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Holt-Oram Syndrome

Last updated Oct. 3, 2018

Approved by: Krish Tangella MD, MBA, FCAP

National Institutes of Health

The child presents bilateral hypoplastic clavicles and radii (A and C) and bilateral triphalangeal thumbs (B). Bradycardia due to atrioventricular block necessitates a pacemaker. This child male presents the typical manifestations of Holt-Oram syndrome.

What are the other Names for this Condition? (Also Known as/Synonyms)

  • Cardiac-Limb Syndrome
  • HOS (Holt Oram Syndrome)
  • Ventriculo-Radial Syndrome

What is Holt-Oram Syndrome? (Definition/Background Information)

  • Holt-Oram Syndrome (HOS) is a congenital disorder characterized by abnormalities in the hands, arms, and heart
  • Bone malformations are usually noticed in the wrists, thumb, forearm, and shoulder. The nature of cardiac problems can be varied and life-threatening
  • Treatment of this genetic condition is using a combination of methods that include medication, surgical measures, and physiotherapy for bone abnormalities
  • The prognosis is dependent upon the severity of HOS, but generally it is good with proper treatment

Who gets Holt-Oram Syndrome? (Age and Sex Distribution)

  • Holt-Oram Syndrome is present congenitally in approximately 1 in 100,000 individuals
  • Both males and females are equally prone to this disorder
  • A wide geographic distribution of HOS is observed; no preference for a particular race or ethnic group is seen

What are the Risk Factors for Holt-Oram Syndrome? (Predisposing Factors)

Risk of Holt-Oram Syndrome is thought to be linked to the following factors:

  • Family history of HOS
  • Family history of any heart- or limb- related deformity

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Holt-Oram Syndrome? (Etiology)

  • Holt-Oram Syndrome is caused by mutations in the TBX5 gene. Mutations in this gene can cause abnormal development of bones in the hands, wrists, and arms, as well as heart defects, prior to birth
  • In a small percentage of population, the abnormal gene is inherited in an autosomal dominant pattern; meaning that at least one of the parents must be affected by the disease, in order to pass it on to their children
  • However, a large majority of the cases occur spontaneously (de novo) and are not inherited. The reasons for spontaneous mutation in TBX5 gene is unknown

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Holt-Oram Syndrome?

The signs and symptoms of Holt-Oram Syndrome may include:

  • Abnormalities in the bones of the wrists are always present, although they may be detected only by an x-ray
  • Abnormalities of the thumb, forearm bones, upper arm, or (underdeveloped) shoulder bones are common. Additionally, the absence of a thumb and loss of some forearm bones may be observed
  • Often, the left side of the body is affected more than the right. However, either side can be affected, and both sides may be equally affected
  • About 75% of HOS-affected individuals will have heart abnormalities. These problems can include an opening between the left and right portions of the heart - atrial septal defect or ventricular septal defect, which are the most common heart defects
  • Defective electrical conduction system of the heart is also possible, which can lead to irregular heart rates or rhythms

How is Holt-Oram Syndrome Diagnosed?

Holt-Oram Syndrome may be diagnosed using the following tools:

  • Complete physical exam with evaluation of medical history, including family history
  • Radiographic studies of the wrists and chest
  • Cardiac echocardiography, ECG
  • Genetic and molecular analysis is helpful to establish a definitive diagnosis of the condition

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Holt-Oram Syndrome?

Some heart-related complications of Holt-Oram Syndrome could lead to sudden death, and these include:

  • Arrhythmia
  • Heart block
  • Congestive heart failure
  • Infectious endocarditis

How is Holt-Oram Syndrome Treated?

An individualized treatment is planned and provided based on the sign and symptoms of individuals with Holt-Oram Syndrome. Since, HOS affects many body systems and organs, the help and support of a diverse set of healthcare professionals are necessary.

The treatment measures may include:

  • For cardiac problems: Use of pacemaker, surgical intervention to correct defects, limited physical activity, drug therapy
  • For limb deformities: Surgical correction with physiotherapy
  • Anticoagulants are used in case of pulmonary hypertension

How can Holt-Oram Syndrome be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Holt-Oram Syndrome genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
  • Regular medical screening at periodic intervals with heart associated tests, scans, and physical examinations, are mandatory

What is the Prognosis of Holt-Oram Syndrome? (Outcomes/ Resolutions)

  • The prognosis of Holt-Oram Syndrome is dependent on the severity of the cardiac abnormalities
  • Nevertheless, with surgical correction of the defects and therapy, the prognosis is generally good

Additional and Relevant Useful Information for Holt-Oram Syndrome:

Holt-Oram Syndrome shares many features with another condition, called Duane-radial ray syndrome. However, both disorders are caused by mutations in different genes.

What are some Useful Resources for Additional Information?

References and Information Sources used for the Article:

Helpful Peer-Reviewed Medical Articles:

Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Aug. 8, 2014
Last updated: Oct. 3, 2018