Tuberous 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
first to be described, and the classic triad of cognitive impairment, facial angiofibromas,
and seizures was delineated shortly thereafter.
As the variability and extent of organ involvement were appreciated, diagnostic criteria
evolved to include major and minor criteria that taken together would lead to a definite,
probable, or possible clinical diagnosis.
Since the most recent refinement of the diagnostic criteria, dramatic advances have
been made in understanding the genetic basis and pathogenesis of TSC, and new treatment
strategies have been established, significantly affecting all aspects of coordinated
care for TSC patients.
The Tuberous Sclerosis Alliance (www.tsalliance.org) convened a Consensus Conference
composed of 8 working groups that generated Revised Diagnostic Criteria
and new Surveillance and Management Guidelines
with the intention of creating “living documents” to accommodate rapid advances and
the need for coordination of care. The conference was informed in part by a recent
constituency survey of key opinion leaders, which summarized interim progress, areas
in need of further research, unmet medical needs, and barriers to progress.
The goals of this report are to highlight the new diagnostic criteria and management
guidelines as they pertain to cardiology and to expand consideration of the issues
relevant to optimal cardiac care of patients with TSC.
TSC is characterized by widespread hamartomas, or abnormal growth of normal tissues.
Cardiac rhabdomyomas are hamartomatous growths or benign tumors composed of cardiac
myocytes, and they represent the classic neonatal manifestation of cardiac disease
in TSC. Additional cardiac diseases such as arrhythmia occur later in life, underscoring
the importance of ongoing cardiology care. Here, we review what is known about the
natural history of cardiac manifestations in TSC with an emphasis on diagnostic testing,
surveillance, and treatment.
The Revised Diagnostic Criteria Include Clinical Genetic Testing
Significant changes have been implemented in the revised diagnostic criteria.
For example, clinical genetic testing has been added as an independent criterion,
sufficient to make the diagnosis of TSC. Since TSC1 and TSC2, the genes that encode
hamartin and tuberlin, were identified as the cause of TSC,
substantial strides have been made in defining the pathogenesis of TSC. Mutations
in the genes TSC1 and TSC2 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 inclusion of a molecular test represents an important
change in the approach to diagnosis. While approximately one‐third of cases have a
positive family history, this has not been included as diagnostic criteria but remains
informative given the various challenges with performing genetic testing. Importantly,
the designation of a definite, probable, or possible clinical diagnosis has been simplified
to either “definite” or “possible.” Additional changes were made in several of the
clinical criteria (Table 1), and changes regarding cardiovascular features are considered
next in detail.
Revised Diagnostic Criteria for TSC
Genetic diagnostic criteria
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal
tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is
defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins
(eg, out of frame indel or nonsense mutation), prevents protein synthesis (eg, large
genomic deletion), or is a missense mutation whose effect on protein function has
been established by functional assessment (www.lovd.nl/TSC1, www.lovd.nl/TSC2,
). Other TSC1 or TSC2 variants whose effect on 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 patients have no mutation identified by conventional genetic testing,
and a normal result does not exclude TSC, or have any effect on the use of Clinical
Diagnostic Criteria to diagnose TSC.
Clinical diagnostic criteria
1. Hypomelanotic macules (≥3, at least 5‐mm diameter)
2. Angiofibromas (≥3) or fibrous cephalic plaque
3. Ungual fibromas (≥2)
4. Shagreen patch
5. Multiple retinal hamartomas
6. Cortical dysplasias*
7. Subependymal nodules
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma
10. Lymphangioleiomyomatosis (LAM)*
11. Angiomyolipomas (≥2)*
1. “Confetti” skin lesions
2. Dental enamel pits (>3)
3. Intraoral fibromas (≥2)
4. Retinal achromic patch
5. Multiple renal cysts
6. Nonrenal hamartomas
Definite diagnosis: 2 major features or 1 major feature with ≥2 minor features. Possible
diagnosis: either 1 major feature or ≥2 minor features. TSC indicates tuberous sclerosis
Includes tubers and cerebral white matter radial migration lines.
A combination of the 2 major clinical features LAM and angiomyolipomas without other
features does not meet criteria for a definite diagnosis.
