diagnostic of TSC (see Suggestive Findings). On physical examination, acne vulgaris, acne rosacea, or multiple trichoepithelioma (see CYLD Cutaneous Syndrome) can be mistaken for angiofibromas, but biopsy easily distinguishes among them.

The shagreen patch of TSC is quite specific based on location and appearance and was retained as a major diagnostic criteria for TSC. However, the diagnostic criteria has been updated to omit use of the term "connective tissue nevus" because this term encompasses a variety of skin lesions with excessive dermal connective tissue that are not necessarily associated with TSC.

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). Two or more ungual fibromas are now required as a major clinical diagnostic criterion for TSC. Ungual fibromas must be distinguished from epithelial inclusion cysts, verruca vulgaris, and infantile digital fibromatosis.

Kidneys

Renal cysts are seen commonly in the population (1%-2%), but uncommonly in individuals younger than age 30 years [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 for TSC2, leading to the conclusion that they occur as a result of loss of function of TSC2 in individuals not affected with tuberous sclerosis complex.

Lungs

Some women who have lymphangioleiomyomatosis (LAM) also have renal angiomyolipomas but no other findings of TSC. These individuals do not transmit TSC or LAM to their offspring. Individuals with LAM and renal angiomyolipomas who have no other features of TSC do not meet diagnostic criteria for TSC [Northrup et al 2013].

Heart

Infants with cardiac rhabdomyomas have a 75%-80% chance of being affected with TSC. While cardiac rhabdomyomas can be observed as an isolated finding, this is unusual. Potentially, sporadically occurring cardiac rhabdomyomas could also have a mechanism similar to the sporadic AMLs described (see Kidneys).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with tuberous sclerosis complex (TSC), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended by the International Tuberous Sclerosis Consensus Conference [Northrup et al 2021] (full text).

Treatment of Manifestations

Subependymal giant cell astrocytomas (SEGAs). Early identification of an enlarging giant cell astrocytoma permits medical therapy with mTOR inhibitors [Krueger et al 2010], which may obviate the need for neurosurgical intervention in many individuals. However, neurosurgery may still be indicated when the size of the SEGA causes life-threatening neurologic symptoms.

Seizures. Early control of seizures is thought to prevent subsequent epileptic encephalopathy and reduce cognitive behavioral consequences [Bombardieri et al 2010]. The efficacy of different treatments for infantile spasms varies among individuals; however a retrospective review found that vigabatrin controlled infantile spasms in 73% of children with TSC [Camposano et al 2008] (see Prevention of Secondary Complications). An ongoing study (see ClinicalTrials.gov) is prospectively investigating the effect of early vigabatrin treatment on developmental outcomes in babies with TSC-associated infantile spasms.

The seizures in TSC may be resistant to polydrug therapy with anticonvulsants. A number of small studies have reported excellent results after epilepsy surgery.

• Jarrar et al [2004] found that unifocal-onset seizures and mild to no developmental delay at the time of surgery predict an 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.

Initial case reports suggested a potential for mTOR inhibitors to help in the treatment of intractable epilepsy in individuals with TSC [Krueger et al 2013]. The EXIST-3 clinical trial [French et al 2016] confirmed the benefit of these therapies; EXIST-3 received FDA approval (4/10/18) as adjunctive treatment of TSC-associated partial-onset seizures.

Renal angiomyolipoma

• For asymptomatic, growing angiomyolipoma measuring >4 cm in diameter or >3 cm and growing rapidly, treatment with an mTOR inhibitor is currently recommended as the most effective first-line therapy in the short term [Davies et al 2011, Bissler et al 2013]. The demonstrated tolerability to date is far preferable to the renal damage caused by angiomyolipoma progression or surgical and embolitic/ablative therapies, though studies are still needed to confirm long-term benefits and safety [Krueger et al 2013].
• Selective embolization followed by corticosteroids, kidney-sparing resection, or ablative therapy for exophytic lesions is acceptable second-line therapy for asymptomatic angiomyolipomas [Bissler et al 2002].
• For acute hemorrhage, embolization followed by corticosteroids is more appropriate [Mourikis et al 1999]. Nephrectomy is to be avoided because of the high incidence of complications and increased risk for future renal insufficiency and end-stage renal failure, and the poor prognosis that results from chronic kidney disease.

Facial angiofibromas. Topical mTOR inhibitor formulations have been shown to be efficacious in the treatment of facial angiofibromas.

Cardiac rhabdomyomas. Previous standard of care for the treatment of newborns with cardiac rhabdomyomas resulting in life-threatening complications (i.e., outflow tract obstruction) was surgery. There have now been several reports of off-label use of mTOR inhibitors to treat cardiac rhabdomyomas in infants with TSC with encouraging results [Dogan et al 2015, Goyer et al 2015, Mlczoch et al 2015]. These reports indicate that mTOR inhibitors may be a better alternative than surgery for clinically significant cardiac rhabdomyomas.

