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.
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.
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.
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. These anomalies are frequently present even in the absence of septal defects.
Holt-Oram syndrome prevalence estimated at 0.95 cases per 100,000 total births. Approximately 85% of cases are attributed to new mutations.
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.
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.
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.
- 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)
Complications
- Congestive heart failure
- Arrhythmia
- Heart block
- Atrial fibrillation
- Infectious endocarditis
- Sudden death
Medical Care
Evaluation can usually be performed in an outpatient setting, but inpatient studies and surgical treatment may be necessary. 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. 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.
Source: WebMD.com
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