Tuberous Sclerosis Complex (TSC)

Overview

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous condition in which benign tumors (called hamartomas) grow in the brain, kidneys, heart, eyes, lungs, and skin.

Child with tuberous sclerosis complex (TSC) and angiofibromas

Although the tumors are generally benign, they may cause medical complications due to their locations. Skin abnormalities, seizures, developmental delay, intellectual disability, autism spectrum disorder, and behavior problems are common in individuals with TSC. Although children are born with TSC, signs and symptoms may not be apparent until months or years after birth, and diagnosis may be delayed unless there is a strong family history or a cardiac rhabdomyoma is large enough to cause symptoms in an infant. Skin abnormalities also may lead to the diagnosis. A high variability of clinical expressivity exists among families and even within the same family.

Other Names & Coding

Bourneville disease

ICD-10 coding

Q85.1, Tuberous sclerosis

ICD-10 for Tuberous Sclerosis (icd10data.com) provides further coding details.

Prevalence

The prevalence of TSC is about 1:20,000. [Northrup: 2013] If undiagnosed cases are taken into account, the actual prevalence could be around 1:10,000, or even higher, especially in the pediatric population. [O'Callaghan: 1998] [Hong: 2016]

Genetics

TSC is inherited in an autosomal dominant manner. The identification of a pathogenic mutation in either TSC1 or TSC2 confirms the diagnosis. A pathogenic mutation in either gene can be detected in up to 90% of affected individuals using a combination of Next Generation Sequencing (NGS) techniques and deletion/duplication analysis. [Peron: 2018] However, a pathogenic mutation is not identifiable in up to 10% of individuals who fulfill clinical diagnostic criteria. It is therefore important to remember that a negative genetic test does not exclude the diagnosis. Approximately 1/3 of children with TSC have a family history; the remaining 2/3 of children are thought to have TSC resulting from spontaneous mutations. The protein products of TSC1 and TSC2 interact in various signaling functions in cells that are important in regulating cell proliferation and growth (the mTOR pathway). TSC1, located on chromosome 9, encodes hamartin; TSC2, located on chromosome 16, encodes tuberin. Tuberin and hamartin interact with other intracellular proteins associated with various signaling pathways important in regulating cell proliferation and growth (the mTOR pathway).
Mutations in TSC2 are more common than in TSC1 and are generally associated with more severe clinical presentations, although exceptions exist. [Peron: 2018] [Orlova: 2010] In families with TSC, mild and severe cases may appear within the same generation. Parents of a child with TSC could harbor a mutation of 1 of the 2 genes but not fulfill clinical diagnostic criteria. This reflects the variability of clinical expressivity of TSC and the possible low-level mosaicism in the unaffected parent who harbors either a TSC1 or TSC2 mutation. Studies have demonstrated that a portion of affected individuals carry mosaic mutations in either TSC1 or TSC2, which means that cells with the mutation and cells without the mutation co-exist in some patients.

Prognosis

TSC is a lifelong condition. Although most individuals with TSC have a normal life expectancy, intractable seizures or malignancies in vital organs may cause disability and premature death.

Practice Guidelines

The following offer consensus recommendations from Tuberous Sclerosis Complex International (TSCi) for diagnostic criteria and management of TSC, updating recommendations published in 2013, and recommendations for closing the gap between the guidelines and available care.

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.
Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations.
Pediatr Neurol. 2021;123:50-66. PubMed abstract

Stuart C, Fladrowski C, Flinn J, Öberg B, Peron A, Rozenberg M, Smith CA.
Beyond the Guidelines: How We Can Improve Healthcare for People With Tuberous Sclerosis Complex Around the World.
Pediatr Neurol. 2021;123:77-84. PubMed abstract

Roles of the Medical Home

The medical home clinician should watch for potential complications of TSC and provide anticipatory guidance. Use of the TSC-Associated Neuropsychiatric Disorders (TAND) Checklist is recommended. Optimal surveillance and management of clinical problems will involve collaboration with relevant subspecialists. In addition to well-child and acute-care visits, consider scheduling annual chronic-care visits.

Clinical Assessment

Pearls & Alerts for Assessment

COVID-19 update (as of January 2021)

Little is known about people with genetic conditions and COVID-19, but useful resources and documents from key leaders in TSC clinical care can be found at Covid-19 & TSC Resources (Tuberous Sclerosis Alliance). A recent study from Europe (and an unpublished update) suggested that patients with TSC are not at increased risk of developing COVID-19, as the prevalence of SARS-CoV-2 infection and the outcomes in those who developed the disease overlap with those in the general population. However, people with multiple comorbidities remain at risk of worse outcomes. [Peron: 2020]

Consider TSC if cardiac tumor is identified

Perinatal identification of cardiac tumor, especially in the intraventricular wall, should lead to consideration of TSC.

Infants with cardiac rhabdomyomas

Infants with TSC may be very ill with respiratory distress, arrhythmias, and cardiomegaly due to cardiac rhabdomyomas.

SEGAs can cause neurologic problems

About 5-15% of children and adolescents have subependymal giant cell astrocytomas (SEGAs). Although they are benign tumors, they can cause serious neurologic problems, including hydrocephalus. Pay attention to unexplained changes in neurological status.

Hypomelanotic macules may not be visible

Hypomelanotic macules may only be visible by Woods lamp skin examination, which can be done at subspecialty clinics during an evaluation of TSC if it is not available in the primary care setting.