Reproduced with permission from Northrup et al.
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 rhabdomyomas
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.
Overall Recommendations Have Shifted to Careful Surveillance and Early Intervention
Guidelines for the management and surveillance of TSC patients were comprehensively
addressed in a companion article to the revised diagnostic criteria.
Given the successful clinical trials establishing mammalian target of rapamycin (mTOR)
inhibition as a new pharmacologic treatment strategy, a variety of surveillance issues
have been considered (Tables 2 and 3). The addition of genetic testing to the diagnostic
criteria has implications for screening that were addressed as well. These recommendations
affect cardiologists directly with respect to surveillance and potentially in rare
circumstances with respect to medical therapy. There is an increasing appreciation
for latent cardiovascular phenotypes, indicating a need for continued surveillance
of these patients. As the natural history of disease in the cardiovascular system
is better understood, continued care in adulthood needs to be defined, underscoring
efforts to transition care from pediatric to adult cardiology and to maintain surveillance
vigilance in adulthood.
Surveillance and Management Recommendations for Newly Diagnosed or Suspected TSC Summary
Organ System or Specialty Area
Obtain 3‐generation family history to assess for additional family members at risk
Offer genetic testing for family counseling or when TSC diagnosis is in question but
cannot be clinically confirmed
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
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
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
Perform a detailed clinical dermatologic inspection/examination
Perform a detailed clinical dental inspection/examination
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
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.
Surveillance and Management Recommendations for Patients Already Diagnosed With Definite
or Possible TSC Summary Table
Organ System or Specialty Area
Offer genetic testing and family counseling, if not done previously, in individuals
of reproductive age or newly considering having children
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
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
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
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
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
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
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
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.
The Natural History and Diagnosis of TSC
The Natural History of Cardiac Rhabdomyomas
Cardiac tumors are rare, and ascertaining incidence is difficult.
Based on clinical studies and autopsy series, primary cardiac tumors occur in 0.2%
Cardiac rhabdomyomas are by far the most common primary cardiac tumor in childhood.
After the advent of echocardiography, but before clinical genetic testing was available,
studies estimated that up to 70% to 90% of children with rhabdomyomas have TSC,
and at least 50% of children with TSC have rhabdomyomas,
representing a significant increase in the proportion of cardiac rhabdomyomas attributed
to TSC compared with historic clinical data.
In 1 study, Allan et al analyzed 52 cardiac tumor cases, among which 44 (86%) were
Tumors are diagnosed more frequently in fetal series than in postnatal series, resulting
in an increased sensitivity when examining fetal echocardiograms.
Cardiac rhabdomyomas tend to appear at 20 to 30 weeks' gestation, with the earliest
diagnosis having been made at 15 weeks at the current technical limits of ultrasonography,
suggesting rhabdomyomas may be present earlier in development. The frequency of fetal
detection is increasing dramatically; therefore, it is reasonable to anticipate that
the rate of fetal diagnosis will increase significantly.
Fetal cardiac tumors may present in utero as a mass on ultrasonography, irregular
heart rhythm, hydrops fetalis, or pericardial effusion. Cardiac rhabdomyomas can increase
in size during the second half of gestation, and this has been attributed to maternal
hormonal changes associated with pregnancy. When larger tumors result in hemodynamic
compromise in utero, intrauterine fetal demise may occur. Fetal loss has been reported
to be ≈11% in 1 small series of 44 cases.
Cardiac rhabdomyomas do not cause symptoms or hemodynamic compromise in the vast majority
of patients but may become symptomatic shortly after birth or in the first year of
life. Tumors may obstruct inflow or outflow, which can cause ventricular dysfunction
and heart failure, as well as redirection of flow across the foramen ovale.
Nearly 100% of fetuses with multiple rhabdomyomas have TSC, underscoring the practical
importance of identifying additional tumors at the time of fetal assessment for diagnosis
In light of emerging human genetic and molecular knowledge, it is a possibility that
the underlying pathogenesis of all rhabdomyomas is a result of a spectrum of TSC disease.
Cardiac rhabdomyomas are typically well circumscribed and nonencapsulated (FigureB).
