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
Holt-Oram 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. [2, 3] The pathophysiologic sequelae are a direct result of malformations of the heart and upper limbs. No contributory environmental factors are known. [4]
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. [5] 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. [6, 7] These anomalies are frequently present even in the absence of septal defects.
Etiology
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. [8, 9]
Molecular genetic studies reveal that the disease is caused by mutations that inactivate the transcription factor TBX5. [10, 11] 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. [6]
Epidemiology
United States data
Holt-Oram syndrome is the most common form of heart-hand syndrome, with prevalence estimated at 1 case per 100,000 total births. Most cases are attributed to new mutations. [12]
Sex-, race-, and age-related demographics
Holt-Oram syndrome has no sexual or racial predilection. [12]
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. [13]
Cardiac conduction disease is progressive with aging.
Middle-aged individuals often present with significant atrioventricular block or atrial fibrillation.
Prognosis
The prognosis of Holt-Oram syndrome is generally good, but it depends on the severity of the cardiac malformations. Significant intracardiac shunts can be associated with sudden death or the development of pulmonary hypertension and Eisenmenger syndrome.
Structural lesions are present at birth. 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.
Patient Education
Ensure that family members are aware that this is an autosomal dominant disorder and that the chance is 50% that offspring of an affected individual will also have the disorder.
Explain that the severity of a lesion in a parent is not an indication of the potential severity in offspring.
For patient education resources, see the Heart Health Center, as well as Atrial Fibrillation (A Fib) and Ventricular Septal Defect.
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Holt-Oram Syndrome. Posteroanterior radiograph of the hands of a patient with Holt-Oram syndrome. The distal phalanx of the left thumb is hypoplastic. The carpal bones of both hands are abnormal, but the abnormalities on the left side are greater than those on the right side. Left-sided upper limb radial ray abnormalities are often greater than those on the right side. The scaphoid and trapezium of the left hand are enlarged and misshapen, resulting in a distal displacement of the thumb. Note the marked abnormalities of the left capitate and hamate. The left radial stylus is flattened.
