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 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.