Tuberous Sclerosis

ABSTRACT

• Tuberous sclerosis is a multisystem hamartomatosis that is transmitted as an autosomal dominant trait with highly variable expression. Prevalence among newborns is estimated to be over 1 in 10,000 and is not thought to show significant geographic variation.

• Frequent manifestations of tuberous sclerosis include seizures, intellectual handicap, behavioral problems, a variety of skin lesions, and renal angiomyolipomas and cysts. Cardiac rhabdomyomas and hepatic angiomas are also common, but usually asymptomatic. The lungs and endocrine system are less frequently involved. Management is directed toward the early detection and treatment of important medical and psychological complications and the provision of genetic counseling.

• Two tuberous sclerosis-determining genes have been identified by positional cloning and are termed TSC1 and TSC2. A wide range of inactivating germ line mutations occur in patients with tuberous sclerosis. Demonstration of loss of heterozygosity or intragenic mutations affecting the corresponding wild-type allele in hamartomas indicates that both genes function as Knudson-type tumor suppressors.

• The TSC1 and TSC2 encoded proteins hamartin and tuberin are not homologous but interact directly with one another to form a largely cytosolic complex. Their cellular roles are not well understood.

• The Eker rat is a naturally occurring model of TSC2 inactivation. Its recognition has facilitated direct experimental confirmation of the tumour suppressor properties of TSC2. The gigas phenotype in Drosophila results from inactivating mutations of a gene orthologous to TSC2. Homozygous gigas −/− cells exhibit a phenotype of cellular hypertrophy and endoreduplication of DNA.

INTRODUCTION

Tuberous sclerosis (MIM 191100, 191092), or the tuberous sclerosis complex (TSC),^1,2 is still sometimes referred to by the eponymous titles of Bourneville disease³ or Pringle disease.⁴ In the past, the now redundant neologism epiloia (epilepsy and anoia or mindlessness) was commonly applied.^5,6 TSC has protean manifestations and may be encountered in any branch of clinical medicine. Two TSC determining genes, TSC1 and TSC2, were identified during the 1990s. Molecular genetic analysis of constitutional mutations in affected individuals and of somatic mutations in TSC-associated hamartomas has elucidated a tumor suppressor mechanism that underlies the phenotypic manifestations in many organs. The TSC1 and TSC2 genes encode novel proteins that have been termed hamartin and tuberin for which the cellular roles are largely unknown.

CLINICAL FINDINGS AND DIAGNOSIS

Central Nervous System Manifestations

Many of the most frequent and serious complications of TSC reflect involvement of the brain. These include epilepsy in approximately 80 percent of patients, intellectual handicap in up to 50 percent, and autism and other behavioral abnormalities in over 50 percent.⁷ Cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas are central nervous system hallmarks of TSC^8,9 (Fig. 282-1). Abnormal white matter migration tracks, abnormalities of myelination, and cerebellar lesions similar to tubers also occur. By contrast, the spinal cord is rarely, if ever, affected. Tubers are discrete areas ...