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. It results from mutations in the genes TSC1 and TSC2 and is known for causing neurological disorders including epilepsy and intellectual disability.
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.
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. 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.
This disease has a highly variable clinical course. Prognosis may be uncertain, and follow-up requires 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.
Tuberous sclerosis complex arises from mutations in the genes TSC1 (9q34) and TSC2 (16p13.3), encoding hamartin and tuberin, respectively. 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.
Among patients who meet the clinical criteria for tuberous sclerosis, approximately 15% have no identifiable genetic mutations.
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. In a longitudinal study involving 125 patients, the median age of presentation was 7 months.
As previously discussed, the clinical presentation of TSC is highly variable, and manifestations will continue developing over a patient’s lifetime. It commonly causes disabling neurological deficits like seizures, intellectual disability, and autism spectrum disorders. A case series involving 125 cases, reported that seizures were the most common presentation in early childhood or infancy, followed by cardiac rhabdomyomas.
As clinical manifestations vary, some tissues such as the skin may be more frequently affected than others. Facial angiofibromas present in 75% of patients , while some neurological manifestations, such as seizures or intellectual disabilities may present in more than 80% of patients.
Various skin manifestations are included in the major criteria for the diagnosis of tuberous sclerosis. Hypomelanotic macules are the most common dermatological manifestation. These are present in approximately 90% of patients and manifest as lighter patches of skin. As previously discussed, facial angiofibromas present in 75% of patients, and commonly follow a butterfly or malar distribution , while shagreen patches present in areas of thicker skin as a leathery lesion with a pebbly texture.
Renal angiomyolipomas may manifest in 55% to 75% of patients. A longitudinal study showed a 75% prevalence of renal angiomyolipomas by the age of 10.5 years. Other studies have shown radiographic evidence of lymphangiomyomatosis in 26% to 39% of female patients with TSC.
Cardiac lesions may present in 50% to 70% of patients.
The diagnosis of tuberous sclerosis, discussed below, consists of major and minor clinical criteria. The diagnosis of tuberous sclerosis is often first made during childhood, when several dermatological features may become apparent.
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 , 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.
As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference the diagnostic criteria for tuberous sclerosis includes the following major and 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.
As previously described, 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 either ultrasonography, CT, or MRI.
The 2012 TSC consensus recommended that patients undergo lifetime surveillance to monitor for common manifestations. For children with tuberous sclerosis, a 1- or 3-year lifetime surveillance, that includes imaging studies has been suggested.
As discussed, 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 posteriorly require laser therapy or surgical removal.
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. 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.
As recommended by the 2012 consensus for tuberous sclerosis, treatment of acutely symptomatic subependymal giant cell astrocytomas (SEGA) is surgical resection. 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. The FDA has approved everolimus for TSC patients with symptomatic SEGA not amenable to surgery.
For patients with lymphangiomyomatosis, some sources recommend follow-up with an annual pulmonary function test to monitor for lung function deterioration.
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.
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.
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 as the general population; however, they will present at a younger age.
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 which carry a higher risk of bleeding.
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.
Central nervous system manifestations are common. Patients with tuberous sclerosis complex may present subependymal nodules, cortical or subcortical tubers, and SEGA.
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.
Seizures are common in tuberous sclerosis and often refractory to medical treatment; for this reason, they may be treated surgically.
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.
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%. 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).
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.
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.
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