Clinical Description
Tuberous sclerosis complex (TSC) involves abnormalities primarily of the skin, brain, kidneys, heart, and lungs (see Table 2), although any organ system can be involved. Central nervous system (CNS)-related problems (including TSC-associated neuropsychiatric disorder [TAND]) are the leading cause of morbidity, whereas kidney disease is the leading cause of mortality [Amin et al 2017, Canevini et al 2018, de Vries et al 2018, Lu et al 2018]. TSC exhibits both inter- and intrafamilial variability.
Table 2.
Tuberous Sclerosis Complex: Frequency of Select Features
View in own window
| Feature | % of Persons w/Feature | Comment |
|---|
|
Skin lesions
| ~100% | Hypomelanotic macules, "confetti" skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas |
|
CNS manifestations
| Subependymal nodules | ~80% 1 | |
| Cortical tubers | ~80% | |
| Subependymal giant cell astrocytoma | 25% 1 | |
| Seizures | ~80% | |
| TSC-associated neuropsychiatric disorder | >90% | Behavioral, psychiatric, intellectual, academic, neuropsychological, & psychosocial difficulties |
|
Kidney lesions
| Benign renal angiomyolipoma | 70% | |
| Epithelial cysts | 20%-30% | |
| Renal cell carcinoma | <3% | |
|
Cardiac rhabdomyomas
| 47%-67% | |
|
Lymphangioleiomyomatosis
| Up to 80% of females | |
|
Retinal lesions
| 30%-50% | |
CNS = central nervous system; TSC = tuberous sclerosis complex
- 1.
Skin
The skin is affected in virtually 100% of individuals with TSC. Skin lesions include hypomelanotic macules (~90% of individuals), "confetti" skin lesions (frequency varies widely from 3% of children to ≤58% overall), facial angiofibromas (~75%), shagreen patches (~50%), fibrous cephalic plaques, and ungual fibromas (20% overall but ≤80% in older affected adults). Among the skin lesions, facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems [Teng et al 2014, Nguyen et al 2018].
Central Nervous System (CNS)
The brain lesions of TSC, including subependymal nodules (SENs) and cortical tubers, occur in approximately 80% of affected individuals, and subependymal giant cell astrocytomas (SEGAs) develop in up to 25% of all individuals with TSC [Kochare et al 2014, Kingswood et al 2017]. Individuals with SEGAs presenting with acute deterioration due to obstructive hydrocephalus should undergo urgent surgical treatment for their SEGA. Minimally invasive surgical techniques with an experienced surgical team may reduce morbidity and mortality. For large tumors, treatment of the hydrocephalus with cerebrospinal fluid (CSF) diversion such as a temporary ventricular drain or ventriculoperitoneal shunt may be required. Mammalian target of rapamycin (mTOR) inhibitor treatment is the primary recommended therapy for growing or large SEGAs, those causing mild-to-moderate symptoms including asymptomatic ventriculomegaly, individuals who are not surgical candidates, and those who prefer medical management to surgery. The EXIST-1 clinical trial found that everolimus treatment resulted in >30% reduction in SEGA volume in 65%-79% of individuals. This effect was maintained for up to three years [Krueger et al 2013a]. Optimal outcome is associated with early detection and treatment.
Seizures
More than 80% of individuals with TSC have seizures, with most displaying features of focal or partial-onset seizures. Up to 75% of affected individuals develop seizures prior to age two years; caregivers should be educated to recognize seizures, especially when they are not present at the time of diagnosis. Two thirds of individuals with TSC experience drug-resistant epilepsy. Developmental delays, autism spectrum disorder, and psychiatric disorders demonstrate a strong association with early-onset and drug-resistant epilepsy.
Early recognition and control of seizures is highly correlated with improved developmental and neurologic outcomes in infants with TSC. Epileptiform activity on EEG can predict the eventual development of epilepsy; pre-emptive treatment with vigabatrin, before the onset of clinical seizures, may prevent infantile spasms and/or delay seizure onset. Pre-emptive treatment with vigabatrin has not, however, been shown to improve developmental or neurologic outcomes over that achieved by early recognition and control of clinical seizures alone.
