TimothySyndrom

Timothy syndrome, also written Timothysyndrom, is a rare congenital disorder characterized by a combination of cardiac, limb, and neurodevelopmental abnormalities. It is most commonly classified as long QT syndrome type 8 (LQT8) and is typically inherited in an autosomal dominant pattern. The condition is caused by mutations in the CACNA1C gene, which encodes the Cav1.2 subunit of L-type calcium channels.

Most cases involve a gain-of-function mutation in CACNA1C, most notably the G406R substitution, which reduces inactivation of Cav1.2 channels. This results in prolonged ventricular repolarization and a markedly extended QT interval on the electrocardiogram. Calcium channel dysfunction can affect multiple tissues, contributing to the array of systemic features observed in Timothy syndrome.

Clinical features commonly include a markedly prolonged QT interval with a risk of torsades de pointes and sudden death. Distinctive physical findings often include syndactyly, particularly of the fingers and toes, along with craniofacial dysmorphisms. Neurodevelopmental issues are also common, with reports of developmental delay and autism spectrum disorders. Other congenital anomalies may be present but are variable between individuals.

Diagnosis relies on recognizing the characteristic combination of clinical features and confirming the CACNA1C pathogenic variant through genetic testing. Differential diagnosis includes other types of long QT syndromes and syndromic conditions with similar limb or facial findings. Management focuses on preventing arrhythmias and may involve beta-blockers, avoidance of QT-prolonging drugs and electrolyte disturbances, and in selected high-risk cases, left cardiac sympathetic denervation or an implantable cardioverter-defibrillator. Ongoing multidisciplinary care is essential for monitoring cardiac status and neurodevelopment. Prognosis depends on the severity of cardiac involvement and the effectiveness of management.