Tuberous sclerosis complex (TSC) is a genetic disease affecting multiple systems of the body, which can present in various ways in pediatric patients to pediatric providers. This inherited condition can cause seizures, cognitive and behavior deficits, cutaneous lesions, and benign tumors (hamartomas) in the renal, cardiac, and central nervous systems (Baskin, 2008; Osborne, Merrifeld, & O'Callaghan, 2008). TSC can occur in both genders and across all racial groups, and about one in 6000–10,000 are affected by this disease (Baskin, 2008; Leung & Robson, 2007; Mann & Siegel, 2009). The name of the condition comes from the description of the sclerotic tubers found in affected patients by Bourneville in 1880 (Crino, Nathanson, & Henske, 2006; Leung & Robson, 2007). This article will review the clinical presentation, disease mechanism, genetics, diagnostic tools, management of TSC, and role of the primary care provider (PCP).
Clinical presentation of disease
In order to be diagnosed as definite TSC, a patient must have two of the major criteria, or one major criterion plus two minor criteria (Curatolo, Bombardieri, & Cerminara, 2008; Leung & Robson, 2007; Schwartz, Fernandez, Kotulska, & Jozwiak, 2007). If a patient has one major criterion and one minor criterion, then the patient is diagnosed as probable TSC, and a patient is diagnosed as possible TSC if the patient has one major criterion or two or more minor criteria (Crino et al., 2006; Leung & Robson, 2007; Schwartz et al., 2007). Tables 1a and 1b detail all the diagnostic criteria for TSC (Curatolo et al., 2008; Leung & Robson, 2007; Schwartz et al., 2007).
One major feature of this condition is large hypomelanotic macules, which are usually “ash-leaf” spots (see Figure 1) or hypopigmented macules shaped like an eastern mountain ash tree leaf (Leung & Robson, 2007; Mann & Siegel, 2009; Schwartz et al., 2007). These well-demarcated lesions range from 1 to 12 cm, and patients can have 3–40 of them (Schwartz et al., 2007). These lesions are a common, early manifestation of TSC, and can be better visualized by a Wood's lamp (Curatolo et al., 2008; Mann & Siegel, 2009; Schwartz et al., 2007).
Manifestations of TSC can also include confetti-like lesions, which are small, hypopigmented macules, ranging from 1 to 3 mm, and usually distributed along the extremities (Schwartz et al., 2007). TSC patients may also present with facial angiofibromas (see Figure 2), which are red- or pink-colored papules made of vascular and connective tissue on a shiny surface, distributed over the cheeks in a butterfly shape (Curatolo et al., 2008; Leung & Robson, 2007; Mann & Siegel, 2009).
Shagreen patches (also called connective tissue nevi) are another manifestation, and these are slightly raised yellowish-red or pink plaques, most commonly found in the lumbar or sacral area (Mann & Siegel, 2009; Schwartz et al., 2007). They contain collagen and have an orange-peel texture (Baskin, 2008; Leung & Robson, 2007; Schwartz et al., 2007). Another symptom of the disease is forehead fibrous plaques, which are yellowish-brown or flesh-colored lesions of different types distributed on the forehead area (Leung & Robson, 2007; Schwartz et al., 2007). Lastly, TSC patients can have ungual or periungual fibromas, which are skin-colored nodules distributed in the nail areas of toes (more than fingers; Leung & Robson, 2007; Mann & Siegel, 2009; Schwartz et al., 2007).
A majority of TSC patients experience seizures in their lifetime, and seizures are a common presenting sign of TSC (Ess, 2009; Holmes, Stafstrom, & the Tuberous Sclerosis Study Group, 2007). Children with TSC can have complex partial, generalized tonic–clonic, or myoclonic seizures, or infantile spasms, which tend to be common in TSC patients (Ess, 2009; Holmes et al., 2007). With electroencephalography, some evidence has shown that infantile spasms in children with TSC are somewhat different from classic infantile spasms (Holmes et al., 2007). In these patients, epilepsy tends to appear when the patient is under 1 year, tends to be quite severe, progressive, resistant to medication, and more likely to adversely affect cognitive abilities (Curatolo, Bombardieri, & Cerminara, 2006; Thiele, 2004).