TSC-Associated Neuropsychiatric Disorder (TAND)
TAND refers to the interrelated functional and clinical manifestations of brain dysfunction common in individuals with TSC, including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties [de Vries 2010a]. Recent studies have provided refined TAND clusters that include concerns in the domains of scholastic, neuropsychological, autism spectrum disorder-like, dysregulated behavior, overactive/impulsive behavior, mood/anxiety, and eat/sleep [de Vries et al 2020b, de Vries et al 2021]. Although more than 90% of children and adults with TSC will experience one or more TAND(s) in their lifetime, only 20% ever receive evaluation and intervention for them [Krueger 2013, de Vries et al 2015, Alperin et al 2021, de Vries et al 2021, Marcinkowska et al 2022]. Presence of TAND has been closely associated with clinical outcome and quality of life [Krueger 2013]. Unaddressed TAND contributes significantly to poor outcome [Lennert et al 2013, Rentz et al 2015].
Autism spectrum disorder (ASD). Individuals with TSC are at high risk for ASD, with an estimated prevalence of 16%-61% [Gillberg et al 1994, Bolton et al 2002, Wong 2006, de Vries et al 2007, Chung et al 2011, Numis et al 2011, Spurling Jeste et al 2014, Kingswood et al 2017, Zwaigenbaum et al 2021]. Signs of ASD in individuals with TSC emerge as early as age nine months [McDonald et al 2017]. ASD classification at age 12 months was predictive of confirmation of ASD by age two years using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) [Capal et al 2017b]. Specific behaviors most likely to distinguish an infant with TSC who will go on to have ASD are the quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors [Capal et al 2021]. Individuals with TSC who have SEGAs are nearly twice as likely to have ASD [Kothare et al 2014], and treatment with everolimus has been found to reduce SEGA size, seizures, and features of ASD [Hwang et al 2016, Kilincaslan et al 2017]. Neurofunctional impairments closely associated with ASD, including impaired language pathways [Lewis et al 2013] and atypical face processing [Spurling Jeste et al 2014, Scherrer et al 2020], have been noted in persons with TSC. Also, tubers affecting the fusiform gyrus (involved in high-order visual information including face processing) provide a 3.7-fold increased risk for developing ASD [Cohen et al 2023]. Children with TSC and ASD are at higher risk for global cognitive impairment than are children with TSC who do not have ASD [Jeste et al 2008]; children with TSC and ASD are also at higher risk for having intellectual disability than children with idiopathic ASD [Mitchell et al 2022]. The ASD profile in toddlers with TSC has been found to have "complete convergence" with young children with nonsyndromic ASD [Jeste et al 2016]. Males with TSC have a higher risk for ASD than females [de Vries et al 2020a]. In children with TSC, ASD has been associated with a higher rate of sleep disorders as compared to children with TSC who do not have ASD [Moavero et al 2022]. However, sleep problems are more frequent in the TSC population as a whole relative to the general pediatric population [Zambrelli et al 2021]. Higher levels of ASD manifestations in children with TSC have also been found to be associated with greater levels of family distress [Uematsu et al 2020].
Attention-deficit/hyperactivity disorder (ADHD) is another common (and potentially seriously debilitating) condition closely associated with TSC. Estimates of ADHD prevalence in individuals with TSC range from 21% to 52% [Gillberg et al 1994, Prather & de Vries 2004, Muzykewicz et al 2007, Kopp et al 2008, Chung et al 2011, Kingswood et al 2017, Ding et al 2021]. Deficits in attention (particularly in dual-task performance), cognitive flexibility, and memory have also been noted in neuropsychological studies of children and adults with TSC [Ridler et al 2007, de Vries et al 2009, Tierney et al 2011, Curatolo et al 2015, de Vries et al 2015].
Learning and cognitive impairment. Individuals with TSC are at high risk for having intellectual disability, with prevalence rates estimated between 44% and 64% [Joinson et al 2003, Goh et al 2005, van Eeghen et al 2012a]. Approximately 36%-58% of children with TSC have serious academic difficulties (e.g., learning disabilities) requiring intervention [de Vries 2010b, Curatolo et al 2015, Kingswood et al 2017]. Even toddlers with TSC present with TAND concerns as well as language delays [McDonald et al 2024]; language delays at age 12 months are associated with a higher risk of an ASD diagnosis at age 36 months [Schoenberger et al 2020]. No significant age or sex differences have been found for academic concerns or neuropsychological deficits [de Vries et al 2020a].
