Holt-Oram syndrome is a genetic disorder that affects multiple organ systems, including the heart and upper limbs. It is inherited in an autosomal dominant pattern, meaning an affected person has a 50% chance of passing the gene to their offspring. The syndrome was first identified in 1960 by Holt and Oram, who observed that family members across four generations had thumb abnormalities and atrial septal defects, that separates the two upper chambers of the heart.
The upper limb abnormalities in Holt-Oram syndrome can include missing or underdeveloped thumbs and other skeletal abnormalities in the hands and arms. Some individuals may also have abnormalities in other body parts, such as the eyes, ears, or kidneys. The heart defects associated with the syndrome can include ASDs, ventricular septal defects, and other structural abnormalities.
Epidemiology
Holt-Oram syndrome affects approximately 1 individual per 100,000 people and does not show any preference for gender, race, ethnicity, or geographic location. No particular group has been found to have a higher incidence of this syndrome.
Since advances in technology have enabled doctors to diagnose better and treat the condition, but Holt-Oram syndrome still affects a significant number of people in both developed and developing countries.
Anatomy
Pathophysiology
Holt-Oram syndrome is a genetic disorder that affects the heart and upper limbs. It is caused by mutations in the TBX5 gene, which provides instructions for making a protein that plays a crucial role in early heart and limb development.
The pathophysiology involves abnormal development of the heart and upper limbs. During fetal development, the heart and upper limbs arise from the same group of cells. The TBX5 protein is essential for regulating the development of these structures, and mutations in the gene can disrupt this process.
The most common cardiac abnormality is a septal defect, a hole in the wall separating the heart’s two upper chambers. This defect can cause blood to flow abnormally between the chambers, leading to symptoms such as fatigue, shortness of breath, and an increased risk of infections.
In addition to cardiac abnormalities, individuals also have upper limb defects, such as abnormalities in the formation of the bones, muscles, and tendons. These defects can lead to a range of limb abnormalities, such as absent or underdeveloped thumbs, shortened forearm bones, and limited range of motion in the shoulders and elbows.
Etiology
Holt-Oram syndrome is caused by a mutation in the TBX5 gene on chromosome 12q24.1, which encodes the transcription factor T-box5. This gene plays an essential role in regulating the expression of other genes during the development of the limbs and heart, specifically in cardiac septation and bone development in hand. More than 85% of individuals with Holt-Oram syndrome have this mutated gene.
The syndrome is inherited in an autosomal dominant manner, meaning that one copy of the mutation is sufficient to cause the condition. If an affected parent has the mutation, there is a 50% chance of passing it on to their offspring. However, most cases of Holt-Oram syndrome occur via spontaneous mutation. Upper-limb abnormalities are always present in individuals with the syndrome, while cardiac defects have a penetrance of 75%.
The severity and specific characteristics of the malformations can vary widely due to the variable expressivity of the gene, making it difficult to predict the phenotype of offspring. However, if the gene is inherited autosomal dominant rather than via spontaneous mutation, the offspring are more likely to have more severe cardiac and limb deformities.
Genetics
Prognostic Factors
Clinical History
Clinical History
Holt-Oram syndrome is a genetic condition characterized by upper limb abnormalities and congenital heart malformations. Among individuals with this syndrome, about 75% are born with heart defects ranging from mild to severe. Holt-Oram syndrome’s most common heart defects are ostium secundum atrial septal defect (ASD) and ventricular septal defect.
Aside from structural heart defects, individuals with Holt-Oram syndrome are also at an increased risk of developing cardiac conduction abnormalities. These abnormalities can manifest at birth as first-degree atrioventricular block or sinus bradycardia and can progress to complete heart block without warning.
Arrhythmias such as atrial fibrillation are commonly seen in individuals with Holt-Oram syndrome. These conduction abnormalities can cause significant symptoms such as dizziness, fatigue, and palpitations and may require medical management such as using pacemakers or antiarrhythmic drugs.
Physical Examination
Physical Examination
Malformations of the upper limb can affect different bones, such as the carpal, thenar, and radial bones. These malformations can be found on one or both sides and may have symmetrical or asymmetrical presentations.
