SPECIAL REPORT

Cardiovascular Manifestations of Tuberous Sclerosis Complex and

Summary of the Revised Diagnostic Criteria and Surveillance and
Management Recommendations From the International Tuberous
Sclerosis Consensus Group
Robert B. Hinton, MD; Ashwin Prakash, MD; Robb L. Romp, MD; Darcy A. Krueger, MD, PhD; Timothy K. Knilans, MD

T uberous sclerosis complex (TSC) is a genetic syndrome

with a highly variable phenotype that may affect several
organ systems. The central nervous system findings were the
guidelines as they pertain to cardiology and to expand
consideration of the issues relevant to optimal cardiac care of
patients with TSC.
first to be described, and the classic triad of cognitive TSC is characterized by widespread hamartomas, or
impairment, facial angiofibromas, and seizures was delineated abnormal growth of normal tissues. Cardiac rhabdomyomas
shortly thereafter.1,2 As the variability and extent of organ are hamartomatous growths or benign tumors composed of
involvement were appreciated, diagnostic criteria evolved to cardiac myocytes, and they represent the classic neonatal
include major and minor criteria that taken together would manifestation of cardiac disease in TSC. Additional cardiac
lead to a definite, probable, or possible clinical diagnosis.3,4 diseases such as arrhythmia occur later in life, underscoring
Since the most recent refinement of the diagnostic criteria, the importance of ongoing cardiology care. Here, we review
dramatic advances have been made in understanding the what is known about the natural history of cardiac manifes-
genetic basis and pathogenesis of TSC, and new treatment tations in TSC with an emphasis on diagnostic testing,
strategies have been established, significantly affecting all surveillance, and treatment.
aspects of coordinated care for TSC patients.
The Tuberous Sclerosis Alliance (www.tsalliance.org) con-
The Revised Diagnostic Criteria Include Clinical
vened a Consensus Conference composed of 8 working
groups that generated Revised Diagnostic Criteria5 and new
Genetic Testing
Surveillance and Management Guidelines6 with the intention Significant changes have been implemented in the revised
of creating “living documents” to accommodate rapid diagnostic criteria.5 For example, clinical genetic testing has
advances and the need for coordination of care. The been added as an independent criterion, sufficient to make
conference was informed in part by a recent constituency the diagnosis of TSC. Since TSC1 and TSC2, the genes that
survey of key opinion leaders, which summarized interim encode hamartin and tuberlin, were identified as the cause
progress, areas in need of further research, unmet medical of TSC,8,9 substantial strides have been made in defining the
needs, and barriers to progress.7 The goals of this report are pathogenesis of TSC. Mutations in the genes TSC1 and TSC2
to highlight the new diagnostic criteria and management cause 75% to 90% of cases (Figure A). Given the increasing
appreciation for disease variability and an assortment of mild
disease phenotypes that may be on the TSC spectrum, the
From the Divisions of Cardiology (R.B.H., T.K.K.) and Neurology (D.A.K.),
inclusion of a molecular test represents an important change
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of in the approach to diagnosis. While approximately one-third
Cardiology, Boston Children’s Hospital, Boston, MA (A.P.); Division of Pediatric of cases have a positive family history, this has not been
Cardiology, University of Alabama at Birmingham, Birmingham, AL (R.L.R.).
included as diagnostic criteria but remains informative given
Correspondence to: Robert B. Hinton, MD, Division of Cardiology, The Heart
Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave,
the various challenges with performing genetic testing.
MLC 2003, Cincinnati, OH 45229. E-mail: [email protected] Importantly, the designation of a definite, probable, or
J Am Heart Assoc. 2014;3:e001493 doi: 10.1161/JAHA.114.001493. possible clinical diagnosis has been simplified to either
ª 2014 The Authors. Published on behalf of the American Heart Association, “definite” or “possible.” Additional changes were made in
Inc., by Wiley Blackwell. This is an open access article under the terms of the several of the clinical criteria (Table 1), and changes
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is regarding cardiovascular features are considered next in
properly cited and is not used for commercial purposes. detail.

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Tuberous Sclerosis Cardiology Consensus Guidelines Hinton et al

SPECIAL REPORT
A B C

D E F

Figure. Genetic basis, pathology, and early and late cardiovascular manifestations of TSC.
Sequencing of TSC2 demonstrates a missense mutation 1513C>T known to cause TSC (A).
Gross pathology shows a discrete well-demarcated nonencapsulated cardiac rhabdomyo-
mas with heterogeneous tissue (B). Histopathologic examination of the rhabdomyomas
demonstrates the classic finding of spider cells representing abnormal myocardial cells (C).
Echocardiography shows multiple cardiac rhabdomyomas in the ventricular myocardium
(D). ECG shows supraventricular tachycardia with aberrant conduction that can result from
cardiac rhabdomyomas or in isolation (E). MRI shows thoracoabdominal aortic aneurysm
(arrows) with tortuosity of the descending thoracic aorta (F). LA indicates left atrium; LV, left
ventricle; MRI, magnetic resonance imaging; TSC, tuberous sclerosis complex.