Risk of TSC and autosomal dominant polycystic kidney disease

A contiguous gene deletion encompassing both TSC2 and PKD1 causes both TSC and autosomal dominant polycystic kidney disease. These individuals have a higher risk than those with TSC alone of developing end-stage renal disease.

Genetic vs. clinical diagnosis

Of the individuals who fulfill clinical diagnostic criteria, up to 10% do not have a documented molecular etiology. A negative genetic test does not exclude the diagnosis.

Screening

Of Family Members

Parents of a newly diagnosed child should be screened for TSC, even if apparently asymptomatic (about 1/3 of individuals diagnosed with TSC have an affected parent). [Northrup: 1993] If the pathogenic variant in TSC1 or TSC2 has been identified, genetic testing for the specific mutation can be offered to both parents. If the pathogenic variant is not known, both parents should be screened clinically. Clinical evaluation includes skin examination, brain MRI, retinal examination, renal ultrasound/MRI, and high-resolution CT scan of the chest (in women only). [Northrup: 2015]

For Complications

Screen for hypertension and features of TSC-associated neuropsychiatric disorders (TAND) at least annually and perform a comprehensive evaluation for TAND at key developmental periods (0-3 years of age, 3-6 years, 6-9 years, 12-16 years, and 18-25 years). [Krueger: 2013] A TSC-Associated Neuropsychiatric Disorders (TAND) Checklist [de: 2015] has been validated in a pilot study. [Leclezio: 2015] The checklist does not use a traditional scoring system; instead, any of the items on the TAND Checklist may be sufficient to lead to an action plan. [de: 2015] In post-pubertal women, screen for symptoms of lymphangioleiomyomatosis (LAM), which include shortness of breath and exertional dyspnea. [Krueger: 2013]

Presentations

Clinical presentations range from barely noticeable to severe. TSC due to mutations in TSC2 is generally more severe than TSC due to mutations in TSC1, but many exceptions exist. The clinical manifestations of TSC have an age-dependent onset, with some of them being present in fetal life and at birth (e.g., cortical tubers, cardiac rhabdomyomas) and other manifestations developing across the lifespan (e.g., retinal hamartomas, angiomyolipomas (AMLs). [Northrup: 2013] Prenatal ultrasound detection of an intracardiac tumor raises the concern for TSC. About 75% of individuals with TSC present in the first year of life with seizures, half of which have infantile spasms or focal seizures; almost all will have an underlying brain cortical dysplasia. Distinct skin findings, hypomelanotic macules or shagreen patch, are another common clinical presentation. Individuals with a milder phenotype can present with seizures; even adults can have onset of seizures or be diagnosed after bleeding of renal AMLs after age 20-30 years, without any other clinical problems. [Chu-Shore: 2010]

Diagnostic Criteria

The following genetic and clinical diagnostic criteria are from [Northrup: 2021].
Genetic diagnostic criteria: The identification of either a TSC1 or TSC2 pathogenic mutation is sufficient to make a definite diagnosis. A pathogenic mutation is defined as a mutation that clearly inactivates either tuberin or hamartin or disrupts their respective functional activity.
Clinical diagnostic criteria: [Northrup: 2021]
Definite TSC - 2 major features, or 1 major feature plus 2 or more minor features
Possible TSC - 1 major feature, or 2 or more minor features
Major features:

Hypomelanotic macules (≥3, at least 5-mm in diameter)
Angiofibromas (≥3) or fibrous cephalic plaque
Ungual fibromas (≥2)
Shagreen patch
Multiple retinal hamartomas
Tubers and cerebral white matter radial migration lines
Subependymal nodules
Subependymal giant cell astrocytoma (SEGA)
Cardiac rhabdomyoma
Lymphangioleiomyomatosis (LAM)
Renal angiomyolipoma (AMLs) (≥2)

When both LAM and renal AMLs are present, other manifestations must be present to diagnose TSC.

child's leg and stomach showing Hypomelanotic patches — Hypomelanotic macules

lower face showing facial angiofibroma — Facial angiofibromas

Minor features

Dental enamel pits (≥3)
Intraoral fibromas (≥2)
Nonrenal hamartoma
Retinal achromic patch
"Confetti" skin lesions
Multiple renal cysts
Sclerotic bone lesions

New diagnostic criteria do not address seizure disorders; nevertheless, clinicians should be aware of the association and consider the diagnosis of TSC for infants with infantile spasms and/or a hypsarrhythmic EEG pattern.

Differential Diagnosis

Infantile spasms, cortical dysplasia, renal cysts, dermal pits, developmental delay, and autism spectrum disorder occur commonly in children who do not have TSC. Hypomelanotic macules alone may be seen in vitiligo, nevus anemicus, and piebaldism. Though isolated rhabdomyoma, angiofibroma, and LAM are not specific to TSC, each should trigger consideration of TSC. Facial angiofibromas can resemble fibrofolliculomas seen in Birt-Hogg-Dubé syndrome and can occur in multiple endocrine neoplasia type 1, although age of onset is later than in TSC.

