Holt-Oram Syndrome Clinical Presentation

Updated: May 05, 2016
  • Author: Craig T Basson, MD, PhD; Chief Editor: Yasmine Subhi Ali, MD, FACC, FACP, MSCI  more...
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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.



Upper limb deformity includes the following features:

  • Always present but may be unilateral or bilateral
  • Left-sided abnormalities often more severe than right arm or hand abnormalities
  • Unequal arm lengths due to aplasia, hypoplasia, fusion, or anomalous development of the radial, carpal, and thenar bones
  • Abnormal forearm pronation and supination
  • Triphalangeal or absent thumbs
  • Possible abnormal opposition of thumb
  • Possible sloping shoulders and restriction of shoulder joint movement
  • Phocomelia

Cardiac involvement includes the following signs:

  • Bradycardia
  • Irregular pulse (ectopy)
  • Irregular pulse that occurs irregularly (atrial fibrillation)
  • Wide, fixed splitting of the second heart sound
  • Pulmonary systolic flow murmur
  • 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:

  • Ulnar bone
  • Lower limbs
  • Kidneys
  • Eyes
  • Auditory
  • Craniofacial
  • Vertebrae (may or may not occur in Holt-Oram syndrome)


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]