What Is Timothy Syndrome?

A newborn baby sleeps in an infant incubator.
YDL / Getty Images
In This Article
Table of Contents

Timothy syndrome (TS) is a rare genetic disorder that causes severe heart rhythm dysfunction, intellectual disability, and seizures. Many children born with the disorder have distinctive facial features, webbing of toes and fingers, and characteristics of autism. Timothy syndrome can be confirmed with genetic testing and is treated with beta-blocker drugs or a pacemaker to normalize heart rhythm problems. A significant number of children born with TS die before age 3, usually as the result of sudden cardiac arrest.

Timothy syndrome is named for Katherine W. Timothy, M.D., of the University of Utah, who identified the disorder in 1989. In 2004, an international team of researchers, including Dr. Timothy, discovered the gene mutation responsible for the disorder.

Fewer than 100 cases of Timothy syndrome have been reported worldwide.

Also Known As:

  • Long QT syndrome with syndactyly
  • Long QT syndrome subtype 8
  • LQT8

Symptoms

The central feature of TS is a condition known as long QT syndrome in which the heart muscle takes longer than normal to recharge between beats. This may be accompanied by structural heart defects and an array of symptoms affecting the nervous system and other parts of the body.

Most children with TS have the classical form, TS type-1, which is characterized by any of a number of symptoms in addition to long QT:

  • Cardiac arrhythmia (abnormal heart rhythms)
  • Syndactyly (webbed fingers and toes)
  • Distinctive facial features: low-set ears, small upper jaw, flattened nasal bridge, thin upper lip
  • Misplaced teeth
  • Frequent cavities
  • Intellectual disability
  • Autism
  • Frequent or recurrent infections
  • Seizures
  • Episodes of hypothermia (low body temperature) and hypoglycemia (low blood sugar)

The second form of TS, known at TS type-2, causes a more severe form of long QT syndrome as well as an increased risk of sudden death. Unlike the classic form, this atypical type does not cause syndactyly and, in fact, may not cause any other symptoms at all.

Complications

Complications of Timothy syndrome that can further undermine a child's health include:

  • Bronchial and sinus infections: Some such infections persist even with aggressive antibiotic therapy and have caused several TS deaths.
  • Severe hypoglycemia: When blood glucose levels drop below 36 milligrams per deciliter (mg/dL) it can trigger arrhythmia in children with TS. This is especially true of those taking beta-blockers for whom the drug can make hypoglycemia worse.

Most early deaths attributed to Timothy syndrome are the result of ventricular tachyarrhythmia in which the lower chambers of the heart contract rapidly and erratically, leading to sudden cardiac arrest. According to a 2016 study in Circulation, the mortality rate in children diagnosed with TS since 2004 is 27%.

Causes

Timothy syndrome is caused by a mutation of the CACNA1C gene, which provides the body with instructions for how to create channels to deliver calcium to cells. Calcium is involved in numerous physiological functions, including heart contractions and cell-to-cell communication (including those in the brain and spinal cord).

In TS, the calcium channels of the body stay open longer than they should, allowing calcium to overload cells. When this occurs in the heart, the normal rhythm is disrupted, leading to arrhythmia and long QT syndrome.

It isn't clear how the overload of calcium affects the development and function of the brain, but it is believed to contribute to intellectual disabilities in those with TS.

CACNA1C has long been known to play a role in the development and survival of nerve cells. It also influences synaptic plasticity (the movement of signals between nerve cells).

Syndactyly and facial dysmorphism (features characteristic of a congenital anomaly) are also believed to be traced to mutations in or deletions of single developmental genes.

Pattern of Inheritance

Timothy syndrome is inherited in an autosomal dominant pattern, meaning it takes only one copy of a mutated CACNA1C gene from one parent for a child to develop the disorder.

Most cases are the result of a new gene mutation since there is no evidence of TS being passed through families. Why a spontaneous CACNA1C mutation occurs in a parent is unknown.

Less often, TS can occur as a result of genetic mosaicism. Mosaicism means that the parent has the mutation in some cells of their body (like the egg or sperm) but not others. Mosaicism is associated with less severe symptoms of TS compared to those who inherit the mutation in an autosomal dominant pattern.

Diagnosis

Because TS is so rare, it is likely overlooked in babies and children who present with arrhythmia (especially if the accompanying symptoms are subtle). In fact, only around half of the children born with TS will have facial dysmorphism. Other features, like intellectual disability, seizures, or dental problems, may not be recognized until a child is older.