Comorbid & Secondary Conditions

Skin manifestations, including hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, and ungual fibromas, occur in virtually everyone with TSC. None of the skin lesions is associated with medical complications, such as skin cancer.
Brain manifestations include cortical tubers, subependymal nodules, SEGAs, and seizures. Some evidence suggests that the number of tubers correlates with the degree of intellectual disability and the number of seizures. [Goodman: 1997] Subependymal nodules (<1 cm) are present in 80% of patients but don’t cause clinical problems. SEGAs are subependymal nodules that are >1 cm and located near the Foramen of Monro. They occur in 5-15% of the patients and rarely develop after 25 years of age. They may enlarge and cause hydrocephalus by obstructing the ventricular CSF outflow system and result in morbidity and death.
Seizures, especially infantile spasms and/or focal seizures, occur in more than 80% of individuals with TSC and, rarely, may be life-threatening. [Asato: 2004] Complications, such as status epilepticus and pneumonia leading to respiratory failure, are leading causes of early death in individuals with TSC. In nearly half of the patients, seizures can be treatment resistant. A combination of more than one antiepileptic drug might be necessary for adequate control. Vigabatrin is the recommended first-line treatment for infantile spasms. Its use has been associated with better outcomes related to seizures and cognitive abilities. [Camposano: 2008]
TAND describes all the TSC-associated neuropsychiatric disorders that occur in up to 90% of patients, regardless of age. These challenges encompass behavioral (aggression, tantrums, sleep problems), psychiatric (autism spectrum disorder, ADHD), intellectual (intellectual disability), academic (learning difficulties), neuropsychological (memory recall, dual-tasking), and psychosocial (self-esteem, relationship) difficulties. [de: 2015] Developmental delay/intellectual disability (ID) is present in 50% of individuals with TSC, and 30% have profound ID. Specific learning difficulties are common in individuals whose IQ is in the normal range. Autism spectrum disorder has been reported in 17-61% of people with TSC. [Curatolo: 2004] In a survey, cognitive and behavioral issues were the manifestations of TSC that caused parents the most concern. [Prather: 2004]
Kidney problems include AMLs and cysts. The majority of pre-teens with TSC have at least 1 renal lesion that tends to increase in size and number with time. Larger AMLs (>4cm in diameter) may abruptly bleed and become life-threatening, or they may replace normal renal tissue and lead to end-stage renal disease.
Heart problems include rhabdomyomas, which are generally present in infancy and regress spontaneously. They can cause arrhythmias in a minority of newborns but require treatment only if they cause ventricular outlet obstruction.
LAM may occur; usually, it is seen only in adult females.
Ophthalmological complications, such as retinal hamartomas and retinal hypopigmented patches, are usually clinically benign and don’t cause visual impairment. [Tuberous: 2006]

History & Examination

Current & Past Medical History

Inquire about newborn problems, symptoms of kidney problems, unusual spasms or movements, or seizure activity. In older children, inquire about relevant symptoms that include seizure frequency and severity, medication use, and symptoms of other organ system involvement, such as renal disease or shortness of breath. Ask about sleep problems, which may be caused by obstructive sleep apnea, and sleep problems related to seizures, autistic features, and intellectual disability.

Family History

Ask about a family history of TSC and hypomelanotic macules in family members (Woods lamp exam included). Obtain a 3-generation pedigree while keeping in mind the high degree of variability in clinical expression and the potential for parental mosaicism.

Pregnancy/Perinatal History

Obtain a standard history with emphasis on prenatal ultrasound and possible cardiac rhabdomyoma.

Developmental & Educational Progress

Perform developmental and behavioral evaluations at diagnosis to establish a baseline. Ask about age of achievement of developmental milestones, cognitive ability, behavior problems, and autistic features. Asking the family to bring their child's neuropsychological test results, Individualized Education Plan (IEP), or 504 plan is an easy way to monitor school progress and future goals. Children who are initially meeting milestones may fall behind later. Frequent seizures and multiple medications to control seizures may make educational performance difficult. Evaluate for TAND using the TSC-Associated Neuropsychiatric Disorders (TAND) Checklist to establish a baseline and annually. [de: 2015]

Social & Family Functioning

Assess family acceptance of the diagnosis and their ability to cope with complications of TSC.

Physical Exam

Vital Signs

HR | RR | BP

Growth Parameters

Length/height | weight | OFC

Skin

Look for hypomelanotic macules, shagreen patches, facial angiofibromas, fibrous cephalic plaques, and ungual fibromas. Be aware that some skin features have an age-dependent course and might not be visible during the first exam. Use a Woods lamp under low-light conditions. Parents and siblings should also be examined for skin abnormalities as part of the genetic evaluation. It is not usually necessary to follow skin lesions unless they are particularly large or cause esthetic problems. Images of classic cutaneous manifestations for TSC can be found at Skin Findings in TSC (TSAlliance.org).

HEENT/Oral

Eye manifestations may include hypopigmented areas of the retina and retinal hamartomas. Teeth may have pitting. Intraoral fibromas may be present.

Chest

Screen for possible signs of LAM (exertional dyspnea, shortness of breath) in adolescent and adult women.

Heart

Monitor for unusual heart sounds or signs of cardiac failure, such as edema and shortness of breath.

Neurologic Exam

Perform full neurologic exam as baseline. Changes in reflexes or papilledema may signal obstruction by a SEGA.

Testing

Sensory Testing

Although eye manifestations do not generally affect visual acuity, the initial evaluation should include a visual evaluation with dilated fundoscopy.
Children require ophthalmological screening before starting vigabatrin due to the chance of developing constriction of the visual fields. Then screen at periodic intervals and after cessation. This should be arranged by the pediatric neurologist who initiates the medication.

Laboratory Testing

Depending on the antiepileptic medication, children with seizures may need drug levels and/or other blood tests. Responsibility for monitoring may be worked out with the pediatric neurologist who initiated the medication.
Assess renal function annually with serum creatinine and urinalysis.

