Holt-Oram Syndrome

Etiology

A heterozygous mutation in the TBX5 gene on chromosome 12q24.1 causes Holt-Oram syndrome. This gene is responsible for encoding a transcription factor, T-box5, which regulates the expression of other genes in the development of the heart and limbs. Specifically, the gene is an important factor in cardiac septation and the development of bones in the arm and hand. More than 85% percent of individuals diagnosed with Holt-Oram syndrome carry the mutated TBX5 gene.

The condition is an autosomal dominant disorder, so one copy of the mutation in each cell will lead to the development of the syndrome. For an affected parent, this means that he or she has a 50% chance of transmitting the mutation to the offspring. However, most cases of Holt-Oram syndrome are sporadic and occur via de novo mutation.

There is complete penetrance for upper-limb abnormalities and 75% penetrance for cardiac defects. The phenotypic spectrum is wide given the variable expressivity of the gene, leading to difficulty in predicting the malformation characteristics of the offspring. However, if the gene is inherited in an autosomal manner rather than de novo mutation, the offspring will often manifest greater severity in cardiac and limb deformities.[5][6]

Epidemiology

The incidence of Holt-Oram syndrome is estimated at 1 in 100,000 individuals, with no predilection for male or female sex. Additionally, a higher prevalence has not been identified in a specific race, ethnicity, or geographic location. 

Pathophysiology

Holt Oram syndrome is an inherited disorder with an autosomal dominant trait. There appear to be mutations in TBX5, which is the transcription factor for the development of the upper limbs and heart.

History and Physical

There should be high suspicion for Holt-Oram syndrome in individuals who present with a family history and/or the following malformations:

• Upper-limb malformation
• Congenital heart malformation
• Cardiac conduction disease
• Family history of a relative with congenital heart defects

Upper-limb malformations can involve the carpal bones, thenar bones, and radial bones. These abnormalities may be unilateral or bilateral and symmetric or asymmetric. Most cases are unilateral and affect the left side. [7] Fusion or anomalous development of the carpal bones may be seen. The thumb may be completely absent, grossly underdeveloped, or triphalangeal. The radius may exhibit aplasia or hypoplasia and abnormal forearm pronation and supination. Phocomelia may also be present.

Congenital heart malformations are present in 75% of individuals with Holt-Oram syndrome, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD). The septal defects may be mild or can be more severe and lead to further problems such as pulmonary hypertension, congestive heart failure, or infective endocarditis.

Individuals with Holt-Oram syndrome are also at an increased risk for cardiac conduction abnormalities. These may manifest at birth as sinus bradycardia or first-degree atrioventricular block and can progress to complete heart block without warning. Arrhythmias, such as atrial fibrillation, are also seen. [8]

Evaluation

Both physical features and family history can help establish the diagnosis of Holt-Oram syndrome. Specifically, a family history of congenital heart malformations should warrant further investigation with an electrocardiogram and echocardiogram. In addition, upper limb x-rays can demonstrate various abnormalities. Finally, genetic testing looking for TBX5 mutations should be a consideration.

 In addition to using physical features to aid in the diagnosis, a lack of certain features are involved, the diagnosis is unlikely: head and face region, eyes, ear malformations or hearing loss, kidneys, vertebrae, lower limbs, or anus.[9][10][11]

Treatment / Management

The treatment of Holt-Oram syndrome is individualized and based on specific symptoms. In some cases, many providers are involved, including pediatricians, cardiologists, cardiovascular surgeons, and orthopedists.

Medications to consider depending on the specific cardiac defects. For example, if congestive heart failure is present, diuretics, angiotensin-converting enzyme inhibitors, beta-adrenergic antagonists, and cardiac glycosides may be warranted. Surveillance is critical and should include an annual electrocardiogram. If a patient has a conduction abnormality, an annual Holter monitor should be considered. Finally, those patients with septal defects should have an echocardiogram every one to 5 years.Upper limb abnormalities may require corrective or reconstructive surgery in addition to physical and occupational therapy. Those with cardiac malformations may require medications, an artificial pacemaker, or surgical correction. Finally, psychosocial aspects should be addressed to allow the individual to reach his or her full potential and enjoy a satisfying quality of life.

During surgical procedures, prophylaxis must be considered to avoid complications of bacterial infective endocarditis and pericarditis. This includes simple procedures, such as tooth extractions, or more complex procedures, such as surgical repair of septal defects. Finally, individuals with Holt-Oram syndrome are more susceptible to respiratory infections and therefore, should be monitored closely; there should be a low threshold for the initiation of antibiotics.

Differential Diagnosis

The following diseases or conditions can be mistaken for Holt-Oram syndrome and should be ruled out:

• Thrombocytopenia-absent radius syndrome
• Teratogen exposure (thalidomide, valproate)
• Heart-hand syndrome type II
• Heart-hand syndrome type III
• Duane-radial ray syndrome
• Ulnar-mammary syndrome
• Long thumb brachydactyly

Prognosis

Life expectancy for Holt-Oram syndrome varies among affected individuals and predominantly depends on the severity of the congenital heart defect. However, patients who have hemodynamically significant intracardiac shunts need treatment; otherwise, they may develop Eisenmenger syndrome later in life.