Holt-Oram Syndrome

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]

NextPathophysiology

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.

PreviousNextEpidemiologyFrequencyUnited 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.

AgeA 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.PreviousProceed to Clinical Presentation , Holt-Oram Syndrome