Tubers, another manifestation of TSC, consist of abnormal cell growth of neuronal and glial cells that can occur during fetal development (Curatolo et al., 2006; Ess, 2009; Holmes et al., 2007). The tubers are visualized by magnetic resonance imaging (MRI), and the amount and location of the tubers may affect the severity of the seizures (Connolly, Hendson, & Steinbok, 2006; Holmes et al., 2007). Research has found that seizures come from the cortical tuber area, and the removal of these tubers can decrease seizures; however, the exact pathophysiology of how the tubers cause epilepsy in TSC patients is still unknown (Curatolo et al., 2006; Holmes et al., 2007).
Cognitive, behavioral, and psychiatric effects
Patients with TSC commonly have cognitive deficits, such as mental retardation and learning difficulties, which can range from moderate to severe (De Vries, Hunt, & Bolton, 2007; Holmes et al., 2007). Severe epilepsy and the TSC2 gene are associated with increased cognitive impairment (Curatolo et al., 2006; Holmes et al., 2007). Although increased amounts of cortical tubers and severe epilepsy have been shown to be associated with cognitive dysfunction in this population, the specific mechanism of how this happens is unclear (Holmes et al., 2007; Jeste, Sahin, Bolton, Ploubidis, & Humphrey, 2007). The decreased cognitive function may be as a result of structural anomalies, seizure sequelae, genetic susceptibilities, or other causes (Jeste et al., 2007).
TSC patients also have higher rates of autism (Ess, 2009; Jeste et al,; 2007) and psychiatric disorders (De Vries et al., 2007; Muzykewicz, Newberry, Danforth, Halpern, & Thiele, 2007). The reason for this may be brain dysfunction as a result of cortical tubers or epilepsy sequelae (Curatolo et al., 2006; Ess, 2009; Holmes et al., 2007). If these children have intractable infantile spasms early, especially in the temporal area of the brain, they are more likely to be autistic as well (Bolton, 2004; Holmes et al., 2007). Some evidence shows that temporal area disturbances can impair social development, such as facial expressions, which may be the mechanism of how temporal lobe infantile spasms can lead to autism (Curatolo et al., 2006; Holmes et al., 2007). TSC patients with autism generally experience seizures early, but TSC patients who are not epileptic can develop autism as well (Holmes et al., 2007).
The most common psychiatric comorbidity in TSC patients is anxiety (Muzykewicz et al., 2007). Other common psychiatric comordities include mood disorders, adjustment disorders, and attention deficit hyperactivity disorder (ADHD; De Vries et al., 2007; Muzykewicz et al., 2007). Some evidence shows that anxiety is more common in patients with the TSC1 gene; however, this may be because these patients are less cognitively impaired and more able to express their anxiety (Muzykewicz et al., 2007). Muzykewicz et al. (2007) studied 241 patients with TSC2 and found that they were more aggressive or had more disruptive behaviors as a result of a greater degree of cognitive impairment. Another finding from this study was that subependymal nodules (SENs) and subpendymal giant cell astrocytomas (SEGAs) in TSC patients are associated with ADHD and aggressive or disruptive behaviors (Muzykewicz et al., 2007).
Another factor that may be causing the high rates of psychiatric conditions in TSC patients is the high rate of epilepsy in this population (Muzykewicz et al., 2007). In general, epileptic children have increased rates of psychiatric conditions, which can be as a result of the side effects of antiepileptic medications (Muzykewicz et al., 2007). Therefore, there may be several reasons for the increased psychiatric diagnoses in TSC patients, including their genes, the severity of their epilepsy, or their mental retardation (Muzykewicz et al., 2007). Another study explored the relationship of mental retardation, TSC, and psychiatric disorders in children (De Vries et al., 2007). According to De Vries et al. (2007), even though TSC children with mental retardation are more likely to have psychiatric disorders, a substantial amount of TSC children without mental retardation have psychiatric comorbidities as well. Therefore, all children with TSC are at risk for psychiatric disorders whether or not they have mental retardation (De Vries et al., 2007).
