Primary steps for primary care: Tuberous sclerosis complex (TSC)
TSC is an autosomal dominant neurocutaneous disorder affecting one in every 6,000-10,000 people. TSC manifests with multi-organ involvement including the skin, central nervous system, heart, lungs, eyes and kidneys. The most common identified cause is a variant in the tumor suppressor genes TSC1 or TSC2, on chromosomes 9p34 and 16p13, respectively. Abnormalities of these genes result in abnormal proteins, hamartin and tuberin, causing a permanent activation of the mTOR pathway which results in the formation of hamartomas in multiple organs. TSC may often come to the attention of primary care providers through recognition of typical skin findings or new onset of seizures.
What are the clinical manifestations of TSC?
- Ash-leaf spots: Hypopigmented leaf-shaped macules, present at birth. When clinically suspected, a careful Wood's lamp skin examination may be needed.
- Facial angiofibromas: Appear within the first decade of life, papules that affect mainly the malar region, nose, forehead and chin.
- Ungual fibromas.
- Connective tissue nevi: Shagreen patches, located mainly in the lumbosacral region.
- Gingival fibromas and enamel pits.
- Renal angiomyolipomas: Extremely common, progressively enlarge in adolescence and early adulthood.
- Renal cysts.
- Lymphangioleiomyomatosis: May affect pulmonary function and primarily seen in adult females.
- Rhabdomyoma: Typically manifest in the fetus and newborn, commonly asymptomatic, and often begin to involute within the first year of life.
- Epilepsy: Present in 70-90% and may present at any age. Typically, seizures are difficult to treat. Careful attention is needed to monitor for infantile spasms, as 10-25% of people with infantile spasms have TSC and this could be the first presentation of TSC. Urgent evaluation and treatment is needed if infantile spasms occur.
- Intellectual deficiency, autism spectrum disorder, mood disorders: Children may present with failure to meet developmental milestones.
- Neuroimaging findings (Figure 1): Cortical dysplasias, cortical and subcortical tubers, subependymal nodules, subependymal giant cell astrocytoma.
- Retinal hamartoma: Present in 30-50%.
How is TSC diagnosed?
TSC can be diagnosed clinically when a combination of major and minor features are present (Table 1). Genetic testing can also be used to support or confirm the diagnosis in the right clinical settings.
|Major criteria||Minor criteria|
|Hypomelanotic macules (> 3, > 5mm in diameter)||“Confetti” skin lesions|
|Angiofibromas (> 3)||Dental enamel pits (> 3)|
|Ungual fibromas (> 2)||Intraoral fibroma (> 2)|
|Shagreen patch||Retinal achromic patch|
|Multiple retinal hamartomas (> 2)||Multiple renal cysts|
|Cortical dysplasia||Nonrenal hamartomas|
|Subependymal giant cell astrocytoma|
|Angiomyolipomas (> 2)|
Definitive diagnosis: Presence of 2 major criteria or 1 major and 2 minor criteria.
Probable diagnosis: Presence of 1 major criterion or 2 or more minor criteria.
What is the initial evaluation and subsequent care for TSC?
The management of TSC typically requires a multidisciplinary approach depending on the manifestations of the disease. Care can be coordinated through a TSC clinic, such as the Genetic Epilepsy Clinic at Cook Children's [SPM1]. Often the treatment team will include members from Genetics, Neurology, Ophthalmology, Pulmonology, Nephrology and Odontology. Routine monitoring for manifestations of TSC are included in the evaluation guidelines below (Table 2). If a primary care provider suspects TSC, initial workup should include MRI of brain and kidneys, along with cardiac echo.
|Brain||Brain MRI every 1-3 years, until age 25, electroencephalogram (EEG) as needed, TSC associated neuropsychiatric disorder (TAND) screen annually|
|Heart||Echocardiogram every 1-3 years, until involution of rhabdomyoma, electrocardiogram (EKG) every 3-5 years|
|Kidneys||Annual blood pressure measurement, annual glomerular filtration rate, abdominal MRI every 1-3 years|
|Lungs||Pulmonary function tests annually, high-resolution chest computed tomography (CT) scan every 5-10 years|
|Skin, eyes||Annual clinical examination|
|Teeth||Bi-annual clinical examination|
|Genetics||Three-generation family history, consider genetic testing, genetic counseling|
To refer a patient to the Tuberous Sclerosis/Genetic Epilepsy Clinic at Cook Children's, call 682-885-2500.