National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Holt-Oram syndrome


Other Names:
Heart-hand syndrome; HOS; Atriodigital dysplasia; Heart-hand syndrome; HOS; Atriodigital dysplasia; Ventriculo-radial syndrome; Atrio digital syndrome; Cardiac-limb syndrome; Heart-hand syndrome, type 1; HOS 1 See More
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Holt-Oram syndrome affects the bones of the hands and arms and may also affect the heart. People with Holt-Oram syndrome have at least one bone in the wrist that did not form (develop) normally. Other bones in the hands, arms, and shoulder may also have developed abnormally. Many of these developmental changes in the bones can only be seen on an x-ray. Most people with Holt-Oram syndrome also have heart problems, including problems due to the way the heart formed (congenital) or problems with the way the heart beats.[1][2]

Holt-Oram syndrome is caused by genetic changes (pathogenic variants or mutations) in the TBX5 gene. The syndrome is inherited in an autosomal dominant manner. A diagnosis of Holt-Oram syndrome may be suspected when a person has symptoms of the syndrome. An x-ray of the hands, wrists, and arms, echocardiogram of the heart, and genetic testing may be used to confirm the diagnosis. Treatment options for Holt-Oram syndrome may include surgeries to treat bone or heart problems, as well as physical therapy.[2] 
Last updated: 5/13/2018
The signs and symptoms of Holt-Oram syndrome include birth defects affecting the hands, wrists, arms, and heart. People with Holt-Oram syndrome have at least one of the bones in the wrist, the carpal bones, that is abnormally formed. Other bones of the upper limbs may also have formed abnormally. These may include having a missing thumb, a long thumb that looks like a finger, bones in the forearm or upper arm partially or completely missing, and problems with the shape of the collar bone or shoulder blades.[1] People with Holt-Oram syndrome may be unable to fully extend or rotate their arms.[2] In some cases, the bone abnormalities associated with Holt-Oram syndrome may only be visible on x-ray.[1]

About 75% of people who have Holt-Oram syndrome have heart problems. The most common problems are holes in the walls that separate the heart into four areas (chambers). These heart defects are known as atrial septal defects (ASD) or ventricular septal defects (VSD) depending on the exact location of the hole. Other heart defects including patent ductus arteriosus (PDA) have been reported.[3] The heart defects associated with Holt-Oram syndrome may not cause any problems or may cause symptoms such as having a hard time breathing, tiring easily (fatigue), having high blood pressure in the arteries of the lungs (pulmonary hypertension), and being smaller than expected (failure to thrive). In some cases, these heart defects may be life-threatening.[2] 

Some people with Holt-Oram syndrome have cardiac conduction disease, which is when the electrical system that coordinates the heartbeat does not work correctly. Cardiac conduction disease can lead to problems such as a slower than expected heart rate (bradycardia) or a rapid and uncoordinated contraction of the heart muscle (fibrillation).[1] Health problems associated with cardiac conduction disease may be more likely to develop as a person gets older.[2][4] 

