eMedicine Specialties > Cardiology > Congenital Heart Disease in the Adult

Holt-Oram Syndrome

Author: Craig T Basson, MD, PhD, FAHA, FACC, Gladys and Roland Harriman Professor of Medicine, Weill Cornell Medical College; Director, Cardiovascular Research, Greenberg Division of Cardiology, Department of Medicine, The New York Presbyterian Hospital
Coauthor(s): Carl J Vaughan, MD, MRCPI, Adjunct Assistant Professor, Department of Internal Medicine, Division of Cardiology, Weill Medical College of Cornell University; Consulting Cardiologist, Mercy University Hospital, Ireland; Luke K Kim, MD, Fellow, Department of Internal Medicine, Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical Center; Deborah A McDermott, MS, CGC, Genetic Counselor/Research Associate, Department of Medicine, Division of Cardiology, Weill Medical College of Cornell University
Contributor Information and Disclosures

Updated: May 28, 2009

Introduction

Background

Holt-Oram syndrome, also called heart-hand syndrome, is an inherited disorder characterized by abnormalities of the upper limbs and heart. Holt and Oram first described this condition in 1960 in a 4-generation family with atrial septal defects and thumb abnormalities.¹

Pathophysiology

The syndrome is inherited as an autosomal dominant trait that is completely penetrant. The disease is due to mutations in the transcription factor TBX5, which is important in the development of both the heart and upper limbs. The pathophysiologic sequelae are a direct result of malformations of the heart and upper limbs. No contributory environmental factors are known.²

Upper limb involvement

Although the clinical manifestations are variable, upper limb abnormalities are always present. Abnormalities may be unilateral or bilateral and asymmetric and may involve the radial, carpal, and thenar bones. Aplasia, hypoplasia, fusion, or anomalous development of these bones produces a spectrum of phenotypes, including triphalangeal or absent thumbs. Occasionally, upper limb malformation can be sufficiently severe to produce phocomelia (a malformation in which the hands are attached close to the body); this has been termed pseudothalidomide syndrome. The most prevalent findings in persons with Holt-Oram syndrome are malformations or fusions of the carpal bones. Carpal bone abnormalities are the only findings present in every affected individual, although these anomalies may be evident only radiographically in some patients.

Cardiac involvement

Approximately 75% of patients have some cardiac abnormality. In most patients, the abnormality is either an atrial septal defect (ASD) or a ventricular septal defect (VSD), which varies in number, size, and location. ASDs are usually of the secundum variety, while VSDs tend to occur in the muscular trabeculated septum. Cardiac anomalies also may include cardiac conduction defects such as progressive atrioventricular block and atrial fibrillation.^3,4 These anomalies are frequently present even in the absence of septal defects.

Frequency

United States

Holt-Oram syndrome is the most common form of heart-hand syndrome, with prevalence estimated at 0.95 cases per 100,000 total births. Approximately 85% of cases are attributed to new mutations.

Mortality/Morbidity

Structural lesions are present at birth. Prognosis depends on the severity of the cardiac lesions.

• Significant intracardiac shunts can be associated with sudden death or the development of pulmonary hypertension and Eisenmenger syndrome.
• The first clinical manifestation of the disease may be heart failure, cardiac arrhythmias (including heart block), or infective endocarditis.
• Considerable physical and psychologic morbidity may be associated with limb abnormalities, particularly in severe cases.

Sex

Holt-Oram syndrome has no sexual predilection.

Age

• A congenital disease, Holt-Oram syndrome is present at birth. Subtle limb involvement may not become clinically apparent until later in life when the cardiac symptoms of the disease manifest or when an individual has a child with a more severe presentation of the syndrome.
• Cardiac conduction disease is progressive with aging.
• Middle-aged individuals often present with significant atrioventricular block or atrial fibrillation.

Clinical

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
  • 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
  • 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)

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
• 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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