Micropathologic examination demonstrates abnormal myocyte architecture, including
vacuolization and pathognomonic “spider cells” (FigureC). The individual cardiac rhabdomyomas
range in size from a few millimeters to several centimeters and are multiple in number
in 90% of cases. There is an equal predilection for left, right. and septal ventricular
Tumors are typically located in the ventricles, where they can compromise ventricular
function and on occasion interfere with valve function or result in outflow obstruction.
Tumors may be located in the atria, where they can compress the coronary arteries,
leading to myocardial ischemia.
Diagnosis of Cardiac Rhabdomyoma
Echocardiography is the imaging modality of choice for assessing cardiac involvement
in TSC. Cardiac rhabdomyomas can be detected prenatally or postnatally. In prenatal
life, ultrasound detection of multiple cardiac tumors is often the first sign of TSC.
Typically, cardiac rhabdomyomas are visible as multiple, echogenic, nodular masses
embedded in the ventricular myocardium, sometimes protruding into the involved chamber
(FigureD). They are homogeneous and hyperechoic compared with normal myocardium. Diagnosis
of cardiac rhabdomyomas is made easily when these typical features are present, but
differentiation from other cardiac tumors may be difficult when there is a large solitary
tumor or when tumors are located in an atypical location, such as the atria. Doppler
echocardiography is also useful in assessing the presence of obstruction to ventricular
inflow or outflow. Echocardiography is also used to assess ventricular function, which
may be impaired by multiple confluent tumors.
Cardiac rhabdomyomas are seen readily in fetal life after 20 weeks of gestation and
are seen in a majority of infants with TSC. Rhabdomyomas can enlarge significantly
in size during gestation and may be seen later in gestation when they are not visible
prior to 20 weeks. Cardiac rhabdomyomas regress spontaneously in a large majority
of patients during the first year of life and as a result are seen with decreasing
frequency in patients with TSC after 2 years of age.
There is some suggestion that the incidence of identifiable cardiac rhabdomyomas in
TSC increases during adolescence,
but this observation has not been validated in additional studies.
Sensitivity and Specificity of Echocardiography to Identify Cardiac Rhabdomyomas
This varies with patient age, related to the previous discussion. In fetal life, of
patients diagnosed with cardiac rhabdomyomas by echocardiography, 75% to 80% are found
to satisfy criteria for TSC postnatally.
The presence of multiple ventricular tumors seems to be the finding best associated
The presence of a family history of TSC also increases the likelihood of TSC.
In fetuses with a single ventricular tumor, only 30% satisfy criteria for TSC postnatally.
Because a diagnosis of TSC during fetal life is often prompted by the presence of
cardiac rhabdomyomas, the negative predictive value of fetal echocardiography is not
In early infancy, the predictive value of echocardiography 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 have identifiable rhabdomyomas
when younger than 2 years.
Beyond 2 years of age, the incidence of identifiable rhabdomyomas is significantly
lower (≈20% to 25%), although if they are readily seen on echocardiography, the likelihood
of TSC likely remains high. In late childhood and adolescence (9 to 14 years of age),
the incidence of cardiac rhabdomyomas in patients with confirmed TSC seems to increase
again (≈40%) in small series.
It has been speculated that this may be related to hormonal changes.
Alternative Imaging Modalities for Cardiac Rhabdomyomas
Cardiac magnetic resonance imaging (MRI) can also be used to detect cardiac rhabdomyomas;
however, its strength lies in more specific tissue characterization.
It can be a useful adjunct to echocardiography in situations where it is unclear whether
a cardiac tumor represents a rhabdomyoma (eg, in patients with a large solitary tumor).
In addition, MRI is more accurate than echocardiography in delineating the proximity
of cardiac tumors to normal myocardium and the great vessels
and therefore may be a useful adjunct to surgical planning once a decision to operate
has been made. It can also provide a more reliable and reproducible estimate of ventricular
systolic function. Cardiac MRI in infants and young children (<8 years of age) requires
general anesthesia or sedation and, hence, its use should be limited by necessity.
Cardiac Arrhythmia Is a Significant Problem in TSC
While arrhythmia is relatively common in individuals with TSC, the range of arrhythmic
substrates is wide and not sufficiently specific to form a specific diagnostic criterion.