Typically, the left side is more affected than the right. Abnormalities in the carpal bones, such as fusion or anomalous development, may occur. The thumb may be absent, poorly developed, or have an extra joint.
Additionally, the radius may have underdevelopment or absence, leading to abnormal forearm movement. Phocomelia, a condition where the limb is underdeveloped, may also be present.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential Diagnoses
Duane-radial ray syndrome
Long thumb brachydactyly
Heart-hand syndrome
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Holt-Oram syndrome treatment is tailored to address individual symptoms, which may require involvement from several medical professionals. Depending on the cardiac defects and associated conditions, specific medication options may be considered, such as diuretics, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, and cardiac glycosides for congestive heart failure.
Regular surveillance is crucial and may include annual electrocardiograms, Holter monitors, and echocardiograms every 5 years for patients with conduction abnormalities and septal defects. Upper limb abnormalities may necessitate reconstructive or corrective surgery and occupational and physical therapy. Patients with cardiac malformations may require medications, artificial pacemakers, or surgical correction.
Additionally, addressing psychosocial aspects is vital to promoting the individual’s potential and quality of life. To prevent bacterial infective endocarditis and pericarditis complications during surgical procedures, prophylaxis must be considered, even for simple procedures such as tooth extractions or more complex surgical interventions. Holt-Oram syndrome patients are more susceptible to respiratory infections; hence close monitoring is necessary, and antibiotics should be initiated promptly.
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Holt-Oram syndrome is a genetic disorder that affects multiple organ systems, including the heart and upper limbs. It is inherited in an autosomal dominant pattern, meaning an affected person has a 50% chance of passing the gene to their offspring. The syndrome was first identified in 1960 by Holt and Oram, who observed that family members across four generations had thumb abnormalities and atrial septal defects, that separates the two upper chambers of the heart.
The upper limb abnormalities in Holt-Oram syndrome can include missing or underdeveloped thumbs and other skeletal abnormalities in the hands and arms. Some individuals may also have abnormalities in other body parts, such as the eyes, ears, or kidneys. The heart defects associated with the syndrome can include ASDs, ventricular septal defects, and other structural abnormalities.
Holt-Oram syndrome affects approximately 1 individual per 100,000 people and does not show any preference for gender, race, ethnicity, or geographic location. No particular group has been found to have a higher incidence of this syndrome.
Since advances in technology have enabled doctors to diagnose better and treat the condition, but Holt-Oram syndrome still affects a significant number of people in both developed and developing countries.
Holt-Oram syndrome is a genetic disorder that affects the heart and upper limbs. It is caused by mutations in the TBX5 gene, which provides instructions for making a protein that plays a crucial role in early heart and limb development.
The pathophysiology involves abnormal development of the heart and upper limbs. During fetal development, the heart and upper limbs arise from the same group of cells. The TBX5 protein is essential for regulating the development of these structures, and mutations in the gene can disrupt this process.
The most common cardiac abnormality is a septal defect, a hole in the wall separating the heart’s two upper chambers. This defect can cause blood to flow abnormally between the chambers, leading to symptoms such as fatigue, shortness of breath, and an increased risk of infections.
In addition to cardiac abnormalities, individuals also have upper limb defects, such as abnormalities in the formation of the bones, muscles, and tendons. These defects can lead to a range of limb abnormalities, such as absent or underdeveloped thumbs, shortened forearm bones, and limited range of motion in the shoulders and elbows.
Holt-Oram syndrome is caused by a mutation in the TBX5 gene on chromosome 12q24.1, which encodes the transcription factor T-box5. This gene plays an essential role in regulating the expression of other genes during the development of the limbs and heart, specifically in cardiac septation and bone development in hand. More than 85% of individuals with Holt-Oram syndrome have this mutated gene.
The syndrome is inherited in an autosomal dominant manner, meaning that one copy of the mutation is sufficient to cause the condition. If an affected parent has the mutation, there is a 50% chance of passing it on to their offspring. However, most cases of Holt-Oram syndrome occur via spontaneous mutation. Upper-limb abnormalities are always present in individuals with the syndrome, while cardiac defects have a penetrance of 75%.