transition care from pediatric to adult cardiology and to

Overall Recommendations Have Shifted to maintain surveillance vigilance in adulthood.
Careful Surveillance and Early Intervention
Guidelines for the management and surveillance of TSC
patients were comprehensively addressed in a companion The Natural History and Diagnosis of TSC
article to the revised diagnostic criteria.6 Given the successful
clinical trials establishing mammalian target of rapamycin
The Natural History of Cardiac Rhabdomyomas
(mTOR) inhibition as a new pharmacologic treatment strategy, Cardiac tumors are rare, and ascertaining incidence is
a variety of surveillance issues have been considered difficult.12,13 Based on clinical studies and autopsy series,
(Tables 2 and 3). The addition of genetic testing to the primary cardiac tumors occur in 0.2% of children.14 Cardiac
diagnostic criteria has implications for screening that were rhabdomyomas are by far the most common primary cardiac
addressed as well. These recommendations affect tumor in childhood.15,16 After the advent of echocardiography,
cardiologists directly with respect to surveillance and poten- but before clinical genetic testing was available, studies
tially in rare circumstances with respect to medical therapy. estimated that up to 70% to 90% of children with rhabdo-
There is an increasing appreciation for latent cardiovascular myomas have TSC,17–19 and at least 50% of children with TSC
phenotypes, indicating a need for continued surveillance of have rhabdomyomas,18 representing a significant increase in
these patients. As the natural history of disease in the the proportion of cardiac rhabdomyomas attributed to TSC
cardiovascular system is better understood, continued care in compared with historic clinical data.20–22 In 1 study, Allan
adulthood needs to be defined, underscoring efforts to et al analyzed 52 cardiac tumor cases, among which 44 (86%)

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SPECIAL REPORT
Table 1. Revised Diagnostic Criteria for TSC increasing dramatically; therefore, it is reasonable to antici-
pate that the rate of fetal diagnosis will increase significantly.
Genetic diagnostic criteria Fetal cardiac tumors may present in utero as a mass on
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA ultrasonography, irregular heart rhythm, hydrops fetalis, or
from normal tissue is sufficient to make a definite diagnosis of TSC. A pericardial effusion. Cardiac rhabdomyomas can increase in
pathogenic mutation is defined as a mutation that clearly inactivates
the function of the TSC1 or TSC2 proteins (eg, out of frame indel or
size during the second half of gestation, and this has been
nonsense mutation), prevents protein synthesis (eg, large genomic attributed to maternal hormonal changes associated with
deletion), or is a missense mutation whose effect on protein function pregnancy. When larger tumors result in hemodynamic com-
has been established by functional assessment (www.lovd.nl/TSC1, promise in utero, intrauterine fetal demise may occur. Fetal loss
www.lovd.nl/TSC2,10,11). Other TSC1 or TSC2 variants whose effect on
has been reported to be 11% in 1 small series of 44 cases.23
function is less certain do not meet these criteria and are not sufficient
to make a definite diagnosis of TSC. Note that 10% to 25% of TSC Cardiac rhabdomyomas do not cause symptoms or hemody-
patients have no mutation identified by conventional genetic testing, namic compromise in the vast majority of patients but may
and a normal result does not exclude TSC, or have any effect on the become symptomatic shortly after birth or in the first year of
use of Clinical Diagnostic Criteria to diagnose TSC.
life. Tumors may obstruct inflow or outflow, which can cause
Clinical diagnostic criteria ventricular dysfunction and heart failure, as well as redirection
Major features of flow across the foramen ovale.19,25,26 Nearly 100% of fetuses
1. Hypomelanotic macules (≥3, at least 5-mm diameter) with multiple rhabdomyomas have TSC, underscoring the
2. Angiofibromas (≥3) or fibrous cephalic plaque practical importance of identifying additional tumors at the time
3. Ungual fibromas (≥2)
of fetal assessment for diagnosis and prognosis.17,27 In light of
emerging human genetic and molecular knowledge, it is a
4. Shagreen patch
possibility that the underlying pathogenesis of all rhabdomyo-
5. Multiple retinal hamartomas
mas is a result of a spectrum of TSC disease.
6. Cortical dysplasias* Cardiac rhabdomyomas are typically well circumscribed and
7. Subependymal nodules nonencapsulated (FigureB). Micropathologic examination dem-
8. Subependymal giant cell astrocytoma onstrates abnormal myocyte architecture, including vacuoliza-
9. Cardiac rhabdomyoma tion and pathognomonic “spider cells” (FigureC). The individual
10. Lymphangioleiomyomatosis (LAM)†
cardiac rhabdomyomas range in size from a few millimeters to
several centimeters and are multiple in number in 90% of cases.
11. Angiomyolipomas (≥2)†
There is an equal predilection for left, right. and septal ventricular
Minor features
myocardium.26,28 Tumors are typically located in the ventricles,
1. “Confetti” skin lesions where they can compromise ventricular function and on occasion
2. Dental enamel pits (>3) interfere with valve function or result in outflow obstruction.
3. Intraoral fibromas (≥2) Tumors may be located in the atria, where they can compress the
4. Retinal achromic patch coronary arteries, leading to myocardial ischemia.29
5. Multiple renal cysts
6. Nonrenal hamartomas Diagnosis of Cardiac Rhabdomyoma
Definite diagnosis: 2 major features or 1 major feature with ≥2 minor features. Possible Echocardiography is the imaging modality of choice for
diagnosis: either 1 major feature or ≥2 minor features. TSC indicates tuberous sclerosis assessing cardiac involvement in TSC. Cardiac rhabdomyo-
complex.
*Includes tubers and cerebral white matter radial migration lines. mas can be detected prenatally or postnatally. In prenatal life,
†
A combination of the 2 major clinical features LAM and angiomyolipomas without other ultrasound detection of multiple cardiac tumors is often the
features does not meet criteria for a definite diagnosis.
Reproduced with permission from Northrup et al.5 first sign of TSC.30 Typically, cardiac rhabdomyomas are
visible as multiple, echogenic, nodular masses embedded in
the ventricular myocardium, sometimes protruding into the
were rhabdomyomas.23 Tumors are diagnosed more involved chamber (FigureD). They are homogeneous and
frequently in fetal series than in postnatal series, resulting hyperechoic compared with normal myocardium. Diagnosis of
in an increased sensitivity when examining fetal echocardio- cardiac rhabdomyomas is made easily when these typical
grams.18,19 Cardiac rhabdomyomas tend to appear at 20 to features are present, but differentiation from other cardiac
30 weeks’ gestation, with the earliest diagnosis having been tumors may be difficult when there is a large solitary tumor or
made at 15 weeks at the current technical limits of ultraso- when tumors are located in an atypical location, such as the
nography,24 suggesting rhabdomyomas may be present atria. Doppler echocardiography is also useful in assessing the
earlier in development. The frequency of fetal detection is presence of obstruction to ventricular inflow or outflow.

