Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that occurs in 1 of 6000 children (1); 85% of cases involve mutations in the TSC1 gene (9q34), which controls the production of hamartin, or in the TSC2 gene (16p13.3), which controls the production of tuberin. These proteins act as growth suppressors. If either parent has the disorder, children have a 50% risk of having it. However, new mutations account for two thirds of cases (1).
Patients with TSC have tumors or abnormalities that manifest at different ages and in multiple organs, including the
Brain
Heart
Eyes
Kidneys
Lungs
Skin
Central nervous system (CNS) tubers interrupt neural circuits, causing developmental delay and cognitive impairment and may cause seizures, including infantile spasms. Sometimes the tubers grow and obstruct flow of cerebrospinal fluid from the lateral ventricles, causing unilateral hydrocephalus. Sometimes tubers undergo malignant degeneration into gliomas, particularly subependymal giant cell astrocytomas (SEGAs).
Cardiac rhabdomyomas may develop prenatally, sometimes causing heart failure in neonates. These rhabdomyomas tend to disappear over time and usually do not cause symptoms later in childhood or in adulthood.
Kidney tumors (angiolipomas) may develop in adults, and polycystic kidney disease may develop at any age. Kidney disease may cause hypertension.
Pulmonary lesions, such as lymphangioleiomyomatosis, may develop, particularly in adolescent girls.
Reference
1. De Waele L, Lagae L, Mekahli D: Tuberous sclerosis complex: The past and the future. Pediatr Nephrol 30(10):1771-1780, 2015. doi: 10.1007/s00467-014-3027-9
Symptoms and Signs of TSC
Manifestations vary greatly in severity. Skin lesions are typically present.
Infants with CNS lesions may present with a type of seizure called infantile spasms. Affected children may also have other types of seizures, intellectual disability, autism, learning disorders, or behavioral problems.
Retinal achromic patches as well as retinal hamartomas are common and may be visible with funduscopy.
Pitting of enamel in permanent teeth is common.
Skin findings include
Initially pale, ash leaf–shaped macules, which develop during infancy or early childhood
Angiofibromas of the face (adenoma sebaceum), which develop during later childhood
Congenital shagreen patches (raised lesions resembling an orange peel), usually on the back
Subcutaneous nodules
Café-au-lait spots
Subungual fibromas (Koenen tumors), which can develop any time during childhood or early adulthood
By permission of the publisher. From Puduvalli V: Atlas of Cancer. Edited by M Markman and R Gilbert. Philadelphia, Current Medicine, 2002.
DR M.A. ANSARY/SCIENCE PHOTO LIBRARY
Photo courtesy of Karen McKoy, MD.
© Springer Science+Business Media
By permission of the publisher. From Puduvalli V: Atlas of Cancer. Edited by M Markman and R Gilbert. Philadelphia, Current Medicine, 2002.
DR M.A. ANSARY/SCIENCE PHOTO LIBRARY
Photo courtesy of Karen McKoy, MD.
© Springer Science+Business Media
Diagnosis of TSC
Clinical criteria
Identification of the skin lesions
Imaging of affected organs
Molecular genetic testing
The International Tuberous Sclerosis Complex Consensus Group has defined major and minor criteria for making a definite or possible diagnosis of TSC (1) (see table International Tuberous Sclerosis Complex (TSC) Diagnostic Criteria).
A definite diagnosis of TSC by these criteria requires either of the following:
The identification of either a TSC1 or TSC2 pathogenic mutation by molecular genetic testing
Two major features or 1 major feature with 2 minor features
A possible diagnosis of TSC by these criteria requires the following:
Either 1 major feature or ≥ 2 minor features
Physical examination is done to check for typical skin lesions. Funduscopy should be done to check for retinal achromic patches.
TSC may be suspected when fetal ultrasonography detects cardiac rhabdomyomas or when infantile spasms occur.
Cardiac or cranial manifestations may be visible on routine prenatal ultrasonography. MRI or ultrasonography of the affected organs is necessary for confirmation.
Specific genetic testing is available.
Diagnosis reference
1. Northrup H, Aronow ME, Bebin EM, et al: Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol 123:50-66, 2021. doi: 10.1016/j.pediatrneurol.2021.07.011
Treatment of TSC
Symptomatic treatment
Sirolimus or everolimus
Treatment of TSC is both symptomatic and specific:
infantile spasms) or sometimes epilepsy surgery
For neurobehavioral problems: Behavior management techniques or medications
For hypertension caused by renal problems: Antihypertensives or surgery to remove growing tumors
For developmental delays: Special schooling or occupational therapy
Although so far they are approved only for the treatment of subependymal giant cell astrocytomas (SEGAs), growing evidence suggests oral sirolimus and its derivative, everolimus, may be used to prevent and treat most of the complications of TSC. These medications have been shown in some patients to shrink brain tubers, cardiac rhabdomyomas that are too large to be resected, and facial lesions and to lessen seizures. Topical sirolimus may be helpful for facial angiofibromas (1). Studies using these medications for these and other complications of TSC are ongoing.
Genetic counseling is indicated for adolescents and adults of childbearing age.
Screening for complications
All patients should be screened regularly to detect complications of TSC early. Typically, the following is done:
MRI of the head to check for intracranial complications (eg, SEGAs) at least every 3 years
Renal ultrasonography or MRI of the abdomen to check for kidney tumors every 3 years in school-aged children and every 1 to 2 years for life in affected adults
In girls ≥ 18 years, screening for exertional dyspnea and shortness of breath annually and high-resolution CT every 5 to 10 years to screen for lymphangioleiomyomatosis
Neuropsychologic testing periodically and behavioral screening in children to help plan for support at school and behavioral interventions
Echocardiography at least every 3 years for asymptomatic children and adolescents with cardiac rhabdomyomas
Regular monitoring must be continued until cardiac rhabdomyomas have regressed.
Clinical monitoring is also important and sometimes prompts more frequent testing. Development of headaches, loss of skills, or new types of seizures may be caused by malignant degeneration or growth of CNS tubers and are indications for neuroimaging.
Treatment reference
1. Darling T: Topical sirolimus to treat tuberous sclerosis complex (TSC). JAMA Dermatol 154(7):761–762, 2018. doi: 10.1001/jamadermatol.2018.0465
Prognosis for TSC
Prognosis depends on symptom severity. Infants with mild symptoms generally do well and live long, productive lives; infants with severe symptoms may have severe disabilities.
Regardless of severity, most children show continued developmental progress.
Key Points
Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs.
Manifestations vary greatly; skin lesions are typically present.
Diagnose using clinical criteria, identification of characteristic skin lesions, imaging of affected organs, and molecular genetic testing.
Treat symptomatically and specifically for the multiple complications.