The severity and specific characteristics of the malformations can vary widely due to the variable expressivity of the gene, making it difficult to predict the phenotype of offspring. However, if the gene is inherited autosomal dominant rather than via spontaneous mutation, the offspring are more likely to have more severe cardiac and limb deformities.
Clinical History
Holt-Oram syndrome is a genetic condition characterized by upper limb abnormalities and congenital heart malformations. Among individuals with this syndrome, about 75% are born with heart defects ranging from mild to severe. Holt-Oram syndrome’s most common heart defects are ostium secundum atrial septal defect (ASD) and ventricular septal defect.
Aside from structural heart defects, individuals with Holt-Oram syndrome are also at an increased risk of developing cardiac conduction abnormalities. These abnormalities can manifest at birth as first-degree atrioventricular block or sinus bradycardia and can progress to complete heart block without warning.
Arrhythmias such as atrial fibrillation are commonly seen in individuals with Holt-Oram syndrome. These conduction abnormalities can cause significant symptoms such as dizziness, fatigue, and palpitations and may require medical management such as using pacemakers or antiarrhythmic drugs.
Physical Examination
Malformations of the upper limb can affect different bones, such as the carpal, thenar, and radial bones. These malformations can be found on one or both sides and may have symmetrical or asymmetrical presentations.
Typically, the left side is more affected than the right. Abnormalities in the carpal bones, such as fusion or anomalous development, may occur. The thumb may be absent, poorly developed, or have an extra joint.
Additionally, the radius may have underdevelopment or absence, leading to abnormal forearm movement. Phocomelia, a condition where the limb is underdeveloped, may also be present.
Differential Diagnoses
Duane-radial ray syndrome
Long thumb brachydactyly
Heart-hand syndrome
Holt-Oram syndrome treatment is tailored to address individual symptoms, which may require involvement from several medical professionals. Depending on the cardiac defects and associated conditions, specific medication options may be considered, such as diuretics, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, and cardiac glycosides for congestive heart failure.
Regular surveillance is crucial and may include annual electrocardiograms, Holter monitors, and echocardiograms every 5 years for patients with conduction abnormalities and septal defects. Upper limb abnormalities may necessitate reconstructive or corrective surgery and occupational and physical therapy. Patients with cardiac malformations may require medications, artificial pacemakers, or surgical correction.
Additionally, addressing psychosocial aspects is vital to promoting the individual’s potential and quality of life. To prevent bacterial infective endocarditis and pericarditis complications during surgical procedures, prophylaxis must be considered, even for simple procedures such as tooth extractions or more complex surgical interventions. Holt-Oram syndrome patients are more susceptible to respiratory infections; hence close monitoring is necessary, and antibiotics should be initiated promptly.
medtigo
Holt-Oram syndrome
Updated :
April 14, 2023
Holt-Oram syndrome is a genetic disorder that affects multiple organ systems, including the heart and upper limbs. It is inherited in an autosomal dominant pattern, meaning an affected person has a 50% chance of passing the gene to their offspring. The syndrome was first identified in 1960 by Holt and Oram, who observed that family members across four generations had thumb abnormalities and atrial septal defects, that separates the two upper chambers of the heart.
The upper limb abnormalities in Holt-Oram syndrome can include missing or underdeveloped thumbs and other skeletal abnormalities in the hands and arms. Some individuals may also have abnormalities in other body parts, such as the eyes, ears, or kidneys. The heart defects associated with the syndrome can include ASDs, ventricular septal defects, and other structural abnormalities.
Holt-Oram syndrome affects approximately 1 individual per 100,000 people and does not show any preference for gender, race, ethnicity, or geographic location. No particular group has been found to have a higher incidence of this syndrome.
Since advances in technology have enabled doctors to diagnose better and treat the condition, but Holt-Oram syndrome still affects a significant number of people in both developed and developing countries.
Holt-Oram syndrome is a genetic disorder that affects the heart and upper limbs. It is caused by mutations in the TBX5 gene, which provides instructions for making a protein that plays a crucial role in early heart and limb development.
