Saturday, April 13, 2024

Genetics of Tuberous Sclerosis

Practice Essentials

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease.
It is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, patients with tuberous sclerosis complex may present with a broad range of clinical symptoms because of variable expressivity. Tuberous sclerosis complex may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic spots known as Fitzpatrick patches (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas. Regarding the genetic sources of epilepsy, tuberous sclerosis complex is among the most common. Epilepsy affects 90% of patients with the neurocutaneous condition, first becoming evident in most such individuals in the initial 2 years of life.
 Tuberous sclerosis complex provides a model for genetic epilepsy development and modification.

Anticonvulsant medication is the first treatment option for seizures, and neurosurgery is rarely required for refractory seizures. Magnetic resonance imaging (MRI), electroencephalography (EEG), and positron emission tomography (PET) scans to localize brain lesions are important prior to neurosurgery.

Mutations in either of two genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, diagnosis continues to be based on clinical manifestations.
. Molecular analysis is helpful in confirming a diagnosis and genetic counseling.

This article elucidates the various neoplasms, along with their clinical significance, and suggest suitable evaluation and management strategies.

Signs and symptoms of tuberous sclerosis complex

The most common and severe central nervous system (CNS) manifestations of tuberous sclerosis complex include seizures, such as infantile spasms, and mental retardation.

Hypomelanotic macules are overwhelmingly the most common early finding in tuberous sclerosis complex,
while renal angiomyolipomas are considered one of the major diagnostic features. Flank pain is the most common renal symptom.

Cardiac rhabdomyomas are often present at birth or during infancy but may be detected as early as 20 weeks’ gestation using fetal ultrasonography.

Lymphangiomyomas (LAM) and pulmonary cysts develop almost exclusively in women in the third or fourth decade of life and are present in fewer than 1% of females with tuberous sclerosis complex. LAM produces cystic lung disease adroitly characterized as a type of perivascular epithelioid cell tumor.
 Symptoms include dyspnea, hemoptysis, and development of spontaneous pneumothorax. Pulmonary fibrosis and hypertension may lead to cor pulmonale.

Most oral fibromas in tuberous sclerosis complex are gingival,
and nearly all patients have dental pits.

Workup in tuberous sclerosis complex

Testing to determine genetic mutations is now available only on a clinical basis. Once a person affected with tuberous sclerosis complex is found to have a mutation in the TSC1 or TSC2 gene, at-risk family members may be tested.

Brain MRI is recommended for the detection and follow-up imaging of cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs).

For renal evaluation, ultrasonography is usually preferred over computed tomography (CT) scanning and MRI because of availability and cost. In addition, ultrasonography is more sensitive in detecting renal lesions than CT scanning.

Obtain an echocardiogram at initial evaluation and in adults with tuberous sclerosis complex as clinically indicated. In children with previously detected cardiac lesions, obtain an echocardiogram every 6-12 months until lesions cease growing or begin to regress.

Obtain a CT scan of the lung in adult females with tuberous sclerosis complex, beginning at age 18 years, even in the absence of symptoms. Pulmonary pathology is almost nonexistent in males.

Management of tuberous sclerosis complex

Medical care is aimed at seizure control using various anticonvulsants. Begin treatment with monotherapy and increase the dose gradually until seizures are well controlled or the dose is limited by adverse effects.

Lymphangioleiomyomatosis (LAM) may respond to therapy using progesterone and oophorectomy.

Consider inotropic agents in patients with evidence of decreased contractility and cardiomyopathy due to rhabdomyoma. Antihypertensive medication may be required in patients with renal disease and subsequent hypertension; an angiotensin-converting enzyme (ACE) inhibitor may be the first drug of choice.

Kidney surgery for angiomyolipomas usually consists of enucleation or partial nephrectomy. Renal arterial embolization is an additional treatment option.

Some believe that early epilepsy surgery is associated with seizure freedom in children with tuberous sclerosis complex and intractable epilepsy.

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