Reported cases of arrhythmia associated with TSC from slow to irregular to fast heart
rhythms. Bradycardia mechanisms have been associated with both sinus and atrioventricular
(AV) nodal dysfunction. Tachycardia mechanisms have been related to atrial, accessory
AV connection reentrant, and ventricular tachycardia.
Ventricular preexcitation associated with abnormal AV connections has also been commonly
reported and has been noted to participate in rapid potentially life‐threatening anomalous
AV conduction during atrial fibrillation.
The mechanisms of arrhythmia have often been directly linked to the location of specific
Indeed, abnormal AV connections associated with TSC have been shown histologically
to be directly related to rhabdomyomas tumor tissue connecting the atrium to the ventricle,
rather than a “typical” accessory pathway.
In addition to the wide range of mechanisms of arrhythmia in these individuals, the
effects of the arrhythmias can be extremely varied. Isolated atrial or ventricular
ectopy may remain without symptoms for a lifetime. Bradycardia, depending on its severity,
may also remain without symptoms but may result in fatigue or syncope. Differentiation
of fatigue related to bradycardia from other organ system dysfunction associated with
tuberous sclerosis may be challenging.
Syncope may also have similar presentation to “drop attacks” and other neurologic
events seen with TSC. Sustained tachyarrhythmia may result in palpitations or, in
some instances, in syncope or cardiac arrest and sudden death.
Developmentally delayed individuals may not report symptomatic palpitations associated
with hemodynamically stable sustained tachyarrhythmia and may present with signs and
symptoms of heart failure due to tachycardia‐mediated cardiomyopathy. Recurrent syncope
may be mistaken for seizures or “drop attacks,” and thus the warning signs of impending
cardiac arrest may not be attended.
The presence of a diagnosis of TSC does not alter treatment recommendations for any
arrhythmia. Observation and treatment of episodes of tachycardia as they occur, antiarrhythmic
medications, catheter and surgical ablation, and implanted pacemakers and defibrillators
remain options for treatment as they do in all individuals. Catheter ablation appears
to have less frequent success than in those without TSC, probably due to the size
of the tumor and possible participation of the entire tumor in the arrhythmia mechanism.
Cardiology Changes to the Diagnostic Criteria
The presence of cardiac rhabdomyomas remains a major criterion (Table 4). There is
no longer a need to specify 1 versus >1 rhabdomyoma. Importantly, because cardiac
rhabdomyomas are often the presenting manifestation of TSC, it is important to emphasize
the need for pediatric cardiologists to initiate and facilitate the TSC evaluation.
Specifically, the pediatric cardiologist making a new diagnosis of rhabdomyomas should
obtain clinical genetic testing and make the appropriate subspecialty referrals; typically
human genetics and neurology, depending on available local resources. Genetic testing
practices may vary by center, prompting a need to be familiar with local processes
and the closest tertiary center with specialized care for patients with TSC. Clinical
genetic testing should be obtained in all multiple cardiac rhabdomyomas and most isolated
or possible rhabdomyomas. Because there is benefit to early diagnosis and potential
added morbidity to late diagnosis, a proactive approach is warranted.
New Cardiology‐Specific Recommendations for Tuberous Sclerosis Complex
Cardiac rhabdomyomas remain a major diagnostic criterion
Echocardiogram at the time of diagnosisIf fetal diagnosis, then serial observation
and at least 1 postnatal echocardiogramSurveillance studies until regression demonstrated
Electrocardiogram at the time of diagnosisSurveillance studies every 3 to 5 yearsHolter
monitor as indicated for appropriate signs and symptoms
Cardiology consultation at time of diagnosisOngoing cardiology surveillance as indicatedMedical
and surgical intervention as indicatedReferral to genetics and neurology when cardiology
makes initial diagnosisPediatric to adult transition plan with ongoing cardiology
The Management of Cardiac Manifestations of TSC
Medical Treatment for Heart Failure
Cardiac rhabdomyomas can lead to hemodynamic compromise and congestive heart failure,
and while this occurrence is rare, it remains one of the most frequent causes of death
among TSC children <10 years old.