The symptoms of Holt-Oram syndrome are similar to those of another syndrome called Duane-radial ray syndrome. However, these syndromes are caused by genetic changes (pathogenic variants or mutations) in different genes.[1] Holt-Oram syndrome may be associated with a wide range of signs and symptoms, even among members of the same family. This is called variable expressivity.[2]
Last updated: 5/13/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
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HPO ID
80%-99% of people have these symptoms
Abnormality of the clavicle
Abnormal collarbone
0000889
Joint stiffness
Stiff joint
Stiff joints
[ more ] 		0001387
Split hand
Claw hand
Claw hand deformities
Claw hands
Claw-hand deformities
Split-hand
[ more ] 		0001171
30%-79% of people have these symptoms
Abnormality of the metacarpal bones
Abnormality of the long bone of hand
0001163
Absent thumb
Absent thumbs
0009777
Aplasia/Hypoplasia of the radius 0006501
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers
[ more ] 		0001631
First degree atrioventricular block 0011705
Kyphosis
Hunched back
Round back
[ more ] 		0002808
Paroxysmal atrial fibrillation 0004757
Scoliosis 0002650
Triphalangeal thumb
Finger-like thumb
0001199
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629
5%-29% of people have these symptoms
Abnormal aortic morphology 0001679
Abnormality of the humerus 0003063
Abnormality of the ribs
Rib abnormalities
0000772
Anomalous pulmonary venous return 0010772
Atrioventricular canal defect 0006695
Broad thumb
Broad thumbs
Wide/broad thumb
[ more ] 		0011304
Down-sloping shoulders
Rounded shoulders
Rounded, sloping shoulders
Sloping shoulders
[ more ] 		0200021
Finger syndactyly 0006101
Hypoplastic left heart
Underdeveloped left heart
0004383
Patent ductus arteriosus 0001643
Pectus excavatum
Funnel chest
0000767
Phocomelia 0009829
Radioulnar synostosis
Fused forearm bones
0002974
Sprengel anomaly
High shoulder blade
0000912
1%-4% of people have these symptoms
Absent radius
Missing outer large bone of forearm
0003974
Aplasia of the pectoralis major muscle 0009751
Aplasia of the ulna 0003982
Finger clinodactyly 0040019
Hypoplasia of the radius
Underdeveloped outer large forearm bone
0002984
Hypoplasia of the ulna
Underdeveloped inner large forearm bone
0003022
Limited elbow extension
Decreased elbow extension
Elbow limited extension
Limitation of elbow extension
Limited extension at elbows
Limited forearm extension
Restricted elbow extension
[ more ] 		0001377
Secundum atrial septal defect 0001684
Short clavicles
Short collarbone
0000894
Short digit 0011927
Short humerus
Short long bone of upper arm
Short upper arms
[ more ] 		0005792
Small thenar eminence 0001245
Syndactyly
Webbed fingers or toes
0001159
Percent of people who have these symptoms is not available through HPO
Abnormal vertebral morphology 0003468
Abnormality of the carpal bones 0001191
Autosomal dominant inheritance 0000006
Partial duplication of thumb phalanx
Partial duplication of the thumb bones
0009944
Thoracic scoliosis 0002943
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Last updated: 7/1/2020
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.[1][4]

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.[4]
Last updated: 5/13/2018
Holt-Oram syndrome is inherited in an autosomal dominant manner.[1] 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.[2][4] 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.[2][4]
Last updated: 5/13/2018
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.[4] 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.[4][5] 
Last updated: 5/13/2018

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Orphanet lists international laboratories offering diagnostic testing for this condition.
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.[2] 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.[4] 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).[2][4]

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.[2][4]

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.[4]
Last updated: 5/13/2018
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.[3][5]  

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.[5]
Last updated: 5/13/2018

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes heart-hand syndrome type 2, heart-hand syndrome type 3, brachydactyly-long thumb, SAL4-related disorders (Okihiro and acro-renal-ocular syndrome), ulnar-mammary syndrome, Slovenian type heart-hand syndrome, Fanconi anemia, distal 22q11.2 microdeletion syndrome, VACTERL association, thalidomide embryopathy, fetal valproate syndrome.
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • Orphanet lists European clinical trials, research studies, and patient registries enrolling people with this condition. 

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Providing General Support

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Holt-Oram syndrome. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Holt-Oram syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Holt-Oram Syndrome. Genetics Home Reference. June 2014; http://ghr.nlm.nih.gov/condition/holt-oram-syndrome.
  2. Picache J and Basson CT. Holt Oram Syndrome. National Organization for Rare Disorders (NORD). 2017; https://rarediseases.org/rare-diseases/holt-oram-syndrome/.
  3. Sinha R and Nema C. Rare cardiac defect in Holt-Oram syndrome. Cardiovascular Journal of Africa. March 12, 2012; 23(2):e3-4. https://www.ncbi.nlm.nih.gov/pubmed/22447508.
  4. McDermott DA, Fong JC, Basson CT. Holt-Oram Syndrome. GeneReviews. October 8, 2015; http://www.ncbi.nlm.nih.gov/books/NBK1111/.
  5. Basson CT, Vaughan CJ, Kim LK, and McDermott DA. Holt-Oram Syndrome. Medscape Reference. May 5, 2016; http://emedicine.medscape.com/article/159911-overview.