NORD gratefully acknowledges Jaqueline Picache, NORD Editorial Intern from the University of Notre Dame, and Craig T. Basson, MD, PhD, Vice President, GlobalTranslational Medicine Head – Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, for assistance in the preparation of this report.
Holt-Oram syndrome is a disorder that affects approximately 1 in 100,000 individuals. It is characterized by abnormalities in the bones of the upper limb, a family or personal history of a congenital heart malformation, and/or an abnormality in the electrical impulses that coordinate the muscle contractions of the heart (cardiac conduction defect). In some affected individuals, an abnormal wrist (carpal) bone is the only evidence of the disease. Seventy-five percent of those affected have a congenital heart malformation. Holt-Oram syndrome is an autosomal dominant genetic condition that is associated with an abnormality in the TBX5 gene. While this mutation can be inherited, most cases result from a new mutation in patients without a family history of the disorder.
The symptoms and physical findings associated with Holt-Oram syndrome vary greatly from person to person, even within the same family. Upper limb malformations range from abnormally long thumbs that look like fingers (triphalangy) to an absent thumb bone or absent thumb. Other types of upper limb malformations may also be present including underdevelopment or absence of the bones in the forearm (radius and ulna), fusion or abnormal development of thumb and wrist bones (thenar and carpal), and abnormal position of the thumb, forearm or shoulders. Affected individuals may be unable to fully extend the arms, rotate the arms inward toward the body with the palms facing down (pronation), or rotate the arms outward with the palms facing upward (supination). More severe cases include a malformation in which the hands are attached to shoulder with absent or shortened arms (phocomelia). In some affected individuals, an abnormal wrist (carpal) bone is the only evidence of the disease.
Seventy-five percent of those affected have a congenital heart malformation. The most common heart malformations are ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD). An ASD is characterized by an abnormal opening in the fibrous partition (septum) that separates the two upper chambers (atria) of the heart. In infants with an atrial septal defect of the secundum type, the opening in the second septum of the fetal heart fails to close properly or the septum secundum may form abnormally during fetal development. As a result, the opening between the atria persists long after it should be closed causing an increase in the workload on the right side of the heart and excessive blood flow to the lungs. Many children with an ASD have no symptoms. In some cases, severely affected children experience poor growth, breathlessness, easy fatigability with exercise, and/or irregular heartbeats (arrhythmias).
A VSD is characterized by an abnormal opening in the septum that divides the heart’s two lower chambers (ventricles). Some infants and children with Holt-Oram syndrome have a single VSD or multiple VSDs, possibly in combination with an ASD. A VSD may occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. A small VSD may close on its own or become less significant as the child matures and grows. A moderate sized defect may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive heart failure). Symptoms associated with heart failure include an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), failure to grow at the expected rate (failure to thrive), and/or other findings. A large VSD may cause life-threatening complications during infancy. Persistent elevation of the pressure within the artery that carries blood away from the heart and to the lungs (pulmonary artery) can cause permanent damage to the lungs.
Individuals with Holt-Oram syndrome are at risk for cardiac conduction defects even if a congenital heart malformation is not present. When there is an interruption of the normal flow of electrical impulses (heart block) through the heart, the two upper chambers of the heart (atria) may beat normally and the two lower chambers (ventricles) may contract less often or “fall behind” the atrial contractions. In the mild form of heart block, there may be a slight delay between the contractions of the atria and of the ventricles (prolonged P-R interval). Other degrees of heart block may also occur in some cases (e.g., right bundle branch block). In some cases, the delay between atrial and ventricular contractions may continue to lengthen until a ventricular beat may be dropped altogether. In other, more severe cases of heart block, only a percentage (e.g., half, quarter, etc.) of atrial beats may be conducted to the ventricles. When complete heart block occurs, the ventricles and the atria beat independently of one another.