Because of this, TS should be suspected if arrhythmia occurs in the first few days of life, is severe, or is accompanied by webbed fingers or toes and/or unusual facial features. Another subtle clue is that newborns with TS tend to be bald.

Evaluations and Lab Tests

If TS is suspected, an electrocardiogram (ECG) can be used to measure the QT interval (the timing between the recharging and release of electricity during a heartbeat). With long QT syndrome, the timing of a heartbeat will be chaotic as the recharging is delayed between beats.

A non-invasive echocardiogram (ultrasound of the heart) may also be used to detect structural problems with the heart itself.

A genetic test called CACNA1C genetic sequencing can confirm TS. It can be performed on saliva or a 2- to 3-milliliter (mL) sample of blood.

It usually takes between two to three weeks for the results of a CACNA1C genetic test to be returned.

Treatment

There are both medications and procedures that may improve the quality of life for a child with TS and perhaps extend their lifespan.

Medications

Chief among these is the use of calcium-channel blockers such as Calan (verapamil) or Procardia (nifedipine) which slow the delivery of calcium to cells. Because beta-blockers can influence blood sugar levels, a child with TS who takes them may need to have regular glucose monitoring to avoid hypoglycemic events.

Antibiotics may be prescribed to treat bacterial infections. Macrolide antibiotics like Zithromax (azithromycin) are typically avoided as they can trigger torsades de pointes (a serious type of arrhythmia) in people with a heart condition.

Procedures

If the arrhythmia is prolonged or recurrent, a pacemaker may be recommended to help normalize heartbeats. Severe cases may benefit from either an internal or external defibrillator to "shock" the heart if it suddenly stops beating. Heart surgery may also be needed to repair structural defects.

Extreme caution is needed when embarking on any surgical procedure as anesthesia can trigger severe arrhythmia in children with TS.

Other Considerations

The psychiatric and development needs of a child with TS may also need to be addressed. Children with autism who struggle with communication and socialization may require applied behavioral therapy, communication therapy, or medications to control hyperactivity, anxiety, and other mood or behavioral disorders.

TS is associated with weak tooth enamel and frequent cavities and so dental hygiene may need to be emphasized to help prevent cavities as well as secondary infections caused by oral disease.

A Word From Verywell

Timothy syndrome is not a diagnosis any parent wants to hear, but it is important to remember that TS has no predestined course or outcome. Some children with TS live for years and, with proper treatment, may avoid many of the more serious manifestations of the disorder.

Early diagnosis is key to the sustained control of TS symptoms. If you suspect your child has TS or wonder why it hasn't been explored after an arrhythmia event, ask your doctor about genetic testing or seek a second opinion from a clinical geneticist.

Was this page helpful?
Article Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Dufendach KA, Timothy K, Ackerman MJ, et al. Clinical outcomes and modes of death in Timothy Syndrome: A multicenter international study of a rare disorder. JACC Clin Electrophysiol. 2018;4(4):459-66. doi:10.1016/j.jacep.2017.08.007

  2. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119(1):19-31. doi:10.1016/j.cell.2004.09.011

  3. National Institutes of Health. Genetics Home Reference. Timothy syndrome. Mar 31, 2020.

  4. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP. Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet A. 2015;167A(3):629-34. doi:10.1002/ajmg.a.36924

  5. Bhat S, Dao DT, Terrillion CE, et al. CACNA1C (Cav1.2) in the pathophysiology of psychiatric diseaseProg Neurobiol. 2012;99(1):1–14. doi:10.1016/j.pneurobio.2012.06.001

  6. Boczek NJ, Best JM, Tester DJ, et al. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet. 2013;6(3):279-89. doI:10.1161/CIRCGENETICS.113.000138

  7. Dufendach KA, Giudicessi JR, Boczek NJ, Ackerman MJ. Maternal mosaicism confounds the neonatal diagnosis of type 1 Timothy syndromePediatrics. 2013;131(6):e1991-e1995. doi:10.1542/peds.2012-2941

  8. Napolitano C, Splawski I, Timothy KW, Bloise R, Priori SG. Timothy syndrome. In: GeneReviews. July 16, 2015.

  9. Beckmann BM, Wilde AAM, Ka, S. Clinical utility gene card for: Long-QT syndrome (types 1–13). Eur J Human Genetics. 2013;21:28. doi:10.1038/ejhg.2013.28

  10. Papineau SD, Wilson S. Dentition abnormalities in a Timothy syndrome patient with a novel genetic mutation: a case report. Pediatr Dent. 2014;36(3):245-9.

Additional Reading