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Table 2. Surveillance and Management Recommendations for Newly Diagnosed or Suspected TSC Summary Table

Organ System or Specialty

Area Recommendation

Genetics  Obtain 3-generation family history to assess for additional family members at risk of TSC
 Offer genetic testing for family counseling or when TSC diagnosis is in question but cannot be clinically confirmed

Brain  Perform MRI of the brain to assess for the presence of tubers, subependymal nodules (SEN), migrational defects,
and subependymal giant cell astrocytoma (SEGA)
 Evaluate for TSC-associated neuropsychiatric disorder (TAND)
 During infancy, educate parents to recognize infantile spasms, even if none have occurred at time of first diagnosis
 Obtain baseline routine electroencephalogram (EEG). If abnormal, especially if features of TAND are also present,
follow up with a 24-hour video EEG to assess for subclinical seizure activity

Kidney  Obtain MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts
 Screen for hypertension by obtaining an accurate blood pressure
 Evaluate renal function by determination of glomerular filtration rate

Lung  Perform baseline pulmonary function testing (PFT and 6-minute walk test) and high-resolution chest computed
tomography (HRCT), even if asymptomatic, in patients at risk of developing lymphangioleiomyomatosis (LAM),
typically female patients 18 years or older. Adult male patients, if symptomatic, should also undergo testing
 Provide counsel on smoking risks and estrogen use in adolescent and adult female patients

Skin  Perform a detailed clinical dermatologic inspection/examination

Teeth  Perform a detailed clinical dental inspection/examination

Heart  Consider fetal echocardiography to detect individuals with high risk of heart failure after delivery when rhabdomyomas
are identified via prenatal ultrasound
 Obtain an echocardiogram in pediatric patients, especially if <3 years old
 Obtain an ECG in all ages to assess for underlying conduction defects

Eye  Perform a complete ophthalmologic evaluation, including dilated fundoscopy, to assess for retinal lesions and visual field
deficits

MRI indicates magnetic resonance imaging; TSC, tuberous sclerosis complex.

Reproduced with permission from Krueger et al.6

Echocardiography is also used to assess ventricular function, rhabdomyomas by echocardiography, 75% to 80% are found to
which may be impaired by multiple confluent tumors. satisfy criteria for TSC postnatally.24,32,33 The presence of
Cardiac rhabdomyomas are seen readily in fetal life after multiple ventricular tumors seems to be the finding best
20 weeks of gestation and are seen in a majority of infants associated with TSC.24 The presence of a family history of
with TSC. Rhabdomyomas can enlarge significantly in size TSC also increases the likelihood of TSC.34 In fetuses with a
during gestation and may be seen later in gestation when they single ventricular tumor, only 30% satisfy criteria for TSC
are not visible prior to 20 weeks. Cardiac rhabdomyomas postnatally.24 Because a diagnosis of TSC during fetal life is
regress spontaneously in a large majority of patients during often prompted by the presence of cardiac rhabdomyomas,
the first year of life and as a result are seen with decreasing the negative predictive value of fetal echocardiography is not
frequency in patients with TSC after 2 years of age.31 There is established.
some suggestion that the incidence of identifiable cardiac
rhabdomyomas in TSC increases during adolescence,31 but In early infancy, the predictive value of echocardiography
this observation has not been validated in additional studies. is similar to that in fetal life, with 80% of infants with
cardiac rhabdomyomas eventually satisfying a diagnosis of
TSC. Conversely, 80% to 85% of children with confirmed TSC
Sensitivity and Specificity of Echocardiography to have identifiable rhabdomyomas when younger than
Identify Cardiac Rhabdomyomas 2 years.31 Beyond 2 years of age, the incidence of identi-
This varies with patient age, related to the previous fiable rhabdomyomas is significantly lower (20% to 25%),
discussion. In fetal life, of patients diagnosed with cardiac although if they are readily seen on echocardiography, the