Heart failure occurs in 2% to 5% of infants and children with TSC‐associated rhabdomyomas.
Pharmacology‐based therapy for congestive heart failure due to TSC‐associated rhabdomyomas
is typically not needed; however, on occasion, medical management for CHF, including
digitalis, angiotensin‐converting enzyme inhibition, and diuresis, may be indicated.
When the cause of heart failure is arrhythmia, then the appropriate antiarrhythmic
treatment is indicated and effective.
However, when the cause of heart failure is inflow or outflow obstruction, typically
“watchful waiting” is used with the anticipation that most cardiac rhabdomyomas will
spontaneously regress over a period of months. If the heart failure is refractory,
then surgery is indicated. When there is hemodynamic compromise in the neonate, prostaglandin
E may be initiated to stabilize the critically ill newborn. A critically ill neonate
with hemodynamic compromise due to cardiac rhabdomyomas at the time of diagnosis should
be transferred to a tertiary center with cardiac intensive care infrastructure and
the ability to perform surgery if needed.
New Treatment Modalities May Have a Role in Cardiology Management
mTOR inhibitors have been successfully used for TSC‐associated tumors in different
and limited observations to date suggest they may also be efficacious in reducing
the size of cardiac rhabdomyomas.
Because mTOR inhibitors are not benign drugs and rhabdomyomas tend to regress, therapy
should be considered only in situations of hemodynamic compromise where there is the
potential to avoid surgery with their use. Given the low frequency of surgical resection
for cardiac rhabdomyomas, it will be challenging to study in a controlled manner.
However, there may be opportunities to use mTOR inhibitors, such as sirolimus (rapamycin)
or everolimus, to induce tumor regression. Based on limited observations, there do
not appear to be significant cardiovascular side effects associated with mTOR inhibitors.
In general, side effects are considered manageable in adults, but because mTOR inhibitors
affect the immune system and cells' ability to grow and proliferate, there may be
an increased risk for infections and malignant tumors over the long term. Case reports
in the context of an infant with cardiac rhabdomyomas and refractory heart failure
in the context of hemodynamic instability demonstrate benefit and avoided surgery,
suggesting that application in cases of malignant arrhythmia may also be therapeutic
and avoid the need for invasive intervention. More studies are needed to define the
role of mTOR inhibitors in this situation, as well as for arrhythmias, aneurysms,
and latent left ventricular dysfunction.
Surgical Intervention for Complete or Partial Cardiac Rhabdomyoma Resection is Indicated
in Rare Circumstances
Because most cardiac rhabdomyomas are asymptomatic and the natural history is spontaneous
regression, surgical resection is not required for the vast majority of infants with
TSC. Among the 2% to 5% of cases that do present with heart failure and/or hemodynamic
instability, only a small proportion require surgery.
Surgical series have reported a rate as high as 20%, but this is likely a reflection
of referral bias.
Because the infant with heart failure requiring surgery may be critically ill, these
patients are relatively high‐risk surgical candidates. However, partial resection
is typically adequate if complete excision would sacrifice vital structures or myocardial
mass. Orthotopic heart transplantation can be considered in extreme cases, such as
in the rare event that tumor replaces myocardium; however, the necessary medical regimen
is associated with significant medical risks. Specifically, the seizure threshold
is lowered, and the risk of infection and malignant cancer is increased. Excellent
short‐ and long‐term results have been reported in multiple series, but cases of early
death have been reported.
To date, late fetal surgical resection has not been reported, but ex utero intrapartum
treatment technology suggests this may be feasible in select situations.
Recommedations Expand Surveillance Efforts
Cardiology Changes to Surveillance Recommendations
Due to the rise of diagnosis on fetal echocardiography, serial imaging during gestation
is now indicated to monitor disease severity and postnatal imaging is indicated to
confirm anatomy and determine the status of disease after birth. Surveillance is now
recommended until regression is demonstrated (Table 4). Because cardiac rhabdomyomas
are often the presenting manifestation of TSC, it is important to emphasize the need
for pediatric cardiologists to make the appropriate subspecialty referrals, typically
human genetics and neurology, depending on available local resources. Given the increasing
appreciation for cardiology issues later in life, including arrhythmias, ECGs are
now recommended every 3 to 5 years. A lower index of suspicion is required during
adolescent ages. Importantly, increasing efforts are required to facilitate transition
from pediatric to adult care.
