Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that occurs in 1 of 6000 children; 85% of cases involve mutations in the TSC1 gene (9q34), which controls the production of hamartin, or 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.
Patients with TSC have tumors or abnormalities that manifest at different ages and in multiple organs, including the
Central nervous system (CNS) tubers interrupt neural circuits, causing developmental delay and cognitive impairment and may cause seizures, including infantile spasms Infantile Spasms Infantile spasms are seizures characterized by sudden flexion of the arms, forward flexion of the trunk, extension of the legs, and hypsarrhythmia on electroencephalography. Treatment is adrenocorticotropic... read more . Sometimes the tubers grow and obstruct flow of cerebrospinal fluid from the lateral ventricles, causing unilateral hydrocephalus Hydrocephalus Hydrocephalus is accumulation of excessive amounts of CSF, causing cerebral ventricular enlargement and/or increased intracranial pressure. Manifestations can include enlarged head, bulging... read more . Sometimes tubers undergo malignant degeneration into gliomas Gliomas Gliomas are primary tumors that originate in brain parenchyma. Symptoms are diverse and vary by location, manifesting as focal neurologic deficits, encephalopathy, or seizures. Diagnosis is... read more , particularly subependymal giant cell astrocytomas Astrocytomas Astrocytomas are childhood central nervous system tumors that develop from astrocytes. Diagnosis is based on MRI. Treatment is a combination of surgical resection, radiation therapy, and chemotherapy... read more (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 Autosomal Dominant Polycystic Kidney Disease (ADPKD) Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more may develop at any age. Kidney disease may cause hypertension.
Pulmonary lesions, such as lymphangioleiomyomatosis Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is an indolent, progressive growth of smooth muscle cells throughout the lungs, pulmonary blood vessels, lymphatics, and pleurae. It is rare and occurs in young... read more , may develop, particularly in adolescent girls.
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 Infantile Spasms Infantile spasms are seizures characterized by sudden flexion of the arms, forward flexion of the trunk, extension of the legs, and hypsarrhythmia on electroencephalography. Treatment is adrenocorticotropic... read more . Affected children may also have other types of seizures, intellectual disability Intellectual Disability Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient 70 to 75) combined with limitations of adaptive functioning... read more , autism Autism Spectrum Disorders Autism spectrum disorders are neurodevelopmental disorders characterized by impaired social interaction and communication, repetitive and stereotyped patterns of behavior, and uneven intellectual... read more , learning disorders Overview of Learning Disorders Learning disorders are conditions that cause a discrepancy between potential and actual levels of academic performance as predicted by the person’s intellectual abilities. Learning disorders... read more , or behavioral problems Overview of Behavioral Problems in Children Many behaviors exhibited by children or adolescents concern parents or other adults. Behaviors or behavioral patterns become clinically significant if they are frequent or persistent and maladaptive... read more .
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
Subungual fibromas, which can develop any time during childhood or early adulthood
Diagnosis of TSC
Identification of the skin lesions
Imaging of affected organs
Molecular genetic testing
The International Tuberous Sclerosis Complex Consensus Conference of 2012 defined major and minor criteria for making a definite or possible diagnosis of TSC (1 Diagnosis reference Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs. Diagnosis requires specific clinical criteria and imaging... read more ; see table International Tuberous Sclerosis Complex (TSC) Consensus Conference Criteria for the Diagnosis of TSC International Tuberous Sclerosis Complex (TSC) Consensus Conference Criteria for the Diagnosis of TSC ).
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.
1. Northrup H, D Krueger D, and on behalf of the International Tuberous Sclerosis Complex Consensus Group: Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49(4):243–254, 2013. doi: 10.1016/j.pediatrneurol.2013.08.001
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 serious disabilities.
Regardless of severity, most children show continued developmental progress.
Treatment of TSC
Sirolimus or everolimus
Treatment of TSC is both symptomatic and specific:
For seizures: Antiseizure drugs (especially vigabatrin for infantile spasms Infantile Spasms Infantile spasms are seizures characterized by sudden flexion of the arms, forward flexion of the trunk, extension of the legs, and hypsarrhythmia on electroencephalography. Treatment is adrenocorticotropic... read more ) or sometimes epilepsy surgery
For skin lesions: Dermabrasion or laser techniques
For neurobehavioral problems: Behavior management techniques or drugs
For hypertension caused by renal problems: Antihypertensives or surgery to remove growing tumors
For developmental delays: Special schooling or occupational therapy
For malignant tumors and some of the benign tumors: Everolimus or sirolimus
Although so far they are approved only for the treatment of subependymal giant cell astrocytomas Astrocytomas Astrocytomas are childhood central nervous system tumors that develop from astrocytes. Diagnosis is based on MRI. Treatment is a combination of surgical resection, radiation therapy, and chemotherapy... read more (SEGAs), growing evidence suggests oral sirolimus and its derivative, everolimus, may be used to prevent and treat most of the complications of TSC. These drugs 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 Treatment reference Tuberous sclerosis complex is a dominantly inherited genetic disorder in which tumors (usually hamartomas) develop in multiple organs. Diagnosis requires specific clinical criteria and imaging... read more ). Studies using these drugs 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.