LAM. Trials have demonstrated efficacy of mTOR inhibitors for LAM [McCormack et al 2011]. The FDA approved use of mTOR inhibitors for treatment of the lung issues in people with TSC (5/28/15). Official guidelines for diagnosis and management of LAM have been published [McCormack et al 2016, Gupta et al 2017].

TAND. Refer to a suitable professional to provide appropriate treatment, which may include ABA therapy for autism spectrum disorders and consideration of medication for those with features of ADHD.

Prevention of Secondary Complications

For those on vigabatrin therapy, vision testing is recommended within four weeks of treatment initiation, every three months during therapy, and three to six months after treatment is discontinued because of the risk for peripheral visual field restriction (Sabril^® prescribing information).

Surveillance

The following routine monitoring is recommended for individuals with TSC (adapted from Northrup et al [2021], Table 3).

Central nervous system

• Obtain MRI of the brain every one to three years in asymptomatic (i.e., having no CNS-related symptoms) individuals with TSC younger than age 25 years to monitor for new occurrence of SEGA. Those with asymptomatic SEGA in childhood should continue to be imaged periodically as adults to ensure that there is no growth.
• In affected individuals with large or growing SEGA causing ventricular enlargement who are still asymptomatic, brain MRI scans should be performed more frequently and these individuals and their families should be educated regarding the potential for new symptoms.
• Perform screening for TAND features at least annually using validated screening tools such as the TAND Checklist. Screening may be done more frequently depending on clinical needs. When any concerns are identified on screening, proceed to further evaluations by appropriate professionals to diagnose and treat the relevant TAND manifestation(s).
• Perform comprehensive formal evaluation for TAND at key developmental points: infancy (0-3 years), preschool (3-6 years), pre-middle school (6-9 years), adolescence (12-16 years), early adulthood (18-25 years), and as needed thereafter.
• Obtain routine EEG in asymptomatic infants with TSC every six weeks up to age 12 months and every three months up to age 24 months, as abnormal EEG frequently precedes onset of clinical seizures.
• Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be determined by clinical need.

Renal

• Obtain MRI of the abdomen to assess for progression of angiomyolipomas and renal cystic disease every one to three years throughout the lifetime of the affected individual.
• Assess renal function (including determination of GFR) and blood pressure at least annually.

Cardiac

• In asymptomatic infants and children with documented cardiac rhabdomyomas, obtain an echocardiogram every one to three years until regression of the cardiac rhabdomyomas is documented.
• More frequent or advanced diagnostic assessment may be required for symptomatic individuals.

Pulmonary

• Perform clinical screening (targeted history) for LAM symptoms including exertional dyspnea and shortness of breath at each clinic visit for women older than age 18 years or those who report respiratory symptoms. Counseling regarding smoking risk and estrogen use should be reviewed at each clinic visit for individuals at risk for LAM.
• Obtain a high-resolution computed tomography (HCRT) of the lungs every five to seven years through menopause in asymptomatic individuals at risk for LAM who have no evidence of lung cysts on baseline HRCT. For individuals with evidence of cystic lung disease consistent with LAM on screening chest CT, follow-up scan intervals should be determined on a case-by-case basis depending on the individual circumstances (e.g., presence or absence of symptoms, ability to perform reliable PFTs, pre-existing use of mTORis for other TSC indications, treatment response or the lack thereof, or development of other pulmonary complications).

Skin. Perform detailed clinical dermatologic inspection/exam annually.

Dental. Perform detailed clinical dental inspection/exam at minimum every six months and panoramic radiographs by age seven years, if not performed previously.

Ophthalmologic. Perform annual ophthalmologic evaluation in all affected individuals, even if there were no previously identified ophthalmologic lesions or vision symptoms at the baseline evaluation.

Agents/Circumstances to Avoid

Avoid the following:

• Smoking
• Estrogen use in adolescent and adult females
• Nephrectomy (See Treatment of Manifestations, Renal angiomyolipoma.)

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and early treatment. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal ultrasound examination) to assess for the clinical features of TSC (see Diagnosis).

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

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Many clinical trials are assessing the effect of drug therapy on the manifestations of TSC (see ClinicalTrials.gov).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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 individuals diagnosed with TSC have an affected parent.
• Two thirds of individuals with TSC have the disorder as the result of a de novo TSC1 or TSC2 pathogenic variant.
• Recommendations for the clinical and genetic evaluation of parents of a child with an apparent de novo pathogenic variant include the following:
  • Targeted molecular genetic testing if the pathogenic variant has been identified in the child
  • If the pathogenic variant has not been identified in the child, skin examination, retinal examination, brain imaging, and renal ultrasound examination of the parents to determine their clinical status
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent. 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 molecularly confirmed germline mosaicism. Of these, one pathogenic variant was in TSC1 and five in TSC2; pathogenic variants included missense and nonsense variants and a one-nucleotide insertion or deletion.
• The family history of some individuals diagnosed with TSC may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the recognition of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent is affected or has the known TSC1 or TSC2 familial pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent or the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to sibs of being affected is low (~1%-2%) but greater than that of the general population 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 TSC1 or TSC2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has the familial pathogenic variant, the parent's family members may be 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.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the TSC1 or TSC2 pathogenic variant in the family.

