Clinical characteristics: Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.
Diagnosis/testing: Timothy syndrome is diagnosed by clinical features and by the presence of a pathogenic variant in CACNA1C, the gene encoding the CaV1.2 calcium channel.
Management: Treatment of manifestations: Treatment includes use of beta-blockers and/or other antiarrhythmic drugs to maintain QT interval stability to prevent ventricular tachyarrhythmia. In some instances pacemakers can be placed during the first days of life to control 2:1 AV block and resultant bradycardia, but an implantable cardioverter defibrillator to prevent sudden cardiac death should be considered in all affected persons. Treatment for congenital heart defects follows usual protocols. Prevention of secondary complications: Because anesthesia is a known trigger for cardiac arrhythmia, close cardiac monitoring is warranted during surgery. Surveillance: Monitoring of serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptoms. Agents/circumstances to avoid: Drugs reported to prolong QT interval; drugs and dietary practices that could lead to hypoglycemia. Evaluation of relatives at risk: Although Timothy syndrome usually occurs as a result of a de novo pathogenic variant, in rare instances sibs could be affected because of parental germline mosaicism; thus, monitoring of fetal cardiac rate and function during at-risk pregnancies is warranted.
Genetic counseling: Due to high mortality Timothy syndrome often results from a de novo pathogenic variant. The risk to sibs of a proband is small; however, because parental germline mosaicism occurs, the sibs of a proband may be at increased risk of inheriting a CACNA1C pathogenic variant. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.
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