The risk of learning and cognitive impairment increases significantly if seizure activity is not controlled. A number of investigations have demonstrated that a history of infantile spasms and/or poor seizure control in general is associated with lower intellectual ability [Joinson et al 2003, Goh et al 2005, Bolton et al 2015, Capal et al 2017a, Wu et al 2019, Gupta et al 2020]. In a small sample (n=6), a dramatic relationship between seizure activity and intellectual impairment was found [Humphrey et al [2014]; estimated intelligence quotient (IQ) dropped from 92 (prior to infantile spasms) to 73 (if infantile spasms duration was <1 month) to 62 (if infantile spasms duration was >1 month). Larger studies have also found that TSC-related epilepsy is associated with an increased risk of intellectual disability, with a risk of severe intellectual disability being associated with epilepsy onset before age two years [Gupta et al 2020, Marcinkowska et al 2022].
Disruptive behaviors and emotional problems are another cluster of debilitating conditions associated with TSC. Aggression has been noted in many individuals with TSC (13%-58%) [de Vries et al 2007, Kopp et al 2008, Staley et al 2008, Chung et al 2011, Eden et al 2014, Kingswood et al 2017, Wilde et al 2017], as has self-injurious behavior (27%-41%) [de Vries et al 2007, Eden et al 2014, Wilde et al 2017]. Even after controlling for intellectual disability, TSC2-related TSC was associated with a higher rate of self-injurious behaviors [de Vries et al 2020a]. Individuals with TSC are also at high risk for anxiety (9%-48%) [de Vries et al 2007, Muzykewicz et al 2007, Kopp et al 2008, Chung et al 2011, Kingswood et al 2017] and depression (6%-43%) [de Vries et al 2015, Kingswood et al 2017].
Given that neuropsychiatric concerns are more frequent in individuals with TSC and that many children and adults with TSC have multiple neuropsychiatric concerns [Toldo et al 2019, Ding et al 2021, Marcinkowska et al 2022], international consensus recommendations for diagnosis and treatment of TAND have been developed [de Vries et al 2023]. Specific recommendations include lifelong monitoring for the emergence of TAND, with screenings at least annually coupled with referral for appropriate follow-up care. Key components of a TAND intervention plan include recognizing the impact of physical health problems and the important role of caregivers and families.
Kidneys
Kidney disease is the leading cause of early death (50%) in individuals with TSC [Amin et al 2017]. An estimated 80% of children with TSC have an identifiable kidney lesion by a mean age of 10.5 years [Ewalt et al 1998].
Five different kidney lesions occur in TSC: benign renal angiomyolipoma (AMLs; 70% of affected individuals); epithelial cysts (20%-30%) [Sancak et al 2005, Au et al 2007]; oncocytoma (benign adenomatous hamartoma) (<1%); malignant AMLs (<1%); and renal cell carcinoma (RCC; <3%) [Patel et al 2005].
Benign renal AMLs are comprised of abnormal blood vessels, sheets of smooth muscle, and mature adipose tissue. In children, benign renal AMLs tend to increase in size or number over time. Benign renal AMLs can cause life-threatening bleeding and can replace renal parenchyma, leading to end-stage kidney disease (ESKD).
Kidney cysts have an epithelial lining of hypertrophic hyperplastic eosinophilic cells. Some affected individuals have features of both TSC caused by deletion of TSC2 and autosomal dominant polycystic kidney disease (ADPKD) caused by deletion of PKD1. In these individuals, progressive enlargement of the cysts may compress functional parenchyma and lead to ESKD [Martignoni et al 2002]. Individuals with the TSC2/PKD1 contiguous gene deletion syndrome are also at risk of developing complications of ADPKD, which include cystic lesions in other organs (e.g., the liver) and Berry aneurysms.
Malignant renal AMLs and RCC may result in death. Although rare, these two tumors are much more common in individuals with TSC than in the general population [Pea et al 1998]. It is estimated that 2%-5% of persons with TSC will develop RCC. The typical age of diagnosis of RCC in those with TSC is 28-30 years – much earlier than the age of diagnosis for sporadic RCC [Crino et al 2006, Borkowska et al 2011]. Note: Common imaging techniques may not distinguish fat-poor renal AMLs from RCC. Immunologic staining for HMB-45 antibody for AMLs and cytokeratin for RCC is recommended to distinguish these tumors.
Heart
Cardiac rhabdomyomas are present in ~50% of individuals with TSC [Kocabaş et al 2013, Ebrahimi-Fakhari et al 2018]. These tumors have been documented to regress with time and eventually disappear. Cardiac rhabdomyomas are often largest during the neonatal period. If cardiac outflow obstruction does not occur at birth, the individual is unlikely to have health problems from these tumors later, with the exception of some individuals who develop arrhythmias. It is postulated that cardiac arrhythmias result from rests of persistent cells that remain after the rhabdomyomas regress. Cardiac rhabdomyomas with outflow obstruction [Chen et al 2021, Nespoli et al 2021, Tsuchihashi et al 2021] and cardiac arrhythmias [Öztunç et al 2015, Ninic et al 2017, Silva-Sánchez et al 2021] have been successfully treated with mTOR inhibitors.
