Holt-Oram syndrome

What causes Holt-Oram syndrome?

Holt-Oram syndrome is caused by changes (pathogenic variants or mutations) in the TBX5 gene. This gene provides instructions to the body for making a protein involved in the development of the heart and upper limbs before birth. This gene seems especially important in dividing the developing heart into four chambers and in controlling the way the bones in the arms, wrist, and hands form. When the TBX5 gene doesn’t function properly, it can cause the heart and bones of the upper limbs to develop incorrectly. This causes the signs and symptoms of Holt-Oram syndrome.

In some cases, people with Holt-Oram syndrome are not found to have pathogenic variants in the TBX5 gene. In these cases, the exact cause of Holt-Oram syndrome is not understood.

Last updated on 05-01-20

How is Holt-Oram syndrome diagnosed?

A diagnosis of Holt-Oram syndrome may be suspected when a person is found to have changes in the way the bones of the wrist and other bones of the upper limb are formed. The diagnosis can be confirmed if a person has specific bone changes and a personal or family history of an atrial septal defect, ventricular septal defect, or cardiac conduction disease. In order to establish the diagnosis, a doctor may order tests including an x-ray of the hands, wrists, and arms, a test that examines the structure of the heart (echocardiogram), and a test of the electrical rhythm of the heart (electrocardiogram). The diagnosis may also be confirmed with genetic testing of the __TBX5 gene.

Last updated on 05-01-20

How is Holt-Oram syndrome inherited?

Holt-Oram syndrome is inherited in an autosomal dominant manner. Like most genes, the TBX5 gene comes in a pair (two copies). Autosomal dominant means that having only one changed copy of the TBX5 gene is enough to cause the signs and symptoms of Holt-Oram syndrome. We inherit one copy of the TBX5 gene from our mother and the other from our father. When a person with Holt-Oram syndrome has children, for each child there is a:

  • 50% chance to inherit the changed copy of the TBX5 gene, meaning the child will have Holt-Oram syndrome
  • 50% chance to inherit the working copy of the TBX5 gene, meaning the child will not have Holt-Oram syndrome

In about 85% of cases, the genetic change (pathogenic variant or mutation) in the TBX5 gene is happening for the first time in the person with Holt- Oram syndrome and is not inherited from a parent. When a pathogenic variant occurs for the first time, it is called de novo.

In some cases, a person with Holt-Oram syndrome inherits the changed copy of the gene from a parent who has one copy of the changed gene, but the parent did not know he or she had Holt-Oram syndrome. This may happen because there may only be slight changes in one or more bones of the wrist and little or no changes in the other bones and in the heart. Remember, the changes caused by Holt-Oram syndrome can differ, even among members of the same family. This is called variable expressivity. Because the symptoms of Holt-Oram syndrome can vary, it is not possible to predict how future children who have a pathogenic variant in the TBX5 gene may be affected.

Last updated on 05-01-20

What is the long-term outlook for people with Holt-Oram syndrome?

The long-term outlook for people with Holt-Oram syndrome may depend on the severity of heart defects. Some people with Holt-Oram syndrome have no heart problems, or the problems are mild and only require occasional monitoring by a cardiologist. In other cases, heart defects associated with Holt-Oram syndrome may be severe and, in some cases, life-threatening.

Differences in the bones of the wrist, hand, arm, and shoulder associated with Holt-Oram syndrome may cause a person to have physical limitations that can affect their everyday lives. These birth defects can also impact social interactions, especially for children whose arms and hands are noticeably different from other children.

Last updated on 05-01-20

How might Holt-Oram syndrome be treated?

Depending on the severity of the bone and heart problems, treatment for Holt- Oram syndrome may require a team of specialists including pediatricians, surgeons, cardiologists, orthopedists, and geneticists. Treatment of wrist bone and other upper limb bone problems may include corrective or reconstructive surgery, the use of limb prosthetics, and physical or occupational therapies. The goal of treatment is to help people with Holt-Oram syndrome have as much use of the upper limbs as possible. These therapies may be most effective if they are started as soon as a person is diagnosed with Holt-Oram syndrome. In some cases, the changes in the way the bones formed in the wrist and upper limbs may not cause any problems or need any treatments. In these cases, the bone abnormalities may not even be noticed unless an x-ray is being performed for another reason (incidental finding).

People with mild heart defects or cardiac conduction disease may not require any treatment. In other cases, cardiac conduction disease may be treated with antiarrhythmic medications or a pacemaker to maintain a regular heart rate. Other heart abnormalities may be treated with surgery. The specific surgical procedure will depend on the location and severity of the heart defect.

People with heart defects may be at an increased risk for bacterial infection and inflammation of the lining of the heart’s chambers and valves (endocarditis). Antibiotics may be prescribed before surgical procedures to reduce the risk for infection.

Last updated on 05-01-20

Name: Congenital Heart Information Network (C.H.I.N.) P.O. Box 3397
Margate City, NJ, 08402-0397, United States
Phone: (609) 823-4507 Fax : 609-822-1574 Email: mb@tchin.org Url: https://www.facebook.com/TCHIN.org?
Name: Kids with Heart National Association for Children's Heart Disorders 1578 Careful Drive
Green Bay, WI, 54304, United States
Email: https://kidswithheart.org/page/contact Url: https://kidswithheart.org/
Name: Little Hearts, Inc. P.O. Box 171
Cromwell, CT, 06416, United States
Phone: (860) 635-0006 Toll Free: (866) 435-4673 Email: https://www.littlehearts.org/ContactForm/default.asp Url: https://www.littlehearts.org

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