What is Holt-Oram Syndrome?
Holt-Oram syndrome, also known as the heart-hand syndrome, is a genetic disorder that causes abnormalities in the upper limbs and heart defects from birth. The syndrome was first described in 1960 by two doctors named Holt and Oram, who noticed thumb anomalies (unusual features) and holes in the heart’s wall (known as atrial septal defects or ASD) running in four generations of a family. Since then, more cases have been identified and technology has advanced, helping us understand this syndrome better. Despite advancements, it’s important to note that people continue to be born with this disorder worldwide, in both developed and less-developed countries.
What Causes Holt-Oram Syndrome?
Holt-Oram syndrome is caused by a genetic mutation in what’s known as the TBX5 gene, found on a specific region of chromosome 12. The TBX5 gene carries the instructions for creating a ‘manager’ protein (transcription factor) responsible for guiding the formation of heart and limb structures in a developing embryo. Specifically, this gene helps with the process of forming the heart’s internal walls (cardiac septation) and developing bones in arms and hands. The majority of people diagnosed with Holt-Oram syndrome – over 85% – have this genetic mutation.
The syndrome is a type of disorder called ‘autosomal dominant’, meaning that the condition can develop even if a person only has one copy of the mutated gene in their cells. In practical terms, this means an affected parent has a 50% chance of passing on the mutated gene to their children. That said, most Holt-Oram syndrome cases are sporadic, which means they occur by chance from a new mutation and are not inherited from either parent.
The syndrome almost always leads to some form of upper-limb abnormalities. In 75% of cases, it leads to heart defects as well. However, the symptoms can vary widely from person to person, due to differences in how the mutated gene is expressed. This makes it challenging to predict exactly how a child may be affected if they inherit the mutated gene. However, if the gene is passed down from a parent, rather than appearing as a new mutation, the child will often exhibit more severe heart and limb abnormalities.
Risk Factors and Frequency for Holt-Oram Syndrome
Holt-Oram syndrome is a relatively rare condition, affecting approximately 1 in 100,000 people. It does not favor any gender, nor is it more commonly found in any particular racial, ethnic, or geographical group.
Signs and Symptoms of Holt-Oram Syndrome
Holt-Oram syndrome is a genetic disorder that affects the heart and arms. People with a family history of this syndrome or with certain physical abnormalities should be evaluated for this condition. The symptoms and features usually observed include:
- Abnormalities in the upper limb
- Birth defects in the heart
- Cardiac conduction disease – a condition that affects the electrical system of the heart
- Family history of a relative with congenital heart defects
Upper limb deformities may involve various bones in the wrist and hand, and the arm bones, including the radius (one of the main bones of the forearm). These abnormalities can present on one or both sides, with the left side most commonly affected. The thumb may be completely missing, seriously underdeveloped, or have an extra joint. Changes in the radius could result in arm movement problems or shortening of the arms.
About 75% of individuals with Holt-Oram syndrome have heart abnormalities at birth, the most common being ostium secundum atrial septal defect (a “hole” in the wall between the heart’s upper chambers) and ventricular septal defect (a “hole” in the heart’s lower chambers). These heart defects can range from mild to severe, potentially leading to additional health issues including high blood pressure in the lungs, heart failure, or infection of the heart’s inner lining.
There is also a greater risk for electrical problems in the heart among those with Holt-Oram syndrome. These issues can result in unnaturally slow heart rates or blocking of the electrical signal (heart block) that can occur suddenly. Irregular heartbeats, such as atrial fibrillation, are also common.
Testing for Holt-Oram Syndrome
Diagnosis of Holt-Oram syndrome, a condition affecting the heart and arms, often relies on physical traits and family medical background. If there’s a history of heart defects in your family, your doctor may want to look further into the possibility of this syndrome. This might involve tests like an electrocardiogram (which checks the heart’s electrical activity) or an echocardiogram (which uses sound waves to create images of your heart).
Additionally, x-rays of the upper limbs can also provide some insight, as people with Holt-Oram syndrome often have certain abnormalities in these areas. Genetic testing for changes in a specific gene, known as the TBX5 gene, might also be recommended, as mutations in this gene have been linked to this syndrome.
It’s also worth mentioning that if certain features are not present, the likelihood of Holt-Oram syndrome is smaller. For instance, the syndrome usually doesn’t involve the head and face, eyes or ears, kidneys, spine, lower limbs or anus. If these areas are affected, the condition might be something else.
Treatment Options for Holt-Oram Syndrome
Holt-Oram syndrome treatment varies from person to person, depending on the specific symptoms that are present. This condition often requires the expertise of many medical professionals, such as child doctors, heart doctors, heart surgeons, and bone doctors.
Medications may be needed if there are specific heart defects. For example, if the heart is having trouble pumping blood, commonly known as congestive heart failure, then diuretics (drugs that help your body get rid of salt and water), angiotensin-converting enzyme inhibitors (drugs that help relax your blood vessels), beta-adrenergic antagonists (drugs that lower your heart rate), and cardiac glycosides (drugs that increase the force of your heart’s contractions and slow its rate) might be used.
Consistent monitoring is a key part of managing Holt-Oram syndrome. This might involve a yearly heart rhythm test (electrocardiogram). If an individual has an irregular heartbeat, they might need to wear a special heart monitor for a day (Holter monitor) every year. People with holes in the wall dividing their heart chambers (septal defects) should have a heart ultrasound (echocardiogram) every one to 5 years.
Deformities in the upper limb might need surgical correction or reconstructive surgery as well as physical and occupational therapy. Heart abnormalities may require medications, an artificial pacemaker to help control abnormal heart rhythms, or surgery. It’s also important to ensure psychological well-being to help each individual reach their full potential and enjoy life.
During surgeries, steps must be taken to prevent any bacterial infections in the heart’s inner lining or in the sac that surrounds the heart (infective endocarditis and pericarditis). This precaution applies to both simple procedures like tooth extractions and more complex ones such as the surgical repair of septal defects. Because people with Holt-Oram syndrome are more prone to lung infections, they should be closely monitored, and antibiotics should be quickly administered if there’s any sign of infection.
What else can Holt-Oram Syndrome be?
When looking to diagnose Holt-Oram syndrome, doctors may need to consider other health issues that can mimic its symptoms. These include:
- Thrombocytopenia-absent radius syndrome
- Teratogen exposure such as from drugs like thalidomide or valproate
- Heart-hand syndrome type II
- Heart-hand syndrome type III
- Duane-radial ray syndrome
- Ulnar-mammary syndrome
- Long thumb brachydactyly
It’s important that other conditions are ruled out to ensure an accurate diagnosis of Holt-Oram syndrome.
What to expect with Holt-Oram Syndrome
The life expectancy for individuals with Holt-Oram syndrome, a genetic condition that affects the heart and arms, can vary greatly. This is largely influenced by how severe the heart defect is in each individual case.
However, for patients who have serious abnormalities in their heart’s blood flow – referred to as ‘hemodynamically significant intracardiac shunts’, treatment is necessary. If not, these individuals could develop a severe condition known as Eisenmenger syndrome later in their lives. This syndrome is a type of high blood pressure that affects the lungs and can lead to various complications.
Preventing Holt-Oram Syndrome
It’s important that all patients, as well as their family members, receive advice and information about genetics from a specialized healthcare provider. This is to ensure everyone understands that Holt-Oram syndrome is a type of genetic disorder that can be passed down through families. If a person has this condition, there’s a 50% chance their children might also have it. Everyone should also understand that even if a parent has a mild form of this syndrome, their children could potentially have a more severe form. So, the severity of this condition in a parent can’t be used to predict how severe it might be in their children.