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Table 3. Surveillance and Management Recommendations for Patients Already Diagnosed With Definite or Possible TSC Summary
Table

Organ System or Specialty

Area Recommendation

Genetics  Offer genetic testing and family counseling, if not done previously, in individuals of reproductive age or newly considering
having children

Brain  Obtain MRI of the brain every 1 to 3 years in asymptomatic TSC patients under the age of 25 years to monitor for new
occurrence of SEGA. Patients with large or growing SEGA, or with SEGA causing ventricular enlargement but still
asymptomatic, should undergo MRI more frequently and the patients and their families should be educated regarding
the potential of new symptoms. Patients with asymptomatic SEGA in childhood should continue to be imaged periodically as
adults to ensure there is no growth.
 Surgical resection should be performed for acutely symptomatic SEGA. Cerebrospinal fluid diversion (shunt) may also be
necessary. Either surgical resection or medical treatment with mTOR inhibitors may be used for growing but otherwise
asymptomatic SEGA. In determining the best treatment option, discussion of the complication risks, adverse effects, cost,
length of treatment, and potential impact on TSC-associated comorbidities should be included in the decision-making
process
 Perform screening for TAND features at least annually at each clinical visit. Perform comprehensive formal evaluation for
TAND at key developmental timepoints: infancy (0 to 3 years), preschool (3 to 6 years), pre–middle school (6 to 9 years),
adolescence (12 to 16 years), early adulthood (18 to 25 years), and as needed thereafter. Management strategies should
be based on the TAND profile of each patient and should be based on evidence-based good practice guidelines/practice
parameters for individual disorders (eg, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety disorder, etc).
Always consider the need for an individual educational program (IEP). Sudden change in behavior should prompt medical/
clinical evaluation to look at potential medical causes (eg, SEGA, seizures, renal disease, etc.)
 Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be
determined by clinical need rather than a specific defined interval. Prolonged video EEG, 24 hours or longer,
is appropriate when seizure occurrence is unclear or when unexplained sleep, behavioral changes, or other alteration
in cognitive or neurological function is present
 Vigabatrin is the recommended first-line therapy for infantile spasms. ACTH can be used if treatment with vigabatrin is
unsuccessful. Anticonvulsant therapy of other seizure types in TSC should generally follow that of other epilepsies. Epilepsy
surgery should be considered for medically refractory TSC patients, but special consideration should be given to children at
younger ages experiencing neurologic regression and is best if performed at epilepsy centers with experience and expertise
in TSC

Kidney  Obtain MRI of the abdomen to assess for the progression of angiomyolipoma and renal cystic disease every 1 to 3 years
throughout the lifetime of the patient
 Assess renal function (including determination of GFR) and blood pressure at least annually
 Embolization followed by corticosteroids is first-line therapy for angiomyolipoma presenting with acute hemorrhage.
Nephrectomy is to be avoided. For asymptomatic, growing angiomyolipoma measuring >3 cm in diameter, treatment with
an mTOR inhibitor is the recommended first-line therapy. Selective embolization or kidney-sparing resection is acceptable
second-line therapy for asymptomatic angiomyolipoma

Lung  Perform clinical screening for LAM symptoms, including exertional dyspnea and shortness of breath, at each clinic visit.
Counseling regarding smoking risk and estrogen use should be reviewed at each clinic visit for individuals at risk of LAM
 Obtain HRCT every 5 to 10 years in asymptomatic individuals at risk of LAM if there is no evidence of lung cysts on their
baseline HRCT. Individuals with lung cysts detected on HRCT should have annual pulmonary function testing (PFT and
6-minute walk) and HRCT interval reduced to every 2 to 3 years
 mTOR inhibitors may be used to treat LAM patients with moderate to severe lung disease or rapid progression. TSC
patients with LAM are candidates for lung transplantation, but TSC comorbidities may affect transplant suitability

Skin  Perform a detailed clinical dermatologic inspection/examination annually

 Rapidly changing, disfiguring, or symptomatic TSC-associated skin lesions should be treated as appropriate for the lesion
and clinical context, using approaches such as surgical excision, laser(s), or possibly topical mTOR inhibitor

Teeth  Perform a detailed clinical dental inspection/examination at minimum every 6 months and panoramic radiographs by age
7 years, if not performed previously
 Symptomatic or deforming dental lesions, oral fibromas, and bony jaw lesions should be treated with surgical excision or
curettage when present