The most common renal symptom is angiomyolipomas (AMLs), and other common renal symptoms include renal cysts, especially in young children, and polycystic kidney disease (PKD; Castagnetti, Vezzu, Laverda, Zampieri, & Rigamonti, 2007; Leung & Robson, 2007). AMLs are benign tumors made of abnormal vessels, smooth muscle, and fat cells, and they can spontaneously hemorrhage if over 3 cm in size (Crino et al., 2006; Curatolo et al., 2008; Leung & Robson, 2007). AMLs greater than 3 cm can be treated by an embolization procedure (Crino et al., 2006; Curatolo et al., 2008). The median age for diagnosis of AMLs in children with TSC is about 10 years (Castagnetti et al., 2007; Leung & Robson, 2007).
Autosomal dominant PKD can occur specifically with TSC2 disease, because the TSC2 gene is close to the PKD1 gene (Castagnetti et al., 2007; Crino et al., 2006; Curatolo et al., 2008). When both genes are deleted, this condition is also known as contiguous gene syndrome, which is when a patient has TSC as well as PKD (Castagnetti et al., 2007). These patients with PKD can develop renal failure (Castagnetti et al., 2007; Leung & Robson, 2007). Also, as with other manifestations of TSC, renal symptoms tend to be more severe in children with TSC2 gene (Castagnetti et al., 2007).
Cardiac rhabdomyomas, a common initial presentation of TSC, are benign tumors that are usually asymptomatic, occur in multiples, span from 3 to 25 mm, are located in the ventricular walls, and tend to recede over time (Curatolo et al., 2008). However, they can be associated with arrhythmias, such as supraventricular tachycardia, as seen in Wolff-Parkinson-White syndrome (Crino et al., 2006; Curatolo et al., 2008; Leung & Robson, 2007). Also, the lesions can also cause cardiac outflow obstruction or valvular problems (Curatolo et al., 2008; Leung & Robson, 2007). However, the lesions generally only cause symptoms during fetal and neonatal life (Curatolo et al., 2008).
Optic and oral symptoms
A common ophthalmic manifestation of TSC is retinal hamartomas, which are benign lesions of the retina (Curatolo et al., 2008; Leung & Robson, 2007). These are usually asymptomatic, but may obstruct vision (Curatolo et al., 2008; Leung & Robson, 2007). There are three types of retinal hamartomas; one type is a “mulberry lesion,” which is a raised, opaque white lesion that looks like a mulberry due to its multiple nodules (Curatolo et al., 2008; Leung & Robson, 2007). The other types include the elevated plaque lesion and the hypopigmented area of the retina (Curatolo et al., 2008; Leung & Robson, 2007).
An oral symptom of TSC is dental enamel pitting, which can be hard to assess in children who do not have permanent teeth (Schwartz et al., 2007). Another oral manifestation of TSC is gingival fibromas, or little nodules that occur on the gums, especially on the upper jaw (Leung & Robson, 2007; Schwartz et al., 2007). Antiepileptic drugs, such as phenytoin, can cause the gingival fibromas to increase in size (Schwartz et al., 2007). Other oral symptoms may include fibrous hyperplasia, hemangioma, bifid uvula, and cleft palate (Leung & Robson, 2007; Schwartz et al., 2007).
