Holt-Oram Syndrome

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]

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.

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]

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.

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.

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.

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 atrial septal defect (ASD), ventricular septal defect (VSD), or cardiac conduction disease.

Physical examination

Upper limb deformity includes the following features:

• 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 includes the following signs:

• 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)

Wrist and hand abnormalities may be appreciated clinically. Radiography is useful in identifying more subtle abnormalities. Echocardiography is also an important feature of the workup of Holt-Oram syndrome.

Genetic evaluation is important.[14, 15] Arrange for patients who may have Holt-Oram syndrome to be evaluated by a cardiologist or geneticist with experience in the management of inherited cardiovascular disease.

Cardiac catheterization can be considered to define the nature and severity of intracardiac shunts in patients at high risk for Eisenmenger syndrome because these patients may require surgical intervention.

Wrist radiography

Limb involvement is determined by physical examination in some cases. If limb involvement is not grossly obvious, obtain upper limb and hand radiographs to detect subtle anomalies of the wrist bones, as shown below.

Individuals without carpal bone abnormalities in the preaxial radial bones do not have Holt-Oram syndrome.

Chest radiography

Findings may demonstrate enlarged pulmonary arteries due to pulmonary hypertension or cardiomegaly. Evidence of congestive heart failure may be present.

Numerous varieties of complex congenital heart disease, including atrial septal defect (ASD), ventricular septal defect (VSD) and mitral valve disease, are associated with Holt-Oram syndrome.[16]

Echocardiography is the imaging study of choice to define the presence of septal defects or other cardiac anomalies. The most common cardiac anomaly is ostium secundum ASD. Some patients also may have an isolated VSD.

Unexplained, significant right atrial enlargement in the fetus may signify Holt-Oram syndrome; consider a thorough evaluation for upper extremity abnormalities and discuss genetic testing with the parents.[17]

Severely affected individuals may present with multiple VSDs (Swiss-cheese septum). Other cardiac anomalies may include abnormal isomerism and anomalous pulmonary venous return.[3]

Perform an ECG to define involvement of the conduction system. If intermittent dysrhythmia is considered, 24-hour Holter monitoring may be useful.

Periodic evaluation for conduction system involvement, even in the absence of cardiac structural disease, is important given the progressive nature of this finding. ECG evaluations should include consideration of atrial fibrillation.

Obtain a detailed family history to ascertain if the disease represents a new mutation or if it is part of a familial syndrome.

Consider wrist radiography of the parents of the patient with Holt-Oram syndrome to establish a familial versus sporadic nature of the syndrome in the family.

In a study of 114 extremities in 62 patients with a diagnosis of Holt-Oram syndrome, Wall et al found that, compared with the typical presentation of radial longitudinal deficiency (RLD), the forearm is more often involved in Holt-Oram syndrome and may show radioulnar synostosis. In addition, the thumb often has first-web syndactyly. They concluded that the presence of radioulnar synostosis and syndactyly of the radial two digits in RLD should prompt a hand surgeon to acquire a cardiac evaluation and consider genetic testing for Holt-Oram syndrome.[18]

Mutational analysis of TBX5 is not available on a routine clinical basis and remains a research tool. TBX5 mutations are detected in about 75% of individuals meeting strict clinical criteria for Holt-Oram syndrome.[6] Clinical features of Holt-Oram syndrome result from missense and extended protein mutations of TBX5, as well as TBX5 intragenic duplications.[19] On a case-by-case basis, specifics regarding genotype-phenotype correlations are not available. The ability to identify the disease causing mutation in a family may allow for expanded reproductive options such as preimplantation genetic diagnosis for couples at 50% risk of having an affected child.[20]

A clinical evaluation can usually be performed in an outpatient setting, but inpatient studies and surgical treatment may be necessary. Admit patients for cardiovascular testing and surgical intervention.

Patients with advanced heart block may require a permanent pacemaker.

Surgical therapy can be used to correct cardiac defects or to possibly improve limb function.

No specific medications are indicated for this condition. However, antibiotic prophylaxis and anticoagulation may be required, depending on the severity of congenital heart disease.

Transfer may be required for further diagnostic evaluation and surgical intervention.

Consultations

Obtain consultations with the following specialists:

• Cardiologist

• Geneticist

• Cardiothoracic surgeon

• Orthopedic surgeon

Diet and activity

No special diet is required. Limit activity if heart failure or persistent cardiac sequelae are present.

Prevention

No known causative environmental factors are described; therefore, no particular deterrent is available.

Long-term monitoring

Follow up with patients with significant congenital heart disease at least annually. Periodic follow-up for cardiac conduction disease is warranted in all affected individuals.

Most cardiac lesions such as ASD and VSD are amenable to complete surgical correction if pulmonary hypertension or ventricular failure has not developed. Several percutaneous transcatheter devices that can be placed to occlude the septum are in US Food and Drug Administration–approved clinical trials and may be nonsurgical options in the future.

Septal defects without hemodynamically significant shunts do not require correction.

Children with severe limb anomalies can be referred to orthopedic surgeons for consideration of procedures such as pollicization of the fifth digit (to improve upper limb function).

Children with severe limb shortening may benefit from prostheses.

No medications are effective in treating the anatomical defects of patients with Holt-Oram syndrome. Antibiotic prophylaxis should be applied following standard American Heart Association/American College of Cardiology guidelines for patients with congenital heart disease.[21] Anticoagulation should be considered in patients with pulmonary hypertension. Cardioversion, antiarrhythmic drug therapy, or anticoagulation should be considered in patients with atrial fibrillation.