Holt-Oram Syndrome Clinical Presentation

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


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]