Holt-Oram Syndrome

Definition

An autosomal dominant heart hand syndrome with upper limb radial ray anomalies and congenital heart defects.

Aetiology

  • TBX5 mutations on chromosome 12q24
  • Complete penetrance with variable expressivity
  • About 1 in 100,000 live births

Clinical Features

  • Upper limb anomaly in all affected people, often bilateral, asymmetric and worse on the left
  • Triphalangeal, hypoplastic or absent thumb
  • Radial longitudinal deficiency, see radial club hand
  • Carpal anomalies are the most consistent sign, including extra or fused carpal bones
  • Phocomelia at the severe end
  • Clavicle and scapular hypoplasia may occur
  • Narrow sloping shoulders and limited forearm rotation
  • Atrial or ventricular septal defects and conduction block
  • Lower limbs unaffected

Investigations

  • Echocardiogram and ECG in every child with a radial ray anomaly
  • Hand, forearm and shoulder radiographs
  • TBX5 genetic testing
  • Cardiac screening of affected relatives

Differential Diagnosis

Management

  • Cardiac assessment first. Septal defect repair before elective limb surgery
  • Pollicisation. Absent or floating thumb
  • Centralisation or radialisation. Radial deviation of the hand from radial deficiency
  • Opponensplasty. Hypoplastic thumb with poor opposition

Prognosis

  • Survival depends on the cardiac lesion
  • Each child of an affected parent has a 50% risk

References

  1. Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997, 15(1), 30-5. PubMed
  2. Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997, 15(1), 21-9. PubMed

Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 19 October 2026.