Diagnostic Accuracy of Clinical Manifestations in Identifying People With Tuberous Sclerosis Complex

Up to 10%-15% of people with tuberous sclerosis complex (PwTSC) do not carry an identifiable pathogenic variant in TSC1 or TSC2 and are diagnosed clinically. In such situations, family members cannot be screened using genetic testing. We aimed to establish the diagnostic accuracy of TSC clinical features to better guide the screening process for the families of PwTSC.

We used the TSC Natural History Database, a longitudinal database of PwTSC from 22 North American centers. We used a definite genetic TSC diagnosis as our gold standard. We estimated the sensitivity (95% CI) of TSC-related skin, structural brain, renal, and cardiac manifestations, as well as combinations of these manifestations. Using a series of sensitivity analyses to test alternate assumptions, we estimated positive predictive values and negative predictive values (PPVs and NPVs).

Among the 1,300 genetics-positive PwTSC, 50.3% were female and the mean age at diagnosis was 3.7 years. The sensitivity of at least one skin or structural brain manifestation was 98.7% (95% CI 98.0-99.2). The PPV and NPV were 83.2 (95% CI 81.6-84.6) and 98.4% (95% CI 97.8-98.8), respectively, while assuming 50% prevalence and 80% specificity. Including cardiac manifestations marginally increased the sensitivity, PPV, and NPV to 99.5% (95% CI 98.9-99.7), 83.3% (95% CI 81.8-84.7), and 99.4% (95% CI 99.0-99.6), respectively. Other combinations of TSC manifestations had lower or similar diagnostic accuracy.

Assessment of brain and skin manifestations in family members of genetics-positive PwTSC is sufficient to screen for TSC in most cases, with excellent sensitivity and NPV. Our findings are potentially applicable to family members of genetics-negative PwTSC. Further cardiac screening may optimize diagnostic accuracy in selected cases.

This study provides Class IV evidence that a combination of brain and skin manifestations is highly sensitive for diagnosing TSC in family members of patients with genetically confirmed TSC.