Considerations in families with apparent de novo pathogenic variant. When neither parent of a proband with TSC has the pathogenic variant or clinical evidence of the disorder, the TSC1 or TSC2 pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies

• Molecular genetic testing. Once the TSC1 or TSC2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for TSC are possible.
• Fetal imaging studies. For families in which a pathogenic variant 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 75%-80% [Northrup et al 2013].

Molecular Pathogenesis

Hamartin and tuberin form heterodimers, suggesting that they act in concert to regulate cell growth and proliferation [Plank et al 1998, van Slegtenhorst et al 1998, Han & Sahin 2011]. Tuberin and hamartin were shown to be key regulators of the AKT/mTOR signaling pathway and to participate in several other signaling pathways including the MAPK, AMPK, b-catenin, calmodulin, CDK, autophagy, 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, Zhang et al 2013]. The hamartin tuberin complex can also regulate mTORC2 complex activity that affects cytoskeleton formation and AKT activation [Han & Sahin 2011]. These observations are consistent with more signaling pathway kinases targeting tuberin than hamartin to destabilize the tuberin-hamartin complex, thereby releasing suppression of mTOR functions allowing protein translation, cell growth, and proliferation.

Most TSC1 pathogenic variants and 70% of TSC2 pathogenic variants are predicted to result in a loss of functional protein products. Subsequent loss of function leads 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 anatomic area) and hamartomas [Au et al 2004].

Additionally, because tuberin and hamartin are subjected to multiple cell signaling pathway regulation, the quantity and quality of both somatic pathogenic variants and environmental factors targeting these pathways are expected to modify disease expression in individuals who have only one normal germline copy of TSC1 or TSC2.

A pathogenic variant is defined as a variant that clearly inactivates the function of the TSC1 or TSC2 proteins (i.e., out-of-frame indel or nonsense variant), prevents protein synthesis (i.e., large genomic deletion), or is a pathogenic missense variant whose effect on protein function has been established by functional assessment (see LOVD Database – TSC1, LOVD Database – TSC2, Hoogeveen-Westerveld et al [2012], and Hoogeveen-Westerveld et al [2013]). Other TSC1 or TSC2 variants whose effects on function are less certain do not meet the criteria for diagnosis of TSC.

Cancer and Benign Tumors

Pulmonary lymphangioleiomyomatosis (LAM). DNA extracted from lung tissue of some individuals with sporadic LAM harbors pathogenic variants in 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]. A recent study demonstrated that not all the cells in sporadic LAM nodules contained pathogenic TSC1 or TSC2 variants; the range was 4%-60% [Badri et al 2013].

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. Six of 11 PEComas studied showed partial to complete responses to mTOR inhibitors [Dickson et al 2013].

Urothelial carcinomas. A significant proportion of urothelial carcinomas were found to have a loss-of-function somatic pathogenic variant in TSC1 and some had a somatic pathogenic variant in TSC2 [Pymar et al 2008, Sjödahl et al 2011]. These findings suggest that a significant proportion of urothelial carcinomas may respond to mTORC1 inhibitors.

Hepatocellular carcinomas. Recent reports showed that approximately 10%-20% of hepatocellular carcinomas are associated with loss-of-function somatic pathogenic variants in TSC2 and suggested that these carcinomas may respond to mTORC1 inhibitors [Huynh et al 2015, Cho et al 2016].

Revision History

• 9 December 2021 (ma) Revision: incorporated updated TSC diagnostic criteria and management guidelines from the 2021 International TSC Consensus Group
• 16 April 2020 (ma) Revision: correction to pdf
• 12 July 2018 (sw) Comprehensive update posted live
• 3 September 2015 (me) Comprehensive update posted live
• 23 November 2011 (me) Comprehensive update posted live
• 7 May 2009 (me) Comprehensive update posted live
• 5 December 2005 (me) Comprehensive update posted live
• 27 September 2004 (cd) Revision: FISH clinically available for TSC2 deletions
• 29 August 2003 (me) Comprehensive update posted live
• 3 December 2002 (bp) Revisions
• 18 April 2001 (me) Comprehensive update posted live
• 13 July 1999 (pb) Review posted live
• 5 February 1999 (hn) Original submission

Published Guidelines / Consensus Statements

• Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX., ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. an official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196:1337–48. [PMC free article: PMC5694834] [PubMed: 29140122]
• McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Available online. 2016. Accessed 6-28-22.
• Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, Krueger DA, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Available online. 2021. Accessed 6-28-22.

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