Imaging

Brain MRI at baseline to identify cortical tubers, subependymal nodules, and SEGAs. Repeat every 1-3 years in patients younger than age 25 years to monitor for new occurrence of SEGAs. Patients with a growing or even asymptomatic SEGA should have brain MRI as indicated for signs of increased intracranial pressure (frequency of scans in recommended range should be clinically determined).
Renal ultrasound (or abdominal MRI, when possible) every 1-3 years through lifetime to detect renal cysts and AMLs, as well as other nonrenal hamartomas. The frequency of imaging is based on presence and size of lesions; MRI should be performed if larger lesions are found.
High-resolution, low-radiation CT (computed tomography) scan of the chest every 5-10 years in adult women to identify LAM
Echocardiography every 1-3 years, or as indicated, in pediatric patients with cardiac rhabdomyoma until regression of the tumor

Genetic Testing

Genetic evaluation is indicated for any child suspected of having TSC, even within families in which all affected individuals have the same TSC1 or TSC2 mutation. Because germ line mosaicism has been found, counseling regarding recurrence risk in a family with 1 affected child must be tempered by the rare possibility that an unaffected parent could harbor a TSC mutation. Molecular identification of a TSC1 or TSC2 mutation in an affected individual allows testing for the same mutation in apparently unaffected parents to detect low-grade mosaicism, which could include the germ line and alter recurrence risk estimates. Confirmation of the status of family members could prove helpful for future clinical trials and reproductive risk counseling, including pre-implantation genetic diagnosis and prenatal screening. Genetic testing should include analyses for the detection of both point mutation (using Next Generation Sequencing) and deletions/duplications in both genes. Although Next Generation Sequencing techniques allow a better detection rate, in up to 10% of patients with a clinical diagnosis of TSC, a mutation in either TSC1 or TSC2 cannot be identified. The failure to detect a mutation does not exclude the diagnosis. (Gene testing information adapted from [Northrup: 2015] )

Other Testing

An EKG and echocardiogram should be performed at diagnosis. An EKG should be repeated every 3-5 years in asymptomatic children and adults.
A baseline EEG should be performed in all children upon diagnosis, especially in infants. EEG monitoring allows early detection of subclinical seizure activity and allows consideration of preventive treatment. [Curatolo: 2012] The frequency of follow-up EEGs in individuals with known seizures should be determined by the pediatric neurologist based on clinical needs.
Periodic neuropsychological and achievement testing should be performed through the school to assess progress and identify opportunities for focused interventions.
Adult women should receive pulmonary function testing.

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [7])

Children who are suspected to have TSC should be referred for help with establishing a diagnosis and provision of anticipatory guidance for surveillance and management of various manifestations. Patients and families should be referred for education about the condition and genetic counseling.

Pediatric Neurology (see UT providers [7])

Seizures in TSC are often difficult to control; refer for needed expertise.

Developmental - Behavioral Pediatrics (see UT providers [9])

Refer for ongoing assessment and treatment that may be helpful for those children with intellectual disability, ADHD, autistic features, and behavior problems.

Pediatric Nephrology (see UT providers [1])

Refer, as needed, for evaluation and follow-up of renal lesions.

Pediatric Cardiology (see UT providers [4])

Refer if there are any concerns about cardiac function.

Pediatric Ophthalmology (see UT providers [4])

Although the eye lesions in TSC don't usually affect vision, an ophthalmologic exam is indicated to identify retinal abnormalities.

Pediatric Pulmonology (see UT providers [3])

Referral may be helpful for concerns about lung problems and are needed for adolescent females for surveillance for LAM.

Sleep Studies/Polysomnography (see UT providers [5])

Children with sleep problems may benefit from sleep evaluations.

Pediatric Dermatology (see UT providers [2])

Individuals with large skin lesions, especially facial angiofibromas, may need referral.

Treatment & Management

Pearls & Alerts for Treatment & Management

Evaluate children on vigabatrin for retinal toxicity

Children on vigabatrin need frequent ophthalmological evaluations for retinal toxicity. Evaluations will generally be arranged by the pediatric neurologist.

Evaluate onset of new headaches promptly

Periodically screen for SEGAs using MRI. Image children with new headaches, particularly if the headaches are accompanied by vomiting.

Consider mTOR inhibitors

Everolimus and sirolimus are effective in reducing the size of growing SEGAs and renal AMLs, stabilizing lung function, and reducing the size of lymphangioleiomyomas. Everolimus has also been approved for the adjunctive treatment of refractory focal-onset seizures in patients older than 2 years of age. Off-label use has shown encouraging results in treating symptomatic cardiac rhabdomyomas and facial angiofibromas (as a topical formulation). [Northrup: 2021]

How should common problems be managed differently in children with Tuberous Sclerosis Complex (TSC)?

Although individuals with TSC need lifelong follow-up for disease manifestations, they generally require the same care as their peers for common problems. Some exceptions include:

Introduction

Although individuals with TSC need lifelong follow-up for disease manifestations, they generally require the same care as their peers for common problems. Some exceptions include:

Development (Cognitive, Motor, Language, Social-Emotional)

Neuropsychological testing prior to first grade should strongly be considered, even if preschool children appear to be doing well.