The effects of conduction defects in individuals with Holt-Oram syndrome are highly variable, ranging from no apparent symptoms to potentially serious complications. For example, those who exhibit prolonged P-R intervals may not exhibit any associated symptoms. Observable symptoms may also not occur in affected individuals who experience dropped beats. In more severe cases of heart block, inadequate blood flow from the ventricles could cause affected individuals may experience breathlessness due to the heart’s inability to pump blood effectively (heart failure), develop chest pains, or experience fainting episodes (syncope). In rare cases, if the ventricular beat slows dramatically or stops, affected individuals may black out, have seizures, or experience life-threatening symptoms. Some individuals with mild symptoms are not diagnosed with Holt-Oram syndrome until middle age when symptoms of cardiac conduction disease occur.
Holt-Oram syndrome can be inherited as an autosomal dominant genetic trait. The only gene known to be associated with Holt-Oram syndrome has been mapped on the long arm (q) of chromosome 12 (12q24.1) and termed the TBX5 gene. A TBX5 gene mutation has been identified in approximately 74% of individuals affected with Holt-Oram syndrome. This is likely to be an underestimate of the true TBX5 mutation frequency, since genetic testing does not always detect all types of mutations. Currently, there are more than 70 known mutations in the TBX5 gene that cause Holt-Oram syndrome. Potential causes for the remainder of affected individuals include incorrect reading and translation of the TBX5 gene during protein production.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Approximately 85% of cases of Holt-Oram syndrome are thought to be due to new mutations in the TBX5 gene. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the gender of the resulting child.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 12q24.1” refers to band 24.1 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Holt-Oram syndrome is a rare genetic disorder that occurs in many racial and ethnic groups; and affects males and females in equal numbers. The estimated prevalence is 1/100,000 livebirths.
The diagnosis of Holt-Oram syndrome is based on physical findings and family history. Hand x-rays are performed for upper limb malformations. Echocardiography, MRI and other imaging modalities and electrocardiography are used to determine the presence and severity of heart defects and/or cardiac conduction disease. Molecular genetic testing for the TBX5 gene is available to confirm the diagnosis. Some individuals with mild symptoms are not diagnosed until middle age when symptoms of cardiac conduction disease occur. Prenatal ultrasound of the fetal heart (echocardiography) has been used to diagnose heart malformations in children of an affected parent.
The treatment of Holt-Oram syndrome is directed toward the management of specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat heart abnormalities (cardiologists), specialists who diagnose and treat skeletal abnormalities (orthopedists), and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Specific therapies for Holt-Oram syndrome are symptomatic and supportive. Depending upon the severity of any upper limb abnormalities, treatment may consist of corrective or reconstructive surgery, the use of artificial replacements for portions of the forearms and hands (limb prosthetics), and/or physical therapy to help individuals enhance their motor skills.
In affected individuals who have mild cardiac conduction abnormalities, treatment may not be required. However, in more severe cases when associated symptoms occur (e.g., fainting episodes), a pacemaker may be used. A pacemaker overrides the heart’s impaired electrical conducting system by sending electrical impulses to the heart that keep the heartbeat at a regular rate.
The primary treatment for structural abnormalities of the heart associated with Holt-Oram syndrome is closure of the defect(s) with surgery or catheters. In such cases, the surgical procedures performed will depend upon the location and severity of the abnormalities and their associated symptoms. Some individuals may be treated with medications and/or other techniques.
Iindividuals with certain structural defects of the heart may be at risk for bacterial infection and inflammation of the lining of the heart’s chambers and valves (endocarditis). Clinical guidelines should be followed to determine if antibiotics should be prescribed before specific surgical procedures. In addition, some affected individuals with certain heart defects may be susceptible to repeated respiratory infections and physicians may closely monitor such individuals to take preventive steps and to institute antibiotic and/or other appropriate therapies should such infections occur.
Early intervention is important to ensure that children with Holt-Oram syndrome reach their potential. Special services that may be beneficial to affected children may include physical therapy and/or other medical, social, and/or vocational services.
Genetic counseling will benefit affected individuals and their families. Family members of affected individuals should also receive thorough clinical evaluations to detect any symptoms and physical findings that may be associated with Holt-Oram syndrome. Family members with normal clinical evaluations should receive x-ray studies of the wrists and arms as well as echocardiograms to help confirm whether they may exhibit a mild form of the disorder.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding and some supported by private industry are posted on this government web site.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., skeletal malformations affecting the upper limbs, heart defects, etc.].)
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