Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple systems. It is inherited in an autosomal dominant fashion and is characterized by an increased predisposition to hamartoma formation.[1] It results from mutations in the genes TSC1 and TSC2 and is known for causing neurological disorders including epilepsy and intellectual disability.[2]
TSC is usually diagnosed in childhood or infancy, and the affected individuals may present with developmental delay, skin manifestations, or seizures. However, it may also be diagnosed earlier or later, based on a wide array of clinical manifestations.[3]
Some manifestations may be present prenatally, such as cardiac rhabdomyomas or cortical tubers. While other signs, including osseous, renal or pulmonary lesions are commonly diagnosed in adulthood.[2][3] The presentation of the disease will vary depending on the developmental stage of the individual. While skin lesions are detected in 90% of patients of all ages, hypopigmented macules are usually found in early childhood. Ungual fibromas appear near puberty, and facial angiofibromas are more common in adolescence.[2]
This disease has a highly variable clinical course. Prognosis may be uncertain, and follow-up requires a comprehensive evaluation, often in specialized institutions. This disorder may be overwhelming for some patients and family members; thus, orientation and counseling play a vital role.[1][4]
Tuberous sclerosis complex arises from mutations in the genes TSC1 (9q34) and TSC2 (16p13.3), encoding hamartin and tuberin, respectively.[1][5] A broad spectrum of mutations has been described in both genes, and while no particular regions seem more liable to mutations, the frequency is consistently higher for TSC2 than TSC1.[2]
Among patients who meet the clinical criteria for tuberous sclerosis, approximately 15% have no identifiable genetic mutations.[6]
Tuberous sclerosis complex affects approximately 1 in 6000 to 1 in 10,000 live births, with an overall prevalence of 1 in 20,000. Clinical presentation is extremely variable, usually affecting multiple organs and involving all racial groups.[1] In a longitudinal study involving 125 patients, the median age of presentation was 7 months.[7]
Tuberous sclerosis is a genetic disease that may affect almost every organ system. It involves mutations in genes (TSC1 and TSC2) that are responsible for the production of proteins that regulate cell division and growth in the body. When this balance is disrupted by the gene mutations, hamartomas may grow in the brain, skin, heart, kidney, liver, and lungs, affecting the function of these organs. [8][9][10]
TSC1 and TSC2 Gene Mutations
There are two specific gene mutations:
It is these genes that are thought to cause the characteristic tumors of the condition.
The gene mutation may be inherited or may occur spontaneously. Most cases present sporadically, with no known family history but approximately 1 in 3 patients inherit a defected TSC1 or TSC2 gene.
If a parent has tuberous sclerosis, their children will carry a 50% risk of inheriting the disease. It follows an autosomal dominant inheritance pattern, and males and females are equally affected.
Hamartin and Tuberin Protein
Hamartin and tuberin play a role in a complex that controls cell growth and division in the body. The exact mechanism of pathology that leads to unregulated cell growth and the appearance of tumors is not clear, but it is thought to be due to changes in the signaling of mTOR. The proteins hamartin and tuberin are thought to modulate gene transcription and suppress tumor growth.
Affected Areas and Organs
Tuberous sclerosis cause tumors to grow in multiple locations as a result, the severity of the condition varies between individuals.
