Disease Profile

Holt-Oram syndrome

Prevalence ?
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of Onset

Neonatal

ICD-10

Q87.2

Inheritance

Autosomal dominant ?A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive ?Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked dominant ?X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked recessive ?Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic ?Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor ?Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other Names (AKA)

Heart-hand syndrome; HOS; Atriodigital dysplasia;

Categories

Congenital and Genetic Diseases; Heart Diseases; Musculoskeletal Diseases

Summary

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-rayMost 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] 

Symptoms

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]

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.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal clavicle morphology
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

Cause

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]

Diagnosis

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 defectventricular 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]

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.

    Treatment

    Depending on the severity of the bone and heart problems, treatment for Holt-Oram syndrome may require a team of specialists including pediatricians, surgeons, cardiologistsorthopedists, 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]

    Organizations

    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

      Learn More

      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.

          References

          1. Holt-Oram Syndrome. Genetics Home Reference. June 2014; https://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; https://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; https://emedicine.medscape.com/article/159911-overview.