The pathophysiology involves abnormal development of the heart and upper limbs. During fetal development, the heart and upper limbs arise from the same group of cells. The TBX5 protein is essential for regulating the development of these structures, and mutations in the gene can disrupt this process.
The most common cardiac abnormality is a septal defect, a hole in the wall separating the heart’s two upper chambers. This defect can cause blood to flow abnormally between the chambers, leading to symptoms such as fatigue, shortness of breath, and an increased risk of infections.
In addition to cardiac abnormalities, individuals also have upper limb defects, such as abnormalities in the formation of the bones, muscles, and tendons. These defects can lead to a range of limb abnormalities, such as absent or underdeveloped thumbs, shortened forearm bones, and limited range of motion in the shoulders and elbows.
Holt-Oram syndrome is caused by a mutation in the TBX5 gene on chromosome 12q24.1, which encodes the transcription factor T-box5. This gene plays an essential role in regulating the expression of other genes during the development of the limbs and heart, specifically in cardiac septation and bone development in hand. More than 85% of individuals with Holt-Oram syndrome have this mutated gene.
The syndrome is inherited in an autosomal dominant manner, meaning that one copy of the mutation is sufficient to cause the condition. If an affected parent has the mutation, there is a 50% chance of passing it on to their offspring. However, most cases of Holt-Oram syndrome occur via spontaneous mutation. Upper-limb abnormalities are always present in individuals with the syndrome, while cardiac defects have a penetrance of 75%.
The severity and specific characteristics of the malformations can vary widely due to the variable expressivity of the gene, making it difficult to predict the phenotype of offspring. However, if the gene is inherited autosomal dominant rather than via spontaneous mutation, the offspring are more likely to have more severe cardiac and limb deformities.
Clinical History
Holt-Oram syndrome is a genetic condition characterized by upper limb abnormalities and congenital heart malformations. Among individuals with this syndrome, about 75% are born with heart defects ranging from mild to severe. Holt-Oram syndrome’s most common heart defects are ostium secundum atrial septal defect (ASD) and ventricular septal defect.
Aside from structural heart defects, individuals with Holt-Oram syndrome are also at an increased risk of developing cardiac conduction abnormalities. These abnormalities can manifest at birth as first-degree atrioventricular block or sinus bradycardia and can progress to complete heart block without warning.
Arrhythmias such as atrial fibrillation are commonly seen in individuals with Holt-Oram syndrome. These conduction abnormalities can cause significant symptoms such as dizziness, fatigue, and palpitations and may require medical management such as using pacemakers or antiarrhythmic drugs.
Physical Examination
Malformations of the upper limb can affect different bones, such as the carpal, thenar, and radial bones. These malformations can be found on one or both sides and may have symmetrical or asymmetrical presentations.
Typically, the left side is more affected than the right. Abnormalities in the carpal bones, such as fusion or anomalous development, may occur. The thumb may be absent, poorly developed, or have an extra joint.
Additionally, the radius may have underdevelopment or absence, leading to abnormal forearm movement. Phocomelia, a condition where the limb is underdeveloped, may also be present.
Differential Diagnoses
Duane-radial ray syndrome
Long thumb brachydactyly
Heart-hand syndrome
Holt-Oram syndrome treatment is tailored to address individual symptoms, which may require involvement from several medical professionals. Depending on the cardiac defects and associated conditions, specific medication options may be considered, such as diuretics, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, and cardiac glycosides for congestive heart failure.
Regular surveillance is crucial and may include annual electrocardiograms, Holter monitors, and echocardiograms every 5 years for patients with conduction abnormalities and septal defects. Upper limb abnormalities may necessitate reconstructive or corrective surgery and occupational and physical therapy. Patients with cardiac malformations may require medications, artificial pacemakers, or surgical correction.
Additionally, addressing psychosocial aspects is vital to promoting the individual’s potential and quality of life. To prevent bacterial infective endocarditis and pericarditis complications during surgical procedures, prophylaxis must be considered, even for simple procedures such as tooth extractions or more complex surgical interventions. Holt-Oram syndrome patients are more susceptible to respiratory infections; hence close monitoring is necessary, and antibiotics should be initiated promptly.
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