Genetics and disease mechanism
Researchers have discovered that abnormalities in the TSC1 and TSC2 genes cause tuberous sclerosis, an autosomal dominant genetic disease (Leung & Robson, 2007; Mann & Siegel, 2009; Schwartz et al., 2007). However, spontaneous genetic mutations are the reason for more than half of the TSC cases (Castagnetti et al., 2007; Leung & Robson, 2007; Schwartz et al., 2007). Table 2 summarizes the differences between the TSC1 and TSC2 genes; Table 3 summarizes important terms for understanding genetic relationships. The TSC1 gene presents as a milder disorder as a result of smaller genetic deletions (Curatolo et al., 2008), whereas the TSC2 gene presents with more severe symptoms as a result of large genetic deletions (Curatolo et al., 2008). Also, the large deletions of TSC2 interfere with the PKD type 1 (PKD1) gene, which is next to TSC2 (Curatolo et al., 2008). Figure 3 illustrates the mechanism of how the TSC gene complexes affect protein synthesis and cell growth. The TSC protein complexes of tuberin and hamartin decrease the Ras homologue enriched in brain (Rheb) activity, which in turn decreases mammalian target of rapamycin (mTOR) pathway activity (Curatolo et al., 2008). The mTOR pathway controls various cell activities, such as the cell replication, cell growth, nutrient intake, protein transcription, and translation, so a decrease in mTOR pathway activity can lead to unregulated cell growth (Crino et al., 2006; Curatolo et al., 2008; Schwartz et al., 2007). Because both TSC1 and TSC2 genes are responsible for tumor suppression, when they are inactivated, this can lead to benign tumor development (Baskin, 2008; Leung & Robson, 2007; Schwartz et al., 2007).
For TSC, there is almost 100% allelic penetrance, but the allelic expression can vary (Leung & Robson, 2007). Even when an affected individual begins with one normal allele and one mutated allele, the normal one becomes damaged as a result of increasing amounts of cell replication (Osborne et al., 2008). This is called a “two-hit” mechanism, which leads to a loss of heterozygosity and results in the growth of benign tumors (Crino et al, 2006; Curatolo et al., 2008; Osborne et al., 2008). Because the second part of the hit is not always predictable, this could be the reason for the different manifestations and variable severity of TSC (Osborne et al., 2008). There may be other possible mechanisms for the benign tumor growth, because sometimes there is no evidence of loss of heterozygosity, even with the growth of benign tumors (Osborne et al., 2008). Table 3 defines terms above.
Molecular genetic testing is available to detect mutations in the TSC1 and TSC2 genes, usually by polymerase chain reaction and then DNA sequencing (Schwartz et al., 2007). A newer diagnostic technique called multiplex ligation-dependent probe amplification can detect mutations, even large deletions, at a rate of about 85% (Curatolo et al., 2008; Schwartz et al., 2007). Genetic testing can be used to confirm a diagnosis of TSC in children too young to present symptoms, to diagnose TSC in fetuses with a positive family history, and for future family planning (Curatolo et al., 2008; Schwartz et al., 2007). However, the test may not be completely accurate because parents may have mosaicism (defined in Table 3), and this may not show up in the genetic testing (Schwartz et al., 2007). As a result of lack of access and economic reasons, the utilization of TSC genetic testing is limited (Schwartz et al., 2007).
Table 4 summarizes diagnostic tests (Curatolo et al., 2008). MRIs are better at detecting SENs, SEGAs, and cortical tubers even if they are not calcified, whereas a computed tomogram (CT) better detects calcifications (Baskin, 2008). The Tuberous Sclerosis Association (2002) recommended MRIs over CTs, because they can show more pathologies and expose the child to less radiation.
Treatment and management
New research has shown that sirolimus (see Table 5) may be an effective treatment option for TSC patients (Curatolo et al., 2008; Schwartz et al., 2007). Traditionally, TSC is managed symptomatically, but sirolimus presents a novel approach to treatment (Curatolo et al., 2008; Schwartz et al., 2007). Sirolimus is an immunosuppressant and can regulate a dysfunctioning mTOR pathway in cells with defective TSC1 or TSC2 genes (Curatolo et al., 2008; Schwartz et al., 2007). Some studies have shown that sirolimus can decrease astrocytomas and renal AMLs (Bissler et al., 2008; Franz et al., 2006). However, more studies are needed as a result of the small sample sizes (Bissler et al., 2008; Franz et al., 2006). These preliminary findings are also complicated by the fact that TSC patients are usually on antiepileptics, which can cause drug–drug interactions (Franz et al., 2006).
