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  • Christopher Williamson, MSMP

Holt-Oram Syndrome

Bilateral Upper Extremity Defects • Xray of the Week

A one-day old infant presents with bilateral upper extremity defects. What is the diagnosis?

Gastric Volvulus CT Scan

Figure 1. Right and left hand radiographs of the one-day old infant presenting with bilateral upper extremity defects.

Holt Oram Syndrome X-ray 2

Figure 2. R. The right hand consists of 4 rays (between red arrows) consisting of metacarpal bones with a triangular rudimentary proximal phalanx present (white arrow) laterally along the right hand. The medial deviated digits contain 2 phalanges while 2 more medial digits contain 3 phalanges (between yellow arrows). Minimal carpal ossification is present.

Figure 2. L. The left hand consists of only 3 rays (between blue arrows) containing a metacarpal and a proximal, middle, and distal phalanx (between green arrows). No left thumb is present. Minimal carpal ossification is present.

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Holt-Oram Syndrome (HOS) is an autosomal dominant disease that occurs at a frequency of 1 out of 100,000 (4). Also, called “Heart-Hand Syndrome” or atriodigital dysphasia, this syndrome is the result of a premature stop code on the product of the TBX5 gene located on the long arm of the 12q2 chromosome (1,4). The TBX5 gene is a T-box containing transcription factor with the primary role in cardiac and forelimb development (2). The mutation thus results in upper extremity and cardiac defects. Patients with HOS present with abnormalities with varying degrees of severity ranging from minor hypoplasia or aplasia of upper extremities, to life threatening cardiac defects.

The most commonly affected structure is the thumb while other affected structures include the upper and lower arm, wrist, hand and other fingers (1,3). Additional abnormalities can include the clavicle and scapula thus compromising the pectoral girdle. The skeletal anomalies can be unilateral or bilateral with the left side typically being more severe than the right (5).

Approximately 85-95% of patients with HOS have cardiac defects (2,3). The most common congenital cardiac anomaly is the ostium secundum type atrial septal defect (ASD) (4). However, ventricular septal defects, patent ductus arteriosus, and ostium primum ASD are other manifestations of HOS cardiac anomalies.


Due to the varying degree of HOS manifestations, it is difficult to ascertain the extent of the effects of the abnormalities. However, based on phenotypic observations, planar x-rays, and ECG, one may be able to determine if an orthopedic and cardiologist consultation is required. Future surgery may be required to repair defects to improve quality of life for the patient.

References: 1. Basson, C. T., Cowley, G. S., Solomon, S. D., Weissman, B., Poznanski, A. K., Traill, T. A., Seidman, J.G., & Seidman, C. E. (1994). The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). New England Journal of Medicine, 330(13), 885-891.

2. Bruneau, B. G., Nemer, G., Schmitt, J. P., Charron, F., Robitaille, L., Caron, S., ... & Seidman, J. G. (2001). A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell, 106(6), 709-721.

3. Newbury-Ecob RA, Leanage R, Raeburn JA, et al. Holt-Oram syndrome: a clinical genetic study. Journal of Medical Genetics 1996;33:300-307.

4. Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., Brook, J.D. (1997). Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nature genetics, 15(1), 21-29.

5. Smith, A. T., Sack, G. H., & Taylor, G. J. (1979). Holt-Oram syndrome. The Journal of pediatrics, 95(4), 538-543.

Christopher Williamson, MSMP

Christopher Williamson, MSMP

1st year medical student

Medical College of Georgia at Augusta University

Yulia Melenevsky, MD

Yulia Melenevsky, MD

Assistant Professor, Musculoskeletal Imaging

Department of Radiology

Medical College of Georgia at Augusta University

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