What Is Timothy Syndrome?

Timothy syndrome (TS) is a rare genetic disorder that causes severe heart rhythm dysfunction, congenital heart defects, and global developmental delay. Many children born with the disorder have distinctive facial features, conjoined toes and fingers (syndactyly), and autism spectrum conditions.

In the past, most children born with TS died before age 3, usually as the result of sudden cardiac arrest, but survival has been improving in recent years.

Although the exact prevalence is not known, TS is thought to be extremely rare due to its severity. In one international group of 12 large pediatric centers, only 17 cases were diagnosed over 22 years.

Timothy Syndrome 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. Long QT syndrome subtype 8 (LQT8) is the genetic subtype that TS patients are affected with.

Long QT syndrome, especially the type seen in TS, is known to cause a ventricular arrhythmia called Torsades de Pointes that can quickly lead to death. This is often 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 classical or typical TS, formerly called TS type 1, which is characterized by any of a number of symptoms in addition to long QT:

• Cardiac arrhythmias: tachycardias, AV block
• Syndactyly (webbed fingers and toes)
• Distinctive facial features: low-set ears, flattened nasal bridge, thin upper lip
• Congenital heart defects: patent ductus arteriosis (PDA), ventral septal defect (VSD), patent foramen ovale (PFO)
• Small, widely spaced teeth
• Weak dental enamel and frequent cavities
• Thin scalp hair, baldness at birth
• Global developmental delay
• Autism
• Frequent or recurrent infections
• Seizures
• Episodes of hypoglycemia (low blood sugar)

There is also an atypical type of TS (formerly TS type 2) which causes a more severe form of long QT syndrome as well as an increased risk of sudden death. Unlike the classical form, the atypical type does not cause webbed fingers or toes. In addition, its symptoms may all be cardiac in nature.

Note, however, that LQT8 may occur without any other signs of Timothy syndrome.

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 contributed to death.
• Severe hypoglycemia: Blood glucose levels that drop below 36 milligrams per deciliter (mg/dL) can trigger arrhythmia in children with TS. This is especially true of those taking beta-blockers, as these drugs can make hypoglycemia symptoms harder to notice.

Causes

Timothy syndrome is caused by a mutation of the CACNA1C gene. This gene 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 in the brain and spinal cord).

In Timothy syndrome, 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 differences in those with TS.

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

Syndactyly and facial dysmorphism are also believed to be related to genetic mutation.

Pattern of Inheritance

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

Most cases are the result of a new gene mutation since there is no evidence of someone with TS having children. Why a spontaneous CACNA1C mutation occurs 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

In one case series, the average age of diagnosis was 17 months old. But some patients were diagnosed at birth and one was over 6 years old. Diagnosis may come sooner rather than later if a baby or child has prominent symptoms of TS (like syndactyly).

But because Timothy syndrome is so rare, many healthcare providers don't have experience diagnosing it.

Heart Tests

A TS diagnosis may only come about after investigation of the reason behind an arrhythmia or a long QT period found on an electrocardiogram (EKG).

The QT period is the timing between the recharging and release of electricity during a heartbeat. With long QT syndrome, the recharging is delayed between beats and the interval is elongated.

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

Genetic Testing

Genetic testing is the next step and the best way to confirm a TS diagnosis. A test called CACNA1C genetic sequencing can confirm TS. It can be performed on saliva or a 2- to 3-milliliter (mL) sample of blood.

If TS is diagnosed in a child, it may be advisable to test any siblings as well, in the event of genetic mosaicism of a parent.

Treatment

There are both medications and procedures that may improve the quality and length of life for a child with TS.

Medications

Chief among the medications that may be used to treat Timothy syndrome are beta-blockers like nadolol or propranolol. These can help maintain a normal QT interval.

Calcium-channel blockers such as Calan (verapamil) or Procardia (nifedipine) have also been used. These drugs slow the delivery of calcium to cells.

Note, however, that because there are are few children with this condition, no medications have been rigorously studied for this purpose in this patient group.

Antibiotics may be prescribed to treat bacterial infections. Macrolide antibiotics like Zithromax (azithromycin) and all other QT-prolonging medications need to be avoided.

Procedures

If a newborn has a severe heart block, a pacemaker may be recommended to help normalize heartbeats.

Once the child is large enough, they usually benefit from either an internal defibrillator (ICD) to "shock" the heart if it suddenly stops beating. Heart surgery may also be needed to repair structural defects.

ICD placement can significantly improve survival of sudden cardiac arrest, should it occur.

Other Considerations

The psychiatric and developmental needs of a child with TS may also need to be addressed.

Children with autism who have communication and socialization challenges may require applied behavioral therapy, communication therapy, and/or medications to control hyperactivity, anxiety, and other mood or behavioral disorders.

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

Because children with TS may have an arrhythmia from hypoglycemia and beta-blocker therapy can mask symptoms, they may need to undergo regular glucose monitoring to avoid low-blood-sugar events.

A Word From Verywell

It is important to remember that Timothy syndrome 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 healthcare provider about genetic testing or seek a second opinion from a clinical geneticist.