Continued

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Table 3. Continued

Organ System or Specialty

Area Recommendation

Heart  Obtain an echocardiogram every 1 to 3 years in asymptomatic pediatric patients until regression of cardiac rhabdomyomas
is documented. More frequent or advanced diagnostic assessment may be required for symptomatic patients
 Obtain an ECG every 3 to 5 years in asymptomatic patients of all ages to monitor for conduction defects. More frequent or
advanced diagnostic assessment such as ambulatory and event monitoring may be required for symptomatic patients

Eye  Perform annual ophthalmologic evaluation in patients with previously identified ophthalmologic lesions or vision symptoms at
the baseline evaluation. More frequent assessment, including those treated with vigabatrin, is of limited benefit and not
recommended unless new clinical concerns arise

TSC indicates tuberous sclerosis complex; MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma; mTOR, mammalian target of rapamycin; TAND, TSC-associated
neuropsychiatric disorder; EEG, electroencephalography; ACTH, adrenocorticotropic hormone; LAM, lymphangioleiomyomatosis; HRCT, high-resolution chest computed tomography; PFT,
pulmonary function tests; GFR, glomerular filtration rate.
Reproduced with permission from Krueger et al.6

likelihood of TSC likely remains high. In late childhood and abnormal AV connections has also been commonly reported
adolescence (9 to 14 years of age), the incidence of cardiac and has been noted to participate in rapid potentially life-
rhabdomyomas in patients with confirmed TSC seems to threatening anomalous AV conduction during atrial fibrilla-
increase again (40%) in small series.31 It has been tion.43–45 The mechanisms of arrhythmia have often been
speculated that this may be related to hormonal changes. directly linked to the location of specific cardiac rhabdomyo-
mas.46 Indeed, abnormal AV connections associated with TSC
have been shown histologically to be directly related to
Alternative Imaging Modalities for Cardiac rhabdomyomas tumor tissue connecting the atrium to the
Rhabdomyomas ventricle, rather than a “typical” accessory pathway.
Cardiac magnetic resonance imaging (MRI) can also be used In addition to the wide range of mechanisms of arrhythmia in
to detect cardiac rhabdomyomas; however, its strength lies in these individuals, the effects of the arrhythmias can be
more specific tissue characterization.35 It can be a useful extremely varied. Isolated atrial or ventricular ectopy may
adjunct to echocardiography in situations where it is unclear remain without symptoms for a lifetime. Bradycardia, depend-
whether a cardiac tumor represents a rhabdomyoma (eg, in ing on its severity, may also remain without symptoms but may
patients with a large solitary tumor). In addition, MRI is more result in fatigue or syncope. Differentiation of fatigue related to
accurate than echocardiography in delineating the proximity bradycardia from other organ system dysfunction associated
of cardiac tumors to normal myocardium and the great with tuberous sclerosis may be challenging.47 Syncope may
vessels36,37 and therefore may be a useful adjunct to surgical also have similar presentation to “drop attacks” and other
planning once a decision to operate has been made. It can neurologic events seen with TSC. Sustained tachyarrhythmia
also provide a more reliable and reproducible estimate of may result in palpitations or, in some instances, in syncope or
ventricular systolic function. Cardiac MRI in infants and young cardiac arrest and sudden death.48 Developmentally delayed
children (<8 years of age) requires general anesthesia or individuals may not report symptomatic palpitations associated
sedation and, hence, its use should be limited by necessity. with hemodynamically stable sustained tachyarrhythmia and
may present with signs and symptoms of heart failure due to
tachycardia-mediated cardiomyopathy. Recurrent syncope may
Cardiac Arrhythmia Is a Significant Problem in be mistaken for seizures or “drop attacks,” and thus the warning
TSC signs of impending cardiac arrest may not be attended.
While arrhythmia is relatively common in individuals with TSC, The presence of a diagnosis of TSC does not alter treatment
the range of arrhythmic substrates is wide and not sufficiently recommendations for any arrhythmia. Observation and treat-
specific to form a specific diagnostic criterion. Reported cases ment of episodes of tachycardia as they occur, antiarrhythmic
of arrhythmia associated with TSC from slow to irregular to medications, catheter and surgical ablation, and implanted
fast heart rhythms. Bradycardia mechanisms have been pacemakers and defibrillators remain options for treatment as
associated with both sinus and atrioventricular (AV) nodal they do in all individuals. Catheter ablation appears to have less
dysfunction. Tachycardia mechanisms have been related to frequent success than in those without TSC, probably due to the
atrial, accessory AV connection reentrant, and ventricular size of the tumor and possible participation of the entire tumor
tachycardia.38–42 Ventricular preexcitation associated with in the arrhythmia mechanism.

