Clinical Description
Tuberous sclerosis complex (TSC) exhibits both inter- and intrafamilial variability in clinical findings. Females tend to have milder disease than males [Sancak et al 2005, Au et al 2007]. Any organ system can be involved in TSC.
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) [Northrup et al 2013]. Among the skin lesions, the facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems.
Central Nervous System (CNS)
CNS tumors are the leading cause of morbidity and mortality in TSC. The brain lesions of TSC, including subependymal nodules (SENs), cortical tubers, and subependymal giant cell astrocytomas (SEGAs), can be distinguished with neuroimaging studies. SENs occur in 80% of individuals and cortical tubers in approximately 90%. SEGAs occur in 5%-15% of all individuals with TSC [Northrup et al 2013]. These giant cell astrocytomas may enlarge, causing pressure and obstruction and resulting in significant morbidity and mortality.
Seizures
More than 80% of individuals with TSC have been reported to have seizures, although this percentage may reflect ascertainment bias of more severely involved individuals. TSC is a known cause of infantile spasms. At least 50% of individuals have developmental delay or intellectual disability. The leading cause of premature death (32.5%) among individuals with TSC is a complication of severe intellectual disability (e.g., status epilepticus and bronchopneumonia) [Shepherd et al 1991].
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]. Although more than 90% of children and adults with TSC will experience one or more TAND concerns in their lifetime, only 20% ever receive evaluation and intervention for them [Krueger 2013, de Vries et al 2015].
Autism spectrum disorder (ASD). Individuals with TSC are at high risk for ASD, with estimates running from 16% to 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], compared to a less than 2% risk in the general population (see Centers for Disease Control and Prevention: Autism Spectrum Disorder Data & Statistics). Signs of ASD in individuals with TSC emerge as early as age nine months [McDonald et al 2017]. Individuals with TSC who have subependymal giant cell astrocytomas 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], have been noted in persons with TSC. 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]. The ASD profile in toddlers with TSC has been found to have "complete convergence" with young children with nonsyndromic ASD [Jeste et al 2016].
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 50% [Gillberg et al 1994, Prather & de Vries 2004, Muzykewicz et al 2007, Kopp et al 2008, Chung et al 2011, Kingswood et al 2017]. 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 2012].
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 (IS) 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 2017]. In a small sample (n=6),
Humphrey et al [2014] demonstrated a dramatic dose-dependent relationship between seizure activity and intellectual impairment: estimated intelligence quotient (IQ) dropped from 92 (prior to IS) to 73 (if IS duration was <1 month) to 62 (if IS duration was >1 month). These findings underscore the crucial need for adequate seizure control in individuals with TSC.
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]. 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].
Assessment. All individuals with TSC should be assessed for the presence of TAND, given that it has been closely associated with clinical outcome and quality of life [Krueger 2013]. The TAND Checklist [de Vries et al 2015], a simple paper-and-pencil screening questionnaire available at no cost, is a promising tool to address the significant gap between clinical need associated with TAND and those receiving intervention for these needs [de Vries et al 2015, Leclezio & de Vries 2015]. Given that unaddressed TAND concerns contribute significantly to poor outcome, and that individuals with TSC have a very high health care resource utilization [Lennert et al 2013, Rentz et al 2015], the importance of recognizing and addressing TAND concerns cannot be overestimated.
Kidneys
Renal disease is the second leading cause of early death (27.5%) in individuals with TSC [Shepherd et al 1991]. An estimated 80% of children with TSC have an identifiable renal lesion by a mean age of 10.5 years [Ewalt et al 1998].
Five different renal lesions occur in TSC: benign angiomyolipoma (70% of affected individuals); epithelial cysts (20%-30%) [Sancak et al 2005, Au et al 2007]; oncocytoma (benign adenomatous hamartoma) (<1%); malignant angiomyolipoma (<1%); and renal cell carcinoma (<3%) [Patel et al 2005].
Benign angiomyolipomas comprise abnormal blood vessels, sheets of smooth muscle, and mature adipose tissue. In children, angiomyolipomas tend to increase in size or number over time. Benign angiomyolipomas can cause life-threatening bleeding and can replace renal parenchyma, leading to end-stage renal disease (ESRD).
Renal 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 ESRD [Martignoni et al 2002]. Individuals with the TSC2/PKD1 contiguous gene deletion syndrome are also at risk of developing the complications of ADPKD, which include cystic lesions in other organs (e.g., the liver) and Berry aneurysms.
Malignant angiomyolipoma and renal cell carcinoma (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 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 angiomyolipomas from RCC. Immunologic staining for HMB-45 for angiomyolipomas and cytokeratin for RCC is recommended.
Heart
Cardiac rhabdomyomas are present in 47%-67% of individuals with TSC [Jones et al 1999, Dabora et al 2001, Sancak et al 2005]. These tumors have been documented to regress with time and eventually disappear. The 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. However, a small number of individuals have arrhythmias postulated to result from rests of persistent cells left after the rhabdomyomas regress. For information regarding treatment options for obstructive lesions, see Management.
Lung
Lymphangioleiomyomatosis (LAM) of the lung primarily affects women and has been estimated to occur in approximately 30%-40% of females with TSC; however, a recent study suggests that the diagnosis of LAM is age dependent and occurs in up to 80% of women with TSC by age 40 years [Adriaensen et al 2011]. Approximately 5%-10% of women with TSC present with symptomatic LAM [Henske et al 2016]. Cystic findings consistent with LAM are observed in 10%-12% of males with TSC [Northrup et al 2013].
The mean age of diagnosis for LAM in those with TSC is 28 years, compared to 35 years for
sporadic LAM.
Individuals with TSC-associated LAM as well as
sporadic LAM may present with shortness of breath or hemoptysis. 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. Some individuals progress to respiratory failure and death.
It is suggested that LAM associated with TSC is milder than
sporadic LAM because persons with TSC and LAM account for only about 15% of registrants in the
NHLBI LAM Foundation [
McCormack 2008]. Furthermore, persons with TSC and LAM have less severe lung cysts than persons with sporadic LAM [
Avila et al 2007].
Multifocal micronodular pneumonocyte hyperplasia (MMPH), characterized by multiple nodular proliferations of type II pneumocytes, was first described in association with TSC in 1991 [Popper et al 1991]. 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 in persons with TSC. MMPH can be confused with atypical adenomatous hyperplasia, which is a premalignant lesion that is not clearly associated with TSC.
Eye
The retinal lesions of TSC include hamartomas (elevated mulberry lesions or plaque-like lesions) observed in 30%-50% of individuals with TSC. These lesions are relatively rare in the general population with a recent case series of 3573 healthy term newborns identifying only two with these lesions [Li et al 2013]. Achromic patches (similar to the hypopigmented skin lesions) have been noted to occur in 39% of individuals with TSC, while the general population incidence is 1:20,000 [Northrup et al 1993]. Although these lesions are usually asymptomatic, a few persons with TSC have had progressively enlarging retinal astrocytic hamartomas with total exudative retinal detachment and neovascular glaucoma [Shields et al 2004].
Neuroendocrine Tumors (NETs)
Dworakowska & Grossman [2009] summarized case reports of persons with TSC who had NETs; the majority of tumors were pituitary adenomas (ACTHoma and GHoma), parathyroid adenomas and hyperplasia, and pancreatic adenomas (insulinoma and islet cell neoplasm). More recently single case reports have included gastrinoma, pheochromocytoma, and carcinoids. Several individuals had a TSC2 pathogenic variant and/or loss of heterozygosity in the islet cell neoplasms.