Prescription Medications

Vigabatrin is the recommended first-line therapy for infantile spasms in TSC and might be useful for focal seizures before age 1. However, the prescribing clinician should be aware of the possible side effects, including visual field constriction. [Curatolo: 2012] Current studies have been evaluating the effectiveness of preventive treatment with vigabatrin before seizure onset. [Kotulska: 2021]
Everolimus has been demonstrated to reduce seizures in patients with refractory focal-onset seizures. [French: 2016] The use of Cannabidiol in patients with TSC is currently being evaluated. [Thiele: 2020]
mTOR inhibitors (everolimus and sirolimus) are effective in reducing the size of growing SEGAs and renal AMLs >3 cm. [Franz: 2013] [Bissler: 2013] Everolimus is FDA-approved in adults and children ≥ 3 years of age for SEGAs, in adults for renal AMLs, and in adults and children ≥2 years of age as adjunctive treatment for refractory focal-onset seizures. Sirolimus is FDA-approved to treat LAM. Due to possible side effects (increased risk of infections, stomatitis, elevation of blood glucose, triglycerides, and cholesterol), use only the minimum effective dose, monitor for side effects, and monitor drug serum levels. Prescribing physicians should be aware that treatment might be lifelong since tumor regrowth has been noticed after treatment discontinuation. [Curatolo: 2016]
mTOR inhibitors also show promise in treating other manifestations of TSC, such as non-renal hamartomas, cardiac rhabdomyomas, and facial angiofibromas (topical formulations); however, rapalogs are not yet approved for these indications.
Adolescent and adult women of childbearing age should be counseled regarding estrogen use because estrogen can worsen LAM.

Other

Minimizing radiation exposure is recommended to diminish somatic mutations in the normal allele of either TSC1 or TSC2. Tumors have double inactivation of either TSC1 or TSC2, therefore induction of somatic mutations of the normal TSC alleles predispose to new tumors.

Systems

Development (general)

The TSC-associated neuropsychological disorders observed in patients are summarized by the umbrella term TAND, indicating the difficulties individuals can experience across multiple levels (intellectual, academic, psychiatric, psychological, behavioral, and social). [de: 2015] About half of individuals with TSC have intellectual disability, and in up to 30%, the disability is severe. Even children with normal cognitive functioning often have specific learning disorders associated with school performances and executive/memory skills difficulties. [de: 2015] Features of autism are found in 17-61% of individuals with TSC, and behavior problems, such as ADHD (44%), self-injury (27%), and aggression (50%), are also common. [Wiznitzer: 2004] [D'Agati: 2009] [Eden: 2014] Anxiety and depressed mood can also be observed.
Children with TSC should have initial developmental and behavioral assessments and then be placed in early childhood intervention programs for therapies (PT, OT, speech) to address specific delays. Reassessments should be performed at regular intervals; IQ and achievement testing should be performed during the preschool and school-age years. Treat seizures as rapidly and completely as possible (see Neurology, below). Early control of TSC-associated seizures, particularly infantile spasms, is associated with improved neurodevelopmental outcomes. [Bombardieri: 2010]
The Portal modules for Intellectual Disability & Global Developmental Delay, Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder, Depression, and Infantile Spasms provide diagnosis and management information for these conditions.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see UT providers [9])

Periodic visits may be helpful for children with developmental delay, autistic features, and/or behavior problems.

Early Intervention for Children with Disabilities/Delays (see UT providers [52])

Children <3 years old should be referred for evaluation and developmental therapies.

Preschools (see UT providers [71])

Children >3 years old should be referred to their local school districts for preschool services including developmental therapies.

Neuropsychiatry/Neuropsychology (see UT providers [6])

Individuals of all ages with TSC may need more extensive educational neuropsychological evaluations for learning disabilities, cognitive impairment, and social communication issues.

Physical Therapy (see UT providers [40])

Referral may be helpful for children significantly behind in gross motor skills.

Occupational Therapy (see UT providers [36])

Referral may be helpful for children significantly behind in fine motor and/or daily living skills.

Speech - Language Pathologists (see UT providers [65])

Children with delayed speech/language may benefit from speech therapy.

Neurology

Brain abnormalities associated with TSC include cortical and subcortical tubers (90%), subependymal nodules, subependymal giant cell astrocytomas (SEGAs), and white matter radial migration lines. The number and localization of tubers have been associated with occurrence of seizures. Between 80-90% of children and adolescents have subependymal nodules. This percentage drops in older adults. The prevalence of SEGAs varies from 5-15% in various TSC clinics. SEGAs generally do not arise after the second decade of life. Cell proliferation and cell growth are abnormal in TSC due to abnormal signaling through the mTOR pathway. Rapamycin and similar compounds (rapalogs) that act as inhibitors of this pathway effectively treat SEGAs and decrease seizure frequency when used as adjunctive therapy to other antiepileptic drugs. [Krueger: 2013]
SEGAs are subependymal nodules that arise near the Monro foramina, which connect the lateral ventricles and the third ventricle. When SEGAs become large enough, they can block the flow of cerebrospinal fluid, leading to hydrocephalus and, if untreated, death. Treatment usually involves close surveillance and removal of enlarging tumors or use of mTOR inhibitors to shrink the tumors before signs of increased intracranial pressure appear. [Berhouma: 2010]
Everolimus and sirolimus, which inhibit the activated mTOR pathway involved in cell proliferation, have been approved for treating SEGAs in both children and adults. [Franz: 2013] Periodic screening for SEGAs is accomplished using MRI, but children with new headaches, particularly accompanied by vomiting, should be imaged acutely. In the absence of new medical or behavior concerns, brain MRI with and without gadolinium is recommended every 1 to 3 years until age 25.
Seizures affect between 65-95% of individuals with TSC; refractory seizures, 20-50%. Seizure frequency may be related to the number of cortical tubers; however, it is probably not the cortical tubers but the surrounding tissue that is epileptogenic. [Major: 2009] Seizures often manifest as infantile spasms, which can be difficult to treat and may be life-threatening. Vigabatrin is currently the drug of choice for infantile spasms associated with TSC, even though there may be retinal toxicity. Because vigabatrin can cause permanent peripheral visual field loss (thought to be due to drug-induced injury to photoreceptors and retinal ganglion cells and their axons), children require ophthalmological screening before starting vigabatrin and then at periodic intervals and after cessation. Screening should be arranged by the pediatric neurologist who initiates the medication. [Kossoff: 2010] Adrenocorticotropic hormone (ACTH) and topiramate may also be used to control infantile spasms, depending on pediatric neurology preference and expertise. In children with localizable foci of epileptogenic activity, surgery may be helpful. Another common type of seizure, focal seizures, can present at any age. Infantile spasms, earlier age at seizure onset, and drug resistance are usually associated with a worse cognitive outcome, making prompt and appropriate treatment crucial.