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enzyme inhibition, and diuresis, may be indicated. When the
Cardiology Changes to the Diagnostic Criteria cause of heart failure is arrhythmia, then the appropriate
The presence of cardiac rhabdomyomas remains a major antiarrhythmic treatment is indicated and effective.52 How-
criterion (Table 4). There is no longer a need to specify 1 ever, when the cause of heart failure is inflow or outflow
versus >1 rhabdomyoma. Importantly, because cardiac rhab- obstruction, typically “watchful waiting” is used with the
domyomas are often the presenting manifestation of TSC, it is anticipation that most cardiac rhabdomyomas will spontane-
important to emphasize the need for pediatric cardiologists to ously regress over a period of months. If the heart failure is
initiate and facilitate the TSC evaluation. Specifically, the refractory, then surgery is indicated. When there is hemody-
pediatric cardiologist making a new diagnosis of rhabdomyo- namic compromise in the neonate, prostaglandin E may be
mas should obtain clinical genetic testing and make the initiated to stabilize the critically ill newborn. A critically ill
appropriate subspecialty referrals; typically human genetics neonate with hemodynamic compromise due to cardiac
and neurology, depending on available local resources. rhabdomyomas at the time of diagnosis should be transferred
Genetic testing practices may vary by center, prompting a to a tertiary center with cardiac intensive care infrastructure
need to be familiar with local processes and the closest and the ability to perform surgery if needed.
tertiary center with specialized care for patients with TSC.
Clinical genetic testing should be obtained in all multiple
New Treatment Modalities May Have a Role in
cardiac rhabdomyomas and most isolated or possible rhab-
domyomas. Because there is benefit to early diagnosis and
Cardiology Management
potential added morbidity to late diagnosis, a proactive mTOR inhibitors have been successfully used for TSC-associ-
approach is warranted. ated tumors in different organ systems,53–55 and limited
observations to date suggest they may also be efficacious in
reducing the size of cardiac rhabdomyomas.56,57 Because
The Management of Cardiac Manifestations mTOR inhibitors are not benign drugs and rhabdomyomas tend
of TSC to regress, therapy should be considered only in situations of
hemodynamic compromise where there is the potential to avoid
Medical Treatment for Heart Failure surgery with their use. Given the low frequency of surgical
Cardiac rhabdomyomas can lead to hemodynamic compro- resection for cardiac rhabdomyomas, it will be challenging to
mise and congestive heart failure, and while this occurrence is study in a controlled manner. However, there may be oppor-
rare, it remains one of the most frequent causes of death tunities to use mTOR inhibitors, such as sirolimus (rapamycin)
among TSC children <10 years old.49 Heart failure occurs in or everolimus, to induce tumor regression. Based on limited
2% to 5% of infants and children with TSC-associated observations, there do not appear to be significant cardiovas-
rhabdomyomas.50,51 Pharmacology-based therapy for conges- cular side effects associated with mTOR inhibitors. In general,
tive heart failure due to TSC-associated rhabdomyomas is side effects are considered manageable in adults, but because
typically not needed; however, on occasion, medical manage- mTOR inhibitors affect the immune system and cells’ ability to
ment for CHF, including digitalis, angiotensin-converting grow and proliferate, there may be an increased risk for
infections and malignant tumors over the long term. Case
Table 4. New Cardiology-Specific Recommendations for reports using sirolimus56 in the context of an infant with cardiac
Tuberous Sclerosis Complex rhabdomyomas and refractory heart failure and everolimus57 in
the context of hemodynamic instability demonstrate benefit
Cardiac rhabdomyomas remain a major diagnostic criterion and avoided surgery, suggesting that application in cases of
Echocardiogram at the time of diagnosis malignant arrhythmia may also be therapeutic and avoid the
If fetal diagnosis, then serial observation and at least 1 postnatal need for invasive intervention. More studies are needed to
echocardiogram
Surveillance studies until regression demonstrated
define the role of mTOR inhibitors in this situation, as well as for
arrhythmias, aneurysms, and latent left ventricular dysfunction.
Electrocardiogram at the time of diagnosis
Surveillance studies every 3 to 5 years
Holter monitor as indicated for appropriate signs and symptoms
Surgical Intervention for Complete or Partial
Cardiology consultation at time of diagnosis
Ongoing cardiology surveillance as indicated
Cardiac Rhabdomyoma Resection is Indicated in
Medical and surgical intervention as indicated Rare Circumstances
Referral to genetics and neurology when cardiology makes initial
Because most cardiac rhabdomyomas are asymptomatic and
diagnosis
Pediatric to adult transition plan with ongoing cardiology surveillance the natural history is spontaneous regression, surgical
resection is not required for the vast majority of infants with