Recommendations for Imaging Surveillance
In fetal life, echocardiography is recommended if there is a 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 assessment
for inflow or outflow obstruction that may lead to hemodynamic compromise postnatally,
evaluation for arrhythmias and ventricular dysfunction, and evidence of hydrops fetalis.
The presence of a complicating factor requires close follow‐up during the pregnancy
along with careful coordination and planning of prenatal and postnatal care with involvement
of specialists from maternal‐fetal medicine, cardiology, and cardiac surgery. Even
in the absence of complicating factors, if cardiac rhabdomyomas are diagnosed or suspected
on fetal echocardiography, consultation with maternal‐fetal medicine and genetics
is recommended to counsel the family regarding the likelihood of TSC and long‐term
prognosis. Because rhabdomyomas can enlarge during gestation, follow‐up imaging later
during gestation (30 to 35 weeks) is recommended.
After birth and in the first 2 years of life, echocardiography is recommended for
any child with a suspected diagnosis of TSC, because of the high correlation between
the presence of cardiac rhabdomyomas and TSC in this age group. In addition, hemodynamic
compromise due to outflow or inflow obstruction is most likely in this age group and
can be easily assessed on echocardiography. If echocardiography is conclusive of the
diagnosis of rhabdomyomas, no further imaging is recommended. In patients who are
suspected but not 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 cardiac MRI under sedation or general anesthesia should be considered for
tissue characterization. However, this decision should be made jointly by experts
in cardiology, neurology, and/or genetics to consider the risk.
In typical cases, and in the absence of inflow/outflow obstruction and ventricular
dysfunction, follow‐up echocardiography is not recommended in the first year of life
but may be considered once between 1 and 3 years of age to document regression of
the tumors. Once regression of tumor size has been documented, follow‐up echocardiography
is not recommended, unless new cardiac concerns such as arrhythmia or syncope arise,
and, in these cases, should be performed in consultation with a pediatric cardiologist.
Closer follow‐up should be considered in atypical cases. In patients with inflow/outflow
obstruction, ventricular dysfunction, or large solitary tumors, more frequent repeat
echocardiography may be necessary and should be coordinated in consultation with a
pediatric cardiologist. In patients suspected with TS beyond 2 years of age, echocardiography
should be considered although the yield is significantly lower. Echocardiography is
recommended if the physical examination is consistent with outflow tract obstruction
(rare in this age group) or if there is concern for arrhythmia or syncope.
Recommendations for Electrophysiologic Surveillance
All individuals with tuberous sclerosis, regardless of age, should have a 12‐ to 15‐lead
ECG performed at the time of diagnosis. Subsequently, in an individual with tuberous
sclerosis and no cardiac symptomatology, a repeat study every 3 to 5 years may be
prudent. Evaluation of symptomatic palpitations should include cardiac event monitoring
as appropriate. Episodes of “drop attacks” or “seizures” that cannot definitively
exclude cardiac syncope should be evaluated with monitors with “looping” memory, either
external or implanted. Particularly concerning cases of syncope or episodes in individuals
with other concerning cardiac manifestations should be evaluated with invasive cardiac
Sudden deaths in individuals with TSC are reported at all ages and have potentially
diverse etiologies, including not only arrhythmia but also epilepsy, intratumor hemorrhage,
obstructive hydrocephalus, and aneurysmal rupture. It remains unclear whether surveillance
with ambulatory ECGs for occult arrhythmia will be able to predict and prevent the
arrhythmic deaths. Periodic ambulatory ECGs seem prudent until the question can be
Future Research Directions and Unresolved Clinical Issues
Animal Models of TSC Provide Potential Insight Into Mechanisms of Tumor Regression
Both TSC1‐ and TSC2‐deficient mice are embryonic lethal with ventricular dysfunction
potentially contributing to death.