Specialty Collaborations & Other Services

Pediatric Neurology (see UT providers [7])

Children with seizures may need periodic consultation, depending on seizure frequency and response to medications. All pediatric patients with known TSC should undergo a baseline electroencephalograph (EEG).

Pediatric Hematology/Oncology (see UT providers [3])

Depending on local expertise, oncology may have a clinical protocol for treatment of intracranial tumors with rapamycin analogs (i.e., everolimus).

Pediatric Neurosurgery (see UT providers [2])

Suspicion of increased intracranial pressure should prompt a consultation. A team approach to cerebrospinal fluid (CSF) flow obstruction is needed to balance surgical and medical intervention.

Renal

About 80% of people with TSC are affected by renal abnormalities: renal AMLs affect 60% of people; renal cysts, 30%; and renal cell carcinoma, 2-4%. [Wataya-Kaneda: 2013] There is an age-related penetrance for renal AMLs. In the second decade of life, the prevalence jumps from about 10% up to 90% and size can increase; 1/3 of individuals with AMLs have lesions larger than 4 cm.
Typically, surveillance consists of renal ultrasounds or abdominal MRI (preferred), every 1-3 years, in individuals without known lesions. Increase frequency of ultrasounds or MRI for those with numerous or larger lesions. MRI of the abdomen provides better resolution for AMLs and should be performed in conjunction with brain MRI in older prepubertal children to prepare for potential growth in adolescence. Depending on their location, large AMLs (>3.5 cm) may be removed prophylactically by renal embolization or partial nephrectomy to prevent hemorrhage into the tumor and pain. Blood pressure monitoring at every clinical visit is recommended, and enhanced renal function monitoring is indicated for those with renal lesions. [Seyam: 2008] mTOR inhibitors are approved and considered the first-line treatment for renal AMLs >3 cm in adults. [Bissler: 2016]

Specialty Collaborations & Other Services

Pediatric Nephrology (see UT providers [1])

Periodic assessments may be helpful in monitoring and managing renal lesions.

Mental Health/Behavior

Mental health and behavioral issues in children with TSC can be complicated and will often require collaboration among developmental-behavioral pediatricians, psychologists, behavioral therapists, neurologists (particularly if the child is having seizures and is on antiepileptic medication), and the rehabilitation team, including hospital-based and education-based therapists. For some children, psychiatry may be helpful. The correct diagnosis for behavioral problems is essential; for instance, a 7-year-old child with intellectual disability who is acting appropriately for his or her mental age, but has a short attention span, might benefit from ADHD medical intervention. The medical home should ensure that assessments of abilities and problems are frequent; use of the TSC-Associated Neuropsychiatric Disorders (TAND) Checklist is recommended. See the screening section (Tuberous Sclerosis Complex (TSC)) for screening frequency and other details. In addition, counseling should be considered to help the family cope with the challenges of the condition.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see UT providers [9])

Periodic visits may be helpful for children with developmental delay or intellectual disability, autistic features, and/or behavior problems.

Mental Health Evaluation/Assessment (see UT providers [132])

Testing may help with diagnosis and management of intellectual disability, autistic features, ADHD, and/or behavior problems.

Neuropsychiatry/Neuropsychology (see UT providers [6])

Testing may help with diagnosis and management of intellectual disability, autistic features, ADHD, and/or behavior problems, particularly for a child with seizures.

Behavioral Therapies (see UT providers [36])

These programs may be helpful in the management of ADHD, autistic features, and/or behavior problems.

Pediatric Neurology (see UT providers [7])

If a child is actively having seizures or is on antiepileptic medication, involvement is recommended in the joint management of behavior problems that could be associated with an underlying seizure disorder or side effects of antiepileptic therapies.

Psychiatry/Medication Management (see UT providers [53])

In cases where behavior problems require medication, referral may be helpful.

Cardiology

Cardiac rhabdomyomas are rarely observed in diseases other than TSC, and they usually do not cause serious medical problems. Children with cardiac rhabdomyomas, depending on size and location, may present at birth with murmur, dysrhythmia, conduction block, or hemodynamic compromise due to inflow or outflow tract obstruction. [Isaacs: 2009] Cardiac tumors consistent with rhabdomyomas also may be observed on fetal ultrasound and sometimes be accompanied by signs of fetal distress, such as hydrops. The prenatal ultrasound detection of a cardiac rhabdomyoma is associated with a 75-80% risk of TSC; there is a higher risk if multiple rhabdomyomas are present. [Krueger: 2013] In an asymptomatic child, rhabdomyomas can be followed clinically and, generally, can be expected to regress with time. Rhabdomyomas affect ~50% of patients <10 years of age; the percentage of those affected decreases in adulthood. Echocardiogram surveillance is important for those <3 years old or with outflow obstruction. Otherwise, periodic ECG monitoring for arrhythmias is indicated. [Günther: 2008] [Burke: 2008] Rarely, older individuals may present with cardiac rhabdomyomas; therefore, individuals with any signs of possible cardiac involvement (e.g., shortness of breath or fatigue) should receive a cardiac evaluation. Surgery is only necessary if there is outflow obstruction and hemodynamic compromise. Recent reports of off-label use of everolimus in critically ill newborns with large cardiac rhabdomyomas have shown tumor regression, which suggests potential use of mTOR inhibitors in infants with hemodynamically significant cardiac rhabdomyomas. [Colaneri: 2016] [Cleary: 2020]