The clinical presentation of TSC is highly variable, and manifestations will continue developing over a patient’s lifetime.[5] It commonly causes disabling neurological deficits like seizures, intellectual disability, and autism spectrum disorders.[1] A case series involving 125 cases, reported that seizures were the most common presentation in early childhood or infancy, followed by cardiac rhabdomyomas.[7]
Some tissues such as the skin may be more frequently affected than others.[2] Facial angiofibromas present in 75% of patients [3], while some neurological manifestations, such as seizures or intellectual disabilities may present in more than 80% of patients.[2][3]
Various skin manifestations are included in the major criteria for the diagnosis of tuberous sclerosis.[3][11] Hypomelanotic macules are the most common dermatological manifestation. These are present in approximately 90% of patients and manifest as lighter patches of skin. Facial angiofibromas commonly follow a butterfly or malar distribution [12], while shagreen patches present in areas of thicker skin as a leathery lesion with a pebbly texture.[3]
Renal angiomyolipomas may manifest in 55% to 75% of patients.[6][13] A longitudinal study showed a 75% prevalence of renal angiomyolipomas by the age of 10.5 years.[13] Other studies have shown radiographic evidence of lymphangiomyomatosis in 26% to 39% of female patients with TSC.[14][15]
Cardiac lesions may present in 50% to 70% of patients.[2]
The diagnosis of tuberous sclerosis, discussed below, consists of major and minor clinical criteria.[2] The diagnosis of tuberous sclerosis is often first made during childhood, when several dermatological features may become apparent.[16]
Tuberous sclerosis is mainly diagnosed based on clinical criteria, but it can also be diagnosed with genetic testing. If a patient fulfills the clinical criteria, however, genetic testing is not required [5], although it may provide useful information for other family members. Genetic testing of TSC1 and TSC2 is positive in 75% to 95% of individuals affected with TSC. Currently, there are reliable screening tests for TSC1 and TSC2, which are based on the detection of pathogenic mutations causing inactivation of the TSC1 or TSC2 proteins, leading to the loss inhibition of mTOR.[17][18]
As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[5][11]:
Major Features
Minor Features
Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[5][11]
The appropriate diagnosis should be made using either the clinical criteria or genetic testing. As most patients present dermatological features, the physical examination should include careful skin examination with the use of a Wood’s lamp, in addition to the funduscopic examination. Imaging tests will prove useful to identify lesions such as cardiac rhabdomyomas through echocardiography, tubers and subependymal tumors through MRI or CT. Renal angiomyolipomas can be adequately characterized with the help of either ultrasonography, CT, or MRI.[2]
The 2012 TSC consensus recommended that patients undergo lifetime surveillance to monitor for common manifestations.[5] For children with tuberous sclerosis, a 1- or 3-year lifetime surveillance, that includes imaging studies has been suggested.[4][11][12]
As discussed, the follow-up for TSC should be comprehensive, and it commonly presents a wide variety of multi-systemic complications. The dermatologic evaluation may aid in early recognition of angiofibromas that may eventually cause cosmetic disfigurations, which may require laser therapy or surgical removal.[2]
For renal angiomyolipomas larger than 3.5 cm, arterial embolization is recommended to avoid total nephrectomy and decrease the incidence of renal complications. Despite this effort, however, the incidence of complications, including chronic kidney disease, is similar in TSC patients who undergo partial versus complete nephrectomy.[19][20] For lesions measuring >3 cm, treatment with mTOR inhibitors is considered first-line therapy. For patients presenting with acutely bleeding renal angiomyolipoma, arterial embolization followed by corticosteroids is considered the treatment of choice.[1]
As recommended by the 2012 consensus for tuberous sclerosis, treatment of acutely symptomatic subependymal giant cell astrocytomas (SEGA) is surgical resection.[11] Surgical resection for symptomatic SEGA, however, is associated with a substantial increase in mortality and comorbidities, including hemiparesis, bleeding, infection, and cognitive decline. Asymptomatic SEGA may be treated with either surgical resection or therapy with mTOR inhibitors.[1] The FDA has approved everolimus for TSC patients with symptomatic SEGA not amenable to surgery.[21]
