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At a glance

Neurodegenerative syndrome characterized by benign tumors and epilepsy. Some patients present with mental retardation and autism. Rhabdomyoma of the heart and astrocytoma in the brain are frequent tumoral presentation.

Synonyms

Bourneville Syndrome; Bourneville-Pringle Syndrome.

History

First described by the French neurologist Désiré-Magloire Bourneville in 1880 and Scottish dermatologist John James Pringle.

Incidence

From 1:25,000 to 1:30,000 live births. Nearly 1 million people worldwide are known to have tuberous sclerosis, including approximately 50,000 in the United States.

Genetic inheritance

Autosomal dominant with variable penetrance. Caused by mutations in either the TSC1 (9q33-34) or TSC2 (16p13) gene. TSC1 encodes the protein hamartin and TSC2 the protein tuberin. If two or more siblings have tuberous sclerosis, one parent always has at least one skin manifestation of tuberous sclerosis. Sporadic transmission rate varies from 58 to 77%. If both parents are normal, a child with tuberous sclerosis must be a new mutation. It is believed that only 33% of all tuberous scleroses are inherited.

Pathophysiology

Multiorganic disease affecting mainly the brain and skin, but also the heart, lung, kidney, bone, and eye. The proteins hamartin and tuberin are widely expressed throughout normal tissue and are involved in the mechanistic target of rapamycin (mTOR) pathway. mTOR is a serine/threonine kinases regulating cell proliferation. It regulates cell growth, size, and proliferation. Deregulation of the mTOR signaling pathway results in tissue overgrowth as the TSC2:TSC1 dimer complex stops mTOR activation.

Diagnosis

Heterogeneous disease with a wide clinical spectrum. The presence and importance of seizures is variable, as is the importance of mental retardation. In general, the youngest children at the moment of clinical presentation have the worse mental retardation. The diagnosis is based on clinical suspicion and demonstration of typical lesions on the skin or retina. A head MRI or CT scan often confirms the diagnosis. Epilepsy, mental retardation, “salaam” seizures, and angiofibromas of numerous organs with intracranial hamartomatous lesions involving subependymal nodules and cerebral cortical tubers are characteristic of this phakomatosis.

Clinical aspects

Clinical signs appear shortly after birth and worsen with age. Mental retardation and uncontrolled seizures occur in half of the cases. The principal finding is that of tuber lesions on the skin or in the brain. Skin lesions include adenoma sebaceum (80% of cases), which are rarely present at birth (onset at 4-6 years of age), and angiofibromas appearing as pink or red papules in patches or a butterfly-shaped distribution around the nose, cheek, and chin. Ash-leaf spots (90% of patients) are hypopigmented oval- or leaf-shaped spots found on the trunk and limbs in a linear orientation. The Shagreen patches (35% of patients) are isolated, “leathery,” raised, and thickened plaques, with an orange-peel consistency ...

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