Specialty Collaborations & Other Services

Pediatric Cardiology (see UT providers [4])

Periodic visits are recommended for children with rhabdomyomas.

Respiratory

About 30-40% of adolescents and women develop LAM; the frequency increases to 80% in older women. Women may be asymptomatic and then present with progressive dyspnea during exercise and recurrent pneumothoraxes. LAM is rare in males. [Krueger: 2013] Sirolimus, an mTOR inhibitor, has been approved for treating LAM and should be used to improve pulmonary function in patients with rapid progression. Individuals with LAM should be advised to avoid smoking and using estrogen. Pregnancy might exacerbate LAM.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see UT providers [3])

Periodic pulmonary function testing is advised In female adolescents.

Maturation/Sexual/Reproductive

Puberty is generally normal in individuals with TSC. Given the high variability of clinical expressivity, individuals with TSC should be properly counseled when entering reproductive age about reproductive options and the risk of having a child with TSC. Women with LAM should be advised about the potential negative effects of estrogen and pregnancy on LAM.

Specialty Collaborations & Other Services

Gynecology: Pediatric/Adolescent; Special Needs (see UT providers [11])

A consultation with a gynecologist familiar with working with children with special health care needs may be very helpful for the adolescent.

Skin & Appearance

Most of the children with TSC show skin findings that usually don’t cause medical problems. Early intervention is indicated only for symptomatic or potentially disfiguring lesions. Laser techniques and topical mTOR inhibitors have been used to treat facial angiofibromas. [Jóźwiak: 2016] [Koenig: 2018]

Specialty Collaborations & Other Services

Pediatric Dermatology (see UT providers [2])

Consider referral if skin lesions are particularly large or cause esthetic problems.

Pediatric Ophthalmology (see UT providers [4])

Consider referral if retinal hamartomas are symptomatic.

Learning/Education/Schools

Children with intellectual disability or specific learning disabilities will need accommodations in the school system. Depending on the degree of disability and the services needed by the child, a 504 plan or an Individualized Education Program (IEP) will be necessary. School Types and Options provides a discussion about federal laws regarding students with disabilities, the IEP process, and much more.

No Related Issues were found for this diagnosis.

Ask the Specialist

If I suspect TSC, what testing should I send?

The diagnosis of TSC is based on established diagnostic criteria (listed above). [Northrup: 2013] Genetic testing can be useful in uncertain cases and for screening family members once the pathogenic mutation has been identified. Consider starting with mutation analysis of TSC1 and TSC2 using next generation sequencing and, if negative, request deletion/duplication analysis of both genes. About half of the patients with a mutation that was not identified in the past carry a mosaic mutation in TSC1 or TSC2. Therefore, re-testing with newer molecular techniques may be warranted if patients were tested before 2015. A mutation cannot be identified in up to 10% of patients, but this does not exclude the diagnosis.

In general, what is the minimum medical work-up to do after diagnosis of TSC?

Since TSC is a multisystemic condition, the initial studies should be aimed at determining the extent of the disease and organ involvement. Testing should include brain MRI, EEG, pediatric neurology evaluation, pediatric ophthalmology evaluation with fundoscopy, echocardiography/ECG, abdominal ultrasound/MRI, genetic evaluation (with assessment of skin findings, if dermatology is not available), and screens for TSC-associated neuropsychiatric disorders.

Will all patients with TSC develop intellectual disability?

No, while about half of the patients diagnosed with TSC have intellectual disability, which can vary from mild to profound, the other half have normal cognitive functioning. Some of these individuals, though, can experience specific learning or behavioral difficulties. Remember, there is a high clinical variability, even within the same family.

What are the most effective therapies for TSC?

Treatment in TSC is multidisciplinary and involves all specialists. Vigabatrin is the first-line treatment for infantile spasms, but possible visual side effects should be monitored. mTOR inhibitors (everolimus and sirolimus) are useful in treating SEGAs, renal AMLs, and LAM. They also are showing promising results in leading to regression of other TSC-related tumors. Side effects are generally well-tolerated, but the treatment might be lifelong.

Resources for Clinicians

On the Web

These Portal modules provide diagnosis and management information for conditions that may be seen in TSC:

Tuberous Sclerosis Complex (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Tuberous Sclerosis 1 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Tuberous Sclerosis 2 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Skin Findings in TSC (TSAlliance.org)
Information and photos for classic cutaneous manifestations of TSC that include hypomelanotic macules, facial angiofibromas, and shagreen patch.

The LAM Foundation
Nonprofit organization that offers information, resources, and grants for research related to lymphangioleiomyomatosis (LAM). The Healthcare Providers tab on the top of the page provides clinical diagnosis and management information. Other tabs provide information and resources for families affected by LAM and TSC.

Helpful Articles

PubMed search for tuberous sclerosis complex in children, last 4 years.

