#OMIM601005 – https://omim.org/entry/601005
Also known as: Long QT syndrome with syndactyly
1. The Disease:
A rare, multiple congenital anomalies syndrome with cardiac involvement as a major feature characterized by QT prolongation, congenital heart defects, syndactyly, facial dysmorphism and neurodevelopmental features. There are three clinical phenotypes recognized, the classical types that present with a prolonged QT interval and either with or without cutaneous syndactyly of fingers and toes. The atypical form causes multi-system health concerns but not necessarily with prolonged QT.
2. The symptoms:
Timothy syndrome often manifests during the neonatal period. However, in many cases it is diagnosed later, between the ages of 2-4 years old. Lack of early signs or symptoms does not exclude the diagnosis.
- In TS cardiac concerns may become apparent under anesthesia during finger separation surgery. Typical cardiac manifestations in all TS include a rate corrected QT interval >480 ms, functional 2:1 atrio-ventricular (AV) block associated with bradycardia, tachyarrhythmias and congenital heart defects (patent ductus arteriosus, patent foramen ovale, atrial or ventricular septal defects, tetralogy of Fallot, hypertrophic cardiomyopathy).
- Facial dysmorphia often includes round face, depressed nasal bridge, low set ears, thin vermilion of the upper lip, and hypoplasic premaxillary. Widely placed teeth with poor enamel is common. Hair is generally sparse. Cutaneous syndactyly is often noted in individuals. In TS without long QT, congenital hip abnormalities and/or hypotonia are often noted.
- Pulmonary health concerns include frequent pneumonia.
- Gastro-intestinal issues include severe constipation, and in some atypical forms, complications of chronic constipation may require surgical removal. Immunodeficiencies are common. Endocrinological concerns includes unusual fluctuations in blood sugar levels resulting in life threatening hypoglycemia, primarily associated with infections, and sleep issues; some children may require growth hormones.
- Neuronal-developmental concerns can be profound, autism or autistic spectrum disorders are noted, delayed speech and other physical, mental and social developmental milestones are generally delayed.
3. Actions to take in case of early diagnosis
- Babies with a positive genetic test (1 pathogenic variants in heterozygous state in the CACNA1C gene), should continue breastfeeding.
- The diagnosis is based on genetic results and clinical features.
- TS is a lifelong condition that requires lifetime management and regular follow-up with a paediatrician specialist in cardiology, geneticist, and a multidisciplinary approach to care.
- The main objective is to prevent ventricular fibrillation (VF) and possible sudden death.
- Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmic drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias.
- Drugs that prolong QT interval should be avoided, and all medical procedures requiring anaesthesia should be performed with caution. Additional congenital heart defects, respiratory infections, hypoglycaemia, and skeletal/smooth muscle anomalies should be managed according to standard protocols. Drugs and dietary practices that could lead to hypoglycaemia should be avoided for patients treated with beta-blockers.
- Genetic counselling is highly recommended for family planning and evaluation of at-risk family members.