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TSC. Among the 2% to 5% of cases that do present with heart and planning of prenatal and postnatal care with involvement of
failure and/or hemodynamic instability, only a small propor- specialists from maternal-fetal medicine, cardiology, and
tion require surgery.58 Surgical series have reported a rate as cardiac surgery. Even in the absence of complicating factors,
high as 20%, but this is likely a reflection of referral bias.26,59 if cardiac rhabdomyomas are diagnosed or suspected on fetal
Because the infant with heart failure requiring surgery may be echocardiography, consultation with maternal-fetal medicine
critically ill, these patients are relatively high-risk surgical and genetics is recommended to counsel the family regarding
candidates. However, partial resection is typically adequate if the likelihood of TSC and long-term prognosis. Because
complete excision would sacrifice vital structures or myocar- rhabdomyomas can enlarge during gestation, follow-up imaging
dial mass. Orthotopic heart transplantation can be considered later during gestation (30 to 35 weeks) is recommended.
in extreme cases, such as in the rare event that tumor After birth and in the first 2 years of life, echocardiography
replaces myocardium; however, the necessary medical regi- is recommended for any child with a suspected diagnosis of
men is associated with significant medical risks. Specifically, TSC, because of the high correlation between the presence of
the seizure threshold is lowered, and the risk of infection and cardiac rhabdomyomas and TSC in this age group. In addition,
malignant cancer is increased. Excellent short- and long-term hemodynamic compromise due to outflow or inflow obstruc-
results have been reported in multiple series, but cases of tion is most likely in this age group and can be easily
early death have been reported.19,25,26 To date, late fetal assessed on echocardiography. If echocardiography is con-
surgical resection has not been reported, but ex utero clusive of the diagnosis of rhabdomyomas, no further imaging
intrapartum treatment technology suggests this may be is recommended. In patients who are suspected but not
feasible in select situations. confirmed to have TSC and have a cardiac tumor on
echocardiography but the diagnosis of rhabdomyoma is
uncertain, referral to a tertiary pediatric cardiac center for
Recommedations Expand Surveillance Efforts cardiac MRI under sedation or general anesthesia should be
considered for tissue characterization. However, this decision
Cardiology Changes to Surveillance should be made jointly by experts in cardiology, neurology,
Recommendations and/or genetics to consider the risk.
Due to the rise of diagnosis on fetal echocardiography, serial In typical cases, and in the absence of inflow/outflow
imaging during gestation is now indicated to monitor disease obstruction and ventricular dysfunction, follow-up echocardi-
severity and postnatal imaging is indicated to confirm ography is not recommended in the first year of life but may
anatomy and determine the status of disease after birth. be considered once between 1 and 3 years of age to
Surveillance is now recommended until regression is demon- document regression of the tumors. Once regression of tumor
strated (Table 4). Because cardiac rhabdomyomas are often size has been documented, follow-up echocardiography is not
the presenting manifestation of TSC, it is important to recommended, unless new cardiac concerns such as arrhyth-
emphasize the need for pediatric cardiologists to make the mia or syncope arise, and, in these cases, should be
appropriate subspecialty referrals, typically human genetics performed in consultation with a pediatric cardiologist. Closer
and neurology, depending on available local resources. Given follow-up should be considered in atypical cases. In patients
the increasing appreciation for cardiology issues later in life, with inflow/outflow obstruction, ventricular dysfunction, or
including arrhythmias, ECGs are now recommended every 3 to large solitary tumors, more frequent repeat echocardiography
5 years. A lower index of suspicion is required during may be necessary and should be coordinated in consultation
adolescent ages. Importantly, increasing efforts are required with a pediatric cardiologist. In patients suspected with TS
to facilitate transition from pediatric to adult care.60 beyond 2 years of age, echocardiography should be consid-
ered although the yield is significantly lower. Echocardiogra-
phy is recommended if the physical examination is consistent
Recommendations for Imaging Surveillance with outflow tract obstruction (rare in this age group) or if
In fetal life, echocardiography is recommended if there is a there is concern for arrhythmia or syncope.
positive family history of TSC in a first-degree relative or if there
is suspicion for TSC based on other criteria. If cardiac
rhabdomyomas are identified, evaluation should include
Recommendations for Electrophysiologic
assessment for inflow or outflow obstruction that may lead to Surveillance
hemodynamic compromise postnatally, evaluation for arrhyth- All individuals with tuberous sclerosis, regardless of age,
mias and ventricular dysfunction, and evidence of hydrops should have a 12- to 15-lead ECG performed at the time of
fetalis. The presence of a complicating factor requires close diagnosis. Subsequently, in an individual with tuberous
follow-up during the pregnancy along with careful coordination sclerosis and no cardiac symptomatology, a repeat study

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Tuberous Sclerosis Cardiology Consensus Guidelines Hinton et al

SPECIAL REPORT
every 3 to 5 years may be prudent. Evaluation of symptomatic Table 5. Cardiology-Specific Future Research Directions
palpitations should include cardiac event monitoring as
appropriate. Episodes of “drop attacks” or “seizures” that Why do cardiac rhabdomyomas regress and other hamartomas do not?
cannot definitively exclude cardiac syncope should be eval- Do cardiac rhabdomyomas completely resolve?
uated with monitors with “looping” memory, either external or What is the incidence of sudden death? Malignant arrhythmia?
implanted. Particularly concerning cases of syncope or Do TSC1 and TSC2 genotypes predict cardiac phenotype or outcome?
episodes in individuals with other concerning cardiac mani-
Does treatment with mTOR inhibitors decrease the long-term risk of
festations should be evaluated with invasive cardiac electro- arrhythmia?
physiology study. What is the incidence of latent left ventricular hypertrophy and/or
Sudden deaths in individuals with TSC are reported at all dysfunction?
ages and have potentially diverse etiologies, including not only What is the incidence and natural history of lipidemia in TSC?
arrhythmia but also epilepsy, intratumor hemorrhage, obstruc-
tive hydrocephalus, and aneurysmal rupture. It remains mTOR indicates mammalian target of rapamycin; TSC, tuberous sclerosis complex.

