History
Patients may have a family history of cardiac and/or limb malformation.
Patients may present in infancy with obvious limb malformations and/or signs of cardiac failure secondary to ASD, VSD, or cardiac conduction disease.
Physical
Upper limb deformity includes the following features:
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Always present but may be unilateral or bilateral
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Left-sided abnormalities often more severe than right arm or hand abnormalities
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Unequal arm lengths due to aplasia, hypoplasia, fusion, or anomalous development of the radial, carpal, and thenar bones
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Abnormal forearm pronation and supination
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Triphalangeal or absent thumbs
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Possible abnormal opposition of thumb
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Possible sloping shoulders and restriction of shoulder joint movement
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Phocomelia
Cardiac involvement includes the following signs:
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Bradycardia
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Irregular pulse (ectopy)
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Irregular pulse that occurs irregularly (atrial fibrillation)
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Wide, fixed splitting of the second heart sound
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Pulmonary systolic flow murmur
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Holosystolic murmur (should raise consideration for a VSD)
Anomalies involving any of the following are indicators that a diagnosis of Holt-Oram syndrome can be excluded:
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Ulnar bone
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Lower limbs
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Kidneys
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Eyes
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Auditory
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Craniofacial
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Vertebrae (may or may not occur in Holt-Oram syndrome)
Causes
Holt-Oram syndrome is a genetic disorder that is autosomal dominant and highly penetrant. Initial linkage studies demonstrate that the gene defect resides on the long arm of chromosome 12. [5, 6]
Molecular genetic studies reveal that the disease is caused by mutations that inactivate the transcription factor TBX5. [7, 8] Sporadic disease may represent a de novo germline mutation in TBX5.
Recognizing that individuals who present with sporadic disease may transmit the disease to offspring is important.
The identification of the role of TBX5 in Holt-Oram syndrome suggests an important but as yet undefined role for TBX5 in human cardiac septation, isomerization, and upper limb development. [3]
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Posteroanterior radiograph of the hands of a patient with Holt-Oram syndrome. The distal phalanx of the left thumb is hypoplastic. The carpal bones of both hands are abnormal, but the abnormalities on the left side are greater than those on the right side. Left-sided upper limb radial ray abnormalities are often greater than those on the right side. The scaphoid and trapezium of the left hand are enlarged and misshapen, resulting in a distal displacement of the thumb. Note the marked abnormalities of the left capitate and hamate. The left radial stylus is flattened.
