Holt-Oram syndrome (HOS) is the name given to the condition of upper limb defects with congenital heart disease caused by variants in the TBX5 gene. The incidence is approximately 1 in 100,000 births.
Last updated November 2017 by Professor Ruth Newbury-Ecob, Consultant in Clinical Genetics, University Hospitals, Bristol, UK.
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At least 75% of people affected by HOS have heart defects. The most common problem is a defect in the muscular wall (septum) that separates the right and left sides of the heart. A hole in the septum between the upper chambers of the heart (atria) is called an atrial septal defect (ASD), and a hole in the septum between the lower chambers of the heart (ventricles) is called a ventricular septal defect (VSD), but other congenital (occurring at birth) heart defects can occur. Cardiac conduction disease, where the electrical signals that cause the heart to beat are abnormal, such as a slower-than-normal heart rate (bradycardia) or a rapid and uncoordinated contraction of the heart muscle (fibrillation) can also occur. Cardiac conduction problems or arrhythmias may be the only problem with the heart.
Abnormalities affect both arms but not necessarily in the same way. The limb defects in HOS are characteristically asymmetrical (not the same on both sides). At least one abnormality in the bones of the wrist (carpal bones) is present in affected individuals. The thumb is usually abnormal (triphalangeal – with three bones, like a finger), absent or underdeveloped. The forearms may be short or absent. The shoulders are usually narrow and sloping. The mildest signs are abnormal bending of the fifth finger and limited rotation of the joints of the forearms which allow the palms of the hands to face up. The most severe involve absence of all or part of the upper limb. These abnormalities may lead to early arthritis.
Sometimes the chest wall is affected, causing funnel or pigeon chest. The lower limbs are not involved and no other abnormalities, apart from those described above, are seen in HOS.
Mutations of the TBX5 gene cause HOS. This gene provides instructions for making a protein that plays a role in the development of the heart and upper limbs before birth. Another gene called SALL4 from the same gene pathway causes Okihiro syndrome, which is very similar to HOS.
The particular pattern of heart defects and upper limb abnormalities will suggest a diagnosis of HOS. X-rays may be needed to assess the abnormalities in the limbs. Echocardiography, imaging of the heart, may reveal heart defects. Conduction disturbances are often seen on electrocardiography (ECG), a test that monitors the electrical activity of the heart. A molecular genetic test on DNA from a blood sample can be used to confirm the diagnosis by finding a mutation in the TBX5 gene.
Surgical correction of heart defects may be possible in some cases. Cardiac conduction disease can be treated with medication or a pacemaker to control the heart rhythm. Occupational therapy, splinting and surgery may be required to improve limb function and a hand surgeon should be consulted to devise a care plan.
HOS is inherited by autosomal dominant inheritance. This means an affected parent has a 50% risk of having an affected child. Because the severity is very variable, a mildly affected parent may have a severely affected child. Unaffected relatives are not at risk of having an affected child.
In families where the specific gene mutation has been identified, genetic prenatal diagnosis may be available. This is carried out by testing DNA from the pregnancy via chorionic villus sampling or amniocentesis.
There is no support group for Holt-Oram syndrome in the UK. Families can use Contact’s freephone helpline for advice, information and, where possible, links to other families. To meet other families with disabled children, join Contact’s closed (private) Facebook group.
Support specifically for the upper limb abnormalities of Holt-Oram syndrome is also available from Reach (see entry Upper Limb Abnormalities).