Diagnosis of Tuberous Sclerosis Complex

E. Steve Roach MD; Steven P. Sparagana MD

Disclosures

J Child Neurol. 2004;19(9):643-649. 

In This Article

Abstract and Introduction

Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with tuberous sclerosis complex make it difficult to exclude the diagnosis of tuberous sclerosis complex in family members.

Tuberous sclerosis complex is a dominantly inherited disorder of cellular differentiation and proliferation that variably affects the brain, skin, kidneys, heart, and other organs. Because of its striking variability of clinical expression and severity, the diagnosis of tuberous sclerosis complex can be difficult, especially in young individuals or in those with subtle findings.[1] The genetics and biologic mechanisms of tuberous sclerosis complex are not nearly as straightforward as once believed. For these reasons, the diagnosis of tuberous sclerosis complex can be challenging.[1,2,3]

In 1998, a panel of international experts revised the diagnostic criteria for tuberous sclerosis complex at the Tuberous Sclerosis Complex Consensus Conference in Annapolis, Maryland.[4,5] The revised criteria ( Table 1 ) reflect an improved understanding of the clinical manifestations of tuberous sclerosis complex and its genetic and molecular mechanisms. Fundamental to the revised criteria was the agreement among the experts that there are no truly pathognomonic clinical signs for tuberous sclerosis complex; the signs that were once regarded as specific sometimes occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis.

Another departure from earlier tuberous sclerosis complex diagnostic criteria was the panel's decision not to include epilepsy and mental retardation as indicators of tuberous sclerosis complex. The group concluded that epilepsy and mental retardation were both so common in the general population and their causes so numerous that neither had sufficient specificity to be useful in the criteria. Additionally, most patients with epilepsy and mental retardation have cortical brain lesions on neuroimaging studies, and the number of such lesions tends to increase in rough proportion to the severity of the neurologic problems. There was concern that including both the symptoms and the lesions that caused the symptoms amounted to counting the same item twice.[1]

The consensus criteria were designed to establish a consistent and reliable standard for the diagnosis of tuberous sclerosis complex. It is much more difficult, however, to devise criteria that will exclude the diagnosis in affected individuals with few tuberous sclerosis complex signs or in younger patients who have yet to develop the full array of manifestations. Nevertheless, the revised criteria are still useful, even in very young patients or when the diagnostic evaluation is incomplete, because once sufficient evidence of tuberous sclerosis complex accumulates, a definite diagnosis can still be made. It is important, however, to periodically reassess these individuals over time or when more evidence becomes available.[6,7]

The revised diagnostic criteria (see Table 1 ) have been widely disseminated and have shown great utility in establishing the clinical diagnosis of tuberous sclerosis complex. Standardized criteria provide a quick, reliable, and economical method of establishing a diagnosis, and they help ensure uniformity in clinical tuberous sclerosis complex research. The addition of DNA-based testing complements clinical diagnosis and allows more precise genetic counseling and, in some cases, prenatal diagnosis. Our aim is to review the clinical features of tuberous sclerosis complex as they relate to diagnosis and the recent developments in confirmatory diagnosis.

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