Although sirolimus has been found to reduce AMLs, the lesions can grow back after treatment stops, suggesting long-term use of immunosuppressant sirolimus may be necessary to effectively control lesions (Bissler et al., 2008; Curatolo et al., 2008; Osborne et al., 2008). Some individuals have experienced serious side effects from the drug, such as rashes, seizures, and behavioral issues (Curatolo et al., 2008; Osborne et al., 2008). Therefore, more research is needed to investigate whether use of sirolimus in pediatric patients is a viable option (Osborne et al., 2008).
Table 6 describes the anticonvulsants used for treating seizures in TSC. Research shows that vigabatrin effectively controls infantile spasms in children with TSC (Connolly et al., 2006; Curatolo et al., 2008; Thiele, 2004). Vigabatrin (recently approved by the FDA) is recommended as a first-line treatment for infantile spasms, but the duration of treatment should be limited to 6 months with routine vision tests, because the medication may cause visual field loss (Stump, 2009). Although prolonged use of vigabatrin may cause ophthalmic side effects, preventing infantile spasms in children up to 5 years in age may stop developmental delays from occurring (Osborne et al., 2008).
Other types of TSC-related seizures can be effectively treated with various medications, such as topiramate, lamotrigine, oxcarbazepine, and levetiracetam (Collins, Tudor, Leonard, Chuck, & Franz, 2006; Leung & Robson, 2007; Thiele, 2004). These medications, however, were studied in small sample sizes (Collins et al. 2006; Curatolo et al., 2006; Thiele, 2004).
Historically, ketogenic (high fat) diets have been shown to be effective for pharmacoresistant seizures (Coppola et al., 2006; Krueger & Franz, 2008; Thiele, 2004). Very little research has been done on the use of ketogenic diet specifically for TSC patients with epilepsy (Coppola et al., 2006; Kossoff, Thiele, Pfeifer, McGrogan, & Freeman, 2005). In one study done specifically on children with TSC, 11 of 12 patients had more than a 50% reduction in seizure occurrence, illustrating that the ketogenic diet can be an effective treatment for these patients (Kossoff et al., 2005). Another study also found that the ketogenic diet effectively controlled seizures (Coppola et al., 2006). However, as a result of the small sample sizes, no concrete recommendation can be made because more studies are needed (Coppola et al., 2006; Kossoff et al., 2005).
Another option to treat pharmacoresistant, progressive seizures is surgery (Connolly et al., 2006; Holmes et al., 2007). Children with TSC tend to have multifocal seizures with various locations of the tubers, but tuber resection surgery can be successful, especially if one tuber is the main cause of the seizures (Connolly et al., 2006; Holmes et al., 2007). Although surgery may affect cognition and behaviors, and seizures may reoccur, it still may be a good option in severely epileptic TSC patients to prevent encephalopathy (Holmes et al., 2007).
Role of the pediatric PCP
Primary care providers (PCPs) should take a full personal and family history and perform a detailed examination, specifically doing a funduscopic examination and using a Wood's lamp to examine skin (Crino et al., 2006; Tuberous Sclerosis Association, 2002). With early diagnosis, PCPs can begin interventions, and symptoms of the disease can be better managed (see Table 9; Datta, Hahn, & Sahin, 2008). New treatments, such as sirolimus, can be more effective when started in the early stages of the disease (Datta et al., 2008).