Heterozygous and conditional mice appear to recapitulate some of TSC phenotypes, with
mouse demonstrating more severe overall disease. Importantly, these mice are responsive
Meikle et al examined ventricular myocytes of mice with Tsc1 insufficiency (haploinsufficiency)
conditionally restricted to the myocardium and demonstrated cardiomyopathy with cell
findings reminiscent of human cardiac rhabdomyomas.
However, most preclinical studies have not focused on cardiac findings, so evaluating
the cardiac phenotype in these mice may provide special insight into early disease
processes. For example, general mechanisms of hypertrophy may be elucidated.
In addition, because rhabdomyomas tend to regress spontaneously, mechanistic insights
into regression may be elucidated, potentially identifying new therapeutic targets.
The mice would also provide a mechanism to preclinically test the benefit of mTOR
inhibitors controlling for regression, which may underscore limited observations in
Unresolved Issues Warrant Consideration for Future Investigation
Several unresolved issues have been identified and require careful examination (Table
5). These research questions require substantial organization. Strategies that may
enhance these efforts include future clinical studies examining mTOR inhibitor effects
on the cardiovascular system. By adding cardiac end points to longitudinal clinical
studies, we will gain 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 >1000 TSC patients from 17 centers (Table 6). The TSC
Alliance is organized to function as a network for this purpose but requires subspecialty
commitments from investigators at large centers where TSC patients are cared for (not
necessarily participating already within the Alliance), highlighting the importance
of coordinated multidisciplinary care and standardized approaches to care. Transitioning
the patient from pediatric to adult cardiology care remains a challenging and important
goal, with a need for careful monitoring and a low index of suspicion for latent manifestations
of cardiovascular disease, including arrhythmias.
Cardiology‐Specific Future Research Directions
Why do cardiac rhabdomyomas regress and other hamartomas do not?
Do cardiac rhabdomyomas completely resolve?
What is the incidence of sudden death? Malignant arrhythmia?
Do TSC1 and TSC2 genotypes predict cardiac phenotype or outcome?
Does treatment with mTOR inhibitors decrease the long‐term risk of arrhythmia?
What is the incidence of latent left ventricular hypertrophy and/or dysfunction?
What is the incidence and natural history of lipidemia in TSC?
mTOR indicates mammalian target of rapamycin; TSC, tuberous sclerosis complex.
Cardiology Variables Maintained in the TSC Alliance Clinical Registry
Medical history, physical examination, family history
ECG, CXR, echocardiogram, MRI, CT
Pathology if available
Other cardiac conditions (malformation, hypertension, lipidemia, aneurysm)
Number, size, and location of cardiac rhabdomyomas
TSC, tuberous sclerosis complex; CXR, chest radiography; MRI, magnetic resonance imaging;
CT, computed tomography.
TSC is a multisystem genetic disorder characterized by variable abnormalities, such
that patients carrying mutations may not fulfill clinical criteria for diagnosis,
raising questions regarding familial screening. For example, does the presence of
fetal cardiac rhabdomyomas warrant a recommendation for family screening, which is
not presently indicated? In mutation‐positive children, parents and siblings can undergo
specific mutation testing as screening, but in parents and siblings of phenotypically
diagnosed children, it may be prudent to perform ECG in parents and both ECG and echocardiography
in children <3 years old. Some studies have demonstrated that cardiac rhabdomyomas
are more frequent in those with TSC2 (54%) versus TSC1 (20%) mutations.
Currently, there is insufficient evidence of absolute risks to recommend surveillance
by TSC1‐ and TSC2‐associated cardiac disease. Variability in pathology or natural
history based on presentation with TSC1 and TSC2 mutations is unclear but potentially
clinically significant. Genetic testing will facilitate early identification and provide
opportunities for disease stratification and early intervention.
The authors participated in the Cardiology Working Group for the TSC Alliance Consensus
Conference (Drs Hinton, Prakash, Romp, and Knilans), from which the concept and design
for this report were conceived (Drs Hinton, Prakash, Romp, and Knilans). The manuscript
was drafted by Drs Hinton, Prakash, and Knilans and revised by Drs Hinton, Prakash,
Romp, Knilans, and Krueger. All authors approved the final manuscript.