For patients with lymphangiomyomatosis, some sources recommend follow-up with an annual pulmonary function test to monitor for lung function deterioration.[2]
The differential diagnosis will vary and depend on the clinical manifestations of each case. Some clinical manifestations may raise the suspicion for tuberous sclerosis complex, including prenatal cardiac rhabdomyomas, infantile seizures, hypopigmented skin macules, and autism spectrum disorders.[22]
Each patient will present different manifestations of the disease and will, therefore, follow different clinical courses. Prognosis should be individualized. Each patient should be monitored annually and screened for common complications.[4]
Tuberous sclerosis affects multiple systems and may manifest in various tissues within a lifetime. Renal manifestations are common in patients with tuberous sclerosis complex. Approximately 55% to 75% of patients will present renal angiomyolipomas. Other common renal lesions include polycystic kidney disease, renal cysts, and renal cell carcinomas (RCC). The latter has a similar lifetime risk like the general population; however, they usually present at a younger age.[2]
Renal angiomyolipomas are commonly asymptomatic. However, these lesions have a risk of rupture and bleeding, and some patients may present with hemorrhage, flank pain, hematuria, or with a tender abdominal mass. Surgery is indicated for larger lesions that carry a higher risk of bleeding.[23]
Lymphangiomyomatosis may present in patients with tuberous sclerosis and is characterized by extensive proliferation of smooth muscle cells and cystic changes within the lung parenchyma. Commonly diagnosed during early childhood, presenting as dyspnea or spontaneous pneumothorax.[2]
Central nervous system manifestations are common. Patients with tuberous sclerosis complex may present subependymal nodules, cortical or subcortical tubers, and SEGA which[24] may manifest in 90% of patients.[24] Several studies have documented an association between the number of tubers with cognitive impairment and seizures.[25][26] SEGA present in approximately 10% to 15% of patients and usually presents in late childhood. These lesions may cause obstructive hydrocephalus due to their location and size. As previously discussed, surgery for these lesions also carries a substantial risk of mortality and other complications.[27][28]
Seizures are common in tuberous sclerosis and often refractory to medical treatment; for this reason, they may be treated surgically.[3]
Tuberous sclerosis is a disease that has a highly variable clinical course and has a wide range of possible manifestations. As such, the uncertainty and complexity of this disease may be daunting, particularly for family members.[1][4]
Genetic counseling is useful for patients and parents of children with tuberous sclerosis complex. Those parents affected should be advised that the risk of having an affected child is approximately 50%.[2] For parents who are not affected by the disease, the risk of having another child with TSC is around 1% to 2%. Parents may also be tested as they may present the disease after their children (parents may present mosaicism).[29]
Primary care providers, particularly community and acute pediatricians providing annual examinations for patients with tuberous sclerosis should focus on the common manifestations and complications of tuberous sclerosis and know which questions should be asked on each visit. Physical examination should also be comprehensive, and consultations to other specialties are done when necessary.[1][17]
Several clinics in the United States specialize in the follow-up and care for patients with tuberous sclerosis. Referral of patients to these centers should ensure that they will receive a comprehensive follow-up. When this is not possible, individual specialty referral should be done for different manifestations, such as epilepsy, or lymphangiomyomatosis, among others.[2]
[1] | De Waele L,Lagae L,Mekahli D, Tuberous sclerosis complex: the past and the future. Pediatric nephrology (Berlin, Germany). 2015 Oct; [PubMed PMID: 25533384] |
[2] | Crino PB,Nathanson KL,Henske EP, The tuberous sclerosis complex. The New England journal of medicine. 2006 Sep 28; [PubMed PMID: 17005952] |
[3] | Manoukian SB,Kowal DJ, Comprehensive imaging manifestations of tuberous sclerosis. AJR. American journal of roentgenology. 2015 May; [PubMed PMID: 25905927] |
[4] | Ng KH,Ng SM,Parker A, Annual review of children with tuberous sclerosis. Archives of disease in childhood. Education and practice edition. 2015 Jun; [PubMed PMID: 25112285] |
[5] | Northrup H,Krueger DA, Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatric neurology. 2013 Oct; [PubMed PMID: 24053982] |
