Intrafamilial phenotypic variability in tuberous sclerosis complex

Clinical manifestations were retrospectively assessed in 5 families with tuberous sclerosis complex, including 1 pair of monozygotic twins. Interfamilial variation in tuber count was significantly larger than intrafamilial variation. Severity of epilepsy and cognitive profiles varied both between and within families, particularly between the monozygotic twins, and IQ was inversely related to tuber count. Cutaneous, renal, and cardiac findings did not appear to cluster within families. Although the monozygotic twins displayed similar physical manifestations of tuberous sclerosis complex (renal and cardiac hamartomas), they differed markedly in neurocognitive profiles. Phenotypic variation within these families may be explained largely as a function of the randomness of second-hit events that cause hamartomas in tuberous sclerosis complex or by as-yet-unidentified genetic modifiers. Familial variation in tuberous sclerosis complex phenotype has important implications for genetic counseling.