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INTRODUCTION

KEY POINTS

  • Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by generalized hamartoma formation in nearly every organ, with various manifestations occurring throughout the individual’s lifetime.

  • Skin manifestations of TSC include angiofibromas, forehead plaques, hypomelanotic macules, shagreen patches, and ungual fibromas.

  • Hypomelanotic macules are observed in more than 90% of patients with TSC and are evident at birth or during early infancy. More than three hypomelanotic macules are useful for the diagnosis of TSC in infant.

  • Hypomelanotic macules are off-white in color and usually oval, polygonal, or ash leaf shaped, but sometimes appear as scattered numerous small white macules. Hypomelanotic macules present on the scalp, eyelashes, and eyebrows cause poliosis.

  • The hypomelanotic macules in TSC have a normal number of melanocytes but decreased number and size of melanosomes.

TUBEROUS SCLEROSIS COMPLEX

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited genetic disorder that can affect any organ in the body, with the most common findings observed in the skin, brain, kidneys, lungs, retina, and heart.1

The first description of TSC was provided in the early1800s by Ryer. TSC was initially described approximately 150 years ago by von Recklinghausen. Bourneville provided a detailed description of the neurologic symptoms and gross pathology in the central nervous system in 1880. Kirpicznik first recognized TSC to be a genetic disease in 1910, and Berg described the dominant inheritance of TSC in 1913. In 1993,2 the TSC2 gene was identified on chromosome 16p13, and in 1997, the TSC1 gene was cloned on chromosome 9q34.3 In 2002, the complex consisting of hamartin and tuberin, which are encoded by tumor suppressor genes TSC1 and TSC2, respectively, was reported to regulate the mammalian target of rapamycin (mTOR).4

Epidemiology

Prior to the 1980s, the incidence of TSC ranged between 1/100,000 and 1/200,000 individuals.5 Recent studies have estimated a frequency of 1/6000 to 1/10,000 live births. TSC occurs in all races and ethnic groups, and in both genders.6

Genetics and Pathogenesis

TSC is an autosomal dominant disease characterized by hamartoma formation. It was recognized to be a genetic disease over 100 years ago (by Kirpicznik in 1910). Two genes, TSC13 and TSC2,2 which encode hamartin and tuberin, respectively, have been shown to be responsible for TSC. Hamartin and tuberin associate physically in vivo and function in the same complex. The hamartin–tuberin complex inhibits the mTOR pathway.7 Therefore, mutations of TSC1 or TSC2, which cause abnormalities in hamartin and tuberin, respectively, result in defects of the inhibition of mTOR signaling. mTOR is a protein kinase with many functions in the regulation of protein synthesis, metabolism, differentiation, growth, and migration. Constitutive activation of mTOR is associated with abnormal cellular proliferation, which occurs in the hamartomatous lesions of TSC.

Clinical Findings

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