Lung
Lymphangioleiomyomatosis (LAM) of the lung primarily affects women and has been estimated to occur in approximately 30%-40% of females with TSC; however, one study suggested that the diagnosis of LAM is age dependent and occurs in up to 80% of women with TSC by age 40 years [Henske et al 2016]. Cystic findings consistent with LAM are observed in 10%-12% of males with TSC [Northrup et al 2013]. LAM unrelated to TSC is rare.
The mean age of diagnosis for LAM in those with TSC is 28 years. Individuals with TSC-associated LAM may present with shortness of breath or hemoptysis [Taveira-DaSilva et al 2015]. Chest radiographs reveal a diffuse reticular pattern and CT examination shows diffuse interstitial changes with infiltrates and cystic changes. Pneumothorax and chylothorax may occur in individuals affected by LAM. Only 5%-10% of women with TSC-related LAM develop respiratory failure [Henske et al 2016].
Multifocal micronodular pneumonocyte hyperplasia (MMPH) is characterized by multiple nodular proliferations of type II pneumocytes. While MMPH does not have known prognostic or physiologic consequences, there have been at least two reports of respiratory failure associated with MMPH [Cancellieri et al 2002, Kobashi et al 2008]. The precise prevalence of MMPH in individuals with TSC is not known but may be as high as 40%-58% [Franz et al 2001, Muzykewicz et al 2009]. Males and females are equally likely to have MMPH, and it may occur in the presence or absence of LAM. MMPH can be confused with atypical adenomatous hyperplasia, which is a premalignant lesion that is not clearly associated with TSC.
Eyes
The retinal lesions of TSC include hamartomas (elevated mulberry lesions or plaque-like lesions), observed in 34% of individuals with TSC [Öhnell et al 2024]. These lesions are relatively rare in the general population; a case series of 3,573 healthy term newborns identified only two infants with retinal hamartomas [Li et al 2013]. Achromic patches (similar to the hypopigmented skin lesions) have been noted in 34% of individuals with TSC, while the general population incidence is 1:20,000 [Öhnell et al 2024].
Neuroendocrine Tumors (NETs)
Functional and non-functional pancreatic NETs have been increasingly identified in individuals with TSC due to recommended abdominal MRI surveillance in individuals with TSC [Krueger et al 2013b]. The most common functional pancreatic NETs reported in individuals with TSC are insulinomas, but gastrinomas, glucagonomas, ACTHomas, and GHomas have also been described. There is also a growing number of reports of non-functional NETs, with pancreatic NETs being the most common [Mowrey et al 2021, Evans et al 2022]. TSC-related pancreatic NETs present earlier; there is no clear evidence that they are more aggressive than sporadic pancreatic NETs [Arya et al 2023]. Malignant and recurrent non-functional pancreatic NETs have been described in association with TSC [Mowrey et al 2021, Sauter et al 2021]. Pancreatic NETs have been seen more commonly associated with TSC2 pathogenic variants [Mowrey et al 2021]. Based on the current data, standard surveillance and management is recommended for non-functional pancreatic NETs in association with TSC [Arya et al 2023].
Sclerotic Bone Lesions
Sclerotic bone lesions are common in individuals with TSC. In one study, 51/70 (73%) children with TSC who underwent abdominal imaging had sclerotic bone lesions. These lesions were discovered much more frequently after surveillance imaging of the abdomen and lungs became standard of care in individuals with TSC. Sclerotic bone lesions in TSC are commonly observed in the posterior vertebral elements and increase in size and number over time [Boronat et al 2016]. Although sclerotic bone lesions are included in the diagnostic criteria for TSC, they do not cause any medical issues [Boronat & Barber 2018, Northrup et al 2021].
Oral and Dental Manifestations
Multiple dental findings are observed in individuals with TSC; the two most common are dental pitting and intraoral fibromas. Dental pitting (small depressions in the dental enamel) results in increased susceptibility to formation of dental caries. Intraoral fibromas are usually observed on the gingival surfaces. Intraoral fibromas typically occur after oral trauma or as a side effect of some anti-seizure medications [Teng et al 2014].
