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Holt Oram Syndrome
Synonyms of Holt Oram Syndrome
- atriodigital dysplasia
- heart-hand syndrome
- HOS1
Disorder Subdivisions
- No subdivisions found.
General Discussion
Holt-Oram syndrome is a disorder that is characterized by abnormalities in the bones of the upper limb and a family or personal history of a congenital heart malformation or an abnormality in the electrical impulses that coordinate the muscle contraction 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.
Symptoms
The symptoms and physical findings associated with Holt-Oram syndrome vary greatly from case to case, even within the same family. Upper limb malformations range from an absent thumb bone (triphalangy) or absent thumb to a malformation in which the hands are attached close to the body (phocomelia). 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). 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 (septum secundum) 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. In some rare cases, affected infants may have an ASD of the "primum type," which is characterized by an abnormal opening in the atrial septum due to abnormal development of the first septum of the fetal heart (septum primum). 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 VSD, 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). For example, 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 be 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, however, if there is inadequate blood flow from the ventricles, 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.
Causes
Holt-Oram syndrome is inherited as an autosomal dominant genetic trait. The only gene known to be associated with Holt-Oram syndrome has been mapped to the long arm (q) of chromosome 12 (12q24.1) and termed the TBX5 gene. A TBX5 gene mutation has been identified in over 70% of individuals affected with Holt-Oram syndrome.
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. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Approximately 85% of cases of Holt-Oram syndrome are thought to be due to new mutations.
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.
Affected Populations
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.
Related Disorders
Symptoms of the following disorders may be similar to those of Holt-Oram syndrome. Comparisons may be useful for a differential diagnosis:
Okihiro syndrome (Duane-radial ray syndrome) is an autosomal dominant genetic condition associated with an abnormality in the SALL4 gene. SALL4-related disorders are characterized by upper limb, vision, hearing and kidney abnormalities and can also be associated with heart defects.
Schinzel syndrome, also known as ulnar-mammary syndrome, is a rare inherited disorder characterized by abnormalities of the bones of the hands and forearms in association with underdevelopment (hypoplasia) and dysfunction of certain sweat (apocrine) glands and/or the breasts (mammary glands). Abnormalities affecting the hands and/or forearms range from underdevelopment of the bone in the tip of the fifth finger (hypoplastic terminal phalanx) to underdevelopment or complete absence of the bone on the outer aspect of the forearm (ulna). Certain sweat glands such as those located under the arms may be underdeveloped or absent, resulting in diminished ability or inability to sweat (perspire). In some cases, the breasts (mammary glands) may also be underdeveloped or absent and as a result, affected females exhibit a diminished ability or an inability to produce milk (lactate). (For more information about this condition, choose "Schinzel" as your search term in the Rare Disease Database.)
Townes-Brocks syndrome is a rare genetic disorder present at birth. Symptoms of the disorder and the severity of these symptoms vary from person to person. Major characteristics may include an absence of an anal opening in association with hand, foot and ear abnormalities. Hearing loss or deafness due to lesions or dysfunctions of part of the internal ear or its nerve tracts and centers (sensorineural hearing loss or deafness) is present in some patients. (For more information about this condition, choose "Townes-Brocks" as your search term in the Rare Disease Database.)
There are additional congenital disorders that may be characterized by malformations affecting the bones of the thumbs, hands, wrists, forearms, and/or upper arms (humerus); other skeletal abnormalities; and/or structural or electrocardiographic conduction abnormalities of the heart similar to those occurring in association with Holt-Oram syndrome. Such disorders usually have other physical features that may differentiate them from Holt-Oram syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
Standard Therapies
Diagnosis
The diagnosis of Holt-Oram syndrome is based on physical findings and family history. Hand x-rays are performed for upper limb malformations. Echocardiography 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.
Treatment
The treatment of Holt-Oram syndrome is directed toward the 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), an artificial pacemaker may be used. An artificial pacemaker overrides the heart's impaired electrical conducting system by sending electrical impulses to the heart that keep the heartbeat at a regular rate.
In some cases, certain structural abnormalities of the heart associated with Holt-Oram syndrome may be treated with certain medications, surgery, and/or other techniques. In such cases, the surgical procedures performed will depend upon the location and severity of the abnormalities and their associated symptoms.
Affected individuals 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) so antibiotics should be prescribed before any surgical procedure including dental procedures such as tooth extractions. In addition, because some affected individuals with certain heart defects may be susceptible to repeated respiratory infections, 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 be of benefit for 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.
Investigational Therapies
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
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Organizations related to Holt Oram Syndrome
(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.].)
References
JOURNAL ARTICLES
Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (hand-heart syndrome). N Engl J Med. 1994;330:885-91.
Brassington AM, Sung SS, Toydemir RM, et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 2003;73:74-85.
Bressan MC, McDermott DA, Spencer RH, et al. TBX5 genetic testing validates strict clincal criteria for Holt-Oram syndrome. Circulation 2003;108(Suppl 4):358, A1675.
Li QY, Newbury-Ecob RA, Terrett JA, et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 1997:15:21-29.
Newbury-Ecob RA, Leanage R, Raeburn JA, et al. Holt-Oram syndrome: a clinical genetic study. J Med Genet 1996;33:330-337.
Sletten LJ and Pierpont ME. Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet 1996;65:128-32.
FROM THE INTERNET
McDermott D and Basson CT. Posted 7/20/04. Holt-Oram Syndrome. In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle, 1997-2005. Available at http://www.genetests.ord. Accessed 6/05.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 142900: Last Update: 4/30/04.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 235800; Last Update:6/11/99.
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Report last updated: 2008/04/28 00:00:00 GMT+0
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