Curatolo P, Jóźwiak S, Nabbout R.
Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations.
Eur J Paediatr Neurol. 2012;16(6):582-6. PubMed abstract

Jansen AC, Vanclooster S, de Vries PJ, Fladrowski C, Beaure d'Augères G, Carter T, Belousova E, Benedik MP, Cottin V, Curatolo P, Dahlin M, D'Amato L, Ferreira JC, Feucht M, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Kingswood JC.
Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.
Front Neurol. 2020;11:904. PubMed abstract / Full Text

de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D'Amato L, Beaure d'Augères G, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Kingswood JC, Jansen AC.
Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND): New Findings on Age, Sex, and Genotype in Relation to Intellectual Phenotype.
Front Neurol. 2020;11:603. PubMed abstract / Full Text

Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA.
Tuberous sclerosis complex.
Nat Rev Dis Primers. 2016;2:16035. PubMed abstract

Manohara D.
Primary care management of tuberous sclerosis complex in children.
J Am Acad Nurse Pract. 2012;24(7):391-9. PubMed abstract / Full Text

Jülich K, Sahin M.
Mechanism-Based Treatment in Tuberous Sclerosis Complex.
Pediatr Neurol. 2013. PubMed abstract

Wataya-Kaneda M, Tanaka M, Hamasaki T, Katayama I.
Trends in the prevalence of tuberous sclerosis complex manifestations: an epidemiological study of 166 Japanese patients.
PLoS One. 2013;8(5):e63910. PubMed abstract / Full Text

Clinical Tools

Clinical Checklists & Visit Tools

TSC-Associated Neuropsychiatric Disorders (TAND) Checklist
A 12-question checklist designed to help guide decisions about further evaluation or treatment; offered for free download by Tuberous Sclerosis Complex International.

Letters of Medical Necessity

Letter of Medical Necessity for TSC - Sample ( Word Document 18 KB)
Template that may be downloaded and edited to secure pre-authorization from insurance companies for diagnosis and management of TSC; Medical Home Portal.

Patient Education & Instructions

An Introduction to TSC (Tuberous Sclerosis Alliance) ( PDF Document 2.1 MB)
A 32-page online booklet that provides information about diagnosis, features, genetics, and support systems for families affected by TSC.

TSC Patient Education Resources (Herscot Center, MGH)
Offers a variety of relevant information and family stories; from the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital.

Resources for Patients & Families

Tuberous Sclerosis Complex (FAQ)

Information on the Web

Tuberous Sclerosis Information Page (NINDS)
Overview of TSC with emphasis on research and inclusion of links to studies and clinical trials; National Institute of Neurological Disorders and Stroke.

Tuberous Sclerosis (Medline Plus)
Overview with links to reliable sources of more detailed information; from the National Library of Medicine.

Genetic Conditions: Tuberous Sclerosis (MedlinePlus)
Excellent, detailed review of the condition for patients and families; National Library of Medicine and National Institutes of Health.

Tuberous Sclerosis (GARD)
Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

National & Local Support

Tuberous Sclerosis Alliance Support Community
An online support community for individuals and families affected by TSC; sponsored by Inspire.com - membership required.

TSC Community Alliances (TSAlliance.org)
Locations of volunteer groups who work with the TS Alliance to facilitate local connections for individuals and families affected by TSC.

Tuberous Sclerosis (NORD)
Information for families that includes synonyms, signs & symptoms, causes, affected populations, related disorders, diagnosis, therapies (both standard and investigational), and support organizations; National Organization of Rare Disorders.

Studies/Registries

Tuberous Sclerosis (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Clinical Trials/Studies Related to TSC (TSAlliance.org)
A list compiled and maintained by the Tuberous Sclerosis Alliance with clinical trials and clinical studies that have obtained Institutional Review Board approval.

Services for Patients & Families in Utah (UT)

Service Categories	UT	NW		NM	NV
Applied Behavior Analysis (ABA)	62	2	17	10	27
Autism Programs	56	1	7	2	4
Behavioral Therapies	36	1	17	21	31
Developmental - Behavioral Pediatrics	9	1	2	3	12
Early Intervention for Children with Disabilities/Delays	52	3	34	31	13
Gynecology: Pediatric/Adolescent; Special Needs	11				3
Medical Genetics	7	1	2	5	4
Mental Health Evaluation/Assessment	132		8	10	24
Neuropsychiatry/Neuropsychology	6		1	3	9
Occupational Therapy	36	1	17	27	20
Pediatric Cardiology	4		3	4	17
Pediatric Dermatology	2	1	3	1	3
Pediatric Hematology/Oncology	3	1	3	6	10
Pediatric Nephrology	1		2	2	10
Pediatric Neurology	7		5	5	17
Pediatric Neurosurgery	2	1	2	4	3
Pediatric Ophthalmology	4	1	6	6	8
Pediatric Pulmonology	3		4	4	6
Physical Therapy	40		12	12	5
Preschools	71		6	31	10
Psychiatry/Medication Management	53		3	45	80
Sleep Studies/Polysomnography	5		2		1
Speech - Language Pathologists	65	4	23	14	32

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: October 2010; last update/revision: September 2021

Current Authors and Reviewers:

Author:	Angela Peron, MD
Reviewer:	David Viskochil, MD, PhD

Authoring history

2021: update: Angela Peron, MD^A

2016: update: Angela Peron, MD^A; David Viskochil, MD, PhD^R

2014: update: David Viskochil, MD, PhD^A

2014: first version: Lynne M. Kerr, MD, PhD^A

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

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