Timothy syndrome (TS) is a rare genetic condition that associates
long QT syndrome, structural heart defects, dysmorphic facial features,
syndactyly,
seizures, developmental delay, and
autism.
Timothy syndrome type 1 is caused by a recurrent de novo mutation (p.Gly406Arg) in exon 8A of the
L-type calcium channel gene CACNA1C.
Timothy syndrome type 2 was originally reported to be associated with a more severe cardiac phenotype but without
syndactyly.
Timothy syndrome type 2 is caused by mutation in an alternatively spliced exon 8 of the CACNA1C gene. Other mutations in CACNA1C are also reported with
long QT syndrome with and without syndromic features overlapping that described in
Timothy syndrome. The purpose of this report is to describe the presentation, physical features and natural history of a 4-year-old girl with
Timothy syndrome type 2 due to the recurrent p.Gly406Arg mutation in exon 8 of CACNA1C. She has similar facial features to
Timothy syndrome type 1 without
syndactyly. She is developmentally delayed without
autism. She recently had her first episode of
torsade de pointes associated with febrile illness and
hypoglycemia. The findings in this case provide further information about the phenotype and natural history of CACNA1C exon 8 mutation and together with previously reported cases of
Timothy syndrome question whether the clinical and molecular distinction between Timothy syndromes types 1 and 2 remains clinically useful.