Another important function of the pediatric PCP is to establish a medical home. Because TSC patients are at an increased risk for various medical, cognitive, behavioral, and psychiatric conditions, they fall under the definition of children with special healthcare needs and should have a medical home (Homer et al., 2008; Strickland et al., 2004). For these patients, PCPs should provide comprehensive, family-centered, coordinated care with a continuity of services, and timely referrals if necessary (see Table 7; Homer et al., 2008; Strickland et al., 2004). By giving this population a medical home and forming a provider-family partnership, these patients are more likely to have access to and utilize needed services and follow through with their care (Strickland et al., 2004). Table 7 lists useful resources for families.
It is also important that these complex patients and their families receive proper genetic counseling, and PCPs should refer them for genetic testing if appropriate (Crino et al., 2006; Osborne et al., 2008; Tuberous Sclerosis Association, 2002). Individuals with confirmed TSC have a 50% chance of passing on the disease to their children because TSC is an autosomal dominant condition (Osborne et al., 2008; Tuberous Sclerosis Association, 2002). Families should understand that both TSC1 and TSC2 genes can cause varying manifestations, genetic tests cannot always detect the mutations or mosaicisms, and drawbacks exist in confirming the diagnosis, such as insurance denial (Osborne et al., 2008). However, if parents want to know whether they will pass the disease to future children, then genetic testing is needed (Crino et al., 2006; Osborne et al., 2008). Also, providers should recommend that the patients' families be screened clinically for TSC (Tuberous Sclerosis Association, 2002; Osborne et al., 2008).
About half of TSC patients have severe cognitive deficits with epilepsy, and about a quarter of TSC patients have epilepsy without severe cognitive deficits (Osbourne et al., 2008). Therefore, PCPs should assess for developmental delays and start interventions early if needed (Tuberous Sclerosis Association, 2002), as well as advocate for their patients to ensure that their special educational needs are met (Leung & Robson, 2007). Also, it is important for providers to adequately screen for and effectively manage autism and behavioral disorders (Tuberous Sclerosis Association, 2002). For this population, providers should follow the American Academy of Pediatrics guidelines for screening and diagnosing autism, as described in Table 8 (Johnson, Myers, & Council on Children with Disabilities, 2007). PCPs need to refer autistic TSC patients for educational interventions as needed, and they should discuss with families about alternative treatments, such as music therapy, which may be helpful but lack strong evidence of benefit (Myers, Johnson, & Council on Children with Disabilities, 2007). For severe behavioral issues, medications such as risperidone may be helpful (Krueger & Franz, 2008). Additionally, PCPs should refer TSC-affected families to the Tuberous Sclerosis Alliance (TSA) website (see Table 7), which is a useful resource for general information, updates, social support, and new treatment options for TSC (Leung & Robson, 2007).
TSC requires a multidisciplinary approach to manage the disease effectively (Leung & Robson, 2007). PCPs should consult with dermatologists, neurologists, nephrologists, cardiologists, and ophthalmologists in order to effectively care for TSC patients (Leung & Robson, 2007). PCPs need to refer appropriately and consistently follow-up on care. It is not recommended for PCPs to concentrate on routine diagnostic tests as a result of a lack of evidence for improved patient outcomes, but instead the primary care focus should be on adherence to seizure medications and management of behavioral issues (Osborne et al., 2008). By ensuring adherence to medications to control seizures, this will help prevent behavioral and cognitive sequelae from the seizures (Krueger & Franz, 2008). Table 9 summarizes the Tuberous Sclerosis Association clinical guidelines for the management of TSC (2002), which are also referenced by Osborne et al. (2008).
TSC is a complex, multisystem disease that requires a lot of knowledge, care, coordination, and follow-up in order for providers to effectively manage these patients. Research has led to newer treatment options; however, TSC is still currently managed symptomatically with a multidisciplinary approach. PCPs should be able to manage, treat, and refer children with TSC appropriately by following evidence-based practice guidelines. PCPs should understand all the pathologies associated with TSC, should be able to educate families about the disease, and be able to provide families with support and resources.
I would like to thank my professor and mentor Dr. Rita Marie John for all her support. She was a tremendous help with editing the paper and advising me through this process.
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