unclear whether surveillance with ambulatory ECGs for occult

arrhythmia will be able to predict and prevent the arrhythmic inhibitor effects on the cardiovascular system. By adding
deaths. Periodic ambulatory ECGs seem prudent until the cardiac end points to longitudinal clinical studies, we will gain
question can be answered definitively. insight into various natural history questions. Some of these
issues may be addressed by using the TSC Alliance Clinical
Registry, which has collected comprehensive clinical data on
Future Research Directions and Unresolved >1000 TSC patients from 17 centers (Table 6). The TSC
Clinical Issues Alliance is organized to function as a network for this purpose
Animal Models of TSC Provide Potential Insight but requires subspecialty commitments from investigators at
large centers where TSC patients are cared for (not neces-
Into Mechanisms of Tumor Regression
sarily participating already within the Alliance), highlighting
Both TSC1- and TSC2-deficient mice are embryonic lethal with the importance of coordinated multidisciplinary care and
ventricular dysfunction potentially contributing to death.61,62 standardized approaches to care. Transitioning the patient
Heterozygous and conditional mice appear to recapitulate from pediatric to adult cardiology care remains a challenging
some of TSC phenotypes, with the Tsc2+/ mouse demon- and important goal, with a need for careful monitoring and a
strating more severe overall disease. Importantly, these mice low index of suspicion for latent manifestations of cardiovas-
are responsive to sirolimus.63 Meikle et al examined ventric- cular disease, including arrhythmias.
ular myocytes of mice with Tsc1 insufficiency (haploinsuffi- TSC is a multisystem genetic disorder characterized by
ciency) conditionally restricted to the myocardium and variable abnormalities, such that patients carrying mutations
demonstrated cardiomyopathy with cell findings reminiscent may not fulfill clinical criteria for diagnosis, raising questions
of human cardiac rhabdomyomas.64 However, most preclin- regarding familial screening. For example, does the presence
ical studies have not focused on cardiac findings, so of fetal cardiac rhabdomyomas warrant a recommendation for
evaluating the cardiac phenotype in these mice may provide family screening, which is not presently indicated? In muta-
special insight into early disease processes. For example, tion-positive children, parents and siblings can undergo
general mechanisms of hypertrophy may be elucidated.65 In specific mutation testing as screening, but in parents and
addition, because rhabdomyomas tend to regress spontane-
ously, mechanistic insights into regression may be elucidated,
Table 6. Cardiology Variables Maintained in the TSC Alliance
potentially identifying new therapeutic targets. The mice
Clinical Registry
would also provide a mechanism to preclinically test the
benefit of mTOR inhibitors controlling for regression, which Medical history, physical examination, family history
may underscore limited observations in human studies.
Current medications
ECG, CXR, echocardiogram, MRI, CT
Unresolved Issues Warrant Consideration for Pathology if available
Future Investigation Other cardiac conditions (malformation, hypertension, lipidemia,
Several unresolved issues have been identified and require aneurysm)
careful examination (Table 5). These research questions Number, size, and location of cardiac rhabdomyomas
require substantial organization. Strategies that may enhance
TSC, tuberous sclerosis complex; CXR, chest radiography; MRI, magnetic resonance
these efforts include future clinical studies examining mTOR imaging; CT, computed tomography.

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Tuberous Sclerosis Cardiology Consensus Guidelines Hinton et al

SPECIAL REPORT
siblings of phenotypically diagnosed children, it may be 6. Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus
Group. Tuberous sclerosis complex surveillance and management: recom-
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demonstrated that cardiac rhabdomyomas are more frequent characterization of the tuberous sclerosis gene on chromosome 16. Cell.
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Currently, there is insufficient evidence of absolute risks to 8. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S,
Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S,
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RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP,
cardiac disease. Variability in pathology or natural history Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ,
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will facilitate early identification and provide opportunities for 9. Whittemore VH. Unlocking a Cure for Tuberous Sclerosis Complex: An
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disease stratification and early intervention. Tuberous Sclerosis Alliance. Silver Spring, MD: Silver Springs; 2011.
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Dunnen JT, van Eeghen A, Thiele E, Mayer K, Dies K, Wen L, Thompson C,
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The authors participated in the Cardiology Working Group for 11. Hoogeveen-Westerveld M, Ekong R, Povey S, Mayer K, Lannoy N, Elmslie F,
Bebin M, Dies K, Thompson C, Sparagana SP, Davies P, van Eeghen AM, Thiele
the TSC Alliance Consensus Conference (Drs Hinton, Prakash, EA, van den Ouweland A, Halley D, Nellist M. Functional assessment of TSC2
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this report were conceived (Drs Hinton, Prakash, Romp, and
12. Marx GR, Moran AM. Cardiac tumors. In: Allen HD, Driscoll DJ, Shaddy RE,
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 Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised
Diagnostic Criteria and Surveillance and Management Recommendations From the
International Tuberous Sclerosis Consensus Group
Robert B. Hinton, Ashwin Prakash, Robb L. Romp, Darcy A. Krueger and Timothy K. Knilans

J Am Heart Assoc. 2014;3:e001493; originally published November 25, 2014;

doi: 10.1161/JAHA.114.001493
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