[6] | Dabora SL,Jozwiak S,Franz DN,Roberts PS,Nieto A,Chung J,Choy YS,Reeve MP,Thiele E,Egelhoff JC,Kasprzyk-Obara J,Domanska-Pakiela D,Kwiatkowski DJ, Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. American journal of human genetics. 2001 Jan; [PubMed PMID: 11112665] |
[7] | Yates JR,Maclean C,Higgins JN,Humphrey A,le Maréchal K,Clifford M,Carcani-Rathwell I,Sampson JR,Bolton PF, The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. Archives of disease in childhood. 2011 Nov; [PubMed PMID: 21813552] |
[8] | Doubková M,Štefániková M,Čan V,Merta Z,Svoboda M, Lymphangioleiomyomatosis. Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti. 2019 Fall [PubMed PMID: 31610670] |
[9] | Lin S,Zeng JB,Zhao GX,Yang ZZ,Huang HP,Lin MT,Wu ZY,Wang N,Chen WJ,Fang L, Tuberous Sclerosis Complex in Chinese patients: Phenotypic analysis and mutational screening of TSC1/TSC2 genes. Seizure. 2019 Oct [PubMed PMID: 31525612] |
[10] | Gruber V,Scholl T,Samueli S,Gröppel G,Mühlebner A,Hainfellner JA,Feucht M, Pathophysiology of neurodevelopmental mTOR pathway-associated epileptic conditions: Current status of biomedical research. Clinical neuropathology. 2019 Sep/Oct [PubMed PMID: 31347492] |
[11] | Krueger DA,Northrup H, Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric neurology. 2013 Oct; [PubMed PMID: 24053983] |
[12] | Jóźwiak S,Schwartz RA,Janniger CK,Michałowicz R,Chmielik J, Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. International journal of dermatology. 1998 Dec; [PubMed PMID: 9888331] |
[13] | Ewalt DH,Sheffield E,Sparagana SP,Delgado MR,Roach ES, Renal lesion growth in children with tuberous sclerosis complex. The Journal of urology. 1998 Jul; [PubMed PMID: 9628635] |
[14] | Franz DN,Brody A,Meyer C,Leonard J,Chuck G,Dabora S,Sethuraman G,Colby TV,Kwiatkowski DJ,McCormack FX, Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. American journal of respiratory and critical care medicine. 2001 Aug 15; [PubMed PMID: 11520734] |
[15] | Costello LC,Hartman TE,Ryu JH, High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clinic proceedings. 2000 Jun; [PubMed PMID: 10852420] |
[16] | Staley BA,Vail EA,Thiele EA, Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics. 2011 Jan; [PubMed PMID: 21173003] |
[17] | Hoogeveen-Westerveld M,Ekong R,Povey S,Mayer K,Lannoy N,Elmslie F,Bebin M,Dies K,Thompson C,Sparagana SP,Davies P,van Eeghen AM,Thiele EA,van den Ouweland A,Halley D,Nellist M, Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. Human mutation. 2013 Jan; [PubMed PMID: 22903760] |
[18] | Caban C,Khan N,Hasbani DM,Crino PB, Genetics of tuberous sclerosis complex: implications for clinical practice. The application of clinical genetics. 2017; [PubMed PMID: 28053551] |
[19] | Curatolo P,Bombardieri R,Jozwiak S, Tuberous sclerosis. Lancet (London, England). 2008 Aug 23; [PubMed PMID: 18722871] |
[20] | Sooriakumaran P,Gibbs P,Coughlin G,Attard V,Elmslie F,Kingswood C,Taylor J,Corbishley C,Patel U,Anderson C, Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated. BJU international. 2010 Jan; [PubMed PMID: 19493268] |
[21] | Jóźwiak S,Nabbout R,Curatolo P, Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): Clinical recommendations. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2013 Jul; [PubMed PMID: 23391693] |
[22] | DiMario FJ Jr,Sahin M,Ebrahimi-Fakhari D, Tuberous sclerosis complex. Pediatric clinics of North America. 2015 Jun; [PubMed PMID: 26022167] |
[23] | Yamakado K,Tanaka N,Nakagawa T,Kobayashi S,Yanagawa M,Takeda K, Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology. 2002 Oct; [PubMed PMID: 12354988] |
[24] | Altman NR,Purser RK,Post MJ, Tuberous sclerosis: characteristics at CT and MR imaging. Radiology. 1988 May; [PubMed PMID: 3357966] |
[25] | Kassiri J,Snyder TJ,Bhargava R,Wheatley BM,Sinclair DB, Cortical tubers, cognition, and epilepsy in tuberous sclerosis. Pediatric neurology. 2011 May; [PubMed PMID: 21481739] |
[26] | Goodman M,Lamm SH,Engel A,Shepherd CW,Houser OW,Gomez MR, Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. Journal of child neurology. 1997 Feb; [PubMed PMID: 9075016] |
[27] | Goh S,Butler W,Thiele EA, Subependymal giant cell tumors in tuberous sclerosis complex. Neurology. 2004 Oct 26; [PubMed PMID: 15505165] |
[28] | Clarke MJ,Foy AB,Wetjen N,Raffel C, Imaging characteristics and growth of subependymal giant cell astrocytomas. Neurosurgical focus. 2006 Jan 15; [PubMed PMID: 16459995] |
[29] | Verhoef S,Bakker L,Tempelaars AM,Hesseling-Janssen AL,Mazurczak T,Jozwiak S,Fois A,Bartalini G,Zonnenberg BA,van Essen AJ,Lindhout D,Halley DJ,van den Ouweland AM, High rate of mosaicism in tuberous sclerosis complex. American journal of human genetics. 1999 Jun; [PubMed PMID: 10330349] |